Holistic Treatment to Reverse Diabetes

Reverse Diabetes Now

Reverse Your Diabetes Today by Matt Traverso gives you instant, online access to a simple, step-by-step system in which Matt teaches you his powerful secrets, techniques, and unique treatment approach for quickly and easily eliminating pre-diabetes and Type 2 diabetes in as little as 21 days. In this guide, you can learn the roots of diabetes to eliminate it rather than making use of prescription drugs or other medications to lessen the diabetes signs and symptoms. With reverse your diabetes today, you can discover the way to protect yourself from terrible signs and symptoms of diabetes type 2 or type 1. The diet advocated by the Reverse Diabetes book is not well known, but I have heard of it for at least 10 years. However, this diet, like all others, can only be good if you follow it. Funny how that works! Wouldnt it be great if we could just read about a diet and get its advantages? Read more here...

Reverse Diabetes Now Overview

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My Reverse Diabetes Now Review

Highly Recommended

This is one of the best books I have read on this field. The writing style was simple and engaging. Content included was worth reading spending my precious time.

As a whole, this manual contains everything you need to know about this subject. I would recommend it as a guide for beginners as well as experts and everyone in between.

Immunoassay Of Endogenous Plasma Insulin In

For years investigators have sought an assay for insulin which would combine virtually absolute specificity with a high degree of sensitivity, sufficiently exquisite for measurement of the minute insulin concentrations usually present in the circulation. Methods in use recently depend on the ability of insulin to exert an effect on the metabolism of glucose in vivo or in excised muscle or adipose tissue. Thus, the insulin concentration in plasma has been estimated a) from the degree of hypoglycemia produced in hypophysec-tomized, adrenalectomized, alloxan-diabetic rats (1) b) from the augmentation of glucose uptake by isolated rat hemidiaphragm (2) or c) from the increased oxidation of glucose- 1-C14 by the rat epididymal fat pad (3). Since there have been reports indicating the presence, in plasma, of inhibitors of insulin action (4) and of noninsulin substances capable of inducing an insulinlike effect (5, 6), these procedures, while yielding interesting information regarding the...

Selected Metabolic Aspects Of Diabetesg

A lay person would describe diabetes as too much sugar in the blood. So would most medical students and physicians. However, hyperglycemia is simply the tip of the iceberg, albeit one of profound pathogenetic impact. Type 2 diabetes is, in fact, a syndrome in which resistance to insulin in peripheral tissues is present for years, if not decades, before hyperglycemia becomes evident. As compensatory pancreatic secretory mechanisms in response to the insulin resistance begin to fail, relative and

Cardiovascular Disease In Type 1 Diabetes

Type 1 diabetes is characterized by an absolute loss of beta cells such that there is almost a total absence of insulin secretion (1). The majority of patients who develop type 1 diabetes have an autoimmune process that destroys the beta cells. There is another group of individuals who have type 1 diabetes in which beta-cell function is severely reduced in the absence of autoimmune destruction and in which the etiology of the beta-cell dysfunction is unknown. In type 1 diabetes, -g Table 4 Differences in Metabolic Profiles Between Insulin-Sensitive and Insulin-Resistant Type 2 Diabetic Patients Insulin-sensitive Insulin-resistant as a consequence of the development of obesity, which appears to be a result of intensive insulin treatment (12) or poorly controlled glycemia that leads to hypertriglyceridemia, excessive activation of vascular cell protein kinase C, increased production of advanced glycosylation end products (AGEs), endothelial dysfunction, and oxidative stress (13). Type 1...

Cardiovascular Disease In Type 2 Diabetes

Type 2 diabetes is very different from type 1 diabetes in its underlying etiology and its natural history. Insulin resistance, which is defined as a less than normal effect of insulin on in vivo glucose uptake and metabolism, occurs in a high proportion of the population of societies embracing western culture (10,26). Factors responsible for the development of insulin resistance are only partially understood. Fetal malnutrition predisposes to insulin resistance in postnatal life (27). Excess calorie intake and reduced physical activity lead to exaggerated lipid deposits and obesity. The proportion of excess calories deposited as lipids in subcutaneous adipose tissue relative to visceral adipose tissue is both genetically and hormonally determined (28). An increase in visceral adiposity but not subcutaneous adiposity is highly correlated with insulin resistance and the components of the metabolic syndrome (29,30). There is a significant correlation between visceral adiposity and both...

Insulin Resistance In The Natural History Of Type 2 Diabetes

Reduced insulin-dependent glucose transport is frequently found in nondiabetic relatives and offspring of patients with type 2 diabetes (5). This observation, as demonstrated in families and populations with a high incidence of type 2 diabetes, suggests that insulin resistance may be a primary factor in the development of type 2 diabetes and the early development of accelerated atherosclerosis. As such, the natural history of type 2 diabetes suggests that patients may be euglycemic and have normal insulin levels for many years before the development of the disease. In the presence of obesity and a family history of diabetes, insulin resistance typically is present and the individual will need to increase insulin secretion, particularly after meals, to compensate for the insulin resistance (1-4). Eugly-cemia is maintained, therefore, as long as the individual continues to sustain the compensatory hyperinsulinemia required to overcome the resistance (1-4). As recently reviewed from the...

Cellular Events Defining Insulin Action

Understanding the cellular mechanism(s) of action in the insulin-sensitive tissues responsible for insulin resistance would be important in the goal of identifying As stated, the aspect of insulin resistance that has been the most well described insulin stimulation (1,5). Specifically, this is represented by a reduction in the insulin-stimulated storage of glucose as glycogen in both muscle and liver in insulin action will be presented in order to fully understand the potential cellular abnormalities contributing to insulin resistance. Figure 2 Schematic representing clinical and laboratory findings in the natural history of type 2 diabetes. (Reprinted with permission from Ref. 92.) Figure 2 Schematic representing clinical and laboratory findings in the natural history of type 2 diabetes. (Reprinted with permission from Ref. 92.) The insulin signaling cascade, which results in the biological action of insulin in insulin-sensitive peripheral tissues (e.g., fat or muscle) begins with...

Insulin Stimulated Glucose Transport

The generation of the second messengers following insulin receptor binding and activation promotes cellular glucose transport into the cell. The enhanced insulin-stimulated glucose transport is mediated by translocation of a large number of glucose transporters from an intracellular pool to the plasma membrane (42). The glucose transporters consist of at least five homologous transmembrane proteins (Glut-1, -2, -3, -4, and -5) encoded by distinct genes, and have distinct specificities, kinetic properties, and tissue distribution that define their clinical role (42). Glut-1 and Glut-4 are two major glucose transporters that have been identified in skeletal muscle. Whereas Glut-1 may be primarily involved in basal glucose uptake, Glut-4 is considered the major insulin-responsive glucose transporter. In addition to skeletal muscle, Glut-4 is expressed in insulin target tissues such as cardiac muscle and adipose tissue. In normal muscle cells, Glut-4 is recycled between the plasma...

Assessment Of Clinical Insulin Resistance

A number of techniques that differ in sophistication, complexity, and sensitivity are currently available to assess the degree of insulin resistance in patients (67,68). lin resistance is the euglycemic hyperinsulinemic clamp technique (67,68). In this procedure, exogenous insulin is infused to maintain a constant plasma insulin level above fasting while glucose is infused at varying rates to keep the blood glucose within a fixed range. The amount of infused glucose required to maintain the blood glucose at the target level over time is an index of insulin sensitivity. As described, the more glucose that has to be infused per unit time in order to maintain the fixed glucose level, the more sensitive the patient is to insulin. With this procedure, the insulin-resistant patient requires much less infused glucose to maintain the basal level of blood glucose. The clamp procedure, therefore, provides a measure of insulin-stimulated whole-body glucose disposal (M value). More specifically,...

Diabetes Selfmanagement

Diabetes self-management education is performed by specially trained nurses, dieticians, pharmacists, and others to provide patients the skills, knowledge, and confidence to manage their own diabetes on a day-to-day basis through analysis of their lifestyle practices and blood glucose patterns to make informed decisions in their insulin doses or other therapy. Self-management education involves a continuum of services ranging from the teaching of survival skills to a comprehensive self-management program. Given the importance of self-management for the attainment of optimal glycemic control, it is recommended that specially trained licensed health-care professionals provide diabetes self-management education. Certified Diabetes Educators (CDEs) must accrue 1000 hours in direct diabetes education and pass a certifying exam from the National Certification Board for Diabetes Educators, with a recertifying exam every 5 years. Certification implies expertise in diabetes knowledge, skills,...

At4 receptor is insulinregulated aminopeptidase

We have purified the AT4 receptor from bovine adrenal membranes and identified it as insulin-regulated aminopeptidase (IRAP) (11). To verify that the AT4 receptor is indeed identical to IRAP, we sought to (1) reconstitute 125I- Nle1 Ang IV binding site and investigate its biochemical properties by expression of IRAP cDNA, and (2) compare the distribution of the 125I- Nle1 Ang IV binding in brain with IRAP mRNA and protein expression. Using HEK 293T cells transfected with the full-length cDNA for IRAP was described as an aminopeptidase colocalized in specialized intracellular vesicles with the glucose transporter, GLUT4, in insulin-responsive tissues, adipose, skeletal muscle, and cardiac muscle (13). IRAP is a member of the M1 family of the zinc-dependent metallopeptidases, and is also known as placental leucine aminopeptidase (P-LAP), or oxytocinase (14). This review focuses on the IRAP AT4 receptor distribution and function in the cardiovascular system and brain. The AT4 receptor...

Insulin Therapy Patient Education

Many individuals are reluctant to initiate insulin therapy. Openly discussing their concerns prior to technical training is of prime importance. In particular, a common fear is that the injections will be painful or complex. Discussing up front the convenience of modern injection systems, and injecting the patient with saline to show the painlessness of the needle may be all that is needed to gain his trust and acceptance. Common concerns and issues are discussed below. Needle phobias are common at any age. Ask about previous injection experiences patients may have had, or observed. Inform the patient that unlike intramuscular (i.m.) injections, which are painful subcutaneous (s.q.) insulin injections with today's syringes and pens are generally painless. Insulin doesn't sting (glargine occasionally causes minor local reactions because of its acidic buffer), but using of alcohol for skin cleansing can sting and is not necessary. Also, injection-assistance devices may help in extreme...

Insulin Injection Technique

Roll vial 10 times excess agitation can damage the insulin and cause precipitation. Pull plunger down to die prescribed number of units. Draw 1-2 units extra to make up for insulin bubbles to be pushed out. Inspect the syringe for any bubbles and tap with a finger or against a table to drive them to the top of the syringe, and then push out. Be sure the correct dose is still in the syringe if it isn't, draw more. Many patients have an unfounded fear of injecting air by mistake but are afraid to discuss it. Every patient should be reassured that in- Do not massage the area. Note any back-leakage of insulin.

Cardiovascular Complications In Diabetes

Diabetes plays a powerful role in the development of cardiovascular diseases (810). The incidence of cardiovascular disease is two times higher in men with diabetes and three times higher in women with diabetes than nondiabetic subjects (10). Haffner et al. (11) reported that the risk of developing a myocardial infarction in type 2 diabetic patients without a previous history of myocardial infarction is similar to that of nondiabetic patients who have had a prior myocardial infarction. Diabetic patients have a twofold increase in the prevalence of hypertension compared with nondiabetic subjects (5). Hypertension is even more common in certain ethnic groups with type 2 diabetes. Almost twice as many African Americans and three times as many Hispanic Americans as compared with white non-Hispanic subjects have coexistent diabetes and hypertension (5). The coexisting hypertension and diabetes continue to rise dramatically in western countries as the overall population ages and as obesity...

Pathogenesis Of Hypertension In Diabetes

Several factors are involved in the pathogenesis of hypertension in patients with diabetes mellitus. These include genetic factors, sodium retention, and hyperin-sulinemia. Genetic predisposition plays an important role in the development of hypertension in both type 1 and type 2 diabetes. The higher prevalence of hypertension in certain ethnic groups, such as African Americans, suggests the role of genetic factors (5). Diabetic patients with hypertension are reported to have high frequencies of family history of hypertension (23). Elevated levels of sodium-lithium countertransport activity (24,25) and sodium-hydrogen countertransport activity (26) have also been found to play a role in the genetic predisposition to hypertension.

Clinical Trials Relevant To Treatment Of Hypertension And Prevention Of Cardiovascular Complications In Diabetes

Treatment of hypertension is crucial for the reduction of cardiovascular complications. There have been a considerable number of prospective randomized trials showing the benefits of treating hypertension in diabetes. The SHEP (Systolic Hypertension in the Elderly Program) trial showed that treatment of isolated sys- -o tolic hypertension in elderly type 2 diabetic patients with a diuretic, chlorthali- Hypertension in Europe (Sys-Eur) Trial, treatment of isolated systolic hypertension in elderly patients with type 2 diabetes with an intermediate-acting calcium channel blocker, nitrendipine, showed a significant decline in cardiovascular J events and mortality compared to placebo (67). In both of these studies, the absolute risk reduction with active treatment compared with placebo was significantly larger for diabetic versus nondiabetic patients, reflecting the higher cardiovascular risk seen in diabetic patients. In the United Kingdom Prospective Diabetes Study (UKPDS), 1148...

Intensive Insulin Therapy

Randomised trials, most notably the DCCT, have provided substantial data on the epidemiology of hypoglycaemia in adults with type 1 diabetes and, in particular, on the impact of intensive insulin therapy. The Diabetes Control and Complications Trial (DCCT) The DDCT was a landmark study and provided diabetes specialists with the long-awaited proof that strict glycaemic control limited the incidence and severity of microvascular complications in people with type 1 diabetes. A total of 1441 patients with type 1 diabetes Table 3.3 Risk factors for severe hypoglycaemia in adults with type 1 diabetes Insulin This table examines the risk factors for severe hypoglycaemia that have been most commonly examined in adults with type 1 diabetes. Studies examining predominantly mild hypoglycaemia were not included. + positive association between risk factor and severe hypoglycaemia no association between risk factor and severe hypoglycaemia. * only a risk factor if awareness of hypoglycaemia not...

Diseases of Insulin Secretion

The ATP-sensitive K+ (KATP) channel plays a key role in glucose-stimulated insulin secretion. It is therefore not surprising that mutations in the genes that encode KATP channel subunits, or that encode proteins involved in the regulation of KATP channel activity, affect insulin secretion. Fig. 8.14 illustrates our current model of insulin secretion. When plasma glucose levels rise, glucose uptake and metabolism by the pancreatic -cell is enhanced, producing an increase in intracellular ATP and a concomitant fall in intracellular MgADP. These changes act synergistically to close KATP channels in the cell membrane because ATP inhibits, whereas MgADP activates, channel activity. Since KATP channel activity determines the -cell resting potential, its closure causes a membrane depolarisation that activates voltage-gated Ca2+ channels, increases Ca2+ influx and so stimulates insulin release. Two classes of therapeutic drugs modulate insulin secretion by interacting with the SUR1 subunit of...

The Coagulation System And Diabetes Mellitus

The final common pathway resulting from activation of the coagulation system is generation of thrombin and thrombin-mediated formation of fibrin from fibrinogen. Generation of thrombin depends on activation of procoagulant factors and is limited by antithrombotic factors and inhibitors. A marker of thrombin activity is fibrinopeptide A (FPA), released when fibrinogen is cleaved by thrombin. This peptide has a very short half-life in the circulation because it is cleared promptly by the kidneys. Elevated concentrations in blood are, therefore, indicative of thrombin activity in vivo. Subjects with diabetes mellitus (both types 1 and 2) have increased concentrations of FPA in blood and in urine compared with those in nondiabetic subjects. The increased concentrations of FPA seen in association with diabetes reflect an altered balance between prothrombotic and antithrombotic phenomena in subjects with diabetes mellitus favoring thrombosis. Patients with diabetes mellitus have increased...

Platelet Function And Diabetes Mellitus

Patients with diabetes, particularly those with macrovascular disease, have an increased circulating platelet mass secondary to increased ploidy of megakaryocytes. In addition, platelets isolated from the blood of subjects with diabetes exhibit impaired capacity to mediate vasodilatation, apparently because of release of a short-acting platelet-derived substance(s) that interferes with the ADP-induced dilatory response seen in normal vessels with intact endothelium. Platelets from diabetic subjects demonstrate increased reactivity. They exhibit increased degranulation and increased aggregation in response to diverse stimuli. In addition, the procoagulant capacity of platelets from subjects with diabetes mellitus is increased. Thus, the generation of coagulation factor Xa and of thrombin is increased by three- to sevenfold in samples of blood containing platelets from diabetic as opposed to nondiabetic subjects. One potential mechanism responsible for the increased platelet reactivity...

Fibrinolysis And Diabetes

Decreased fibrinolytic system capacity is observed consistently as judged from analysis of blood from patients with diabetes mellitus, particularly those with type 2 diabetes. We have found that impaired fibrinolysis in subjects with type 2 diabetes mellitus, not only under baseline conditions but also in response to insulin-resistant states such as obesity, hypertension, and the polycystic ovarian syndrome. Increased expression of PAI-1 is a marker of increased risk of acute myo-cardial infarction as judged from its presence in relatively young, long-term survivors of acute myocardial infarction compared with age-matched subjects who had not experienced any manifestations of overt coronary artery disease. Because the endogenous fibrinolytic system influences the evolution and persistence of thrombosis and the rapidity and extent of lysis of thrombi associated with vascular damage and its repair, overexpression of PAI-1 is likely to exacerbate both development and persistence of...

Effects of fatty acids on insulinotrophic gut hormones

One of the limitations of the isolated beta cell islet studies is that, largely, they fail to take account of other factors that modulate insulin secretion in vivo. Such factors include the incretin hormones glucagon-like-peptide-1 (GLP-1) and glucose-dependent insulinotrophic peptide. It has been reported in both healthy humans (Thomsen et al., 1999) and those with type 2 diabetes (Thomsen et al., 2003) that olive oil intake caused increased GLP-1 response compared with butter intake. Furthermore, postprandial plasma GLP-1 concentrations were increased more after an oral fat test containing MUFAs compared to PUFAs and SFAs (Beysen et al., 2002). Recent work has suggested that fatty acids may modulate the effects of GIP on GLP-1 and thereby insulin secretion. Experiments using an isolated ileal L cell model suggest that improvements in glycaemic response seen in MUFA compared with SFA fed rats may be due to increased GLP-1 receptor activation in response to increased GIP secretion...

Medical Complications of Glucose Intolerance and Diabetes Mellitus

Hyperglycemia and diabetes mellitus are associated with acute and chronic complications associated with significant morbidity and mortality. Diabetic ketoacidosis (DKA), an acute complication of diabetes mellitus, is seen more often in patients with type I than in patients with type II diabetes mellitus and is a serious and potentially fatal complication. Ketoacidosis is defined by low serum pH (< 7.35), low serum bicarbonate levels (< 15), and an anion gap in the presence of ketonemia (Westphal 1996). The diabetic patient is also susceptible to a variety of chronic complications that affect the cardiovascular system, nervous system, eyes, kidneys, and wound-healing capabilities. Macrovascular disease in the form of atherosclerosis increases the risk of cardiovascular and cerebrovascular events such as myocardial infarction and stroke, accounting for much of the disability and death among diabetic patients (Haupt and Newcomer 2001 Henderson 2001a). According to data amassed by...

Summary cellular mechanisms involved in fatty aciddependent effects on insulin sensitivity

In summary, there are various mechanisms proposed to explain the biochemical pathways involved in the progressive development of dietary fat-induced insulin resistance (Fig. 2.2). Fatty acids seem able to modulate the intracellular metabolism of glucose either directly (e.g. glucose fatty acid cycle), or indirectly via their effects on the insulin signalling cascade and on insulin secretion. This cross-talk between glucose (and insulin) and fatty acids plays a vital role in the coordination of whole body and cellular energy metabolism. Fatty acid stimulation of insulin secretion ensures a heightened insulin response under conditions where the adverse effects of the glucose-fatty acid cycle would otherwise result in impaired glucose uptake and hyperglycaemia. However, under conditions of chronic over-provision (either via the diet or through excessive release into the circulation from adipose tissues stores as in obesity), excess fatty acids may lead to intracellular accumulation of LC...

The Insulin Receptor Is a Tyrosine Specific Protein Kinase

Insulin regulates both metabolism and gene expression the insulin signal passes from the plasma membrane receptor to insulin-sensitive metabolic enzymes and to the nucleus, where it stimulates the transcription of specific genes. The active insulin receptor consists of two identical a chains protruding from the outer face of the plasma membrane and two transmembrane 3 subunits with their carboxyl termini protruding into the cytosol (Fig. 12-6, step d). The a chains contain the insulin-binding domain, and the intracellular domains of the 3 chains contain the protein kinase activity that transfers a phosphoryl group from ATP to the hydroxyl group of Tyr residues in specific target proteins. Signaling through the insulin receptor begins (step d) when binding of insulin to the a chains activates the Tyr ki-nase activity of the 3 chains, and each a3 monomer phosphorylates three critical Tyr residues near the car-boxyl terminus of the 3 chain of its partner in the dimer. This...

Nutrition Strategies For Insulin Therapy

Strategies for nutrition management as part of insulin therapy will vary based on whether the patient has type 1 or type 2 diabetes and whether he or she is following a conventional or intensive insulin program (2). In either case, an individualized meal plan based on the patient's food preferences and usual pattern of daily meals and snacks should be developed with a registered dietitian, and agreed to by the patient prior to initiating insulin therapy. It is important for the patient to consistently follow the meal plan as the insulin program is initiated and insulin doses are adjusted. Consistent timing of meals and snacks as well as the quantity of foods consumed (especially carbohydrates) will help to optimize glycemic control. As the patient learns the onset, peak, and duration of his or her insulins, adjustments can be made in the meal plan, insulin program, or both to achieve target blood glucose levels (2).

Human Insulin And Counterregulation

At present there is no consistent evidence that the species of insulin is an important determinant of the counterregulatory response to hypoglycaemia. Over 25 clinical laboratory studies have examined the effect of insulin species on the counterregulatory response to hypogly-caemia induced by an intravenous bolus, intravenous infusion, or subcutaneous injection of insulin (Fisher and Frier, 1993 Jorgensson et al., 1994). Most of the studies showed no significant differences between the hormonal responses. Two studies showed a reduction in the epinephrine response to hypoglycaemia, and both of these studies also reported diminished autonomic symptoms to hypoglycaemia after human insulin (Schluter et al., 1982 Heine et al., 1989). A meta-analysis comparison of the effects of human and animal insulin as well as of the adverse reaction profiles did not show clinically relevant differences between species especially in terms of risk and responses to hypoglycaemia (Richter and Neises, 2005).

Hypoglycemia Associated With Insulin Therapy

A hypoglycemic reaction can vary in severity and may occur in anyone with diabetes. Insulin therapy significantly increases the risk, incidence, and severity of hypoglycemic reactions. Hypoglycemia can be the result of too much insulin, too little food (i.e., skipped or delayed meals and snacks), alcohol intake, or exercise. It can often be prevented by monitoring blood glucose levels, taking insulin and oral medications as prescribed, following a meal plan, limiting alcohol intake, and planning extra snacks if needed to cover the hypoglycemic effects of exercise. The symptoms of hypoglycemia include hunger, headache, irritability, confusion, lethargy, and, in severe cases, seizure or loss of consciousness. Patients treated with insulin or oral hypoglycemic medications should know how to recognize and promptly treat hypoglycemic reactions.

Causes Of Insulin Resistance

Insulin resistance may be caused by rare genetic defects that alter insulin binding to its cellular receptors or cause defects in receptor or postreceptor signal trans-duction (1). Recently, defects in the nuclear receptor, PPARy, have also been linked to syndromes of severe insulin resistance (2). In addition, some endocrine-metabolic syndromes, such as Cushing's syndrome, acromegaly, and polycystic ovary syndrome, are associated with insulin resistance because of the hormonal imbalances associated with these conditions. However, in the most common forms of insulin resistance, single gene defects have not been identified and the development of insulin resistance represents a complex interaction among a poorly understood array of predisposing genetic factors and acquired environmental factors that modify insulin sensitivity. Among the latter, the most prominent are obesity (particularly intra-abdominal obesity), physical inactivity, and increasing age. It is also now well documented...

Insulin Resistance And Glucose Metabolism

When insulin resistance is present, fasting and postprandial blood glucose con- centrations are maintained in the normal range by a compensatory increase in insulin secretion and the development of hyperinsulinemia. As long as the pancre- Ja may develop. This is characterized by the maintenance of a normal fasting blood glucose concentration but a value that is intermediate between normal and the diabetic range 2 h after a 75-g oral glucose load. With further impairment of beta-cell function, both fasting and postprandial blood glucose concentrations increase and overt diabetes mellitus develops. This sequence of events has been demonstrated in prospective studies of insulin resistance and beta-cell function in several populations, including studies of Pima Indians who have either progressed sequentially from normal glucose tolerance to IGT and then to diabetes or who have maintained normal glucose tolerance (NGT) over several years (6). In those who progressed to diabetes, there was...

The Insulin Resistance Syndrome

Insulin resistance and hyperinsulinemia are frequently associated with a cluster of clinical and biochemical abnormalities that have been described with increasing detail and given a variety of names including deadly quartet, syndrome X, insulin resistance syndrome, metabolic syndrome, and cardiovascular dysmeta-bolic syndrome (9-13). Many prefer to call it insulin resistance syndrome because insulin resistance and the resulting hyperinsulinemia appear to be the underlying abnormalities from which the other features of the syndrome are derived (see Chap. 7). The hallmarks of insulin resistance syndrome are obesity, particularly central or intra-abdominal obesity, glucose intolerance, or type 2 diabetes mellitus, hypertension, a dyslipidemia characterized by elevated triglycerides, low HDL cholesterol and small dense LDL cholesterol, a hypercoagulable state has been added to the list of characteristic features of the insulin resistance syn- J pected in anyone who has a personal or a...

Relationship Between Obesity And Type 2 Diabetes Mellitus

Animal models of obesity are highly associated with observations of reduced glucose tolerance (61), and in the non-human primate this glucose intolerance precedes overt type 2 diabetes, as recently Longitudinal in vivo studies in rhesus monkeys have shown that as obese monkeys begin to make the final transition from impaired insulin sensitivity and impaired glucose tolerance at the whole body to overt type 2 diabetes, increasing fasting plasma glucose very closely parallels increasing basal hepatic glucose production (63). In a related event, as hyperinsulinemia progresses to high levels, hepatic extraction of insulin (the proportion of the insulin presented to the liver which is removed by the liver) declines (64). quently generally declines as fasting plasma glucose begins to rise in the early stages of overt diabetes (notably shown in Figure 14.4) (67). Nevertheless, at the time of diagnosis of diabetes, insulin levels are usually still elevated above normal, and cell...

Measurement Of Insulin Resistance

Several methods have been used to assess insulin resistance, but most are not readily available or practical for use in clinical practice. The easiest approach is to measure fasting plasma glucose and insulin concentrations or the glucose and insulin responses during an OGTT or test meal. The higher the insulin concentration in relation to the glucose level, the more insulin resistant the subject. One can also obtain similar information by measuring the C-peptide concentration in the fasting and stimulated states. Various methods have been developed to analyze glucose and insulin data, one of the most widely used being the homeostasis model (HOMA) that is most effectively used in large-population studies to assess insulin resistance and beta-cell function (44,45). A major drawback for using plasma insulin concentrations from individual patients is the wide range of normal values and lack of standardization of insulin assays used by clinical laboratories, both of which make...

Conclusions fatty acids and insulin sensitivity

There are plausible biological mechanisms by which excessive provision, cellular uptake and metabolism of fatty acids may lead to impaired peripheral uptake and metabolism of glucose. These include direct attenuation of glucose-metabolising pathways and or antagonism of the action of insulin at receptor or post-receptor level, or activation inhibition of transcription factors involved in the regulation of glucose and lipid homeostasis at cellular level. Fatty acid-induced enhancement of glucose-stimulated insulin secretion (GSIS) appears to be a normal part of the whole body response to excessive fatty acid provision which ensures a compensatory increase in secretion of insulin under such circumstances. However in the long term this compensatory response can lead to hyper-insulinaemia and, ultimately, failure in beta cell secretion of insulin, leading to diabetes. There is some evidence, from cell and animal studies, that SFA are more likely than other fatty acids to promote an...

Proinsulin Biosynthesis pCell Mass and Insulin Secretion

Insulin is synthesized in pancreatic 3 cells, where it is processed from its precursor, proinsulin, into c-peptide (connecting peptide) and insulin (9). Processed insulin is stored in insulin vesicles. There are 2000 P cells in an islet and I million islets in the pancreas of an adult human. The p cell is shaped like a truncated cone, with the base of the cell exposed first to the blood flowing into the islet capillary bed. The membrane at the base of the cell has the glucose-2-transporter proteins that permit glucose access to the cell. Metabolism and oxidation of this glucose to carbon dioxide and water generate ATP. The increased ATP prompts exocytosis of stored insulin vesicles that discharge insulin from the apex of the p cell into the capillary and then into the portal vein. Although the prevailing glucose concentration is the best-recognized stimulant for insulin secretion, fatty acids are also important regulators of insulin secretion. Evidence is increasing that the p-cell...

Glycogen Synthase Kinase 3 Mediates the Actions of Insulin

As we saw in Chapter 12, one way in which insulin triggers intracellular changes is by activating a protein ki-nase (protein kinase B, or PKB) that in turn phosphor-ylates and inactivates GSK3 (Fig. 15-29 see also Fig. 12-8). Phosphorylation of a Ser residue near the amino terminus of GSK3 converts that region of the protein to a pseudosubstrate, which folds into the site at which the priming phosphorylated Ser residue normally binds (Fig. 15-28b). This prevents GSK3 from binding the priming site of a real substrate, thereby inactivating the enzyme and tipping the balance in favor of dephosphor-ylation of glycogen synthase by PP1. Glycogen phosphorylase can also affect the phosphorylation of glycogen synthase active glycogen phosphorylase directly inhibits PP1, preventing it from activating glycogen syn-thase (Fig. 15-27). Although first discovered in its role in glycogen metabolism (hence the name glycogen synthase kinase), GSK3 clearly has a much broader role than the regulation of...

Insulin Changes the Expression of Many Genes Involved in Carbohydrate and Fat Metabolism

In addition to its effects on the activity of existing enzymes, insulin also regulates the expression of as many as 150 genes, including some related to fuel metabolism (Fig. 15-31 Table 15-3). Insulin stimulates the transcription of the genes that encode hexokinases II and IV, PFK-1, pyruvate kinase, and the bifunctional enzyme PFK-2 FBPase-2 (all involved in glycolysis and its regulation), several enzymes involved in fatty acid synthesis, and two enzymes that generate the reductant for fatty acid synthesis (NADPH) via the pentose phosphate pathway (glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase). Insulin also slows the expression of the genes for two enzymes of gluconeoge-nesis (PEP carboxykinase and glucose 6-phosphatase). These effects take place on a longer time scale (minutes to hours) than those mediated by covalent alteration of enzymes, but the impact on metabolism can be very significant. When the diet provides an excess of glucose, the resulting rise...

Insulin resistance and hypertension

Hypertension is frequently associated with decreased insulin sensitivity (3) reduced insulin sensitivity has been observed in normotensive offspring of first-degree relatives of hypertensive patients, independent of obesity (4). Insulin resistance also predates hypertension in normotensive persons. In a prospective investigation of CVD risk factors involving 840 normotensive persons, insulin sensitivity was inversely related to development of hypertension over a 5-yr period (5). This observation has been confirmed in other large studies (6). There is accumulating data that insulin resistance is associated with abnormalities of the renin-angiotensin system (3,7). For example, the level of insulin resistance in hypertensive persons is influenced by a relatively common polymorphism of the angiotensin-converting enzyme (ACE) gene, their being a significantly greater insulin resistance with the DD geno type (8). Recent evidence suggests that tissue overexpression of the RAS leads to...

Other Risks Of Intensified Insulin Therapy Diabetic Ketoacidosis and Hyperinsulinaemia

Although severe hypoglycaemia was indisputably the major metabolic side-effect of intensive insulin therapy in the DCCT, concerns have been expressed that some intensive treatment regimens may also increase the risk of developing ketosis. This was primarily related to the use of CSII (with insulin pump therapy) and was thought to relate to the absence of any intermediate-acting or background insulin in the event of pump failure. In insulin pump therapy, soluble or fast-acting analogue insulin is delivered steadily by a slow infusion of very low doses throughout the day. The insulin delivery is accelerated before meals to deliver boluses, akin to giving intermittent subcutaneous injections of short-acting insulin. Because the basal insulin is delivered in a very low volume and there is no depot of intermediate-acting insulin in the subcutaneous tissues to act as a reservoir, an interruption in the delivery of insulin can rapidly lead to hyperglycaemia and even ketosis, especially if...

Heart Disease And Prediabetic States

The duration of diabetes influences the development of CAD in patients with type 1 diabetes, but such a relationship has not been demonstrated in those with type 2. Therefore, it is unclear whether the duration of asymptomatic hyperglyce-mia, or the state of impaired glucose tolerance, may have an important role on the development of CAD preceding the overt manifestations of type 2 diabetes (31,32). Several studies have shown that the mortality rate due to CAD was higher in patients with impaired glucose tolerance compared to normoglycemic men, although it was smaller when compared to that of patients with overt diabetes. At least one study has demonstrated that the risk of CAD increases linearly with fasting blood glucose levels in patients with impaired glucose tolerance, whereas the fasting insulin level has been implicated as a possible independent risk factor for CAD mortality in another study. Early impairment of LV diastolic function has been documented not only in patients...

Insulin And Oral Hypoglycemic Agents

Intensive blood glucose control has, in large intervention trials, been shown to increase body weight in both type 1 and type 2 diabetic patients (82,83). In the Diabetes Control and Complications Trial (DCCT), intensive treatment with either multiple daily injections of insulin or continuous subcutaneous insulin infusion resulted in a 60 increased risk of a body weight more than 120 of the ideal body weight. On average, the intensively treated patients had a weight gain of 5 kg compared to the patients treated with conventional insulin regimens (82). Most of the weight changes appeared during the first year of treatment (82,84). In another DCCT substudy it was concluded that the changes in lipid levels and blood pressure that occur with excessive weight gain with intensive therapy were similar to those seen in the insulin resistance syndrome and may increase the risk of coronary artery disease in this subset of subjects with time (85). Not surprisingly, more female than male patients...

Role Of Diabetes In The Genesis Of

There are several clinical, angiographic, and biological features particular to DM that increase the propensity for developing CAD in diabetic patients. In the aggregate, these risk factors increase the likelihood for sustaining a clinical event and have important prognostic implications. Endothelial dysfunction, platelet and coagulation abnormalities, and metabolic disorders associated with DM play a major role in accelerating the process of atherosclerosis and generating coronary thrombosis. The interplay of these factors and processes affects healing after arterial wall injury. The diffuse and distal nature of coronary atherosclerosis may contribute to incomplete revascularization and may increase the risk of surgical or percutaneous revascularization in diabetic patients.

ROS May Contribute to Insulin Resistance

Adipocytes exposed to H2O2 in vitro manifest impaired lipid synthesis, glycogen synthetase activity, and glucose uptake in response to insulin (105). Type II diabetics show an inverse relationship between measures of oxidant stress and insulin action (106,107). Antioxidant therapy with vitamin E was associated with improved glucose metabolism in some studies of diabetics (108). Collectively, the studies implicate oxidant stress in the metabolic components of insulin resistance observed in subjects with the risk factor cluster.

Insulin Glucose Infusion

Long-term mortality in diabetic patients who are hospitalized for acute MI may be reduced by an insulin-glucose infusion followed by multidose insulin treatment. In the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study, an infusion of insulin and glucose followed by daily subcutaneous injections of insulin resulted in a 52 reduction in mortality within 1 year after myocardial infarction among patients with DM. This beneficial effect was attributed to improved metabolic control in the presence of an extreme increase in the level of catecholamines in blood and ischemic myocardium that is associated with sudden ischemic episodes. Insulin therapy appeared to beneficially influence acute cardiovascular mortality. A striking reduction in the incidence of fatal reinfarction and left ventricular failure was seen. These results are consistent with favorable effects in reducing mortality among diverse groups of patients treated with a glucose-insulin-potassium...

Surgical And Interventional Management Of Cad In Diabetics

Several clinical trials have demonstrated that outcomes after myocardial revas-cularization are different in diabetic patients compared to nondiabetic patients. These differences should influence treatment decisions. Over the last decade, percutaneous coronary intervention (PCI) has gained increasing acceptance as an alternative to CABG surgery in selected patients. However, several reports demonstrating reduced long-term survival in diabetic patients treated with standard coronary balloon angioplasty have led to concerns regarding the use of PCI in this group of patients. A complete understanding of the mechanisms responsible for the reduced survival is of critical importance in the management of diabetic patients. The operative and procedural management of diabetics with symptomatic CAD will be discussed based on the type of intervention employed. This section will detail the short- and long-term clinical outcomes associated with standard balloon PCI, PCI with stents, and CABG...

Diabetes Mellitus and Stress Hyperglycemia

Diabetes mellitus increases the relative risk of in-hospital mortality by at least 1.5-2 compared with nondiabetic patients (15). Diabetic women in particular have a relatively poor prognosis, in part related to an increased incidence of congestive heart failure, rein-farction, and recurrent ischemic events (15-18). Late mortality is significantly increased in diabetic compared with nondiabetic patients (19). Stress hyperglycemia at the time of MI is strongly correlated with mortality rates. In a meta-analysis conducted by Capes et al. (20), data from 15 trials reporting admission glucose concentrations in relation to in-hospital mortality or heart failure rates after AMI were reviewed. In the patients without known diabetes, those with a glucose concentration > 109-143 mg dL had a 3.9-fold higher risk of death compared to patients with lower glucose concentrations. At glucose concentrations of > 143-180 mg dL, the risk of cardiogenic shock or heart failure was increased 3-fold....

B Cabg Surgery in Patients with Symptomatic CAD and Diabetes Mellitus

As described previously, the BARI trial has shown that patients with DM and angiographic multivessel CAD randomized to an initial strategy of CABG surgery have a striking reduction in mortality compared to diabetic patients randomized to balloon PCI. Further, post hoc analyses of three smaller trials comparing CABG with balloon PCI in patients with stable CAD demonstrated potentially conflicting results in diabetic subjects. In the CABRI trial, diabetic patients fared worse in a manner similar to that seen in BARI. By contrast, the RITA-1 and EAST trials demonstrated similar outcomes in diabetic patients treated with CABG or balloon PCI. Results from retrospective studies and registries bear on the role of CABG in diabetic subjects. A caveat in the interpretation of these results is that such databases of diabetic patients who have undergone coronary intervention may not be generalizable to more unselected groups. Further, the prognosis in such nonrandomized cohorts can be influenced...

Insulin and glucagon regulate blood glucose levels

Before the 1920s, diabetes mellitus* was a fatal disease, characterized by weakness, lethargy, and a dramatic loss of body mass. The disease was known to be connected somehow with the pancreas, a gland located just below the stomach (see Figure 42.2), and with abnormal glucose metabolism, but the link was not clear. Today we know that diabetes mellitus is caused by a lack of the protein hormone insulin (type I or juvenile onset diabetes) or by a lack of insulin receptors on the target tissues (type II or adult onset diabetes). For patients in which the hormone is lacking, insulin replacement therapy is an extremely successful treatment. At present, more than 1.5 million people with diabetes in the United States lead almost normal lives through the use of manufactured insulin. *The name diabetes refers to the copious production of urine. Mellitus (Greek for honey) reflects the fact that the urine of an untreated diabetic is sweet. Insulin binds to a receptor on the plasma membrane of a...

In Patients With Diabetes

Most diabetic patients with CHF have it in conjunction with some other known cause(s) of CHF, usually coronary artery disease and or hypertension. Thus, there are relatively few patients with CHF in whom the only predisposing factor is diabetes. Stated another way, although there is strong evidence that cardiomyopa-thy is caused by diabetes, it is unusual for it to account for overt CHF by itself. Moreover, in an individual patient, it is usually impossible to delineate the qualitative and quantitative contributions of diabetic cardiomyopathy as opposed to hypertension or ischemia caused by coronary artery disease. As noted above, diabetes in combination with hypertension and coronary artery disease is not merely additive, but interacts with either or both in a way that seems to potentiate myocardial failure. Accordingly, when diabetic patients have CHF in association with coronary artery disease, they typically have conventional manifestations of myocardial ischemia (i.e., acute and...

Effect of Inulin Type Fructans on Lipid Parameters in Noninsulin Dependent Diabetic Niddm Subjects

Administration of oligofructose in a packed coffee drink or coffee jelly for 14 d to uncontrolled diabetics (8 men and 10 women) fed a diabetic diet (55 carbohydrates, 25 fat, and 20 proteins) reduced total (8 ) and LDL cholesterol (10 ), compared with a control group given sucrose in the same food vehicles. No effects on other serum lipids but a decrease in blood glucose concentrations were observed.42 3. In NIDDM subjects (n 12) oligofructose (20 g d in habitual diet) had no effect on total or lipoprotein-bound cholesterol, plasma TAGs, hepatic glucose production, or insulin resistance.44 diabetics Diabetic diet (55 CHO,3 25 fat, 20 proteins) Decreased blood glucose No effect on cholesterol in lipoproteins or in plasma glucose and insulin

Management of Diabetes in Patients with Heart Failure

Poorly controlled diabetes should be managed aggressively in any patient with CHF because the attendant metabolic stress can certainly have adverse effects on myocardial function. Stringent control of blood glucose reduces the incidence of several complications of diabetes, specifically retinopathy, neuropathy, and nephropathy, but no data are available pertaining to the long-term effects of stringent control on diabetic cardiomyopathy or CHF in general in patients with diabetes. To the extent that diabetic cardiomyopathy is caused by hyperglycemia per se (e.g., matrix glycosylation) or the intracellular metabolic effects of reduced glucose transport (e.g., free radical damage to membranes), normalization of carbohydrate metabolism makes intuitive sense. Moreover, stringent control has been shown to modestly reduce event rates after an index myocardial infarction. On the other hand, prolonged hyperinsulinemia may be atherogenic and pro-thrombotic in type II diabetic patients. Thus, it...

Frequency Of Hypoglycaemia In Type 2 Diabetes

Mild hypoglycaemia is defined by the ability to self-treat, while the need for external assistance denotes a severe episode. The frequency of hypoglycaemia in people with type 1 diabetes is described in Chapter 3. Mild hypoglycaemia occurs on average around twice weekly (Pramming et al., 1991 Pedersen-Bjergaard et al., 2004) and the estimated incidence of severe hypoglycaemia ranges from 1.0 to 1.7 episodes per patient per year (MacLeod et al., 1993 ter Braak et al., 2000 Pedersen-Bjergaard et al., 2004) with an annual prevalence of between 30 (MacLeod et al., 1993 The Diabetes Control and Complications Trial Research Group, 1993 Stephenson et al., 1994) and 40 (ter Braak et al., 2000). The frequency of hypoglycaemia in type 2 diabetes cannot be summarised in an equally succinct manner because of the heterogeneity of this disorder and the range of treatment modalities available. Furthermore, many people with type 2 diabetes are elderly and the frequency of hypoglycaemia is often...

Selfassociation of Insulin A Protein Protein Interaction

Protein-protein interactions mediate the majority of life processes. An understanding of these interactions is critical to understanding cell regulation 66 and to preventing human disease that can arise from errors in protein-protein interactions 67 . A clear understanding of these interactions points the way to developing new targets and discovering new drugs 68 . Insulin, a protein with 51 residues in two chains 69 , is a good model system for testing whether a PLIMSTEX-like approach can determine protein self association. Oligomerization of insulin also has implications in the treatment of type I diabetes. The large size of the hexamer, which contains two Zn2+, of insulin prevents its efficient absorption into the blood stream 70 , whereas aggregation is prevented by using analogs of insulins that are stable in monomeric form 71 . PLIMSTEX can be used to study the self-association properties of various insulins 33 and may be a promising method for investigating protein-protein...

Modified Version of Plimstex for Insulin Selfassociation

To obtain data similar to that from PLIMSTEX, the concentration of insulin in solution is varied and amide exchange is initiated, followed by quenching the exchange, and injecting the ice-cold solution into the ESI source of a mass spectrometer. After the quench, the oligomers dissociate into monomers, but the increase in mass of the monomer (compared to the control) gives a weighted average of the increase in mass of the various oligomers. These data can be used to obtain a species-specific deuterium number for each oligomer and to calculate the association constants for the oligomerization. For fitting the insulin self-association The insulin amide exchange during the self-association shows that the number of exchangeable hydrogens decreases with increasing concentration of insulin, demonstrating that, as the self-association occurs, fewer amide hydrogens undergo exchange. The AD values in the case of insulin represent changes in the solvent accessibility of the oligomer compared to...

Insulin Counters High Blood Glucose

Insulin stimulates glucose uptake by muscle and adipose tissue (Table 23-3), where the glucose is converted to glucose 6-phosphate. In the liver, insulin also activates glycogen synthase and inactivates glycogen phosphory-lase, so that much of the glucose 6-phosphate is channeled into glycogen. Insulin also stimulates the storage of excess fuel as fat (Fig. 23-26). In the liver, insulin activates both the oxidation of glucose 6-phosphate to pyruvate via gly-colysis and the oxidation of pyruvate to acetyl-CoA. If not oxidized further for energy production, this acetyl-CoA is used for fatty acid synthesis in the liver, and the fatty acids are exported as the TAGs of plasma lipopro-teins (VLDLs) to the adipose tissue. Insulin stimulates TAG synthesis in adipocytes, from fatty acids released from the VLDL triacylglycerols. These fatty acids are ultimately derived from the excess glucose taken up from the blood by the liver. In summary, the effect of insulin is to favor the conversion of...

Diabetes Mellitus Arises from Defects in Insulin Production or Action

Diabetes mellitus, caused by a deficiency in the secretion or action of insulin, is a relatively common disease nearly 6 of the United States population shows some degree of abnormality in glucose metabolism that is indicative of diabetes or a tendency toward the condition. There are two major clinical classes of diabetes mellitus type I diabetes, or insulin-dependent diabetes mellitus (IDDM), and type II diabetes, or non-insulin-dependent diabetes mellitus (NIDDM), also called insulin-resistant diabetes. In type I diabetes, the disease begins early in life and quickly becomes severe. This disease responds to insulin injection, because the metabolic defect stems from a paucity of pancreatic 3 cells and a consequent inability to produce sufficient insulin. IDDM requires insulin therapy and careful, lifelong control of the balance between dietary intake and insulin dose. Characteristic symptoms of type I (and type II) diabetes are excessive thirst and frequent urination (polyuria),...

The Benefits Of Insulin Therapy

Despite the reservations of many practitioners about initiating insulin therapy, there should be no question about the ability of insulin to help patients with type 2 diabetes reach therapeutic goals. A number of studies have documented the success of progressive treatment regimens that include graduated insulin therapy (16,17). Obviously, recognition of a progressive 3-cell defect leads to the conclusion that exogenous insulin will be required when overall insulin secretion is inadequate to reach an HbA,c of 7.0 . However, insulin has a number of other benefits that are important to understand. As blood glucose elevates due to failure of oral agent therapy or due to other factors such as an intercurrent illness, the elevated glucose levels create a vicious cycle often referred to as glucotoxicity. This term applies to the ability of hyperglycemia to increase insulin resistance and to further inhibit p-cell function (18). Insulin therapy has proven to be the most predictable and rapid...

Effects of Diabetes on LDL Oxidation

Diseases that enhance LDL oxidation include diabetes and hypertriglyceridemia (115). Hyperglycemia increases LDL oxidation, in part, through an increase in glycation products, which subsequently enhances free radical production in stimulated inflammatory cells (115). Insulin and IGF-I cause an upregulation of LDL receptor and down regulation of HDL receptor (281). Insulin increases uptake and esterification of LDL-C by VSMC (3). LDL from diabetic patients is more atherogenic and more likely to be bound (by affinity chromatography on Ricinus communis agglutinin-agarose). Bound LDL has lower sialic acid content and higher fructosyl lysine level, and induces cholesterol accumulation in cultured cells and has lower neutral lipids. Desialylated LDL has a low neutral carbohydrate level, decreased content of major lipids, small size, high density, increased electronegative charge, less phospholipids, and unesterified cholesterol on their surface, with resultant altered tertiary Apo B...

Summary Drug Table Insulin Preparations

TYPES OF INSULIN Rapid-Acting Insulins insulin injection (regular) insulin lispro (insulin analog) insulin aspart solution (insulin analog) Intermediate-Acting Insulin isophane insulin suspension (NPH) insulin zinc suspension (Lente) Long-Acting Insulins Insulin glargine solution extended insulin zinc suspension (Ultralente) Mixed Insulins isophane insulin suspension and insulin injections (NPH) isophane insulin suspension and insulin injection High-Potency Insulin insulin injection concentrated insulin injection concentrated

Oral Antidiabetic Drugs

The oral antidiabetic drugs are used to treat patients with type 2 diabetes that is not controlled by diet and exercise alone. These drugs are not effective for treating type 1 diabetes. Five types of oral antidiabetic drugs are currently in use Additional drugs are listed in the Summary Drug Table Antidiabetic Drugs.

Summary Drug Table Antidiabetic Drugs Continued

Type 2 diabetes with a sulfonylurea or insulin to improve glycemic control Type 2 diabetes in combination with metformin to improve glycemic control Type 2 diabetes in combination with metformin to improve glycemic control Type 2 diabetes with sulfonylurea, metformin, or insulin to improve glycemic control Type 2 diabetes in combination with metformin to improve glycemic control Headache, pain, myalgia, aggravated diabetes, infections, fatigue Antidiabetic Combination Drugs Type 2 diabetes Other initial monotherapy options Acarbose Miglitol Pioglitazone Rosiglitazone Repaglinide Insulin Other combination options Metformin or a Sulfonylurea plus Acarbose Miglitol, or Pioglitazone Rosiglitazone or Repaglinide (with metformin), or Insulin Add intermediate bedtime insulin or add third oral agent or switch to insulin monotherapy or refer to specialist *If initial presentation with fasting glucose > 260 mg dL is a symptomatic patient, consider insulin as initial intervention. Preferred in...

The Art and Science of Insulin Pump Therapy

The appropriate delivery of insulin for achieving euglycemia has been the goal of diabetes therapies in cases of both absolute and relative insulin deficiency. The fact that insulin is the most effective therapeutic choice for lowering blood sugars to normal or near-normal levels was established almost 80 years ago. All people with diabetes mellitus need to achieve the well-known goal of glucose control, set around the world at an HbA C of 6.5 . The fact that achieving this target results in prevention, stabilization, and reversal of complications associated with diabetes is equally well known as a result of multiple landmark interventional studies. These studies all met the most rigorous of scientific criteria and -g have set the standards of glucose control to be achieved. The causes of failure to achieve both euglycemia and improvements in the adverse outcomes of pa- tients with diabetes need to be examined, and these factors require rectification. Investigators and clinicians...

Pancreas Transplantation Offers a Cure for Diabetes Mellitus

One of the more common diseases in the United States is diabetes mellitus. This disease is caused by malfunction of insulin-producing islet cells in the pancreas. Transplantation of a pancreas could provide the appropriately regulated levels of insulin necessary to make the diabetic individual normal. Recently, one-year success rates for pancreas transplantation of about 55 have been reported. Transplantation of the complete pancreas is not necessary to restore the function needed to produce insulin in a controlled fashion transplantation of the islet cells alone could restore function. Kidney failure is a frequent complication of advanced diabetes occurring in about 30 of diabetics, therefore kidney and pancreas transplants are indicated. In 2000, there were 420 pancreas transplants and 904 simultaneous kidney pancreas transplants. A group at the University of Wisconsin reports that they have overcome surgical and medical barriers to the dual transplant and have achieved survival...

The Insulin Glucagon Ratio Determines Metabolic Status

In most instances, insulin and glucagon produce opposing effects. Therefore, the net physiological response is determined by the relative levels of both hormones in the blood plasma, the insulin-glucagon ratio (I G ratio). Inappropriate I G Ratios in Diabetes. A good example of the profound influence of the I G ratio on metabolic status is in insulin-deficient diabetes. Insulin levels are low, so pathways that insulin stimulates operate at a reduced level. However, insulin is also necessary for alpha cells to sense blood glucose appropriately,- in the absence of insulin, the secretion of glucagon is inappropriately elevated. The result is an imbalance in the I G ratio and an accentuation of glucagon effects well above what would be seen in normal states of low insulin, such as in fasting.

Treatment Of The Hormonal And Metabolic Abnormalities Of Diabetes

Control of hyperglycemia retards progression of microvascular disease in both type 1 and type 2 diabetes. Accordingly, stringent glycemic control is imperative. Yet glycemic control exerts only a modest impact in retarding progression of macrovascular disease. Clearly other steps are needed. The recently initiated BARI 2D trial has been designed to provide information useful in this regard. Patients are being assigned randomly to stringent and comparable glycemic control with regimens that are either insulin-sensitizing (focusing on glitazones and metformin) or inulin-providing (focusing on insulin and sulfonylureas) regimens. Thus, the potential value of reduction of insulin resistance is being assessed. The effects of the two approaches on activation of coagulation, platelets, and fibrinolysis will be clarified as well. Because patients with type 2 diabetes are insulin-resistant, provision of exogenous insulin may be the most successful means for providing an adequate supply of...

Cefalu Wt 2000. Insulin Resistance In Medical Management. Of Dm. New York. Marcel Dekker Inc Pp 57 76.

Sites CK, Calles-Escandon J, Brochu M, Butterfield M, Ashikaga T, Poehlman ET. Relation of regional fat distribution to insulin sensitivity in postmenopausal women. Fertil Steril 2000 73(1) 61-65. 84. Cefalu WT, Wang ZQ, Werbel S, Bell-Farrow A, Crouse JR, Hinson WH, Terry JG, Anderson R. Contribution of visceral fat mass to the insulin resistance of aging. Metabolism 1995 44 954-959. 85. Goodpaster BH, Thaete FL, Kelley DE. Thigh adipose tissue distribution is associated with insulin resistance in obesity and in type 2 diabetes mellitus. Am J Clin Nutr 2000 71 885-892. 88. Grundy SM. Hypertriglyceridemia, insulin resistance, and the metabolic syndrome. Am J Cardiol 1999 83 25F-29F. 89. Lamarche B, Lemieux I, Despres JP. The small, dense LDL phenotype and the risk of coronary heart disease epidemiology, patho-physiology and therapeutic aspects. Diabetes Metab 1999 25 199-211. 90. Sheu WH, Jeng CY, Young MS, Le WJ, Chen YT. Coronary artery disease risk predicted by insulin...

Insulin and Glucagon Postabsorptive State

Formation Ketone Bodies

The plasma glucose concentration is maintained surprisingly constant during the fasting, or postabsorptive, state because of the secretion of glucose from the liver. This glucose is derived from the processes of glycogenolysis and gluconeogenesis, which are promoted by a high secretion of glucagon coupled with a low secretion of insulin. Glucagon stimulates and insulin suppresses the hydrolysis of liver glycogen, or glycogenolysis. Thus during times of fasting, when glucagon secretion is high and insulin secretion is low, liver glycogen is used as a source of additional blood glucose. This results in the liberation of free glucose from glucose 6-phosphate by the action of an enzyme called glucose 6-phosphatase (chapter 5 see fig. 5.4). Only the liver has this enzyme, and therefore only the liver can use its stored glycogen as a source of additional blood glucose. Since muscles lack glucose 6-phosphatase, the glucose 6-phosphate produced from muscle glycogen can be used for glycolysis...

Future medical devices for the management of diabetes Implantable insulin pumps

The long-term implantable insulin pump (LIIP) is a high risk, Class III device. It is currently limited to investigational use in the United States. This device has received approval for marketing in the European Community. The LIIP is implanted into the anterior abdominal cavity and a catheter implanted through the abdomen into the peritoneal wall. Like the external pump, the device is comprised of a pumping mechanism, drug reservoir, and a programmable microprocessor. As opposed to the external infusion pumps, the system requires the use of an external communicator which allows for remote setting of basal and bolus dosages. The LIIP differs from the external pump in that insulin is delivered directly into the peritoneal cavity resulting in more physiologic insulin delivery. Intraperitoneal insulin delivery results in lower peripheral insulin levels due to faster clearance when compared to that of subcutaneous delivery. This rapid clearance and lower peripheral insulin levels may...

Regulation of Insulin and Glucagon Secretion

Insulin Release Glucagon

Insulin and glucagon secretion is largely regulated by the plasma concentrations of glucose and, to a lesser degree, of amino acids. The alpha and beta cells, therefore, act as both the sensors and effectors in this control system. Since the plasma concentration of glucose and amino acids rises during the absorption of a meal and falls during fasting, the secretion of insulin and glucagon likewise fluctuates between the absorptive and postabsorptive states. These changes in insulin and gluca-gon secretion, in turn, cause changes in plasma glucose and amino acid concentrations and thus help to maintain homeosta-sis via negative feedback loops (fig. 19.6). As described in chapter 6, insulin stimulates the insertion of GLUT4 channels into the plasma membrane (due to the fusion of intracellular vesicles with the plasma membrane see fig. 6.15) of its target cells, primarily in the skeletal and cardiac muscles, adipose tissue, and liver. This permits the entry of glucose into its target...

Type 1 Diabetes Mellitus

Type 1 diabetes mellitus results when the beta cells of the islets of Langerhans are progressively destroyed by autoimmune attack. Recent evidence in mice suggests that killer T lymphocytes (chapter 15) may target an enzyme known as glutamate decarboxylase in the beta cells. This autoimmune destruction of the beta cells may be provoked by an environmental agent, such as infection by viruses. In other cases, however, the cause is currently unknown. Removal of the insulin-secreting beta cells causes hyperglycemia and the appearance of glucose in the urine. Without insulin, glucose cannot enter the adipose cells the rate of fat synthesis thus lags behind the rate of fat breakdown and large amounts of free fatty acids are released from the adipose cells. In a person with uncontrolled type 1 diabetes, many of the fatty acids released from adipose cells are converted into ketone bodies in the liver. This may result in an elevated ketone body concentration in the blood (ketosis), and if the...

Basalbolus Intensive Insulin Therapy What Is Basal Bolus Insulin Treatment

BasaJ-bolus coverage combines the available insulin preparations (Table 1) into programs that take into account the unique dietary, exercise and other habits of your patient to mimic as closely as possible physiological insulin delivery i.e., provide insulin in approximately the correct amount when needed, and not provide it when unnecessary in order to attain near-normal daytime and nighttime glycemia. By necessity, multiple shots and frequent self-blood-glucose monitoring (SBGM) are required. Diabetes education is also a core element along with dietary instruction in how to regularize nutritional intake or, alternatively, how to use analysis techniques such as carbohydrate counting to determine insulin dosages for meals (see Chapter 4).

External insulin infusion pumps

Continuous subcutaneous insulin infusion pumps (CSII) are small programmable devices, about the size of a pager, with a reservoir filled with insulin. Insulin is delivered through a catheter, inserted under the abdomen, to the subcutaneous tissue. The device allows programming of different pre-selected rates (basal rate) as well as bolus doses. CSII allows the user to program different pre-selected basal rates of insulin infusion based on patterns of perceived needs. The device also allows the diabetic user to select from several types of mealtime boluses. The earliest insulin infusion pumps received FDA approval in the late 1980's. Since then a number of different pumps continue to be cleared through the 510(k) regulatory approval process as class II devices. To date, over 35 external insulin infusion pumps have been cleared 13 . Most recently, technological advancement has allowed the pump to incorporate communication software via an infrared interface allowing the user and the...

Nutrition Therapy Goals for Type 2 Diabetes

The management goal is to achieve and maintain optimal blood glucose and lipid control by making nutrition and lifestyle changes. Recommendations are to space meals and snacks throughout the day. make healthy food choices. moderate total fat, saturated fat. and calorie intake, and increase physical activity. Insulin sensitivity improves with even a modest amount of weight loss. It is recommended that a moderate calorie restriction. 250 to 500 calories less than average daily intake, be implemented. The long-term goal is to attain and maintain the healthiest weight possible. Tables 23-2 and 23-3 summarize the nutritional assessment and therapy of pediatric patients with diabetes. Table 23-2. Special Aspects of Nutritional Assessment in Diabetes growth and weight gain, activity pattern, psychosocial economic issues, smoking, medical history (celiac disease, nephropathy, hyperllpidemia, eating disorder, high blood pressure, asthma, attention deficit disorder, hypothyroidism, and other...

Ftiii The hormones insulin and glucagon I 0 control fuel metabolism

' f During the absorptive period, blood glucose levels rise as carbohydrates are digested and absorbed. During this time, the P cells of the pancreas release a hormone called insulin (see Chapter 42). Insulin plays a major role in directing glucose to where it will be used or stored. Insulin enhances the uptake of glucose from the blood and its conversion to glycogen by liver and muscle cells. It stimulates fat cells to take up glucose from the blood and convert it to stored fat, and it stimulates cells in most tissues of the body to preferentially use glucose as their metabolic fuel. The metabolism of fuel molecules is largely controlled by insulin, and to a lesser extent, by another pancreatic hormone called glucagon. Glucagon has the opposite effect of insulin It stimulates liver cells to break down glycogen and to carry out gluconeogenesis. Thus, under the influence of glucagon, the liver produces glucose and releases it into the blood (Figure 50.19). During the postabsorptive...

Factors Predisposing Patients to Severe Hypoglycaemia in Intensified Insulin Therapy

The relationship between impaired symptomatic awareness of hypoglycaemia and an increased rate of severe hypoglycaemia is well established (Hepburn et al., 1990 Gold et al., 1994 Clarke et al., 1995), although affected patients in these studies were not subject to strict glycaemic control. The association between counterregulatory failure and increased risk of severe hypoglycaemia is also well recognised (Ryder et al., 1990). Indeed, counterregulatory failure was proposed as a predictor of risk of severe hypoglycaemia in the subsequent application of intensified therapy (White et al., 1983), and it was not until later that the ability of intensified therapy to cause counterregulatory failure was suggested (Simonson et al., 1985a). It is indeed very important to appreciate that neither asymptomatic nor severe hypoglycaemia are restricted to people using intensified insulin therapy. Apart from a previous history of severe hypoglycaemia, the greatest risk may be the degree of insulin...

Diabetes Mellitus and Hypoglycemia

Inadequate secretion of insulin, or defects in the action of insulin, produce metabolic disturbances that are characteristic of diabetes mellitus. A person with type 1 diabetes requires injections of insulin a person with type 2 diabetes can control this condition by other methods. In both types, hyperglycemia and glycosuria result from a deficiency and or inadequate action of insulin. A person with reactive hypoglycemia, by contrast, secretes excessive amounts of insulin and thus experiences hypoglycemia in response to the stimulus of a carbohydrate meal. Chronic high blood glucose, or hyperglycemia, is the hallmark of diabetes mellitus. The name of this disease is derived from the fact that glucose spills over into the urine Table 19.6 Comparison of Type 1 and Type 2 Diabetes Mellitus Insulin secretion Insulin injections Diet and exercise oral stimulators of insulin sensitivity when the blood glucose concentration is too high (mellitus is derived from a Latin word meaning honeyed or...

Insulin Acts in the Arcuate Nucleus to Regulate Eating and Energy Conservation

Insulin Receptors Nucelus

Insulin secretion reflects both the size of fat reserves (adiposity) and the current energy balance (blood glucose level). Insulin acts on insulin receptors in the hypothalamus to inhibit eating (Fig. 23-33). Insulin receptors in the orexigenic neurons of the arcuate nucleus inhibit the release of NPY, and insulin receptors in the anorexigenic neurons stimulate a-MSH production, thereby decreasing fuel intake and increasing thermo-genesis. By mechanisms discussed in Section 23.3, insulin also signals muscle, liver, and adipose tissues to increase catabolic reactions, including fat oxidation, which results in weight loss. Leptin makes the cells of liver and muscle more sensitive to insulin. One hypothesis to explain this effect suggests cross-talk between the protein tyrosine kinases activated by leptin and those activated by insulin (Fig. 23-35) common second messengers in the two signaling pathways allow leptin to trigger some of the same downstream events that are triggered by...

Pattern of Insulin Secretion

Insulin secretion has a diurnal rhythm, with an increased rate of secretion during the day and decreased secretion at night (12). Also, insulin is secreted in both an ultradian (13) and a high-frequency pulsatile pattern (14). The ultradian pulses occur with a frequency of one pulse each 40 minutes, a rate that is decreased in patients with type 2 diabetes. The high-frequency pulses occur at one pulse per 6 minutes. Almost all insulin is secreted in these high-frequency discrete insulin secretory pulses. The amplitude of the resulting insulin concentration oscillations in the portal vein (1000-4000 pmol L) is very large, but hepatic insulin clearance results in a marked attenuation of these oscillations by the time they reach the systemic circulation (amplitude 10 pmol L) (15). The pacemaker responsible for generating this high-frequency pulsatile rhythm is unknown, but each islet independently secretes insulin in a comparable pulsatile manner so the property must be present within...

Insulindependent Diabetes Mellitus

Goodpasture Renal Biopsy Fluorescence

A disease afflicting 0.2 of the population, insulin-dependent diabetes mellitus (IDDM) is caused by an autoimmune attack on the pancreas. The attack is directed against specialized insulin-producing cells (beta cells) that are located in spherical clusters, called the islets of Langerhans, scattered throughout the pancreas. The autoimmune attack destroys beta cells, resulting in decreased production of insulin and consequently increased levels of blood glucose. Several factors are important in the destruction of beta cells. First, activated CTLs migrate into an islet and begin to attack the insulin-producing cells. Local cytokine production during this Photomicrographs of an islet of Langerhans (a) in pancreas from a normal mouse and (b) one in pancreas from a mouse with a disease resembling insulin-dependent diabetes mellitus. Note Photomicrographs of an islet of Langerhans (a) in pancreas from a normal mouse and (b) one in pancreas from a mouse with a disease resembling...

Relevance of fatty acid modulation of GSIS in the pathogenesis of insulin resistance and type 2 diabetes

While on the one hand fatty acid-mediated increases in insulin secretion may be important in ensuring adequate insulin release in situations where both FFA and glucose are elevated, on the other hand chronic over-exposure to fatty acids could lead to hypersecretion of insulin and hyperinsulinaemia. Boden (1997) propose that in non-diabetic and moderately insulin-resistant subjects, FFA stimulation of gluconeogenesis is counteracted by the FFA stimulation of insulin secretion, and is thereby an important counter-regulatory mechanism for maintaining circulating glucose concentration. However, in the development of type 2 diabetes in obese subjects, FFAs fail to stimulate the required compensatory insulin response, resulting in peripheral under-utilisation and hepatic overproduction of glucose, with resultant hyperglycaemia. It has been proposed that chronic over-exposure to FFA and LC acyl CoA results in the accumulation of lipid components within the beta-cell, with lipotoxicity and...

Pulsatile Insulin Secretion

Pulsatile Testosterone Secretion Men

Secretory cell types the a-cells secrete glucagon, the -cells secrete insulin, and the 5-cells secrete somatostatin. Glucagon and insulin have complementary actions. A high concentration of glucose in the bloodstream (corresponding to an overabundance of nutrients) stimulates the production of insulin, which in turn induces storage of excess nutrient and decreases the rate at which nutrients are mobilized from storage areas such as adipose tissue or the liver. Insulin acts principally on three tissues striated muscle (including the heart), liver, and adipose tissue. All the actions of insulin apparently stem from its interaction with a specific receptor in the plasma membrane of insulin-sensitive cells. How this interaction leads to the many actions of insulin on the cell is not fully understood. In striated muscle and adipose tissue, one important action of insulin is to stimulate the transport of glucose into the cell by a specific carrier (or carriers) in the plasma membrane. It...

Mechanisms by Which the Atypical Antipsychotic Agents May Cause Diabetes Mellitus

There are a number of ways in which the atypical antipsychotic medications could lead to hyperglycemia and diabetes mellitus. As discussed earlier in this chapter, decreased sensitivity (increased resistance) to insulin and decreased insulin secretion as a result of decreased beta cell function are involved in the development of type II diabetes mellitus. A few controlled studies suggest that the atypical antipsychotic medications affect insulin resistance rather than causing a primary defect in insulin secretion (Henderson et al. 2000b Selke et al. 2000). The insulin resistance seen during atypical antipsychotic treatment may be a result of increased central adiposity, or it may arise from the direct effect of the medication's action on the glucose transporter function (Haupt and Newcomer 2001). Dwyer et al. (1999) studied the effects of atypical antipsychotic agents on glucose transporter function. They suggested that a structure-function relationship exists in which similar drugs,...

Neutral Protamine Hagedorn Insulin

The most commonly used intermediate-acting insulin is neutral protamine Hagedorn (NPH) insulin (isophane). It was developed in the Novo-Hagedorn laboratories in Denmark in 1946 by Krayenbuhl and Rosenberg (37), based on the original observation of Hagedorn that insulin's effect was prolonged when combined with proteins such as protamine (38), and that of Scott and Fisher showing that small amounts of zinc lengthened the action of protamine insulin (39). NPH contains equal amounts of protamine and insulin with a small amount of zinc at neutral pH. Protamine is a basic, highly negatively charged protein derived from fish sperm. It is essentially nonimmunogenic. The commercial preparations of NPH are a suspension of oblong tetragonal crystals with essentially no unprecipi-tated (Regular) insulin (5). Because of the symmetric, even structure of the insu-lin-protamine crystals, and because protamine and insulin are used in equimolar amounts, the term isophane (Greek iso, even and phane,...

ET Antagonists in Heart Failure Renal Failure and Diabetes Mellitus

Selective ETA antagonists have prevented the progression of diabetic nephropathy in rat models (84). In an acute, randomized, placebo-controlled, double-blind, four-way crossover study, the selective ETa (BQ-123) and ETb (BQ-788) receptor antagonists Hyperinsulinemic insulin-resistant individuals have relatively elevated circulating levels of immunoreactive ET, suggesting that ET-1 plays a role in endothelial dysfunction and vascular damage found in these conditions (86). In patients with type 2 diabetes, ETa receptor blockade restored impaired vasodilatation (87). In nondiabetic obese and in type 2 diabetic subjects, arterial administration of BQ-123 produced significant vasodilatation (83). ETa blockade did not affect basal NO flux, which suggests the presence of increased ET constrictor tone in these subjects. Stimulated NO flux increased in response to ETa blockade in obese and type 2 diabetic subjects. Thus, ET contributes to endothelial dysfunction and the regulation of vascular...

Acute and Chronic Exercise Increases Insulin Sensitivity Insulin Receptor Density and Glucose Transport into Muscle

Insulin Exercise Response

Exercise suppresses insulin secretion by increasing sympathetic tone at the pancreatic islets. Despite acutely falling levels of circulating insulin, both non-insulin-dependent and insulin-dependent muscle glucose uptake increase during exercise. Exercise recruits glucose transporters from their intracellular storage sites to the plasma membrane of active skeletal muscle cells. Because exercise increases insulin sensitivity, patients with type 1 diabetes (insulin-dependent) require less insulin when activity increases. However, this positive result can be treacherous because exercise can accelerate hypoglycemia and increase the risk of insulin coma in these individuals. Chronic exercise, through its reduction of insulin requirements, up-reg-ulates insulin receptors. This effect appears to be due less to training than simply to a repeated acute stimulus, the effect is full-blown after 2 to 3 days of regular physical activity and can be lost as quickly. Consequently, healthy active...

Insulin Induced Actin Remodeling GluT4 Translocation and Caveolae

Adipocytes are terminally differentiated and are not dividing. They are also not migrating or spreading on the extracellular matrix, and they do not have well-formed stress fibers. Therefore, what is the significance of caveolin phosphorylation and Csk-induced attenuation of Src-family kinase activity in response to insulin in these cells Insulin increases glucose transport in fat and muscle cells by stimulating the translocation of GluT4 from intracellular vesicles to the plasma membrane. Insulin induces cortical actin remodeling which is required for Glut4 translocation 116,117 . Therefore, the regulation of cortical actin assembly is a key process in the stimulation of glucose transport by insulin. In a manner analogous to cell migration, cortical actin remodeling would require that the tension between the cell surface and the actin cytoskeleton first be transiently relieved, followed by rapid formation of new initiation sites for actin assembly at the membrane. Based on other...

Low Testosterone Shbg And Diabetes Mellitus

Total testosterone levels are lower than normal in men with type 2 diabetes even when controlling for body mass index (2,61-63). Much of this difference may result from lower SHBG, because the calculated value for free testosterone was not different from controls (2), although another study found lower levels of free testosterone using an analog assay (63). Several prospective studies found that low SHBG levels predict the development of type 2 diabetes (64-66). This finding follows logically from the inverse correlation between SHBG and obesity (25) and insulin resistance (50) and the propensity for obese and insulin-resistant individuals to develop type 2 diabetes. In the Massachusetts Male Aging Study (66), not only total but also free-testosterone levels were 17 lower in men who developed type 2 diabetes 7-10 yr later than in those with no diabetes. Free-testosterone levels that were 10 lower at baseline were also found in men in the Multiple Risk Factor Intervention Trials...

Epidemiological studies of dietary fatty acids insulin sensitivity and diabetes

Although many epidemiological and human experimental studies have investigated the role of dietary fatty acids in coronary heart disease (CHD), and on cardiovascular risk biomarkers such as cholesterol, there are only a limited number of human studies that have investigated the role of dietary fat, specifically, in the development of insulin resistance. A number of prospective studies have focused on associations between dietary fatty acid intakes or plasma and tissue fatty acid compositions in relation to either insulin action or risk of type 2 diabetes. In the Nurses' Study, intakes of dietary SFA or MUFA were neutral, but intakes of PUFA were negatively, and trans fatty acids were positively, related to increased risk of type 2 diabetes (Salmeron et al., 2001). Other prospective studies have shown that risk of type 2 diabetes is greatest in subjects showing relatively high proportions of SFA and low proportions of unsaturated fatty acids in blood lipids at baseline (Vessby et al.,...

Insulin Oscillations with Intermediate Frequency

Insulin also oscillates with a period of about 10-20 minutes (Figs. 19.11 and 19.12). Because these oscillations occur in islets and the isolated pancreas, it appears that unlike the ultradian oscillations, they are caused by a mechanism intrinsic to the pancreatic islets. These oscillations also occur in the experimental perifusion system depicted in Fig. 19.16. A thin layer of insulin-secreting -cells is sandwiched between beads and exposed to the flow of a solution, the perifusate, with flow rate f. By collecting the solution exiting the bottom of the perifusion system, one can determine how the rate of insulin release of the cells in the bed depends on the composition and flow rate of the influx solution. After a step increase in perifusate glucose concentration (to synchronize the cells), regular oscillations in the rate of insulin release are seen (Fig. 19.12). The insulin oscillations are influenced by both the flow rate and glucose concentration of the perifusate. This...

Blood Glucose Regulation And Diabetes Eug Ackerman

Effect of excessive weight gain with intensive therapy of type I diabetes on lipid levels and blood pressure results from the DCCT. JAMA 280(2) 140-146, 1998. 8. The Diabetes Control and Complications Trial Research Group. Hypoglycemia in the Diabetes Control and Complications Trial. Diabetes 46(2) 271-286, 1997. 9. Reichard P, Nilsson BY, Rosenqvisc (J. The effect oT long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med 329 304-309, 1993. 10. Reichard P, Pihl M. Mortality and Lreaiment side-effects during long-term intensified conventional insulin treatment in the Stockholm Diabetes Intervention Study. Diabetes 43(2) 313 317, 1994. 11. Cox DJ, Gonder-Frederick LA. Kovatchev BP, Young-Hyman DL, Donner TW, Julian DM, Clarke WL. Biopsychobehavioral model of severe hypoglycemia. 1 . Understanding the risk of severe hypoglycemia. Diabetes Care 22( 12) 2018-2025, 1999. 12. Kinsley BT, Weinger K, Bajaj M, Levy CJ,...

Familial Persistent Hyperinsulinaemic Hypoglycaemia of Infancy PHHI

Persistent hyperinsulinaemic hypoglycaemia or PHHI is a disorder of glucose homeostasis that is characterised by unregulated insulin secretion and profound hypoglycaemia. Both familial and sporadic forms have been identified. Familial PHHI is an autosomal recessive disease which occurs at low frequency in Europeans ( 1 in 40,000) but reaches incidences as high as 1 in 2,700 live births in Arabic families or Ashkenazi Jews, due to the much higher frequency of consanguineous marriages. It usually manifests at birth or within the first year of life and by the time the disease is recognised and treated, the infant may have suffered severe hypoglycaemia and consequent brain damage. The disease is probably under-diagnosed and may contribute to the incidence of post-natal deaths from unknown causes. Diagnosis of PHHI is made on the basis of persistent hypoglycaemia associated with raised insulin levels. Glucose infusions are required to maintain the plasma glucose level during diagnosis and...

Testosterone Shbg And Insulin

The mechanism for the association between obesity and low testosterone and SHBG has received considerable attention. Many studies have shown that testosterone levels are inversely correlated with insulin and c-peptide concentrations (50,51). This association is partly through SHBG, because fasting insulin likewise correlates negatively with SHBG levels (52), and insulin infusion lowered circulating SHBG, albeit slighty (53). Moreover, lowering circulating insulin levels with diazoxide increased plasma SHBG in men (54) and in obese women with PCOS (55). The regulation of SHBG expression by insulin has been studied directly using cultures of HepG2 hepatoma cells that express the SHBG gene (56). In these cells, adding insulin reduced SHBG mRNA levels (13) and protein secretion (12). As noted in the section on the SHBG gene, this insulin effect may be mediated by the liver-enriched transcription factor HNF-4 (hepa-tocyte nuclear factor-4) that transactivates the SHBG promoter (57)....

Screening For Obesity To Prevent Type 2 Diabetes

The primary prevention of type 2 diabetes is an urgent issue and weight control in the population seems to be the most important part of the preventive process. The drastic predictions concerning the time trends of obesity and type 2 diabetes call urgently for research aimed at finding a solution or more probably several solutions to the problem. One approach could be a mass screening programme examining the whole population for body weight and offering obese individuals the opportunity to participate in a weight management programme. Another approach could be a selective Type 2 Diabetes and its Complications a Serious Health Problem People with diabetes have a substantially reduced life expectancy. Atherosclerosis is the most common long-term complication of diabetes, at least in Caucasian populations. People with diabetes are two to three times more likely to die from coronary heart and cerebrovascular disease than are people without diabetes. The relationship is even more...

The Pancreas Secretes Insulin or Glucagon in Response to Changes in Blood Glucose

When glucose enters the bloodstream from the intestine after a carbohydrate-rich meal, the resulting increase in blood glucose causes increased secretion of insulin (and decreased secretion of glucagon). Insulin release by the pancreas is largely regulated by the level of glucose in the blood supplied to the pancreas. The peptide hormones insulin, glucagon, and somatostatin are produced by clusters of specialized pancreatic cells, the islets of Langerhans (Fig. 23-24). Each cell type of the islets produces a single hormone a cells produce glucagon 3 cells, insulin and 8 cells, somatostatin. triggers the release of insulin by exocytosis. Stimuli from the parasympathetic and sympathetic nervous systems also stimulate and inhibit insulin release, respectively. A simple feedback loop limits hormone release insulin lowers blood glucose by stimulating glucose uptake by the tissues the reduced blood glucose is detected by the 3 cell as a diminished flux through the hexokinase reaction this...

180 Mg 100 Ml Of Blood Sugar

It is evident that variation in the volumes of solution applied to the paper strips is of no consequence. Generally 100 to 200 fil is applied, the larger volume permitting use of a smaller quantity of tracer beef insulin-I131 for the same counting rate. Assay of insulin in plasma. Mixtures containing unknown samples are prepared at the same time and in the same way as are standard solutions except that the unknown sample is substituted for the human insulin. Plasma insulin is best determined in a 1 10 final dilution unless the insulin concentration is unusually high then a 1 20 or 1 40 dilution may be used. Mixtures may be made up to any desired volume. However, since only 100 to 200 *1 is applied to the paper strips, it is convenient to prepare all mixtures in 0.2 or 0.5 ml volumes containing 20 or 50 n of plasma, respectively. Since insulin may be damaged by plasma during incubation (22), an effect which is more marked in concentrated plasma than in diluted plasma, and at 37 rather...

Type 2 Diabetes Mellitus Primarily Originates in the Target Tissue

Acute Complications Diabetes Mellitus

Type 2 diabetes mellitus results primarily from impaired ability of target tissues to respond to insulin. There are multiple forms of the disease, each with a different etiology. In some cases, it is a permanent, lifelong disorder,- in others, it results from the secretion of counterregulatory hormones in a normal (e.g., pregnant) or pathophysiological (e.g., Cushing's disease) state. Gestational diabetes occurs in 2 to 5 of all pregnancies but usually disappears after delivery. Women who have had gestational diabetes have an increased risk of developing type 2 diabetes later in life. Insulin Resistance in Type 2 Diabetes. In most cases of type 2 diabetes, normal or higher-than-normal amounts of insulin are present in the circulation. Therefore, there is no impairment in the secretory capacity of pancreatic beta cells but only in the ability of target cells to respond to insulin. In some instances, it has been demonstrated that the fundamental defect is in the insulin receptor. In...

Viral Pancreatitis and Diabetes

Several viruses occasionally infect the pancreas in humans. Mumps, for example, can be complicated by severe pancreatitis, and coxsackie B viruses or various other enteroviruses have been incriminated also. Of greater research interest is the question of whether viruses may trigger juvenile diabetes mellitus of the insulin-dependent type (IDDM). Children born with the congenital rubella syndrome quite often develop IDDM before the age of 20. Mumps infections often affect the p cells of the pancreas. Mumps virus, reovirus, and coxsackie B viruses have all been demonstrated to induce diabetes in mice, but there is still no proof that these viruses induce IDDM in humans. The association of IDDM with particular human leukocyte antigen (HLA) types has encouraged a hypothesis that pancreatic infection with any of perhaps several viruses may trigger autoimmune destruction of fi cells.

Nutrition Strategies For Type 1 Diabetes

The goals of nutrition therapy for the type 1 diabetic patient are listed in Table i. The usual food intake and exercise habits should be determined prior to the initiation of either conventional or intensive insulin therapy, because it is important to integrate insulin therapy into the patient's accustomed routine. It is recommended that all patients starting insulin therapy meet with a registered dietitian to develop an individualized meal plan that incorporates their food preferences, usual pattern of meals and snacks, and exercise habits. An initial meal plan should Type 1 diabetes Type 2 diabetes The ideal meal plan integrates insulin therapy into usual eating and exercise habits Patients on conventional insulin therapy need to eat at consistent times to coordinate with the action time of insulin Adequate calories should be provided to maintain a reasonable body weight in adults and meet the nutritional needs for growth, development, pregnancy, lactation, and illness Patients...

Effects of fatty acids on insulin signalling pathways

In addition to their possible effects on the coordination of energy metabolism, FFAs may also have effects on the critical actions of insulin through, for example, the insulin signalling cascade. This cascade is essential for insulin-stimulated responses such as insulin-stimulated glucose uptake. The signalling cascade involves tyrosine phosphorylation of the insulin receptor substrate 1 (IRS-1) protein and thereby stimulation of phosphatidyl inositol 3 kinase (PI-3 kinase) activity which is essential for the expression of glucose transporters (GLUT4) that enable glucose uptake. Elevated FFA can adversely affect insulin-stimulated glucose uptake at the glucose transport phosphorylation stage. This may occur either due to direct effects of FFA on the glucose transporter, GLUT4, or via indirect effects through upstream modification of the insulin signalling cascade, which regulates GLUT4 density in response to insulin secretion (Boden & Shulman, 2002). Impaired insulin signalling may...

How Is a Hormone Discovered The Arduous Path to Purified Insulin

Insulin Purification From Pancreas

Millions of people with type I (insulin-dependent) diabetes mellitus inject themselves daily with pure insulin to compensate for the lack of production of this critical hormone by their own pancreatic 3 cells. Insulin injection is not a cure for diabetes, but it allows people who otherwise would have died young to lead long and productive lives. The discovery of insulin, which began with an accidental observation, illustrates the combination of serendipity and careful experimentation that led to the discovery of many of the hormones. In 1889, Oskar Minkowski, a young assistant at the Medical College of Strasbourg, and Josef von Mering, at the Hoppe-Seyler Institute in Strasbourg, had a friendly disagreement about whether the pancreas, known to contain lipases, was important in fat digestion in dogs. To resolve the issue, they began an experiment on fat digestion. They surgically removed the pancreas from a dog, but before their experiment got any farther, Minkowski noticed that the...

Increased Blood Glucose Stimulates the Secretion of Insulin

Chemoreceptors That Detect Blood Acidity

A variety of factors, including other pancreatic hormones, are known to influence insulin secretion. The primary physiological regulator of insulin secretion, however, is the blood glucose concentration. Proinsulin Synthesis. The gene for insulin is located on the short arm of chromosome 11 in humans. Like other hormones and secretory proteins, insulin is first synthesized by ribosomes of the rough ER as a larger precursor peptide that is then converted to the mature hormone prior to secretion (see Chapter 31). The insulin gene product is a 110-amino acid peptide, preproinsulin. Proinsulin consists of 86 amino acids (Fig. 35.2) residues 1 to 30 constitute what will form the B chain of insulin, residues 31 to 65 form the connecting peptide, and residues 66 to 86 constitute the A chain. (Note that connecting peptide should not be confused with C-peptide.) In the process of converting proinsulin to insulin, two pairs of basic amino acid residues are clipped out of the proinsulin...

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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