Normal Glucose Homeostasis

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Humans evolved as hunter-gatherers and, unlike people today, did not consume regular meals. Mechanisms therefore evolved for the body to store food when it was in abundance, and to use these stores to provide an adequate supply of energy, in particular in the form of glucose when food was scarce. Cahill (1971) originally described the 'rules of the metabolic game' which humans had to follow to ensure their survival. These rules were modified by Tattersall (personal communication) and are as follows:

1. Maintain glucose within very narrow limits.

2. Maintain an emergency energy source (glycogen) which can be tapped quickly for fleeing or fighting.

3. Waste not want not, i.e., store (fat and protein) in times of plenty.

4. Use every trick in the book to maintain protein reserves.

Hypoglycaemia in Clinical Diabetes, 2nd Edition. Edited by B.M. Frier and M. Fisher © 2007 John Wiley & Sons, Ltd

Insulin and glucagon are the two hormones controlling glucose homeostasis, and therefore the mechanisms enabling the 'rules' to be followed. The most important processes governed by these hormones are:

• Glycogen synthesis and breakdown (glycogenolysis): Glycogen, a carbohydrate, is an energy source stored in the liver and skeletal muscle. Liver glycogen is broken down to provide glucose for all tissues, whereas the breakdown of muscle glycogen results in lactate formation.

• Gluconeogenesis: This is the production of glucose in the liver from precursors: glycerol, lactate and amino acids (in particular alanine). The process can also occur in the kidneys, but this site is not important under physiological conditions.

• Glucose uptake and metabolism (glycolysis) by skeletal muscle and adipose tissue.

The actions of insulin and glucagon are summarised in Boxes 1.1 and 1.2. Insulin is an anabolic hormone, reducing glucose output by the liver (hepatic glucose output), increasing the uptake of glucose by muscle and adipose tissue (increasing peripheral uptake) and increasing protein and fat formation. Glucagon opposes the actions of insulin in the liver. Thus insulin tends to reduce, and glucagon to increase, blood glucose concentrations.

Box 1.1 Actions of insulin Liver t Glycogen synthesis (t glycogen synthetase activity) t Glycolysis t Lipid formation t Protein formation

I Glycogenolysis (^ phosphorylase activity) I Gluconeogenesis I Ketone formation

Muscle t Uptake of glucose amino acids ketone potassium t Glycolysis t Synthesis of glycogen protein I Protein catabolism I Release of amino acids

Adipose tissue t Uptake glucose potassium Storage of triglyceride

Box 1.2 Actions of glucagon Liver t Glycogenolysis t Gluconeogenesis t Extraction of alanine t Ketogenesis

No significant peripheral action

The metabolic effects of insulin and glucagon and their relationship to glucose homeostasis are best considered in relationship to fasting and the postprandial state (Siegal and Kreisberg, 1975). In both these situations it is the relative and not absolute concentrations of these hormones that are important.

Fasting (Figure 1.1a)

During fasting, insulin concentrations are reduced and glucagon increased, which maintains blood glucose concentrations in accordance with rule 1 above. The net effect is to reduce peripheral glucose utilisation, to increase hepatic glucose production and to provide non-glucose fuels for tissues not entirely dependent on glucose. After a short (for example overnight) fast, glucose production needs to be 5-6 g/h to maintain blood glucose concentrations, with the brain using 80% of this. Glycogenolysis provides 60-80% and gluconeogenesis 20-40% of the required glucose. In prolonged fasts, glycogen becomes depleted and glucose production is primarily from gluconeogenesis, with an increasing proportion from the kidney compared to the liver. In extreme situations renal gluconeogenesis can contribute as much as 45% of glucose production. Thus glycogen is the short term or 'emergency' fuel source (rule 2), with gluconeogenesis predominating during more prolonged fasts. The following metabolic alterations enable this increase in glucose production to occur:

• Muscle: Glucose uptake and oxidative metabolism are reduced and fatty acid oxidation increased. Amino acids are released.

• Adipose tissue: There are reductions in glucose uptake and triglyceride storage. The increase in the activity of the enzyme hormone-sensitive lipase results in hydrolysis of triglyceride to glycerol (a gluconeogenic precursor) and fatty acids, which can be metabolised.

• Liver: Increased cAMP concentrations result in increased glycogenolysis and gluconeo-genesis thus increasing hepatic glucose output. The uptake of gluconeogenic precursors (i.e. amino acids, glycerol, lactate and pyruvate) is also increased. Ketone bodies are produced in the liver from fatty acids. This process is normally inhibited by insulin and stimulated by glucagon, thus the hormonal changes during fasting lead to an increase in ketone production. Fatty acids are also a metabolic fuel used by the liver and provide a source of energy for the reactions involved in gluconeogenesis.

NORMAL GLUCOSE METABOLISM AND RESPONSES f glucagon,,!insulin |Insulin, J glucagon




Amino acids^- Protein t



Free FA
Glucose Homeostasis Liver

I Hepatic glucose output

Figure 1.1 Metabolic pathways for glucose homeostasis in muscle, adipose tissue and liver during fasting (left) and postprandially (right). FA = fatty acids; TG = triglyceride (associated CO2 production excluded for clarity)

"THepatic glucose output

I Hepatic glucose output

Figure 1.1 Metabolic pathways for glucose homeostasis in muscle, adipose tissue and liver during fasting (left) and postprandially (right). FA = fatty acids; TG = triglyceride (associated CO2 production excluded for clarity)

The reduced insulin: glucagon ratio favours a catabolic state, but the effect on fat metabolism is greater than protein, and thus muscle is relatively preserved (rule 4). These adaptations meant that not only did hunter-gatherers have sufficient muscle power to pursue their next meal, but also that brain function was optimally maintained to help them do this.

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