Endocrinol Metab 1999 13 279-294.

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uated intravenous, subcutaneous (both Regular and fast-acting), and inhaled insulin. Heinemann et al. demonstrated in 1997 that the relative effectiveness of inhaled insulin was approximately 10% with regard to intravenous insulin administration and 8% with regard to subcutaneous insulin administration. In addition, Heise et al. reported that the onset of action of inhaled insulin appears to be more rapid than that of subcutaneous insulin. Inhaled insulin demonstrated a faster onset of action than subcutaneous Regular insulin and even insulin lispro (early ti0%: 32, 48, and 40 minutes, respectively). The maximal metabolic action (based on glucose infusion rates) was comparable with that of Regular insulin and lower than that of lispro. The duration of action of inhaled insulin (late ts was between that of lispro and Regular insulin (382, 309, and 413 minutes, respectively) (Figure 2). In addition to the above, it appears from several other evaluations that the pharmacokinetic and pharmacodynamic profiles of pulmonary delivery of insulin mimic those of the normal physiological response.

Clinical Results with Inhaled Insulin

On a clinical level, however, studies have suggested that inhaled insulin may be effective in both type I and type 2 subjects who are taking insulin and is effective in type 2 diabetic patients failing on oral agents. In 1999, Weiss et al. examined the effect of adding inhaled insulin (using a dry-powder formulation) to oral

agents in a study in 69 patients with poorly controlled type 2 diabetes (HbA 8.1 -11.9% despite receiving therapeutic doses of a sulfonylurea and/or metformin). Patients were randomized to either continue with their current oral agent alone or take the oral agent in combination with inhaled insulin (one or two inhalations three times daily, i.e., before meals). Inhaled insulin treatment was observed to significantly improve HbA,c in subjects receiving inhaled insulin compared with the level in those receiving an oral agent alone (—2.28 vs. —0.06%, respectively; p < 0.001). Inhaled insulin therapy was well tolerated, with only one report of severe hypoglycemia. In addition, pulmonary function tests remained Stable over the 3-month study period.

Two phase 2 studies have been reported on clinical use of the dry-powder formulation for treatment of type I and 2 diabetic subjects who were on insulin injections. Skyler et al. recently evaluated 73 patients with type 1 diabetes who received either their usual insulin regimen of two or three injections daily or pre-meal inhaled insulin plus an injection of Ultralente insulin at bedtime, for 12 weeks. At 12 weeks, there was no significant difference in HbAk or fasting or postprandial glucose concentrations between those randomized to inhaled insulin versus those taking subcutaneous insulin. In a study of 26 patients with type 2 diabetes who were receiving insulin therapy prior to study, patients were administered one or two inhalations of the dry-powder insulin formulation (between 3 and 18 units, according to the glucose response) before each meal plus bedtime Ultralente insulin. Insulin doses were adjusted at weekly intervals to achieve the target preprandial glucose of 100-160 mg/dl. Mean HbAlc levels were observed to significantly decrease by 0.71% when compared with the baseline value. The limitation of both the type 1 and 2 studies of inhaled insulin versus subcutaneous insulin is that they were of open-label design. Nevertheless, these studies strongly suggested that inhaled insulin may be a viable option for patients with either type 1 or type 2 diabetes currently on insulin therapy.

An important component of the early inhaled-insulin protocols is that patients appeared to be very satisfied with inhaled-insulin treatment. Patient-satisfaction surveys have confirmed that, after I year of treatment, patients receiving inhaled dry-powder Insulin maintained their satisfaction with significantly greater improvements than those using conventional insulin injections, in global satisfaction and convenience/ease of use. Gerber et al. found that patients who switched from subcutaneous insulin to inhaled insulin showed a significant improvement (p < 0.05) in global satisfaction (20% improvement), convenience/ease of use (28% improvement), and social stigma (16% improvement). In contrast, patients who switched from inhaled to subcutaneous insulin showed a trend toward worsening satisfaction. Thus, adherence to treatment with inhaled insulin may be better than that observed with injection regimens, although this must await confirmation by long-term studies.


It is now unquestioned that glycemic control is required lo prevent progression of diabetic complications. This has been firmly established not only for type 1 diabetes but also for type 2 diabetes. Insulin is the only treatment for type 1. and the natural history of type 2 diabetes suggests that insulin may be required for it too, given the progressive nature of the disease. Thus, regardless of the type of diabetes, multiple injection therapy may be required to adequately control glucose levels. Unfortunately, a number of barriers exist at both the patient and physician levels that may prevent the advancement to intensive insulin therapy. In addition to other relevant concerns, one obstacle is that injection remains the only viable means of administering insulin. However, numerous approaches have been evaluated to administer insulin noninvasively. Although the research is still very active in this area, pulmonary delivery, at this date, appears to have the most potential to become a clinically viable alternative to insulin injections. The clinical evidence shows that inhaled insulin is effective and well tolerated. It has a more physiological insulin profile than conventional subcutaneous insulin making it ideal for preprandial administration. Inhaled insulin, in the early studies, has met with increased patient satisfaction. The additional studies needed to confirm long-term efficacy and long-term pulmonary safety are underway. However, the evidence to date suggests that pulmonary insulin delivery may offer the potential to improve compliance and thereby help reduce the number of complications associated with diabetes.

(ic amounts of insulin across the intact mammalian skin. Biochim Biophys Acta 1368:201-215. 1998.

Cheity DJ, Chien YW. Novel methods of insulin delivery: an update. Crit Rev Ther Drug Carrier Syst 15:629-670, 1998.

Coates PA, Ismail IS, Luzio SD, Griffiths 1, Ollenon RL, Volund A, et al. Intranasal insulin: the effects of three dose regimens on postprandial glycaemic profiles in type II diabetic subjects. Diabet Med 12:235-239, 1995.

Davis SS. Overcoming barriers to the oral administration of peptide drugs. Trends Pharmacol Sei 11:353-355, 1990.

Diabetes Control and Complications Trial (DCCT) Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977-986. 1993.

Dimitriadis GD, Gerich JE. Importance of timing of preprandial subcutaneous insulin administration in the management of diabetes mellitus. Diabetes Care 6:374-377, 1983.

European Diabetes Policy Group. Guidelines for Diabetes Care: A Desktop Guide to Type 2 Diabetes Mellitus. Brussels: International Diabetes Federation (Europe), 1999.

Frauman AG. Jerums G, Louis WJ. Effects of intranasal insulin in non-obese type D diabetics. Diabetes Res Clin PracL 3:197-202, 1987.

Galloway JA, Spradlin CT. Nelson RL. Went worth SM, Davidson JA, S warner JL. Factors influencing (he absorption, serum insulin concentration, and blood glucose responses after injections of regular insulin and various insulin mixtures. Diabetes Care 4:366-376, 1981.

Gänssien M. Über Inhalation von Insulin. Klin Wochenschr 4:71. 1925.

Gel fand RA, Schwartz SL, Horton M, Law GG, Pun EF. et al. Pharmacological reproducibility of pre-meal inhaled insulin is comparable to injected insulin in patients with type 2 diabetes. Diabetes 47(suppl 1):A99, 1998.

Gerber RA, Cappelleri JC, Bell-Farrow AD, English JS, Agramante RF, Gel fand EA, et al. Improved patient satisfaction with inhaled insulin in subjects with type 1 diabetes mellitus after one year: results From a muliicenter extension trial. Diabetes 49(suppl I ):AI08, 2000.

Gizurason S, Bechgaard E. Intranasal administration of insulin to humans. Diabetes Res Clin Pract 12:71-84, 1991.

Golden MP, Haymond M, Hinnen DA, Kruger DF, Schumacher OP. Position statement on jet injections. Diabetes Care 11:600-601, 1988.

Graff MR, McClanahan MA. Assessment by patients with diabetes mellitus of two insulin pen delivery systems versus a vial and syringe. Clin Ther 20:486-496, 1988.

Greener MJ. Leading applications of inhaled delivery systems for systemically active drugs. Spectrum Drug Deliv Reform Tech 2:1 16, 2000.

Heinemann L, Traut T, Heise T. Time-action profile of inhaled insulin. Diabetic Med 14: 63-72, 1997.

Heise T, Rave K, Bott S. Sha S, Willavize SA, Carroll RS, et al. Time-aciion profile of an inhaled insulin preparation in comparison to insulin lispro and regular insulin. Diabetes 49(suppl 1):A10. 2000.

Heller SR. Diabetic hypoglycaemia. Baillieres Best Pract Res Clin Endocrinol Metab 13: 279-294, 1999.

Hilsted J. Madsbad S, Hvidberg A, Ramussen MH, Krarup T, lpsen H, et al. Intranasal insulin therapy: the clinical realities. Diabetologia 38:680-684, 1995.

Hirata Y, Kohama T, Ooi K. Nasal administration of insulin in healthy subjects and diabetic patients. In: Sakamoto N, Alberti KGMM, eds. Current and Future Therapies with Insulin. Amsterdam: Excerpt a Medica, pp 263-271, 1982.

Hoffman A. Ziv E. Pharmacokinetic considerations of new insulin formulations and routes of administration. Clin Pharmacokiner 33:285-301, 1997.

Hunt LM, Valenzuela MA, Puch JA. NIDDM patients' Fears and hopes about insulin therapy: the basis of patient reluctance. Diabetes Care 20(3):292-298, 1997.

Jacobs MAJM, SchreuderRH, Jap-A-Joe K, Nanta JJ, Andersen PM, Heine RJ, et al. The pharmacodynamics and activity of intranasal administered insulin in healthy male volunteers. Diabetes 42:1649-1655. 1993.

Kanikkannan N, Singh J, Ramarao P. Transdermal iontophoretic delivery of bovine insulin and monomeric human insulin analogue. J Controlled Release 59:99-105, 1999.

Klonoff DC. Inhaled insulin. Diabetes Tech Ther 1:307-313, 1999.

Köhler D, Schlüter KJ, Kerp L, Matlhys H. [Non-radioactive method to measure lung permeability: inhalation of insulin.] Atemw Lungenkrh 13:230-232, 1987.

Laube BL, Benedict GW, Dobs AS. The lung as an alternative route of delivery for insulin in controlling postprandial glucose levels in patients with diabetes. Chest 114: 1734-1739, 1998.

Laube BL, Benedict GW, Dobs AS. Time to peak insulin level, relative bioavailibility, and effect of site of deposition of nebulized insulin in parients with noninsulin-dependent diabetes mellitus, i Aerosol Med 11:153-173, 1998.

Laube BL, Georgopoulus A, Adams GK ID. Aerosolized insulin delivered through the lungs is effective in normalizing plasma glucose levels in non-insulin dependent diabetic subjects (N1DD). J Biopharm Sei 3:163-169, 1993.

Mitragotri S, Blankschtein D, Langer R. Ultrasound-mediated transdermal protein delivery. Science 269:850-853, 1995.

Moses AC, Gordon GS, Carey MC, Flier JS. Insulin administered intranasalIy as an insulin-bile salt aerosol: effectiveness and reproducibility in normal and diabetic subjects. Diabetes 32:1040-1047, 1983.

National Institute of Diabetes and Digestive and Kidney Diseases. Diabetes Statistics. NIH Publication 99-3892: Bethesda, MD: National Institutes of Health, 1999.

Patton J. Nature Biotechnol, 1998.

Pattrick AW, Cullen A, Matthews DM, Mac in tyre CCA, Clark BF. The importance of the time interval between injection and breakfast in determining postprandial glycemic control: a comparison between human and porcine insulin. Diabetes Med 5:32-35, 1988.

Pontiroli AE, Alberetlo M, Secchi A, Dossi G, Bosi 1, Pozza G, el al. Insulin given intranasal^ induces hypoglycaemia in normal and diabetic subjects. 8r Med J 294:303306, 1982.

Ramdas M. Diieep KJ. Anitha Y.Paul W.Sharma CP. Alginate encapsulated bioadhesive chitosan microspheres for intestinal drug delivery. J Biomater Appl 13:290-296. 1999.

Ruige JB, Assendelft WJ. Dekker JM, Kostense PJ, Heine RJ, Bouter LM. Insulin and risk of cardiovascular disease: a meta-analysis. Circulation 97:996-1001, 1998.

Saudek CD. Novel forms of Insulin delivery. Endocrinol Melab Clin North Am 26:599610, 1997.

Schilling RJ, Mitra AK. Degradation of insulin by trypsin and a I pha-ch ymoirypsin. Pharm Res 8:721 -727, 199).

Schlüter KJ, Köhler D, Enzmann F, Kerp L. Pulmonary administration of human insulin in volunteers and type 1 diabetes. Diabetes 33(suppl):298, 1984.

Silversiein JH, Rosenbloom AL. New developments in type I (insulin-dependent) diabetes. Clin Pediatr (Phila) 39:257-266, 2000.

Skyler JS, Cefa I u WT, Kourides IA, Landschulz WH, Balagtas CC, Cheng S-L, et al. on behalf of the Inhaled Insulin Phase LI Study Group. Efficacy of inhaled insulin in type I diabetes mellitus: a randomised proof-of-concept study. Lancet 357:331335, 2001.

Taylor R, Home PD, Alberti KGMM. Plasma free insulin profiles after administration of insulin by jet and conventional syringe injection. Diabetes Care 4:377-379, 1981.

UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet 352:837-853, 1998.

Wallace TM, Matthews DR. Poor glycemic control in type 2 diabetes: a conspiracy of disease, suboptimal therapy and altitude. Q J Med 93:369-374, 2000.

Weiss SR. Berger S, Cheng S-L. Kourides IA. Landschulz WM, Gelfand RA. et al. Adjunctive therapy with inhaled insulin in type 2 diabetic patients failing oral agents: a multicenter phase D trial. Diabetes 48(suppl l):AI2, 1999.

Wigley GM, Londono JH. Wood SI-I, Shipp JC. Waldman RH, et al. Insulin across respiratory mucosae by aerosol delivery. Diabetes 20:552-556, 1971.

Winter LB. On the absorption of insulin from the stomach. J Physiol 58:18-21, 1923.

Zambanini A, Newson RB. Maisey M, Feher MD. Injection related anxiety in insulin-treated diabetes. Diabetes Res Clin Pract 46:239-246, 1999.

Ziel FH, Davidson MB, Harris MD, Rosenberg CS. The variability in regular insulin action is more dependent on changes in tissue sensitivity than absorption. Clin Res 35: 160-166, 1987.

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Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

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