The Human Amylin Analog, Pramlintide, Reduces Postprandial Hyperglucagonemia in Patients with Type 2 Diabetes Mellitus

Abstract

Aims: Amylin is a second beta-cell hormone that is normally co-secreted with insulin in response to meals; it complements the effects of insulin in postprandial glucose control, in part by suppressing glucagon secretion. In patients with type 2 diabetes, mealtime administration of the human amylin analog pramlintide markedly improves postprandial glucose excursions. The aim of this study was to examine whether pramlintide reduces the postprandial hyperglucagonemia that is often seen in this patient population. Methods: Utilizing a single-blind, placebo-controlled crossover design, 24 patients with type 2 diabetes, 12 insulin-treated and 12 non-insulin-treated, underwent a standardized mixed meal test on 2 occasions during which they received, in randomized order, a five-hour intravenous infusion of placebo or pramlintide (100 µg/h). Results: During the placebo infusion, plasma glucose and plasma glucagon concentrations increased substantially after the meal. During the pramlintide infusion, postprandial plasma glucose and plasma glucagon responses were significantly (p < 0.05, all) reduced following ingestion of the same meal, both in the insulin-treated and non-insulin-treated subgroups. Conclusion: Supplementation of mealtime amylin with pramlintide reduces postprandial hyperglucagonemia in patients with type 2 diabetes, a mechanism that likely contributes to pramlintide’s postprandial glucose-lowering effect.

Glucagon - Islet Hormones - Hyperglycemia - Insulin - Beta-Cell Hormones

References

• 1 Moore C X, Cooper G JS. Co-secretion of amylin and insulin from cultured islet beta cells: Modulation by nutrient secretagogues, islet hormones and hypoglycemic agents.  Biochem Biophys Res Commun. 1991;  179 1-9
• 2 Hartter E, Svoboda T, Ludvik B, Schuller M, Lell B, Kuenberg E, Brunnbauer M, Woloszczuk W, Prager R. Basal and stimulated plasma levels of pancreatic amylin indicate its co-secretion with insulin in humans.  Diabetologia. 1991;  34 52-54
• 3 Weyer C, Maggs D G, Young A A, Kolterman O G. Amylin replacement with pramlintide as an adjunct to insulin therapy in type 1 and 2 diabetes mellitus: A physiological approach toward improved metabolic control.  Curr Pharm Des. 2001;  7 1353-1373
• 4 Brom A K, Klevesath M S, Borcea V, Kasperk C, Seibel M J, Wahl P, Ziegler R, Naworth P P. The effect of pramlintide (amylin analogue) treatment on bone metabolism and bone density in patients with type 1 diabetes mellitus.  Horm Metab Res. 1999;  31 472-475
• 5 Edelman S V, Weyer C. Unresolved challenges with insulin therapy in type 1 and type 2 diabetes: Potential benefit of replacing amylin, a second β-cell hormone.  Diabetes Technol Ther. 2002;  4 175-189
• 6 Young A, Moore C, Herich J, Beaumont K. Chapter 9: Neuroendocrine actions of amylin. In: Poyner D, Marshall I, Brain S (eds) Calcitonin Gene-Related Peptide (CGRP). Austin, Texas; R.G. Landes 1999: 91-102
• 7 Koda J E, Nyholm B, Fineman M S, Hove K Y, Schmitz O. Plasma concentrations of amylin reflect insulin sensitivity in relatives of patients with NIDDM and in healthy subjects.  Diabetologia. 1996;  39 A68 (abstract 250)
• 8 Fineman M S, Giotta M P, Thompson R G, Kolterman O G, Koda J E. Amylin response following Sustacal® ingestion is diminished in type II diabetic patients treated with insulin.  Diabetologia. 1996;  39 A149 (abstract 566)
• 9 Scherbaum W A. The role of amylin in the physiology of glycemic control.  Exp Clin Endocrinol Diabetes. 1998;  106 97-102
• 10 Thompson R G, Gottlieb A, Organ K, Koda J, Kisicki J, Kolterman O G. Pramlintide: A human amylin analog reduced postprandial plasma glucose, insulin and c-peptide concentrations in patients with type II diabetes.  Diabet Med. 1997;  14 547-555
• 11 Ratner R, Want L L, Fineman M S, Velte M J, Ruggles J A, Gottlieb A, Weyer C, Kolterman O G. Adjunctive therapy with the amylin analogue pramlintide leads to a combined improvement in glycemic and weight control in insulin-treated patients with type 2 diabetes.  Diabetes Technol Ther. 2002;  4 51-61
• 12 Fineman M, Gottlieb A, Skare S, Kolterman O. Pramlintide as an adjunct to insulin therapy improved glycemic and weight control in people with type 2 diabetes during treatment for 52 weeks.  Diabetes. 2000;  49 106 (428-P)
• 13 Thompson R G, Pearson L, Schoenfeld S L, Kolterman O G. Pramlintide, a synthetic analog of human amylin, improves the metabolic profile of patients with type 2 diabetes using insulin.  Diabetes Care. 1998;  21 987-993
• 14 Kong M F, Stubbs T, King P, Lambourne J, Macdonald I, Blackshaw E, Perkis A, Parker J, Tattersall R. Effect of single doses of pramlintide on gastric emptying of two meals in type 1 diabetes.  Diabetologia. 1998;  41 577-583
• 15 Samsom M, Szarka L A, Camilleri M, Vella A, Zinsmeister A R, Rizza R A. Pramlintide, an amylin analog, selectively delays gastric emptying: potential role of vagal inhibition.  Am J Physiol. 2000;  278 G946-G951
• 16 Young A A, Gedulin B, Vine W, Rink T J. Gastric emptying is accelerated in diabetic BB rats and is slowed by subcutaneous injections of amylin.  Diabetologia. 1995;  38 642-648
• 17 Rayner C K, Samsom M, Jones K L, Horowitz M. Relationships of upper gastrointestinal motor and sensory function with glycemic control.  Diabetes Care. 2001;  24 371-381
• 18 Silvestre R A, Rodriguez-Gallardo J, Jodka C, Parkes D G, Pittner R A, Young A A, Marco J. Selective amylin inhibition of the glucagon response to arginine is extrinsic to the pancreas.  Am J Physiol. 2001;  280 E443-E449
• 19 Unger R H, Orci L. The role of glucagon in the endogenous hyperglycemia of diabetes mellitus.  Annu Rev Med. 1977;  28 119-130
• 20 Reaven G M, Chen Y D, Golay A, Swislocki A L, Jaspan J B. Documentation of hyperglucagonemia throughout the day in nonobese and obese patients with noninsulin-dependent diabetes mellitus.  J Clin Endocrinol Metab. 1987;  64 106-110
• 21 Frank J W, Saslow S B, Camilleri M, Thomforde G M, Dinneen S, Rizza R A. Mechanism of accelerated gastric emptying of liquids and hyperglycemia in patients with type II diabetes mellitus.  Gastroenterology. 1995;  109 755-765
• 22 Wahren J, Felig P, Hagenfeldt L. Effect of protein ingestion on splanchnic and leg metabolism in normal man and in patients with diabetes mellitus.  J Clin Invest. 1976;  57 987-999
• 23 Shah P, Vella A, Basu A, Basu R, Schwenk W F, Rizza R A. Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus.  J Clin Endocrinol Metab. 2000;  85 4053-4059
• 24 Percy A J, Trainor D A, Rittenhouse J, Phelps J, Koda J E. Development of sensitive immunoassays to detect amylin and amylin-like peptides in unextracted plasma.  Clin Chem. 1996;  42 576-585
• 25 Fineman M S, Koda J E, Shen L X, Strobel S A, Maggs D G, Weyer C, Kolterman O G. The human amylin analog, pramlintide, corrects postprandial hyperglucagonemia in patients with type 1 diabetes.  Metabolism. 2002;  51 636-641
• 26 Gedulin B, Percy A, Jodka C, Young A. Endogenous amylin inhibits glucagon secretion, as demonstrated by studies using neutralizing antibody and the antagonist AC187.  Diabet Med. 1997;  14 S18 (abstract 5)
• 27 Gedulin B R, Rink T J, Young A A. Dose response for glucagonostatic effect of amylin in rats.  Metabolism. 1997;  46 67-70
• 28 Sexton P M, Paxinos G, Kenney M A, Wookey P J, Beaumont K. In vitro autoradiographic localization of amylin binding sites in rat brain.  Neuroscience. 1994;  62 553-567
• 29 Edwards G L, Gedulin B, Jodka C, Dilts R, Miller C, Young A. Area postrema (AP)-lesions block the regulation of gastric emptying by amylin.  Neurogastroenterol Motil. 1998;  10 26
• 30 Lutz T A, Delprete E, Scharrer E. Subdiaphragmatic vagotomy does not influence the anorectic effect of amylin.  Peptides. 1995;  16 457-462
• 31 Taborsky G J, Ahren B, Havel P J. Autonomic mediation of glucagon secretion during hypoglycemia: Implications for impaired α-cell responses in type 1 diabetes.  Diabetes. 1998;  47 995-1005