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Adjunct therapy for type 1 diabetes mellitus

Nature Reviews Endocrinology volume 6, pages 326–334 (2010)Cite this article

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Abstract

Insulin replacement therapy in type 1 diabetes mellitus (T1DM) is nonphysiologic. Hyperinsulinemia is generated in the periphery to achieve normal insulin concentrations in the liver. This mismatch results in increased hypoglycemia, increased food intake with weight gain, and insufficient regulation of postprandial glucose excursions. Islet amyloid polypeptide is a hormone synthesized in pancreatic β cells and cosecreted with insulin. Circulating islet amyloid polypeptide binds to receptors located in the hindbrain and increases satiety, delays gastric emptying and suppresses glucagon secretion. Thus, islet amyloid polypeptide complements the effects of insulin. T1DM is a state of both islet amyloid polypeptide and insulin deficiency. Pramlintide, a synthetic analog of islet amyloid polypeptide, can replace this hormone in patients with T1DM. When administered as adjunctive therapy to such patients treated with insulin, pramlintide decreases food intake and causes weight loss. Pramlintide therapy is also associated with suppression of glucagon secretion and delayed gastric emptying, both of which decrease postprandial plasma glucose excursions. Pramlintide therapy improves glycemic control and lessens weight gain. Agents that decrease intestinal carbohydrate digestion (alpha-glucosidase inhibitors) or decrease insulin resistance (metformin) might be alternative adjunctive therapies in T1DM, though its benefits are marginally supported by clinical data.

Key Points

  • Islet amyloid polypeptide is a hormone that is cosecreted with insulin from pancreatic β cells

  • Islet amyloid polypeptide binds to receptors located in the hindbrain and its effects are mediated through the central nervous system

  • Pramlintide is a synthetic analog of islet amyloid polypeptide that does not aggregate but has the same biological activity as human islet amyloid polypeptide

  • Administration of pramlintide to patients with type 1 diabetes mellitus (T1DM) increases satiety, reduces food intake, decreases body weight, delays gastric emptying and decreases glucagon secretion

  • The administration of pramlintide to patients with T1DM or insulin-treated type 2 diabetes mellitus before meals is associated with decreased HbA1c concentrations and decreased body weight

  • Other potential adjunctive therapies for patients with T1DM are agents that inhibit carbohydrate digestion (alpha-glucosidase inhibitors) or agents that decrease insulin resistance (metformin)

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Figure 1: Amino-acid sequence of pramlintide.
Figure 2: Pharmacologic effects of pramlintide.
Figure 3: Effects of pramlintide given at meal times on postprandial glucose excursions in patients with type 1 diabetes mellitus.
Figure 4: Effects of pramlintide on patients with type 1 diabetes mellitus.
Figure 5: Adverse effects of pramlintide therapy.

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References

  1. [No authors listed] Adverse events and their association with treatment regimens in the diabetes control and complications trial. Diabetes Care 18, 1415–1427 (1995).

  2. Pambianco, G., Costacou, T. & Orchard, T. J. The prediction of major outcomes of type 1 diabetes: a 12-year prospective evaluation of three separate definitions of the metabolic syndrome and their components and estimated glucose disposal rate: the Pittsburgh Epidemiology of Diabetes Complications Study experience. Diabetes Care 30, 1248–1254 (2007).

    Article  Google Scholar 

  3. McGill, M., Molyneaux, L., Twigg, S. M. & Yue, D. K. The metabolic syndrome in type 1 diabetes: does it exist and does it matter? J. Diabetes Complications 22, 18–23 (2008).

    Article  Google Scholar 

  4. Thorn, L. M. et al. Metabolic syndrome as a risk factor for cardiovascular disease, mortality, and progression of diabetic nephropathy in type 1 diabetes. Diabetes Care 32, 950–952 (2009).

    Article  Google Scholar 

  5. Shishko, P. I., Kovalev, P. A., Goncharov, V. G. & Zajarny, I. U. Comparison of peripheral and portal (via the umbilical vein) routes of insulin infusion in IDDM patients. Diabetes 41, 1042–1049 (1992).

    Article  CAS  Google Scholar 

  6. Frystyk, J. et al. Comparison of pancreas-transplanted type 1 diabetic patients with portal-venous versus systemic-venous graft drainage: impact on glucose regulatory hormones and the growth hormone/insulin-like growth factor-1 axis. J. Clin. Endocrinol. Metab. 93, 1758–1766 (2008).

    Article  CAS  Google Scholar 

  7. Purnell, J. Q. et al. Effect of excessive weight gain with intensive therapy of type 1 diabetes on lipid levels and blood pressure: results from DCCT. JAMA 280, 140–146 (1998).

    Article  CAS  Google Scholar 

  8. Thorn, L. M. et al. Metabolic syndrome in type 1 diabetes: association with diabetic nephropathy and glycemic control (the FinnDiane study). Diabetes Care 28, 2019–2024 (2005).

    Article  Google Scholar 

  9. Gromada, J., Franklin, I. & Wolheim, C. B. α-Cells of the endocrine pancreas: 35 years of research but the enigma remains. Endocr. Rev. 28, 84–116 (2007).

    CAS  PubMed  Google Scholar 

  10. Dunning, B. E. & Gerich, J. E. The role of α-cell dysregulation in fasting and postprandial hyperglycemia in type 2 diabetes and therapeutic implications. Endocr. Rev. 28, 253–283 (2007).

    Article  CAS  Google Scholar 

  11. Cooperberg, B. A. & Cryer, P. E. Beta-cell mediated signaling predominates over direct alpha-cell signaling in the regulation of glucagon secretion in humans. Diabetes Care 32, 2275–2280 (2009).

    Article  CAS  Google Scholar 

  12. Quesada, I., Tudurí, E., Ripoll, C. & Nadal A. Physiology of the pancreatic α-cell and glucagon secretion: role in glucose homeostasis and diabetes. J. Endocrinol. 199, 5–19 (2008).

    Article  CAS  Google Scholar 

  13. Andrew, S. F., Dinh, T. T. & Ritter, S. Localized glucoprivation of hindbrain elicits corticosterone and glucagon secretion. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R1792–R1798 (2007).

    Article  CAS  Google Scholar 

  14. Grill, H. J. & Hayes, M. R. The nucleus tractus solitarius: a portal for visceral afferent signals processing, energy status assessment and integration of their combined effects on food intake. Int. J. Obes. (Lond.) 33 (Suppl. 1), S11–S15 (2009).

    Article  CAS  Google Scholar 

  15. Brown, R. J., Sinaii, N. & Rother, K. I. Too much glucagon, too little insulin: time course of pancreatic islet dysfunction in new-onset type 1 diabetes. Diabetes Care 31, 1403–1404 (2008).

    Article  CAS  Google Scholar 

  16. Shah, P., Basu, A., Basu, R. & Rizza, R. Impact of lack of suppression of glucagon on glucose tolerance in humans. Am. J. Physiol. 277, E283–E290 (1999).

    CAS  PubMed  Google Scholar 

  17. Horowitz, M., Edelbroek, M. A., Wishart, J. M. & Straathof, J. W. Relationship between oral glucose tolerance and gastric emptying in normal healthy subjects. Diabetologia 36, 857–862 (1993).

    Article  CAS  Google Scholar 

  18. Jones, K. L. et al. Relationships between gastric emptying, intragastric meal distribution and blood glucose concentrations in diabetes mellitus. J. Nucl. Med. 36, 2220–2228 (1995).

    CAS  PubMed  Google Scholar 

  19. Woerle, H. J. et al. Importance of changes in gastric emptying for postprandial plasma glucose fluxes in healthy humans. Am. J. Physiol. Endocrinol. Metab. 294, E103–E109 (2008).

    Article  CAS  Google Scholar 

  20. Barnett, J. L. & Owyang, C. Serum glucose concentration as a modulator of interdigestive gastric motility. Gastroenterology 94, 739–744 (1988).

    Article  CAS  Google Scholar 

  21. Fraser, R. J. et al. Hyperglycemia slows gastric emptying in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 30, 675–680 (1990).

    Article  Google Scholar 

  22. Schwarcz, E., Palmér, M., Aman, J., Lindkvist, B. & Beckman, K.-W. Hypoglycemia increases gastric emptying rate in patients with type 1 diabetes mellitus. Diabet. Med. 10, 660–663 (1993).

    Article  Google Scholar 

  23. Woerle, H. J. et al. Impaired hyperglycemia-induced delay in gastric emptying in patients with type 1 diabetes deficient for islet amyloid polypeptide. Diabetes Care 31, 2325–2331 (2008).

    Article  CAS  Google Scholar 

  24. Young, A. Amylin physiology and pharmacology: clinical studies. Adv. Pharmacol. 52, 289–320 (2005).

    Article  CAS  Google Scholar 

  25. Moore, C. X. & Cooper, G. J. Co-secretion of amylin and insulin from cultured islet beta cells: modulation by nutrient secretogogues, islet hormones and hypoglycemic agents. Biochem. Biophys. Res. Commun. 179, 1–9 (1991).

    Article  CAS  Google Scholar 

  26. Schmitz, O., Brock, B. & Rungby, J. Amylin agonists: a novel approach in the treatment of diabetes. Diabetes 53 (Suppl. 3), S233–S238 (2004).

    Article  CAS  Google Scholar 

  27. Hay, D. L., Christopoulos, G., Christopoulos, A. & Sexton, P. M. Amylin receptors: molecular composition and pharmacology. Biochem. Soc. Trans. 32, 865–867 (2004).

    Article  CAS  Google Scholar 

  28. Beaumont, K., Kenney, M. A., Young, A. A. & Rink, T. J. High affinity amylin binding sites in rat brain. Mol. Pharmacol. 44, 493–497 (1993).

    CAS  PubMed  Google Scholar 

  29. Riediger, T., Zuend, D., Becskei, C. & Lutz, T. A. The anorectic hormone amylin contributes to feeding-related changes of neuronal activity in key structures of the gut-brain axis. Am. J. Physiol. Regul. Integr. Comp. Physiol. 286, R114–R122 (2004).

    Article  CAS  Google Scholar 

  30. Rowland, N. E., Crews, E. C. & Gentry, R. M. Comparison of Fos induced in rat brain by GLP-1 and amylin. Regul. Pept. 71, 171–174 (1997).

    Article  CAS  Google Scholar 

  31. Roth, J. D., Maier, H., Chen. S. & Roland, B. L. Implications of amylin receptor agonism: integrated neurohormonal mechanisms and therapeutic applications. Arch. Neurol. 66, 306–310 (2009).

    Article  Google Scholar 

  32. Lutz, T. A. et al. Lesion of the area postrema/nucleus of the solitary tract (AP/NTS) attenuates the anorectic effects of amylin and calcitonin gene-related peptide (CGRP) in rats. Peptides 19, 309–317 (1998).

    Article  CAS  Google Scholar 

  33. Lutz, T. A., Mollet, A., Rushing, P. A., Riediger, T. & Scharrer, E. The anorectic effect of a chronic peripheral infusion of amylin is abolished in area postrema/nucleus of the solitary tract (AP/NTS) lesioned rats. Int. J. Obes. Relat. Metab. Disord. 25, 1005–1011 (2001).

    Article  CAS  Google Scholar 

  34. Gedulin, B. R., Jodka, C. M., Herrmann, K. & Young, A. A. Role of endogenous amylin in glucagon secretion and gastric emptying in rats demonstrated with the selective antagonist, AC187. Regul. Pept. 137, 121–127 (2006).

    Article  CAS  Google Scholar 

  35. Kruger, D., Gatcomb, P. M. & Owen, S. K. Clinical implications of amylin and amylin deficiency. Diabetes Educ. 25, 389–397 (1999).

    Article  CAS  Google Scholar 

  36. Young, A. A. et al. Preclinical pharmacology of pramlintide in the rat: comparisons with human and rat amylin. Drug Dev. Res. 37, 231–248 (1996).

    Article  CAS  Google Scholar 

  37. Colburn, W. A., Gottlieb, A. B., Koda, J. &, Kolterman, O. G. Pharmacokinetics and pharmacodynamics of AC137 (25, 28, 29 tripro amylin, human) after intravenous bolus and infusion doses in patients with insulin dependent diabetes. J. Clin. Pharmacol. 36, 13–24 (1996).

    Article  CAS  Google Scholar 

  38. Chapman, I. et al. Low-dose pramlintide reduced food intake and meal duration in healthy, normal-weight subjects. Obesity 15, 1179–1186 (2007).

    Article  CAS  Google Scholar 

  39. Chapman, I. et al. Effect of pramlintide on satiety and food intake in obese subjects and subjects with type 2 diabetes. Diabetologia 48, 838–848 (2005).

    Article  CAS  Google Scholar 

  40. Smith, S. R. et al. Pramlintide treatment reduces 24-h caloric intake and meal sizes and improves control of eating in obese subjects: a 6-wk translational research study. Am. J. Physiol. Endocrinol. Metab. 293, E620–E627 (2007).

    Article  CAS  Google Scholar 

  41. Aronne, L. et al. Progressive reduction in body weight after treatment with the amylin analog pramlintide in obese subjects: a phase 2, randomized, placebo-controlled, dose-escalation study. J. Clin. Endocrinol. Metab. 92, 2977–2983 (2007).

    Article  CAS  Google Scholar 

  42. Smith, S. R. et al. Sustained weight loss following 12-month pramlintide treatment as an adjunct to lifestyle intervention in obesity. Diabetes Care 31, 1816–1823 (2008).

    Article  Google Scholar 

  43. Kong, M. F. et al. The effect of single doses of pramlintide on gastric emptying of two meals in men with IDDM. Diabetologia 41, 577–583 (1998).

    Article  CAS  Google Scholar 

  44. Kong, M. F. et al. Infusion of pramlintide, a human amylin analogue, delays gastric emptying in men with IDDM. Diabetologia 40, 82–88 (1997).

    Article  CAS  Google Scholar 

  45. Jodka, C., Green, D., Young, A. & Gedulin, B. Amylin modulation of gastric emptying in rats depends upon an intact vagus nerve [abstract]. Diabetes 45, 235A (1996).

    Google Scholar 

  46. Samsom, M. et al. Pramlintide, an amylin analog, selectively delays gastric emptying: a potential role of vagal inhibition. Am. J. Physiol. Gastrointest. Liver Physiol. 278, G946–G951 (2000).

    Article  CAS  Google Scholar 

  47. Fineman, M. S. et al. The human amylin analog, pramlintide, corrects postprandial hyperglucagonemia in patients with type 1 diabetes. Metabolism 51, 636–641 (2002).

    Article  CAS  Google Scholar 

  48. Fineman, M., Weyer, C., Maggs, D. G., Strobel, S. & Kolterman, O. G. The human analog, pramlintide, reduces postprandial hyperglucagonemia in patients with type 2 diabetes. Horm. Metab. Res. 34, 504–508 (2002).

    Article  CAS  Google Scholar 

  49. Heptulla, R. A., Rodriguez, L. M., Bomgaars, L. & Haymond, M. W. The role of amylin and glucagon in the dampening of glycemic excursions in children with type 1 diabetes. Diabetes 54, 1100–1107 (2005).

    Article  CAS  Google Scholar 

  50. Liljenquist, J. E. et al. Evidence for an important role of glucagon in the regulation of hepatic glucose production in normal man. J. Clin. Invest. 59, 369–374 (1977).

    Article  CAS  Google Scholar 

  51. Weyer, C. et al. Pramlintide reduces postprandial glucose excursions when added to regular insulin or insulin lispro in subjects with type 1 diabetes: a dose-timing study. Diabetes Care 26, 3074–3079 (2003).

    Article  CAS  Google Scholar 

  52. Levetan, C. et al. Impact of pramlintide on glucose fluctuations and postprandial glucose, glucagon, and triglyceride excursions among patients with type 1 diabetes intensively treated with insulin pumps. Diabetes Care 26, 1–8 (2003).

    Article  CAS  Google Scholar 

  53. Ceriello, A. et al. Effects of pramlintide on postprandial glucose excursions and measures of oxidative stress in patients with type 1 diabetes. Diabetes Care 28, 632–637 (2005).

    Article  CAS  Google Scholar 

  54. Singh-Franco, D., Robles, G. & Gazze, D. Pramlintide acetate injection for the treatment of type 1 and type 2 diabetes mellitus. Clin. Ther. 29, 535–562 (2007).

    Article  CAS  Google Scholar 

  55. Whitehouse, F. et al. A randomized study and open-label extension evaluating the long-term efficacy of pramlintide as an adjunct to insulin therapy in type 1 diabetes. Diabetes Care 25, 724–730 (2002).

    Article  CAS  Google Scholar 

  56. Ratner, R. E. et al. Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in type 1 diabetes mellitus: a 1-year, randomized controlled trial. Diabet. Med. 21, 1204–1212 (2004).

    Article  CAS  Google Scholar 

  57. Hollander, P. A. et al. Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes: a 1-year randomized controlled trial. Diabetes Care 26, 784–790 (2003).

    Article  CAS  Google Scholar 

  58. Ratner, R. E. et al. Adjunctive therapy with the amylin analogue pramlintide leads to a combined improvement in glycemic and weight control in insulin-treated subjects with type 2 diabetes. Diabetes Technol. Ther. 4, 51–61 (2002).

    Article  CAS  Google Scholar 

  59. Marrero, D. G. et al. Effect of adjunctive pramlintide treatment on treatment satisfaction in patients with type 1 diabetes. Diabetes Care 30, 210–216 (2007).

    Article  CAS  Google Scholar 

  60. Hoogwerf, B. J., Doshi, K. B. & Diab, D. Pramlintide, the synthetic analogue of amylin: physiology, pathophysiology, and effects on glycemic control, body weight, and selected biomarkers of vascular risk. Vasc. Health Risk Manag. 4, 355–362 (2008).

    Article  CAS  Google Scholar 

  61. FDA. Medication guide SYMLIN® (pramlintide acetate) injection NDA 21–332 FDA [online], (2005).

  62. Edelman, S. et al. A double-blind, placebo-controlled trial assessing pramlintide treatment in the setting of intensive insulin therapy in type 1 diabetes. Diabetes Care 29, 2189–2195 (2006).

    Article  CAS  Google Scholar 

  63. Chase, H. P., Lutz, K., Pencek, R., Zhang, B. & Porter, L. Pramlintide lowered glucose excursions and was well-tolerated in adolescents with type 1 diabetes: results from a randomized, single-blind, placebo-controlled, crossover study. J. Pediatr. 155, 369–373 (2009).

    Article  CAS  Google Scholar 

  64. Heptulla, R. A., Rodriguez, L. M., Mason, K. J. & Haymond, M. W. Twenty-four-hour simultaneous subcutaneous basal-bolus administration of insulin and amylin in adolescents with type 1 diabetes decreases postprandial hyperglycemia. J. Clin. Endocrinol. Metab. 94, 1608–1611 (2009).

    Article  CAS  Google Scholar 

  65. Fennoy, I. Pramlintide in pediatric type 1 diabetes. J. Pediatr. 155, 308–309 (2009).

    Article  Google Scholar 

  66. Lebovitz, H. E. Alpha-glucosidase inhibitors. Endocrinol. Metab. Clin. North Am. 26, 539–551 (1997).

    Article  CAS  Google Scholar 

  67. Tattersall, R. B. Alpha-glucosidase inhibition as an adjunct to the treatment of type 1 diabetes. Diabet. Med. 10, 688–693 (1993).

    Article  CAS  Google Scholar 

  68. Hanefeld, M. Cardiovascular benefits and safety profile of acarbose therapy in prediabetes and established type 2 diabetes. Cardiovasc. Diabetol. 6, 20 (2007).

    Article  Google Scholar 

  69. Hollander, P., Pi-Sunyer, X. & Coniff, R. F. Acarbose in the treatment of type 1 diabetes. Diabetes Care 20, 248–253 (1997).

    Article  CAS  Google Scholar 

  70. Dimitriadis, G., Karaiskos, C. & Raptis, S. Effects of prolonged (6 months) alpha-glucosidase inhibition on blood glucose control and insulin requirements in patients with insulin-dependent diabetes mellitus. Horm. Metab. Res. 18, 253–255 (1986).

    Article  CAS  Google Scholar 

  71. Riccardi, G. et al. Efficacy and safety of acarbose in the treatment of type 1 diabetes mellitus: a placebo-controlled, double-blind, multicentre study. Diabet. Med. 16, 228–232 (1999).

    Article  CAS  Google Scholar 

  72. Bailey, C. J. in Therapy for Diabetes Mellitus and Related Disorders 5th edn Ch. 21 (ed. Lebovitz, H. E.) 235–253 (American Diabetes Association, Alexandria, USA, 2009).

    Google Scholar 

  73. Vella, S. et al. The use of metformin in type 1 diabetes: a systematic review of efficacy. Diabetologia doi:10.1007/s00125-009-1636-9.

  74. Meyer, L. et al. The benefits of metformin therapy during continuous subcutaneous insulin infusion treatment of type 1 diabetic patients. Diabetes Care 25, 2133–2158 (2002).

    Article  Google Scholar 

  75. Jacobsen, I. B., Henriksen, J. E. & Beck-Nielsen, H. The effect of metformin in overweight patients with type 1 diabetes and poor metabolic control. Basic Clin. Pharmacol. Toxicol. 105, 145–149 (2009).

    Article  CAS  Google Scholar 

  76. Lund, S. S. et al. Effect of adjunct metformin treatment in patients with type-1 diabetes and persistent inadequate glycaemic control. A randomized study. PLoS ONE 3, e3363 (2008).

    Article  Google Scholar 

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  1. Department of Medicine, Division of Endocrinology, State University of New York Health Science Center at Brooklyn, 450 Clarkson Avenue, New York, 11203, NY, USA

    Harold E. Lebovitz

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The author is a consultant for Amylin Pharmaceuticals, AstraZeneca, Biocon, Enzymotec, GlaxoSmithKline, MetaCure, Novo Nordisk and Sanofi-aventis; is in the Advisory Board of Amylin Pharmaceuticals, ATCC, Biocon, Indigene, Intarca Pharmaceuticals, Merck, MetaCure and Poxel; is in the Speaker's Bureau of Eli Lilly and GlaxoSmithKline; and is a stockholder in Amylin Pharmaceuticals and Merck.

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Lebovitz, H. Adjunct therapy for type 1 diabetes mellitus. Nat Rev Endocrinol 6, 326–334 (2010). https://doi.org/10.1038/nrendo.2010.49

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