Elsevier

Metabolism

Volume 48, Issue 7, July 1999, Pages 935-941
Metabolism

The amylin analog pramlintide improves glycemic control and reduces postprandial glucagon concentrations in patients with type 1 diabetes mellitus

https://doi.org/10.1016/S0026-0495(99)90232-9Get rights and content

Abstract

To explore further the effects of the human amylin analog pramlintide on overall glycemic control and postprandial responses of circulating glucose, glucagon, and metabolic intermediates in type 1 diabetes mellitus, 14 male type 1 diabetic patients were examined in a double-blind, placebo-controlled, crossover study. Pramlintide (30 μg four times daily) or placebo were administered for 4 weeks, after which a daytime blood profile (8:30 am to 4:30 pm) was performed. Serum fructosamine was decreased after pramlintide (314 ± 14 μmol/L) compared with placebo (350 ± 14 μmol/L, P = .008). On the profile day, the mean plasma glucose (8.3 ± 0.7 v 10.2 ± 0.8 mmol/L, P = .04) and postprandial concentrations (incremental areas under the curve [AUCs] from 0 to 120 minutes) were significantly decreased during pramlintide administration (P < .01 for both) despite comparable circulating insulin levels (359 ± 41 v 340 ± 35 pmol/L). Mean blood glycerol values were reduced (0.029 ± 0.004 v 0.040 ± 0.004 mmol/L, P = .01) and blood alanine levels were elevated (0.274 ± 0.012 v 0.246 ± 0.008 mmol/L, P = .03) after pramlintide versus placebo. Blood lactate concentrations did not differ during the two regimens. During pramlintide administration, the AUC (0 to 120 minutes) for plasma glucagon after breakfast was diminished (P = .02), and a similar trend was observed following lunch. In addition, peak plasma glucagon concentrations 60 minutes after breakfast (45.8 ± 7.3 v 72.4 ± 8.0 ng/L, P = .005) and lunch (47.6 ± 9.0 v 60.9 ± 8.2 ng/L, P = .02) were both decreased following pramlintide. These data indicate that pramlintide (30 μg four times daily) is capable of improving metabolic control in type 1 diabetics. This may relate, in part, to suppression of glucagon concentrations. Longer-term studies are required to ascertain whether these findings are sustained over time.

References (41)

  • D Bretherton-Watt et al.

    Very high concentrations of islet amyloid polypeptide are necessary to alter the insulin response to intravenous glucose in man

    J Clin Endocrinol Metab

    (1992)
  • JPH Wilding et al.

    Lack of acute effect of amylin (islet associated polypeptide) on insulin sensitivity during hyperinsulinemic euglycaemic clamp in humans

    Diabetologia

    (1994)
  • B Nyholm et al.

    Acute effects of the human amylin analogue AC137 on basal and insulin-stimulated euglycemic and hypoglycemic fuel metabolism in patients with insulin-dependent diabetes mellitus

    J Clin Endocrinol Metab

    (1996)
  • M-F Kong et al.

    Infusion of pramlintide, a human amylin analogue, delays gastric emptying in men with IDDM

    Diabetologia

    (1997)
  • R Learning et al.

    Amylin modulates insulin secretion in humans

  • RH Unger

    Glucagon physiology and pathophysiology

    N Engl J Med

    (1971)
  • PJ Lefebvre

    Glucagon and its family revisited

    Diabetes Care

    (1995)
  • PC Butler et al.

    Contribution to postprandial hyperglycemia and effects on initial splanchnic glucose cycling in glucose-intolerant or NIDDM patients

    Diabetes

    (1991)
  • RE Dobbs et al.

    Glucagon: Role in the hyperglycemia of diabetes mellitus

    Science

    (1975)
  • H Ørskov et al.

    Wick-chromatography for rapid and reliable immunoassay of insulin, glucagon and growth hormone

    Nature

    (1968)
  • Cited by (104)

    • Mono and dual agonists of the amylin, calcitonin, and CGRP receptors and their potential in metabolic diseases

      2021, Molecular Metabolism
      Citation Excerpt :

      Hence, in terms of glucagon and hepatic glucose production, individuals with diabetes, metaphorically, have one foot on the gas pedal and no brake. Pre-prandial pramlintide partially compensates for this, as it suppresses inappropriate glucagon secretion, thereby avoiding glucagon-induced hyperglycemia [155,161,162]. As has also been shown preclinically, pramlintide therapy in humans promotes long-term satiety [133] and reduces caloric intake in single-injection studies [163].

    • Glucagon-like peptide 1 (GLP-1)

      2019, Molecular Metabolism
      Citation Excerpt :

      Amylin dose-dependently suppresses arginine-mediated glucagon secretion in rats [597] whereas pharmacological inhibition of amylin signaling enhances glucagon secretion [598]. Pramlintide, a synthetic amylin receptor agonist, improves glycemic control in diabetic patients via inhibition of postprandial glucagon secretion and inhibition of gastric emptying [599,600]. Interestingly, amylin does not affect glucagon secretion in isolated islets [601] nor in the perfused rat pancreas [602,603], suggesting that amylin regulation of glucagon is not cell autonomous.

    • Non-insulin drugs to treat hyperglycaemia in type 1 diabetes mellitus

      2016, The Lancet Diabetes and Endocrinology
      Citation Excerpt :

      The neuroendocrine hormone amylin, also known as islet amyloid polypeptide, is a 37-aminoacid peptide that is synthesised in the pancreatic β cells, stored in the pancreas with insulin (1:100), and is co-secreted with insulin in a high-frequency, pulsatile manner every 4 to 6 min.25 Amylin seemingly exerts its actions centrally by activating receptors in the area postrema, stimulating satiety centres and triggering efferent nervous impulses that inhibit glucagon secretion, and thereby reduce hepatic glucose production and delay gastric emptying.26–29 These actions imply that amylin reduces postprandial glucose excursions by modulating the rate of glucose influx into the circulation.

    • Prevention of type 2 Diabetes Mellitus: Potential of pharmacological agents

      2016, Best Practice and Research: Clinical Endocrinology and Metabolism
      Citation Excerpt :

      Similar to GLP-1, it also inhibits post-prandial glucagon secretion, which contributes to hyperglycemia [72]. Pramlintide is a synthetic analog of amylin, with three amino acid substitutions to decrease toxicity while still enabling activation of amylin receptors [73,74]. Pramlinitide is injected at mealtimes thrice daily.

    • Pramlintide an Adjunct to Insulin Therapy: Challenges and Recent Progress in Delivery

      2024, Journal of Pharmacology and Experimental Therapeutics
    View all citing articles on Scopus

    Supported by Amylin Pharmaceuticals, Oxford, UK, and San Diego, CA.

    View full text