Role of amylin in insulin secretion and action in humans

Antagonist studies across the spectrum of insulin sensitivity

Kieren J. Mather, Giancarlo Paradisi, Rosalind Leaming, Ginger Hook, Helmut Steinberg, Naomi Fineberg, Rochelle Hanley, Alain D. Baron

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Background. Amylin is a peptide co-secreted with insulin by pancreatic β-cells. A role for amylin in the pathogenesis of type 2 diabetes mellitus (DM2) has been suggested by in vitro and in vivo studies indicating an effect of amylin to cause insulin resistance and/or inhibit insulin secretion. Methods. We have determined the effect of endogenous amylin on insulin secretion and insulin action in humans by performing 4-h hyperglycemic clamps during infusion of placebo or a specific amylin receptor antagonist (ARA) in paired, double-blinded, crossover studies. We studied nine healthy lean, ten healthy obese (BMI>27) and ten obesity-matched DM2 subjects. Results. Infusion of ARA alone had no effect on basal insulin, glucose or glucose turnover in any group. Under combined hyperglycemia and ARA infusion, lean subjects displayed a 32% augmentation in insulin levels [AUC 33 565 ± 3556 (placebo) to 44 562 ± 1379 (ARA) pmol/l/min, p<0.01]. The concomitant increase in glucose disposal rate (GDR) was proportionate, indicating no change in insulin sensitivity (ISI 27.7 ± 2.7 vs 27.3 ± 2.1, p = NS). In obese subjects, basal insulin and the rise in insulin during the clamp were greater (AUC I 44% increase from 82 054 ± 15 407 to 117 922 ± 27 085, p < 0.01), and also accompanied by a proportionate rise in GDR reflecting an unchanged insulin sensitivity (ISI 12.1 ± 2.9 vs 10.8 ± 3.0, p = NS). In lean and obese subjects, the C-peptide response to hyperglycemia was also augmented by ARA (p = 0.007). No effect of ARA on insulin secretion or action was observed in diabetic subjects. Conclusions. The present data are consistent with an effect of endogenous amylin on the β-cell to modulate and/or restrain insulin secretion, and indicate that endogenous amylin does not affect insulin action. These observations provide the first human evidence that amylin plays a role in the modulation of insulin secretion.

Original languageEnglish (US)
Pages (from-to)118-126
Number of pages9
JournalDiabetes/Metabolism Research and Reviews
Volume18
Issue number2
DOIs
StatePublished - May 15 2002

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Islet Amyloid Polypeptide
Islet Amyloid Polypeptide Receptor
Insulin Resistance
Insulin
Glucose
Hyperglycemia
Area Under Curve
Insulin Antagonists
Placebos
C-Peptide
Cross-Over Studies
Type 2 Diabetes Mellitus
Obesity

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Role of amylin in insulin secretion and action in humans : Antagonist studies across the spectrum of insulin sensitivity. / Mather, Kieren J.; Paradisi, Giancarlo; Leaming, Rosalind; Hook, Ginger; Steinberg, Helmut; Fineberg, Naomi; Hanley, Rochelle; Baron, Alain D.

In: Diabetes/Metabolism Research and Reviews, Vol. 18, No. 2, 15.05.2002, p. 118-126.

Research output: Contribution to journalArticle

Mather, Kieren J. ; Paradisi, Giancarlo ; Leaming, Rosalind ; Hook, Ginger ; Steinberg, Helmut ; Fineberg, Naomi ; Hanley, Rochelle ; Baron, Alain D. / Role of amylin in insulin secretion and action in humans : Antagonist studies across the spectrum of insulin sensitivity. In: Diabetes/Metabolism Research and Reviews. 2002 ; Vol. 18, No. 2. pp. 118-126.
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abstract = "Background. Amylin is a peptide co-secreted with insulin by pancreatic β-cells. A role for amylin in the pathogenesis of type 2 diabetes mellitus (DM2) has been suggested by in vitro and in vivo studies indicating an effect of amylin to cause insulin resistance and/or inhibit insulin secretion. Methods. We have determined the effect of endogenous amylin on insulin secretion and insulin action in humans by performing 4-h hyperglycemic clamps during infusion of placebo or a specific amylin receptor antagonist (ARA) in paired, double-blinded, crossover studies. We studied nine healthy lean, ten healthy obese (BMI>27) and ten obesity-matched DM2 subjects. Results. Infusion of ARA alone had no effect on basal insulin, glucose or glucose turnover in any group. Under combined hyperglycemia and ARA infusion, lean subjects displayed a 32{\%} augmentation in insulin levels [AUC 33 565 ± 3556 (placebo) to 44 562 ± 1379 (ARA) pmol/l/min, p<0.01]. The concomitant increase in glucose disposal rate (GDR) was proportionate, indicating no change in insulin sensitivity (ISI 27.7 ± 2.7 vs 27.3 ± 2.1, p = NS). In obese subjects, basal insulin and the rise in insulin during the clamp were greater (AUC I 44{\%} increase from 82 054 ± 15 407 to 117 922 ± 27 085, p < 0.01), and also accompanied by a proportionate rise in GDR reflecting an unchanged insulin sensitivity (ISI 12.1 ± 2.9 vs 10.8 ± 3.0, p = NS). In lean and obese subjects, the C-peptide response to hyperglycemia was also augmented by ARA (p = 0.007). No effect of ARA on insulin secretion or action was observed in diabetic subjects. Conclusions. The present data are consistent with an effect of endogenous amylin on the β-cell to modulate and/or restrain insulin secretion, and indicate that endogenous amylin does not affect insulin action. These observations provide the first human evidence that amylin plays a role in the modulation of insulin secretion.",
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T1 - Role of amylin in insulin secretion and action in humans

T2 - Antagonist studies across the spectrum of insulin sensitivity

AU - Mather, Kieren J.

AU - Paradisi, Giancarlo

AU - Leaming, Rosalind

AU - Hook, Ginger

AU - Steinberg, Helmut

AU - Fineberg, Naomi

AU - Hanley, Rochelle

AU - Baron, Alain D.

PY - 2002/5/15

Y1 - 2002/5/15

N2 - Background. Amylin is a peptide co-secreted with insulin by pancreatic β-cells. A role for amylin in the pathogenesis of type 2 diabetes mellitus (DM2) has been suggested by in vitro and in vivo studies indicating an effect of amylin to cause insulin resistance and/or inhibit insulin secretion. Methods. We have determined the effect of endogenous amylin on insulin secretion and insulin action in humans by performing 4-h hyperglycemic clamps during infusion of placebo or a specific amylin receptor antagonist (ARA) in paired, double-blinded, crossover studies. We studied nine healthy lean, ten healthy obese (BMI>27) and ten obesity-matched DM2 subjects. Results. Infusion of ARA alone had no effect on basal insulin, glucose or glucose turnover in any group. Under combined hyperglycemia and ARA infusion, lean subjects displayed a 32% augmentation in insulin levels [AUC 33 565 ± 3556 (placebo) to 44 562 ± 1379 (ARA) pmol/l/min, p<0.01]. The concomitant increase in glucose disposal rate (GDR) was proportionate, indicating no change in insulin sensitivity (ISI 27.7 ± 2.7 vs 27.3 ± 2.1, p = NS). In obese subjects, basal insulin and the rise in insulin during the clamp were greater (AUC I 44% increase from 82 054 ± 15 407 to 117 922 ± 27 085, p < 0.01), and also accompanied by a proportionate rise in GDR reflecting an unchanged insulin sensitivity (ISI 12.1 ± 2.9 vs 10.8 ± 3.0, p = NS). In lean and obese subjects, the C-peptide response to hyperglycemia was also augmented by ARA (p = 0.007). No effect of ARA on insulin secretion or action was observed in diabetic subjects. Conclusions. The present data are consistent with an effect of endogenous amylin on the β-cell to modulate and/or restrain insulin secretion, and indicate that endogenous amylin does not affect insulin action. These observations provide the first human evidence that amylin plays a role in the modulation of insulin secretion.

AB - Background. Amylin is a peptide co-secreted with insulin by pancreatic β-cells. A role for amylin in the pathogenesis of type 2 diabetes mellitus (DM2) has been suggested by in vitro and in vivo studies indicating an effect of amylin to cause insulin resistance and/or inhibit insulin secretion. Methods. We have determined the effect of endogenous amylin on insulin secretion and insulin action in humans by performing 4-h hyperglycemic clamps during infusion of placebo or a specific amylin receptor antagonist (ARA) in paired, double-blinded, crossover studies. We studied nine healthy lean, ten healthy obese (BMI>27) and ten obesity-matched DM2 subjects. Results. Infusion of ARA alone had no effect on basal insulin, glucose or glucose turnover in any group. Under combined hyperglycemia and ARA infusion, lean subjects displayed a 32% augmentation in insulin levels [AUC 33 565 ± 3556 (placebo) to 44 562 ± 1379 (ARA) pmol/l/min, p<0.01]. The concomitant increase in glucose disposal rate (GDR) was proportionate, indicating no change in insulin sensitivity (ISI 27.7 ± 2.7 vs 27.3 ± 2.1, p = NS). In obese subjects, basal insulin and the rise in insulin during the clamp were greater (AUC I 44% increase from 82 054 ± 15 407 to 117 922 ± 27 085, p < 0.01), and also accompanied by a proportionate rise in GDR reflecting an unchanged insulin sensitivity (ISI 12.1 ± 2.9 vs 10.8 ± 3.0, p = NS). In lean and obese subjects, the C-peptide response to hyperglycemia was also augmented by ARA (p = 0.007). No effect of ARA on insulin secretion or action was observed in diabetic subjects. Conclusions. The present data are consistent with an effect of endogenous amylin on the β-cell to modulate and/or restrain insulin secretion, and indicate that endogenous amylin does not affect insulin action. These observations provide the first human evidence that amylin plays a role in the modulation of insulin secretion.

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