Role of amylin in insulin secretion and action in humans: antagonist studies across the spectrum of insulin sensitivity.
BACKGROUND
Amylin is a peptide co-secreted with insulin by pancreatic beta-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 beta-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.
Mather
Kieren J
KJ
Indiana University Medical Center, Indianapolis, IN 46202, USA.
Paradisi
Giancarlo
G
Leaming
Rosalind
R
Hook
Ginger
G
Steinberg
Helmut O
HO
Fineberg
Naomi
N
Hanley
Rochelle
R
Baron
Alain D
AD
D000328:Adult; D000682:Amyloid / Q000097:blood / Q000502:physiology*; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism*; D015992:Body Mass Index; D002096:C-Peptide / Q000097:blood; D003920:Diabetes Mellitus / Q000097:blood / Q000503:physiopathology*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000503:physiopathology*; D005260:Female; D005934:Glucagon / Q000097:blood; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000502:physiology*; D000078790:Insulin Secretion; D058228:Islet Amyloid Polypeptide; D008297:Male; D009765:Obesity / Q000097:blood / Q000503:physiopathology*; D058287:Receptors, Islet Amyloid Polypeptide; D018000:Receptors, Peptide / Q000037:antagonists & inhibitors / Q000097:blood; D012016:Reference Values
D000682:Amyloid; D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D058287:Receptors, Islet Amyloid Polypeptide; D018000:Receptors, Peptide; D005934:Glucagon