Acute effects of the human amylin analog AC137 on basal and insulin-stimulated euglycemic and hypoglycemic fuel metabolism in patients with insulin-dependent diabetes mellitus.
Amylin has been reported to decrease glycogen storage in rodent skeletal muscles and produce insulin resistance in intact rats. To test the acute effect of a human amylin analog (AC137) on glucose metabolism in man, seven IDDM patients were infused in a randomized, double blind, cross-over study with AC137 (100 micrograms/h, n = 1; 50 micrograms/h, n = 6) or placebo for 330 min during a two-step euglycemic clamp (insulin infusion rates, 0.2 and 0.6 mU/kg.min; basal and hyperinsulinemic period, respectively) followed by a hyperinsulinemic hypoglycemic clamp (insulin infusion rate, 1.5 mU/kg.min; hypoglycemic period). During euglycemia, no differences were found in glucose disposal (step 1, 2.43 +/- 0.20 vs. 2.03 +/- 0.26; step 2, 4.28 +/- 0.54 vs. 4.11 +/- 0.45 mg/kg.min; AC137 vs. placebo, mean +/- SEM), arteriovenous substrate balances across the forearm, or hepatic glucose production. During hypoglycemia, glucose fluxes were also similar. However, lactate release from the forearm was more pronounced (P < 0.05) with the analog than with placebo (area under the curve, -11.2 +/- 4.6 vs. -1.4 +/- 2.2 mmol/min.L). Despite similar plasma glucose nadirs (2.7 +/- 0.0 vs. 2.6 +/- 0.1 mmol/L; AC137 vs. placebo), circulating cortisol and GH rose to significantly higher levels during hypoglycemia with the amylin analog (P < 0.05). In conclusion, acute administration of the amylin analog AC137 did not influence insulin-stimulated glucose metabolism during euglycemic conditions. During imposed hypoglycemia, lactate release from skeletal muscle was, however, enhanced, and the rise in cortisol and GH was augmented.
Nyholm
B
B
Medical Department M (Endocrinology and Diabetes), Aarhus Kommunehospital, Denmark.
Møller
N
N
Gravholt
C H
CH
Orskov
L
L
Mengel
A
A
Bryan
G
G
Moyses
C
C
Alberti
K G
KG
Schmitz
O
O
D000328:Adult; D000682:Amyloid / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D004734:Energy Metabolism / Q000187:drug effects*; D005542:Forearm / Q000098:blood supply; D005947:Glucose / Q000378:metabolism; D006728:Hormones / Q000097:blood; D006801:Humans; D007003:Hypoglycemia / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D058228:Islet Amyloid Polypeptide; D008297:Male; D012016:Reference Values; D012039:Regional Blood Flow; D013997:Time Factors
D000682:Amyloid; D006728:Hormones; D007004:Hypoglycemic Agents; D007328:Insulin; D058228:Islet Amyloid Polypeptide; C105254:pramlintide; D005947:Glucose