Effects of the amylin analogue pramlintide on hepatic glucagon responses and intermediary metabolism in Type 1 diabetic subjects.
OBJECTIVE
Hepatic glycogen stores have been shown to be depleted, and glucagon stimulated hepatic glucose production reduced, in Type 1 diabetic subjects. Co-administration of amylin and insulin has been shown to replete hepatic glycogen stores in diabetic animal models. The aim of the present study was to investigate the effect of amylin replacement on hepatic glucagon responsiveness in humans.


METHODS
Thirteen Type 1 diabetic men were studied in a double-blind, placebo-controlled, cross-over study after 4 weeks of subcutaneous pramlintide (30 microg q.i.d.) or placebo administration. Following an overnight fast, plasma glucose was kept above 5 mmol/l (baseline 210-240 min) with an insulin infusion rate of 0.25 mU x kg(-1) x min(-1). To control portal glucagon levels, somatostatin was infused at a rate of 200 microg/h. Basal growth hormone (2 ng x kg(-1) x min(-1)) and glucagon (0.7 ng x kg(-1) x min(-1)) were replaced. Glucagon infusion was increased to 2.1 ng x kg(-1) x min(-1) at 240-360 min (step 1) and to 4.2 ng x kg(-1) x min(-1) at 360-420 min (step 2).


RESULTS
Baseline plasma glucose (5.59+/-0.16 vs. 5.67+/-0.25 mmol/l) and endogenous glucose production (EGP) (1.32+/-0.22 vs. 1.20+/-0.13 mg x kg(-1). min(-1)) were similar and the response to glucagon was unaffected by pramlintide (glucose: step 1; 6.01+/-0.31 vs. 5.94+/-0.38 mmol/l, step 2; 6.00+/-0.37 vs. 5.96+/-0.50 mmol/l, EGP: step 1; 1.91+/-0.18 vs. 1.83+/-0.15 mg x kg(-1) x min(-1), step 2; 2.08+/-0.17 vs. 1.96+/-0.16 ng x kg(-1) x min(-1), pramlintide vs. placebo). Glucose disposal rates were similar at baseline (2.44+/-0.13 vs. 2.28+/-0.09 mg x kg(-1) x min(-1), pramlintide vs. placebo) as well as during the glucagon challenge (P-values all > 0.2).


CONCLUSIONS
Co-administration of pramlintide and insulin to Type 1 diabetic subjects for 4 weeks does not change the plasma glucose or endogenous glucose production response to a glucagon challenge, following an overnight fast. In addition, pramlintide administration does not appear to alter insulin-mediated glucose disposal.
Orskov
L
L
Department of Medicine C, University Hospital of Arhus, Denmark.
Nyholm
B
B
Yde Hove
K
K
Gravholt
C H
CH
Møller
N
N
Schmitz
O
O
D000328:Adult; D000682:Amyloid / Q000008:administration & dosage / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D002395:Catecholamines / Q000097:blood; D018592:Cross-Over Studies; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000378:metabolism; D004311:Double-Blind Method; D005215:Fasting; D005934:Glucagon / Q000008:administration & dosage / Q000378:metabolism*; D019382:Human Growth Hormone / Q000097:blood; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000008:administration & dosage / Q000627:therapeutic use; D058228:Islet Amyloid Polypeptide; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010919:Placebos
D000682:Amyloid; D001786:Blood Glucose; D002395:Catecholamines; D007004:Hypoglycemic Agents; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D010919:Placebos; D019382:Human Growth Hormone; D005934:Glucagon; C105254:pramlintide