The insulinotropic effect of acute exendin-4 administered to humans: comparison of nondiabetic state to type 2 diabetes.
Exendin-4 is a potent and long-acting agonist of the glucagon-like peptide-1 (GLP-1) receptor. GLP-1 is an insulinotropic gut peptide and is being evaluated for the regulation of plasma glucose in type 2 diabetes. The purpose of the present study was to ascertain whether exendin-4 is insulinotropic and whether it has long-lived biological effects in nondiabetic and type 2 diabetic subjects. Because incretins are glucose dependent with respect to their insulin-releasing capacity, we used the hyperglycemic glucose clamp technique to begin to address these issues in two separate protocols. In one protocol, we infused exendin-4 (0.15 pmol x kg(-1) x min(-1)) in seven nondiabetic and seven type 2 diabetic subjects during the second hour of a 5-h hyperglycemic clamp in which fasting plasma glucose was raised by 5.4 mmol/liter. The second protocol was identical to the first except that plasma glucose was allowed to fall to the fasting levels during the fourth hour and again raised by 5.4 mmol/liter during the fifth hour in four nondiabetic and four diabetic subjects. With the initiation of exendin-4 infusion at 60 min, plasma insulin response was potentiated 4- to 5-fold in both groups. Despite termination of exendin-4 at the end of the second hour, the insulin levels remained elevated for several hours and hyperglycemia was maintained. All volunteers ate a meal 5.5 h after inducing hyperglycemia. Postprandial plasma glucose, insulin, and GLP-1 did not rise in any subject, possibly because of delayed gastric emptying by exendin-4 even though its infusion had been terminated 4 h previously. We concluded that exendin-4 is a potent and long-lasting insulinotropic agent in nondiabetic and diabetic subjects.
Egan
Josephine M
JM
Diabetes and Metabolism Section, Laboratory of Clinical Investigation, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
Clocquet
Astrid R
AR
Elahi
Dariush
D
D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D000077270:Exenatide; D005260:Female; D015309:Glucose Clamp Technique; D006207:Half-Life; D006801:Humans; D007328:Insulin / Q000097:blood*; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D019518:Postprandial Period; D012016:Reference Values; D014688:Venoms
D001786:Blood Glucose; D007328:Insulin; D010455:Peptides; D014688:Venoms; D000077270:Exenatide