Insulin Reciprocally Regulates Glucagon Secretion in Humans

• Published in: Diabetes (New York, N.Y.) Vol. 59; no. 11; pp. 2936 - 2940
• Main Authors: COOPERBERG, Benjamin A, CRYER, Philip E
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.11.2010
• Subjects: Adolescent; Adult; Age of Onset; Biological and medical sciences; Care and treatment; Child; Complications; Diabetes; Diabetes Mellitus, Type 1 - blood; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Genetic aspects; Glucagon; Glucagon - blood; Glucagon - drug effects; Glucagon - secretion; Glucose; Glucose Clamp Technique; Glycated Hemoglobin A - metabolism; Homeostasis; Humans; Hypoglycemia; Hypotheses; Insulin; Insulin - blood; Insulin - pharmacology; Insulin - physiology; Islands of Langerhans; Islets of Langerhans; Male; Medical sciences; Nervous system; Physiological aspects; Physiology; Plasma; Research design; Risk factors; Type 1 diabetes; Young Adult; United States; Endocrinopathy; Human; Pancreatic hormone; Glucagon; Secretion; Diabetes mellitus; Peptide hormone; Insulin
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db10-0728

We tested the hypothesis that an increase in insulin per se, i.e., in the absence of zinc, suppresses glucagon secretion during euglycemia and that a decrease in insulin per se stimulates glucagon secretion during hypoglycemia in humans. We measured plasma glucagon concentrations in patients with type 1 diabetes infused with the zinc-free insulin glulisine on three occasions. Glulisine was infused with clamped euglycemia (∼95 mg/dl [5.3 mmol/l]) from 0 to 60 min on all three occasions. Then, glulisine was discontinued with clamped euglycemia or with clamped hypoglycemia (∼55 mg/dl [3.0 mmol/l]) or continued with clamped hypoglycemia from 60 to 180 min. Plasma glucagon concentrations were suppressed by -13 ± 3, -9 ± 3, and -12 ± 2 pg/ml (-3.7 ± 0.9, -2.6 ± 0.9, and -3.4 ± 0.6 pmol/l), respectively, (all P < 0.01) during zinc-free hyperinsulinemic euglycemia over the first 60 min. Glucagon levels remained suppressed following a decrease in zinc-free insulin with euglycemia (-14 ± 3 pg/ml [-4.0 ± 0.9 pmol/l]) and during sustained hyperinsulinemia with hypoglycemia (-14 ± 2 pg/ml [-4.0 ± 0.6 pmol/l]) but increased to -3 ± 3 pg/ml (-0.9 ± 0.9 pmol/l) (P < 0.01) following a decrease in zinc-free insulin with hypoglycemia over the next 120 min. These data indicate that an increase in insulin per se suppresses glucagon secretion and a decrease in insulin per se, in concert with a low glucose concentration, stimulates glucagon secretion. Thus, they document that insulin is a β-cell secretory product that, in concert with glucose and among other signals, reciprocally regulates α-cell glucagon secretion in humans.