title: Decrease in glucose-stimulated insulin secretion with aging is independent of insulin action.
abstract: While the incidence of diabetes increases with age, a decrease in beta-cell function independent of age-related insulin resistance has not been conclusively determined. We studied insulin secretion (by hyperglycemic clamp) in 3-, 9-, and 20-month-old chronically catheterized, awake, Sprague Dawley (SD) rats (n = 78). Insulin action was modulated in a group of old rats by caloric restriction (CR) or by surgical removal of visceral fat (VF-). During the first 2 h of the clamp (11 mmol/l glucose), insulin secretion and insulin resistance (S(i hyper clamp)) demonstrated the characteristic hyperbolic relationship. However, after hyperglycemia for an additional 2 h, the ability to maintain insulin secretion, commensurate with the degree of insulin resistance, was decreased in all aging rats (P < 0.05). Increasing plasma glucose levels to 18 mmol/l glucose, after clamp at 11 mmol/l, increased insulin secretion by approximately threefold in young rats, but failed to induce similar magnitude of response in the aging rats ( approximately 50%). However, elevation of plasma free fatty acid (FFA) levels by twofold (by intralipid infusion during 11 mmol/l glucose clamp) resulted in a robust, approximate twofold response in both young and old rats. Thus, prolonged stimulation by hyperglycemia unveiled a functional defect in insulin secretion with aging. This age-related defect is independent of insulin action and is specific to glucose and not FFAs. We suggest that prolonged hyperglycemic stimulation can be a tool to identify functional defects in insulin secretion, particularly in the context of the hyperbolic relationship with insulin action, in elderly subjects or those at risk for type 2 diabetes.
authors.affiliation: Division of Pediatric Endocrinology, Children's Hospital at Montefiore, Institute for Aging Research and Diabetes Research and Training Center, and the Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Radhika
authors.initials: R
authors.lastname: Muzumdar
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Ma
authors.forename: Gil
authors.initials: G
authors.lastname: Atzmon
authors.forename: Patricia
authors.initials: P
authors.lastname: Vuguin
authors.forename: Xiaoman
authors.initials: X
authors.lastname: Yang
authors.forename: Nir
authors.initials: N
authors.lastname: Barzilai
mesh_terms: D000368:Aged; D000375:Aging / Q000502:physiology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D004038:Diet, Reducing; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005947:Glucose / Q000494:pharmacology*; D015309:Glucose Clamp Technique; D006801:Humans; D006943:Hyperglycemia; D007328:Insulin / Q000097:blood* / Q000378:metabolism* / Q000502:physiology; D000078790:Insulin Secretion; D023421:Models, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D005947:Glucose