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The Effect of Age and Glycemic Level on the Response of the ß-Cell to Glucose-Dependent Insulinotropic Polypeptide and Peripheral Tissue Sensitivity to Endogenously Released Insulin¹

Department of Medicine (G.S.M., K.L.M., D.E.), Division of Gerontology, Beth Israel Hospital, Harvard Medical School, Boston, Massachusetts 02215; Geriatric Medicine Unit (K.L.M., D.E.), Division of General Internal Medicine, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114; Department of Medicine (G.S.M.), Division of Geriatric Medicine, University of British Columbia, Vancouver V6T 1Z3 British Columbia; Department of Medicine (A.S.R., D.E.), University of Maryland School of Medicine and Geriatrics Research Education and Clinical Center/Baltimore Veterans’ Administration Medical Center, Baltimore, Maryland 21201

Address all correspondence and requests for reprints to: Dariush Elahi, Ph.D., Geriatrics Research Laboratory, GRJ 1215, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114-2696.

Normal aging is characterized by a progressive impairment in glucose tolerance. An important mechanism underlying the glucose intolerance of aging is an impairment in glucose-induced insulin release. These studies were conducted to determine whether the age-related impairment in insulin release was caused by a decreased ß-cell sensitivity to glucose-dependent insulinotropic polypeptide (GIP). Thirty-one Caucasian men were divided into four groups: two young groups (age range: 19–26 yr, n = 15) and two old groups (age range: 67–79 yr, n = 16). Each volunteer participated in three studies (n = 93 clamps). Hyperglycemic clamps were conducted at two doses [basal plasma glucose (G) + 5.4 mmol/L and G + 12.8 mmol/L] for 120 min. In the initial hyperglycemic clamp, only glucose was infused. In subsequent studies, GIP was infused at a final rate of 2 or 4 pmol/kg^-1·min^-1 from 60–120 min. Basal plasma insulin and GIP levels were similar in the young (41 ± 6 and 51 ± 6 pmol/L) and the old subjects (42 ± 6 and 66 ± 12 pmol/L) in all studies. First- and second-phase insulin responses were similar during the control study and during the first 60 min of each GIP infusion study in both groups. The 90–120 min GIP values were similar between groups and between hyperglycemic plateaus during the 2 and 4 pmol/kg^-1·min^-1 GIP infusion (young: 342 ± 28 and 601 ± 44 pmol/L, old: 387 ± 45 and 568 ± 49 pmol/L). In response to the GIP infusions, significant increases in insulin occurred in young and old at both glucose levels (P < 0.01). The potentiation of the insulin response caused by GIP was greater in the young subjects than in the old, in the G + 5.4 mmol/L studies (P < 0.05). However, the insulin response to GIP was similar in both young and old during the G + 12.8 mmol/L clamps. The insulinotropic effect of the incretin was higher in the young and in the old, in the G + 12.8 mmol clamps, than in the G + 5.4 mmol/L clamps.

We conclude that normal aging is characterized by a decreased ß-cell sensitivity to GIP during modest hyperglycemia, which may explain, in part, the age-related impairment in glucose-induced insulin release. We also find that the insulinotropic effect of GIP is increased with increasing levels of hyperglycemia.

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