Mechanisms of the Age-Associated Deterioration in Glucose Tolerance Contribution of Alterations in Insulin Secretion, Action, and Clearance Rita Basu, 1 Elena Breda, 5 Ann L. Oberg, 2 Claudia C. Powell, 2 Chiara Dalla Man, 5 Ananda Basu, 1 Janet L. Vittone, 3 George G. Klee, 4 Puneet Arora, 1 Michael D. Jensen, 1 Gianna Toffolo, 5 Claudio Cobelli, 5 and Robert A. Rizza 1 Glucose tolerance decreases with age. For determining the cause of this decrease, 67 elderly and 21 young (70.1  0.7 vs. 23.7  0.8 years) participants ingested a mixed meal and received an intravenous injection of glucose. Fasting glucose and the glycemic response above basal were higher in the elderly than in the young participants after either meal ingestion (P < 0.001) or glucose injection (P < 0.01). Insulin action (Si), mea- sured with the meal and intravenous glucose tolerance test models, was highly correlated (r  0.72; P < 0.001) and lower (P < 0.002) in the elderly than in the young participants. However, when adjusted for differences in percentage body fat and visceral fat, Si no longer dif- fered between groups. When considered in light of the degree of insulin resistance, all indexes of insulin se- cretion were lower (P < 0.01) in the elderly partici- pants, indicating impaired -cell function. Hepatic insulin clearance was increased (P < 0.002), whereas total insulin clearance was decreased (P < 0.002) in the elderly subjects. Multivariate analysis (r  0.70; P < 0.001) indicated that indexes of insulin action (Si) and secretion (Phi total ) but not age, peak oxygen uptake, fasting glucose, degree of fatness, or hepatic insulin clearance predicted the postprandial glycemic response. We conclude that the deterioration in glucose tolerance that occurs in healthy elderly subjects is due to a decrease in both insulin secretion and action with the severity of the defect in insulin action being explained by the degree of fatness rather than age per se. Diabetes 52:1738 –1748, 2003 B oth diabetes and glucose intolerance are com- mon in the elderly. The pathogenesis of carbo- hydrate intolerance in the elderly has been an area of active investigation. Many (1– 6) but not all (7–11) studies have reported that older individuals are more insulin resistant than are younger individuals. The effect of aging on insulin secretion also has been a source of debate. Insulin secretion during a hyperglycemic clamp has been reported not to differ in elderly and young subjects (3,12,13). Conversely, insulin secretion in response to an intravenous glucose injection has been reported to be abnormal in elderly subjects in most (1,7,14) but not all (8,11) studies. In addition, there seems to be disagreement as to the cause of this abnormality. Studies have variably reported decreased early insulin secretion (14), normal early insulin secretion (8,11), or normal first-phase insulin secretion but decreased second-phase insulin secretion (1,7). Similarly, insulin concentrations after glucose inges- tion have been reported to be either higher (2,15,16) or no different (4,10) in elderly and young subjects. Many of these discrepancies may be more apparent than real. Insulin concentrations commonly have been used to assess insulin secretion (1– 4,8,10,12,16,17). This intro- duces uncertainty because hepatic insulin extraction has been reported to change with age (7,14). Insulin secretion (18,19) and perhaps insulin action (20) are modulated by incretin hormones after glucose ingestion but not intrave- nous glucose injection. A variety of factors may influence insulin action and secretion, including the degree and type of obesity (21), level of fitness (22,23), and the prevailing counter insulin (e.g., glucagon, growth hormone, cortisol) hormone concentrations (24 –26). In addition, the appro- priateness of insulin secretion needs to be interpreted in light of the degree of insulin resistance (27–29). No difference in insulin secretion in the presence of a decrease in insulin action denotes relative -cell failure. A decrease in insulin secretion after intravenous injection of glucose that is not observed after ingestion of glucose suggests a compensa- tory effect of the gastrointestinal incretin hormones. Androgen concentrations fall with age (30,31). It is not known whether this fall impairs carbohydrate tolerance or whether replacement of either gonadal or adrenal andro- From the 1 Endocrine Research Unit, Mayo Medical School, Rochester, Min- nesota; 2 Department of Health Service Research, Mayo Medical School, Rochester, Minnesota; 3 Department of General Internal Medicine, Mayo Medical School, Rochester, Minnesota; and 4 Department of Laboratory Med- icine & Pathology, Mayo Medical School, Rochester, Minnesota; and 5 Depart- ment of Information Engineering, University of Padua, Padua, Italy. Address correspondence and reprint requests to Robert A. Rizza, MD, Mayo Clinic Rochester, 200 First St. SW, Rm. 5-194 Joseph, Rochester, MN 55905. E-mail: rizza.robert@mayo.edu. Received for publication 4 December 2002 and accepted in revised form 21 March 2003. Bio T, bioavailable testosterone; IVGTT, intravenous glucose tolerance test; VO 2max , peak oxygen uptake. © 2003 by the American Diabetes Association. 1738 DIABETES, VOL. 52, JULY 2003