Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion in a glucose-dependent manner, but its short half-life limits its therapeutic potential. We tested NN2211, a long-acting GLP-1 derivative, in 10 subjects with type 2 diabetes (means ؎ SD: age 63 ؎ 8 years, BMI 30.1 ؎ 4.2 kg/m 2 , HbA 1c 6.5 ؎ 0.8%) in a randomized, double-blind, placebo-controlled, crossover study. A single injection (7.5 g/kg) of NN2211 or placebo was administered 9 h before the study. ␤-cell sensitivity was assessed by a graded glucose infusion protocol, with glucose levels matched over the 5-12 mmol/l range. Insulin secretion rates (ISRs) were estimated by deconvolution of C-peptide levels.

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Human aging is associated with impaired beta-cell sensitivity to glucose and impaired beta-cell compensation to insulin resistance.

Context: Studies in older people have shown inconsistent agreement between homeostasis model assessment of insulin resistance (HOMA-IR) and dynamic measures of insulin action and have not evaluated HOMA ␤-cell. Objective:We compared measures of insulin sensitivity and ␤-cell function from the frequently sampled iv glucose tolerance test (FSIGT) to HOMA models.Design/Patients/Setting/Intervention: Two hundred fourteen young and old with normal glucose tolerance (NGT) and old with impaired glucose tolerance (IGT) participated in a retrospective analysis of FSIGT data in a university medical setting.Main Outcome Measure: Sensitivity to insulin (S I ) and acute insulin response to glucose (AIRg) from FSIGT were compared with HOMA models.Results: S I and HOMA-IR measures identified similar patterns of increasing insulin resistance in the two older groups, compared with younger people with NGT, with the greatest degree of insulin resistance in older people with IGT (P Ͻ 0.05 vs. young and old NGT for both S I and HOMA-IR). Agreement between HOMA-IR and S I was moderate (weighted kappa ϭ 0.51). AIRg was similar in young and old NGT but was markedly decreased in old IGT (P Ͻ 0.05 vs. young and old NGT). HOMA-␤-cell was similar in the three groups. Agreement between HOMA ␤-cell and AIRg was weak (weighted kappa ϭ 0.35).Conclusions: HOMA-IR may detect age-related insulin resistance when comparing large populations of older people. However, dynamic testing appears to be necessary to quantitate diminished insulin secretion in older people. (J Clin Endocrinol Metab 91: 629 -634, 2006)T HE PREVALENCE OF type 2 diabetes and impaired glucose tolerance (IGT) increases with age (1). Multiple risk factors for type 2 diabetes including obesity and decreased physical activity associated with aging likely predispose older people to develop glucose intolerance and increased insulin resistance. ␤-Cell dysfunction has been consistently demonstrated even with normal aging, with greater defects in older people with IGT (1, 2). Thus, availability of simple, accurate measures to quantify the degree of insulin resistance and impaired ␤-cell function in the older population would be of great value.The homeostasis model assessment (HOMA) is a commonly used method to assess insulin resistance and ␤-cell function and requires only fasting glucose and insulin levels.The HOMA model of insulin resistance (HOMA-IR) has been found to correlate with the hyperinsulinemic glucose clamp and the minimal model measures of insulin action and ␤-cell function, primarily in younger and middle-aged people with normal glucose tolerance (3-5) and smaller groups of middle-aged people with type 2 diabetes (3,5,6).Previous studies have suggested that HOMA-IR may not be a good predictor of insulin resistance when compared with the euglycemic clamp in older men with IGT (7) and older men and women with diabetes (8). Evaluation of HOMA measures of ␤-cell function in older people, particularly those with IGT, has not been performed. In the present study, we compared meas...

2004.-Glucose tolerance declines with age, resulting in a high prevalence of diabetes and impaired glucose tolerance (IGT) in the older population. Hyperglycemia per se can lead to impaired ␤-cell function (glucose toxicity). We tested the role of glucose toxicity in age-related ␤-cell dysfunction in older people (65 Ϯ 8 yr) with IGT treated with the ␣-glucosidase inhibitor acarbose (n ϭ 14) or placebo (n ϭ 13) for 6 wk in a randomized, double-blind study. Baseline and posttreatment studies included 1) an oral glucose tolerance test (OGTT), 2) 1-h postprandial glucose monitoring, 3) a frequently sampled intravenous glucose tolerance test (insulin sensitivity, or S I), and 4) glucose ramp clamp (insulin secretion rates, or ISR), in which a variable glucose infusion increases plasma glucose from 5 to 10 mM. The treatment groups had similar baseline body mass index; fasting, 2-h OGTT, and 1-h postprandial glucose levels; and S I. In these carefully matched older people with IGT, both fasting (5.7 Ϯ 0.2 vs. 6.3 Ϯ 0.2 mM, P ϭ 0.002) and 1-h postprandial glucose levels (6.9 Ϯ 0.3 vs. 8.2 Ϯ 0.4 mM, P ϭ 0.02) were significantly lower in the acarbose than in the placebo group. Despite this reduction of chronic hyperglycemia in the acarbose vs. placebo group, measures of insulin secretion (ISR area under the curve: 728 Ϯ 55 vs. 835 Ϯ 81 pmol/kg, P ϭ 0.9) and acute insulin response to intravenous glucose (329 Ϯ 67 vs. 301 Ϯ 54 pM, P ϭ 0.4) remained unchanged and impaired. Thus short-term improvement of chronic hyperglycemia does not reverse ␤-cell dysfunction in older people with IGT.␤-cell function; glucose intolerance; aged humans THE PREVALENCE OF TYPE 2 DIABETES and impaired glucose tolerance (IGT) increases with age (6). More than 25% of the older population meets current diagnostic criteria for type 2 diabetes (15, 24). An additional 20% of this population meets criteria for IGT, defined as a 2-h glucose level Ն7.8 mM but Ͻ11.1 mM by oral glucose tolerance testing (OGTT) and a fasting glucose Ͻ7.0 mM (15). Isolated postchallenge hyperglycemia, defined as a 2-h glucose level Ն11.1 mM by OGTT, but a fasting glucose level Ͻ7.0 mM, is particularly common in people over age 60 (1,10,11,29).IGT, as with type 2 diabetes, is characterized by both insulin resistance (13,20) and defects in ␤-cell function (13,20,30). Multiple risk factors for type 2 diabetes associated with aging may predispose older people to develop glucose intolerance and increased insulin resistance. Insulin secretory defects have been consistently demonstrated even with normal aging, with greater defects in older people with IGT (2, 6, 8). Over time, chronic exposure to hyperglycemia in older people with IGT may cause a further decline in ␤-cell function. Studies in animal models and humans suggest that chronic hyperglycemia may have adverse effects on insulin secretion, an effect called glucose toxicity (25).␣-Glucosidase inhibitors, such as acarbose, act by inhibiting enzymes in the small intestine, thereby decreasing glucose absorption and improving po...