Chang, Annette M., and Jeffrey B. Halter. Aging and insulin secretion. Am J Physiol Endocrinol Metab 284: E7-E12, 2003; 10.1152/ ajpendo.00366.2002.-Glucose tolerance progressively declines with age, and there is a high prevalence of type 2 diabetes and postchallenge hyperglycemia in the older population. Age-related glucose intolerance in humans is often accompanied by insulin resistance, but circulating insulin levels are similar to those of younger people. Under some conditions of hyperglycemic challenge, insulin levels are lower in older people, suggesting ␤-cell dysfunction. When insulin sensitivity is controlled for, insulin secretory defects have been consistently demonstrated in aging humans. In addition, ␤-cell sensitivity to incretin hormones may be decreased with advancing age. Impaired ␤-cell compensation to agerelated insulin resistance may predispose older people to develop postchallenge hyperglycemia and type 2 diabetes. An improved understanding of the metabolic alterations associated with aging is essential for the development of preventive and therapeutic interventions in this population at high risk for glucose intolerance. aged humans; ␤-cell function GLUCOSE TOLERANCE PROGRESSIVELY DECLINES with age, resulting in a high prevalence of type 2 diabetes and impaired glucose tolerance in the older population (21). The interaction of many factors associated with aging likely contributes to the alterations in glucose tolerance in this population. These factors include increased adiposity, decreased physical activity, medications, coexisting illness, and insulin secretory defects associated with the aging process. The mechanism of age-related glucose intolerance is not completely clear. This article will review the epidemiology of age-related glucose intolerance and the effects of aging on insulin secretion in humans. EPIDEMIOLOGY OF AGE-RELATED CHANGES IN GLUCOSE METABOLISMAs shown in Fig. 1, according to the Third National Health and Nutrition Examination Survey (NHANES III) conducted from 1988 to 1994, the prevalence of type 2 diabetes in Americans 60-74 yr of age is Ͼ20% (22, 41). This percentage includes cases previously diagnosed by medical history and those newly diagnosed by fasting glucose or by oral glucose tolerance testing (OGTT). An additional 20% of this population meets criteria for impaired glucose tolerance (IGT), defined as a 2-h glucose level Ն140 mg/dl but Ͻ200 mg/dl by OGTT, and a fasting blood glucose not in the diabetic range (Ͻ126 mg/dl) (22). Prevalence data from 1976 to 1980 from NHANES II for diabetes and IGT in Americans 60-74 yr of age were similar (23); thus the high prevalence of glucose intolerance in the older population has persisted over the past two decades. Additional studies of older adults, including the Cardiovascular Health Study and Honolulu Heart Study, show that the high prevalence of diabetes and IGT continues in people over age 75 (46, 43).Isolated postchallenge hyperglycemia (IPH), defined as a 2-h glucose level Ն200 mg/dl by OGTT but a fasting glucose...

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.

OBJECTIVETo evaluate the efficacy and safety of basal insulin peglispro (BIL) versus insulin glargine in patients with type 2 diabetes (hemoglobin A1c [HbA 1c ] £9% [75 mmol/mol]) treated with basal insulin alone or with three or fewer oral antihyperglycemic medications. RESEARCH DESIGN AND METHODSThis 52-week, open-label, treat-to-target study randomized patients (mean HbA 1c 7.42% [57.6 mmol/mol]) to BIL (n = 307) or glargine (n = 159). The primary end point was change from baseline HbA 1c to 26 weeks (0.4% [4.4 mmol/mol] noninferiority margin). RESULTSAt 26 weeks, reduction in HbA 1c was superior with BIL versus glargine (20.82% [28.9 mmol/mol] vs. 20.29% [23.2 mmol/mol]; least squares mean difference 20.52%, 95% CI 20.67 to 20.38 [25.7 mmol/mol, 95% CI 27.3 to 24.2; P < 0.001); greater reduction in HbA 1c with BIL was maintained at 52 weeks. More BIL patients achieved HbA 1c <7% (53 mmol/mol) at weeks 26 and 52 (P < 0.001). With BIL versus glargine, nocturnal hypoglycemia rate was 60% lower, more patients achieved HbA 1c <7% (53 mmol/mol) without nocturnal hypoglycemia at 26 and 52 weeks (P < 0.001), and total hypoglycemia rates were lower at 52 weeks (P = 0.03). At weeks 26 and 52, glucose variability was lower (P < 0.01), basal insulin dose was higher (P < 0.001), and triglycerides and aminotransferases were higher with BIL versus glargine (P < 0.05). Liver fat content (LFC), assessed in a subset of patients (n = 162), increased from baseline with BIL versus glargine (P < 0.001), with stable levels between 26 and 52 weeks. CONCLUSIONSBIL provided superior glycemic control versus glargine, with reduced nocturnal and total hypoglycemia, lower glucose variability, and increased triglycerides, aminotransferases, and LFC.

Aims: To compare effects of basal insulin peglispro (BIL), a hepatopreferential insulin, to insulin glargine (glargine) on aminotransferases and liver fat content (LFC) in patients with type 1 and type 2 diabetes (T1D, T2D). Materials and Methods:Data from two Phase 2 and five Phase 3 randomized trials comparing BIL and glargine in 1709 T1D and 3662 T2D patients were integrated for analysis of liver laboratory tests. LFC, measured by magnetic resonance imaging (MRI) at baseline, 26 and 52 weeks, was analyzed in 182 T1D patients, 176 insulin-naïve T2D patients and 163 T2D patients previously treated with basal insulin.Results: Alanine aminotransferase (ALT) increased in patients treated with BIL, was higher than in glargine-treated patients at 4-78 weeks (difference at 52 weeks in both T1D and T2D: 7 international units/litre (IU/L), P < .001), and decreased after discontinuation of BIL. More BIL patients had ALT ≥3× upper limit of normal (ULN) than glargine. No patient had ALT ≥3× ULN with bilirubin ≥2× ULN that was considered causally related to BIL. In insulin-naїve T2D patients, LFC decreased with glargine but was unchanged with BIL. In T1D and T2D patients previously treated with basal insulin, LFC was unchanged with glargine but increased with BIL.In all three populations, LFC was higher after treatment with BIL vs glargine (difference at 52 weeks: 2.2% to 5.3%, all P < .01).Conclusions: Compared to glargine, patients treated with BIL had higher ALT and LFC at 52-78 weeks. No severe drug-induced liver injury was apparent with BIL treatment for up to 78 weeks.

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