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Background, Glucagon-like peptide-1 (GLP-1) is an intestinal insulinotropic hormone that augments glucose-induced insulin secretion in patients with type 2 diabetes. It has also been proposed that a substantial component of the glucose-lowering effects of GLP-1 occurs because this hormone enhances insulin-mediated glucose disposal. However, interpretations of the studies have been controversial. This study determines the effect of GLP-1 on insulin-mediated glucose disposal in elderly patients with type 2 diabetes. Methods. Studies were conducted on 8 elderly patients with type 2 diabetes (age range, 76 [+ or -] 1 years; body mass index, 28 [+ or -] 1 kg/[m.sup.2]). Each subject underwent two 180-minute euglycemic (insulin infusion rate, 40 mU/[m.sup.2]/min) insulin clamps in random order. Glucose production (Ra) and disposal (Rd) rates were measured using tritiated glucose methodology. In one study, glucose and insulin alone were infused. In the other study, a primed-continuous infusion of GLP-1 was administered at a final rate of 1.5 pmol * [kg.sup.-1] * [min.sup.-1] from 30 to 180 minutes. Results. Glucose values were similar between the control and GLP-1 infusion studies. 120- to 180-minute insulin values appeared to be higher during the GLP-1 infusion study (control, 795 [+ or -] 63 pmol/l; GLP-1, 1140 [+ or -] 275 pmol/l; p = not significant [NS]). The higher insulin values were largely due to 2 subjects who had substantial insulin responses to GLP-1 despite euglycemia and hyperinsulinemia. The 120- to 180-minute insulin values were similar in the other 6 subjects (control, 746 [+ or -] 35 pmol/l; GLP-1,781 [+ or -] 41 pmol/l; p = NS). Basal (control, 2.08 [+ or -] 0.05 mg/kg/min; GLP-1, 2.13 [+ or -] 0.04 mg/kg/min; p = NS) and 120- to 180-minute (control, 0.50 [+ or -] 0.18 mg/kg/min; GLP-1, 0.45 [+ or -] 0.14 mg/kg/min; p = NS) Ra was similar between studies. The 120- to 180-minute Rd values were higher during the GLP-1 infusion studies (control, 4.73 [+ or -] 0.39 mg/kg/min; GLP-1, 5.52 [+ or -] 0.43 mg/kg/min; p < .01). When the 2 subjects who had significant insulin responses to GLP-1 during the euglycemic clamp were excluded, the 120- to 180-minute Rd values were still higher in the GLP-1 infusion study (control, 5.22 [+ or -] 0.32 mg/kg/min; GLP-1, 6.05 [+ or -] 0.37 mg/kg/min; p < .05). Conclusions. We conclude that GLP-1 may enhance insulin sensitivity in elderly patients with diabetes.

Glucose intolerance is a common feature of the aging process, and aging per se is an etiologic factor for Type H diabetes mellitus. To characterize the beta cell abnormalities that occur with aging, we looked at the serum glucose and insulin levels of six young (3-month) and six old (22-month) Wistar rats at 0, 2, 4, 7, 10, 15, 20, and 30 minutes after an intravenous glucose load (IVGTT, 0.5g/kg glucose). We found that the fasting glucose and insulin levels were not significantly different between young and old rats. However, peak glucose levels were significantly higher in the old (349 [+ or -] 10 mg/dl) compared to the young (250 [+ or -] 7 mg/dl) animals (p < .0001). Insulin levels in the young animals peaked at 2 minutes (859 [+ or -] 171 pmol/l) with a quick return toward fasting levels by 7 minutes. The old animals had a delayed and blunted insulin response to glucose, achieving lower peak insulin levels (656 [+ or -] 164 pmol/l) 7 minutes after the glucose load. As insulin levels are also positively modulated by incretin hormones, we quantitated the fasting insulin responses of young and old animals to .05, 0.1, 0.2, 0.4, and 0.5 nmol/kg intravenous glucagon-like peptide-1 (GLP-1), the most potent incretin known. Insulin responses were similar in both age groups, with maximum insulin responses seen at 0.4 nmol/kg. GLP-1, in conjunction with the IVGTT, restored the acute insulin response to glucose and increased the clearance of glucose in the old animals. It therefore appears that old animals have an impaired glucose-mediated insulin release but maintain their insulin responsivity to GLP-1. This makes it a likely candidate in the treatment of Type II diabetes.

Aging is an etiologic factor in non-insulin-dependent diabetes mellitus. While the effect of aging on insulin secretion has been described by several classic studies, the characterization of the molecular basis of [Beta]-cell abnormalities is still under way. We recently demonstrated in rats that aging is associated not only with a reduction in insulin secretion but also with diminished levels of intracellular insulin content and the mRNA for insulin. In this study, we investigated whether the molecular abnormalities previously described in the rat [Beta] cell were also present in the mouse (C57BL/6J). Total cellular RNA was isolated from individual pancreata of 3-, 9-, and 30-month-old mice (n = 6 per age group). Samples were subjected to slot-blot analysis by using homologous probes for insulin, glucagon, somatostatin, glucose transporter-2 (glut-2), glucokinase, elastase-I, and [Beta]-actin. We observed a progressive age-dependent decrease in insulin mRNA levels: insulin mRNA levels decreased by 40% with age (p = .007). This paralleled decreases in glut-2 (p = .001) mRNA levels, but it was in contrast with glucokinase mRNA levels which increased markedly (p = .0003). Somatostatin mRNA levels were unchanged, glucagon mRNA levels decreased modestly (p = .01), and mRNA levels for elastase-I and [Beta]-actin increased with age (p = .0001 for either one). In summary, it appears that in the mouse a progressive decline in the activity of the endocrine pancreas occurs with aging. This phenomenon seems to affect only the [Beta] cells and not the [Alpha] or [Delta] cells of the islet of Langerhans or the exocrine pancreas. This progressive decline may represent the biological features of the age-dependent risk for the development of diabetes.

A cDNA termed reg (for regenerating gene) has been isolated from a rat pancreatic DNA library. Reg expression has been shown to correlate with changes in [Beta] cell mass and function. This finding has been recently challenged by studies showing a non-[Beta]-cell-dependent regulation of reg expression. All studies to date, however, have neglected the fact that two nonallelic reg genes (reg-I and reg-II) exist in several species. In studying the regulation of each individual copy gene, we investigated reg-I and -II gene expression in a naturally occurring modification of [Beta]-cell physiology: normal aging. RNA was isolated from individual pancreata of 1-, 3-, 9-, 20-, and 30-month-old C57BL/6J mice (n [greater than or equal to] 3 per group) and subjected to slot-blot analysis using homologous probes for reg-I, reg-II, insulin, and elastase-I. A progressive age-dependent decrease in total reg mRNA levels (reg-I and -II) was detected. At 30 months of age, total reg mRNA levels were approximately 45% of the level detected in 1-month-old mice (p = .01). This paralleled the decrease in insulin mRNA levels (p = .01), which fell below 50%; by contrast, mRNA levels for elastase-I increased with age (p = .05). Analysis of RNA isolated from purified islets did not reveal any mRNA for reg, suggesting that in the normal mouse, reg is primarily a product of the exocrine pancreas. Reg mRNA were detectable in RNA extracts from stomach, duodenum, and small intestine. By hybridization of total pancreatic RNA with oligonucleotide probes which specifically recognize reg-I or reg-II sequences, we show that reg-I mRNA levels declined with age (p = .001) while reg-II mRNA levels remained unchanged. These data demonstrate that in mouse pancreas the two nonallelic reg genes are differentially expressed during aging and that the decrease in reg-I mRNA levels parallels the decrease in insulin gene expression. Differential regulation of reg-I and reg-II genes may explain the presence of conflicting data in the current literature.

Glucose-induced insulin release from single pancreatic beta cells, insulin mRNA levels in beta-cell-specific genes and total pancreatic insulin content were measured in aging rats to test the hypothesis that age-dependent progressive decline in beta-cell activity is one cause of non-insulin-dependent diabetes mellitus (NIDDM). The results show that there is a progressive decline in the activity of insulin-secreting beta-cells with age, indicating a progressive increase in NIDDM risk with age.

Experimental data to define the role of L-Arginine (L-Arg) in the glucose metabolism in differentiated 3T3-LI adipocytes in culture indicates that the L-Arg's metabolic degradation is unrelated to the citric acid cycle activity in the process to enhance insulin-stimulated glycogen synthesis. L-Arg is found to have no effect on 2-deoxyglucose uptake or basal glycogen synthesis. The response to insulin is not altered by L-lysine, but the effect of L-Arg is attenuated by L-lysine.