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Insulin-dependent diabetes mellitus (IDDM) is assumed to be a T cell–mediated autoimmune disease. To investigate the role of Fas-mediated cytotoxicity in pancreatic β cell destruction, we established nonobese diabetic (NOD)-lymphoproliferation (lpr)/lpr mice lacking Fas. Out of three genotypes, female NOD-+/+ and NOD-+/lpr developed spontaneous diabetes by the age of 10 mo with the incidence of 68 and 62%, respectively. In contrast, NOD-lpr/lpr did not develop diabetes or insulitis. To further explore the role of Fas, adoptive transfer experiments were performed. When splenocytes were transferred from diabetic NOD, male NOD-+/+ and NOD-+/lpr developed diabetes with the incidence of 89 and 83%, respectively, whereas NOD-lpr/lpr did not show glycosuria by 12 wk after transfer. Severe mononuclear cell infiltration was revealed in islets of NOD-+/+ and NOD-+/lpr, whereas islet morphology remained intact in NOD-lpr/lpr. These results suggest that Fas-mediated cytotoxicity is required to initiate β cell autoimmunity in NOD mice. Fas–Fas ligand system might be critical for autoimmune β cell destruction leading to IDDM.

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Abstract. This study assessed the dose-dependent efficacy and safety of exenatide over 12 weeks in Japanese patients with type 2 diabetes suboptimally controlled despite therapeutic doses of sulfonylurea (SU), SU plus biguanide, or SU plus thiazolidinedione. Patients were randomly assigned to placebo (N = 40), 2.5 µg (N = 38), 5 µg (N = 37), or 10 µg (N = 38) exenatide administered subcutaneously twice daily (bID). Patients randomly assigned to 10 µg exenatide received 5 µg bID for the first 4 weeks, with the dose escalated to 10 µg bID for the final 8 weeks. Patients were 60.3 ± 9.7 years old, with body mass index 25.3 ± 4.3 kg/m 2 and hemoglobin a1c (Hba1c) 8.0 ± 0.8%. baseline-to-endpoint Hba1c changes (%) were +0.02 ± 0.1 (placebo), -0.9 ± 0.1 (2.5 µg), -1.2 ± 0.1 (5 µg), and -1.4 ± 0.1 (10 µg) (all p < 0.001 vs. placebo). Of patients with baseline HbA1c ≥7%, 5.1% (placebo), 50.0% (2.5 µg), 71.4% (5 µg), and 79.4% (10 µg) achieved Hba1c <7% at endpoint (p < 0.001, trend test). baseline-to-endpoint fasting plasma glucose changes (mg/dL) were +6.0 ± 4.8 (placebo), -18.6 ± 5.7 (2.5 µg), -25.0 ± 7.0 (5 µg), and -28.9 ± 5.9 (10 µg) (all p ≤ 0.001 vs. placebo). Treatment-emergent adverse events were mostly mild; dose-dependent increases in incidence were observed for hypoglycemia, nausea, anorexia, decreased appetite, and diarrhea (all p ≤ 0.044, trend test). Over 12 weeks, exenatide dose-dependently improved glycemic control in Japanese patients with type 2 diabetes.

We examined the effect of glucagonlike peptides (GLPs), which are cleaved from preproglucagon in the enteroglucagon cells, on rat endocrine pancreas with the isolated perfused system. GLP-I-(7-36)-amide, a truncated form of full-sequence GLP-I-(1-37), showed a potent inhibitory effect on glucagon secretion. This inhibitory effect of GLP-I-(7-36)-amide was demonstrated at concentrations of 0.25, 2.5, and 25 nM in 11.2 and 2.8 mM glucose. In contrast, insulin release was significantly stimulated by GLP-I-(7-36)-amide at its concentration from 0.025 to 25 nM in a high glucose concentration, whereas in a low glucose concentration, the stimulation was seen only at the highest concentration (25 nM). Neither GLP-I-(1-37) nor GLP-II showed any effect on glucagon and insulin release. Although several gastrointestinal hormones have been nominated as incretins, none of them may suppress the glucagon secretion. A truncated form of GLP-I, GLP-I-(7-36)-amide thus seems to be a unique incretin that exerts glucagonostatic action.

Aims/Introduction:  To evaluate the efficacy and safety of the glucagon‐like peptide‐1 receptor agonist, exenatide, in Japanese patients with type 2 diabetes mellitus suboptimally controlled despite therapeutic doses of a sulfonylurea alone or combined with a biguanide or thiazolidinedione.Materials and Methods:  Patients were randomized to a placebo or exenatide, either 5 or 10 μg, given subcutaneously b.i.d. in addition to oral therapy. Patients randomized to 10 μg exenatide received 5 μg b.i.d. for the first 4 weeks, followed by 10 μg b.i.d. for the last 20 weeks.Results:  A total of 179 patients received the study drug and composed the full analysis set (n = 35, placebo; n = 72, exenatide 5 μg; n = 72, exenatide 10 μg; 68% male; 58 ± 10 years; body mass index 25.5 ± 4.1 kg/m2; HbA1c 8.2 ± 0.9%; means ± standard deviations). Baseline to end‐point (least‐squares means ± standard errors) HbA1c changes (%) were −0.28 ± 0.15 (placebo), −1.34 ± 0.11 (exenatide 5 μg) and −1.62 ± 0.11 (exenatide 10 μg) (both P < 0.001, exenatide vs placebo). Baseline to end‐point bodyweight changes (kg) were −0.47 ± 0.39 (placebo), −0.39 ± 0.28 (exenatide 5 μg) and −1.54 ± 0.27 (exenatide 10 μg; P = 0.026, exenatide 10 μg vs placebo). Nausea, generally mild to moderate, was reported in 8.6% (placebo), 25.0% (exenatide 5 μg) and 36.1% (exenatide 10 μg) of patients. Mild to moderate hypoglycemia was reported in 22.9% (placebo), 51.4% (exenatide 5 μg) and 58.3% (exenatide 10 μg) of patients.Conclusions:  Over 24 weeks, exenatide vs the placebo improved glycemic control, reduced bodyweight (10 μg) and was well tolerated in Japanese patients with type 2 diabetes mellitus suboptimally controlled, despite oral therapy including a sulfonylurea. This trial was registered with ClinicalTrials.gov (no. NCT00577824). (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00084.x, 2011)