BACKGROUND: The expression of interleukin-1-receptor antagonist is reduced in pancreatic islets of patients with type 2 diabetes mellitus, and high glucose concentrations induce the production of interleukin-1beta in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell proliferation, and apoptosis. METHODS: In this double-blind, parallel-group trial involving 70 patients with type 2 diabetes, we randomly assigned 34 patients to receive 100 mg of anakinra (a recombinant human interleukin-1-receptor antagonist) subcutaneously once daily for 13 weeks and 36 patients to receive placebo. At baseline and at 13 weeks, all patients underwent an oral glucose-tolerance test, followed by an intravenous bolus of 0.3 g of glucose per kilogram of body weight, 0.5 mg of glucagon, and 5 g of arginine. In addition, 35 patients underwent a hyperinsulinemic-euglycemic clamp study. The primary end point was a change in the level of glycated hemoglobin, and secondary end points were changes in beta-cell function, insulin sensitivity, and inflammatory markers. RESULTS: At 13 weeks, in the anakinra group, the glycated hemoglobin level was 0.46 percentage point lower than in the placebo group (P=0.03); C-peptide secretion was enhanced (P=0.05), and there were reductions in the ratio of proinsulin to insulin (P=0.005) and in levels of interleukin-6 (P<0.001) and C-reactive protein (P=0.002). Insulin resistance, insulin-regulated gene expression in skeletal muscle, serum adipokine levels, and the body-mass index were similar in the two study groups. Symptomatic hypoglycemia was not observed, and there were no apparent drug-related serious adverse events. CONCLUSIONS: The blockade of interleukin-1 with anakinra improved glycemia and beta-cell secretory function and reduced markers of systemic inflammation. (ClinicalTrials.gov number, NCT00303394 [ClinicalTrials.gov].). T h e n e w e ng l a n d j o u r na l o f m e dic i n e

Studies were done to determine whether the minimal model approach and the glucose clamp measure equivalent indices of insulin action. Euglycemic glucose clamps (glucose, G: 85 mg/dl) were performed at two rates of insulin (I)

The intestinally derived hormone glucagon-like peptide 1 (GLP-1) (7-36 amide) has potent effects on glucosemediated insulin secretion, insulin gene expression, and ␤-cell growth and differentiation. It is, therefore, considered a potential therapeutic agent for the treatment of type 2 diabetes. However, the dose-response relationship between GLP-1 and basal and glucose-stimulated prehepatic insulin secretion rate (ISR) is currently not known. Seven patients with type 2 diabetes and seven matched nondiabetic control subjects were studied. ISR was determined during a graded glucose infusion of 2, 4, 6, 8, and 12 mg ⅐ kg ؊1 ⅐ min ؊1 over 150 min on four occasions with infusion of saline or GLP-1 at 0.5, 1.0, and 2.0 pmol ⅐ kg ؊1 ⅐ min ؊1 . GLP-1 enhanced ISR in a dose-dependent manner during the graded glucose infusion from 332 ؎ 51 to 975 ؎ 198 pmol/kg in the patients with type 2 diabetes and from 711 ؎ 123 to 2,415 ؎ 243 pmol/kg in the control subjects. The ␤-cell responsiveness to glucose, expressed as the slope of the linear relation between ISR and the glucose concentration, increased in proportion to the GLP-1 dose to 6 times relative to saline at the highest GLP-1 dose in the patients and 11 times in the control subjects, but it was 3 to 5 times lower in the patients with type 2 diabetes compared with healthy subjects at the same GLP-1 dose. During infusion of GLP-1 at 0.5 pmol ⅐ kg ؊1 ⅐ min ؊1 in the patients, the slope of ISR versus glucose became indistinguishable from that of the control subjects without GLP-1. Our results show that GLP-1 increases insulin secretion in patients with type 2 diabetes and control subjects in a dose-dependent manner and that the ␤-cell responsiveness to glucose may be increased to normal levels with a low dose of GLP-1 infusion. Nevertheless, the results also indicate that the dose-response relation between ␤-cell responsiveness to glucose and GLP-1 is severely impaired in patients with type 2 diabetes. Diabetes 52:380 -386, 2003 G lucagon-like peptide 1 (7-36) amide (GLP-1) is an incretin hormone, secreted from the L-cells of the small intestine in response to ingestion of a meal (1-3). Together with the related hormone glucose-dependent insulinotropic polypeptide (GIP), GLP-1 is responsible for the augmentation of insulin secretion that results from oral, compared with intravenous, stimulation of insulin secretion with nutrients (4). Unlike GIP, the insulinotropic effect of GLP-1 is preserved in patients with type 2 diabetes (5), in whom intravenous infusion of ϳ1 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 of GLP-1 may actually normalize fasting hyperglycemia (6). Part of this effect may be due to simultaneous inhibition of glucagon secretion, resulting in a diminished hepatic glucose production (6,7). However, despite multiple studies examining the effect of GLP-1 in healthy volunteers (8,9) and in subjects with type 1 and type 2 diabetes (8,10 -12), a dose-response relationship for GLP-1 and insulin secretion has not been established, even though this is relevant for the long-term treatment ...

The protracted action of detemir is primarily achieved through slow absorption into blood. Dihexamerization and albumin binding of hexameric and dimeric detemir prolongs residence time at the injection depot. Some further retention of detemir occurs in the circulation where albumin binding causes buffering of insulin concentration. Insulin detemir provides a novel principle of protraction, enabling increased predictability of basal insulin.

Due to the inherent pharmacokinetic properties of available insulins, normoglycemia is rarely, if ever, achieved in insulin-dependent diabetic patients without compromising their quality of life. Subcutaneous insulin absorption is influenced by many factors, among which the associated state of insulin (hexameric) in pharmaceutical formulation may be of importance. This review describes the development of a series of human insulin analogues with reduced tendency to self-association that, because of more rapid absorption, are better suited to meal-related therapy. DNA technology has made it possible to prepare insulins that remain dimeric or even monomeric at high concentration by introducing one or a few amino acid substitutions into human insulin. These analogues were characterized and used for elucidating the mechanisms involved in subcutaneous absorption and were investigated in preliminary clinical studies. Their relative receptor binding and in vitro potency (free-fat cell assay), ranging from 0.05 to 600% relative to human insulin, were strongly correlated (r = 0.97). In vivo, most of the analogues exhibited approximately 100% activity, explainable by a dominating receptor-mediated clearance. This was confirmed by clamp studies in which correlation between receptor binding and clearance was observed. Thus, an analogue with reduced binding and clearance gives higher circulating concentrations, counterbalancing the reduced potency at the cellular level. Absorption studies in pigs revealed a strong inverse correlation (r = 0.96) between the rate of subcutaneous absorption and the mean association state of the insulin analogues. These studies also demonstrated that monomeric insulins were absorbed three times faster than human insulin. In healthy subjects, rates of disappearance from subcutis were two to three times faster for dimeric and monomeric analogues than for human insulin. Concomitantly, a more rapid rise in plasma insulin concentration and an earlier hypoglycemic response with the analogues were observed. The monomeric insulin had no lag phase and followed a monoexponential course throughout the absorption process. In contrast, two phases in rate of absorption were identified for the dimer and three for the normal hexameric human insulin. The initial lag phase and the subsequent accelerated absorption of soluble insulin can now be explained by the associated state of native insulin in pharmaceutical formulation and its progressive dissociation into smaller units during the absorption process. In the light of these results, the effects of insulin concentration, injected volume, temperature, and massage on the absorption process are now also understood.(ABSTRACT TRUNCATED AT 400 WORDS)