Search

The authors reflect on a study by B. Hibbert and colleagues on the potency of glycogen synthase kinase-3β (GSK3β) inhibitors on diabetic patients' endothelial progenitor cells (D-EPCs). They cite the need for revascularization through surgery and endovascular to reestablish tissue function and intromission. They also discuss the study's emphasis on the function of cathepsin B enzymatic protein in GSK3β-intervened regulation of EPC dysfunction in diabetic patients.

The majority of small G-proteins undergo posttranslational modifications (e.g., isoprenylation) at their C-terminal cysteine residues. Such modifications increase their hydrophobicity, culminating in translocation of the modified proteins to their relevant membranous sites for interaction with their respective effectors. Previously, we reported glucose-dependent activation and membrane association of Racl in INS 832/13 cells. We also demonstrated modulatory roles for Racl/GDP dissociation inhibitor in glucose-stimulated insulin secretion (GSIS) in INS 832/13 cells, further affirming roles for Racl in GSIS. Herein, we demonstrate that geranylgeranyltransferase inhibitor-2147 (GGTI-2147), an inhibitor of protein prenylation, markedly increased cytosolic accumulation of Racl and elicited significant inhibition of GSIS from INS 832/13 cells. In the current study, we also examined the localization of protein prenyltransferases (PPTases) and regulation of GSIS by PPTases in INS 832/13 cells. Western blot analyses indicated that the regulatory α-subunit and the structural β-subunit of PPTase holoenzyme are predominantly cytosolic in their distribution. Overexpression of an inactive mutant of the regulatory α-subunit of PPTase markedly attenuated glucose- but not KCl-induced insulin secretion from INS 832/13 cells. Together, our findings provide the first evidence for the regulation of GSIS by PPTase in INS 832/13 cells. Furthermore, they support our original hypothesis that prenylation of specific G-proteins may be necessary for GSIS. Diabetes 56:204-210, 2007 [ABSTRACT FROM AUTHOR]

p21cip1, a regulatory molecule upstream of the G1/0 checkpoint, is increased in β-cells in response to mitogenic stimulation. Whereas p21cip1 can variably stimulate or inhibit cell cycle progression, in vitro studies suggest that p21cip1 acts as an inhibitor in the pancreatic β-cell. To determine the functional role of p21cip1 in vivo, we studied p21-null mice. Surprisingly, islet mass, β-cell replication rates, and function were normal in p21-null mice. We next attempted to drive β-cell replication in p21-null mice by crossing them with rat insulin II promoter-murine PL-1 (islet-targeted placental lactogen transgenic) mice. Even with this added replicative stimulus of PL, p21-null islets showed no additional stimulation. A G1/S proteome scan demonstrated that p21cip1 loss was not associated with compensatory increases in other cell cycle inhibitors (pRb, p107, p130, p16, p19, and p27), although mild increases in p57 were apparent. Surprisingly, p18, which had been anticipated to increase, was markedly decreased. In summary, isolated p21cip1 loss, as for pRb, p53, p18, and p27 and other inhibitors, results in normal β-cell development and function, either because it is not essential or because its function is subserved or complimented by another protein. These studies underscore marked inhibitory pressure and the complexity and plasticity of inhibitory pathways that restrain β-cell replication. Diabetes 55: 3271-3278, 2006 [ABSTRACT FROM AUTHOR]

Free Fatty Acids (FFA) induce activation of the inflammatory pathway IKK/Ikappa B/NF-kappaB in mononuclear cells Adiponectin is an anti-inflammatory and insulin sensitizing adipocytokine. To determine whether adiponectin counters the monocyte inflammatory response produced by FFA in vitro, cultured monocytes (U937 cells) were incubated for 6 hrs in the presence or absence of 0.4mM palmitate/2.4% BSA and in the presence or absence of adiponectin (2 µg/ml). 6 hr exposure of cultured monocytes to the saturated fatty acid palmitate stimulated IκBα degradation and the nuclear translocation of NF-kappa B by ∼50%. Adiponectin inhibited palmitate-induced IκBα degradation and nuclear translocation of NF-kappaB. In summary, adiponectin inhibits palmitate-induced IKappa;Bα degradation and the nuclear translocation of NF-kappaB in U937 cells. We conclude that FFA-induced activation of monocyte inflammation is ameliorated by adiponectin in vitro. Drugs that increase circulating adiponectin levels may ameliorate the vascular inflammation seen in obesity and type 2 diabetes both of which are associated with elevated circulating FFA concentrations and hypoadiponectinemia. [ABSTRACT FROM AUTHOR]

BI 1356 is a novel, potent, and selective DPP-IV inhibitor currently in development for type 2 diabetes. The safety, pharmacokinetics, and pharmacodynamic properties of BI 1356 were investigated in a randomised, double-blind, placebo-controlled study in patients with type 2 diabetes. Forty-seven male type 2 diabetic patients, aged 21-65 and with a BMI of 18-35 kg/m², were treated once daily with 1, 2.5, 5, or 10 mg BI 1356, or placebo for 12 days. Treatment with BI 1356 was well tolerated. The incidence of adverse events in patients treated with BI 1356 (54%) was not higher when compared to placebo (75%). There were no serious adverse events and no episodes of hypoglycaemia. BI 1356 plasma concentrations and exposure increased less than proportionally with dose. The maximum plasma concentrations of BI 1356 at steady-state ranged from 4.5 nmol/L (1 mg dose group) to 13.6 nmol/L (10 mg), with a median t[sub max] of 1.5 h. Reductions in plasma DPP-IV activity were well correlated with plasma concentrations of BI 1356. Two hours after administration of 2.5 mg BI 1356, DPP-IV activity was reduced by >80% and remained at that level at steady-state. Levels of GLP-1 were increased by more than 2-fold. Following an oGTT on day 13, 24 h after the last dose of BI 1356, area under the plasma glucose excursions were reduced by 53 (1 mg BI 1356), 106 (2.5 mg), 82 (5 mg), 111 (10 mg), and 25 (placebo) mg.h/dL, respectively. Despite the small group sizes, these reductions reached statistical significance for 2.5, 5, and 10 mg BI 1356 compared to baseline and compared to placebo (p<0.05 for both). In summary, 24 h after the last dose, DPP-IV inhibition was >70% after administration of BI 1356 doses of > 1 mg, and significant improvements in glucose parameters were observed in patients with type 2 diabetes. Given this potency and duration of action, BI 1356 has the potential to be a best in class DPP-IV inhibitor. [ABSTRACT FROM AUTHOR]

Efficacy and safety of sitagliptin (SITA) were examined in patients with type 2 diabetes and inadequate glycemic control (A1C 7.5% to 10.5%) on glimepiride (G) alone or G plus metformin (G+MF). After a titration/stabilization period on G (≥4 mg/day) ± MF (≥ 1500 mg/day) and a 2-week placebo (PBO) run-in, 441 patients (mean baseline A1C 8.3%) were randomized to the addition of SITA 100 mg q.d. or PBO for 24 weeks. Of these patients, 212 were on G alone (106 each on SITA or PBO), and 229 on G+MF (116 on SITA, 113 on PBO). The primary endpoint was A1C change from baseline for the entire cohort. After 24 weeks, the addition of SITA reduced A1C by -0.7% (p<0.001) relative to PBO (LS mean change from baseline -0.5% with SITA, +0.3% with PBO) in the entire cohort. Patients on G+MF had a PBO-subtracted A1C change from baseline of -0.9%, and patients on G alone had a PBO-subtracted change from baseline of -0.6%. For the entire cohort, SITA significantly (p<0.001) reduced fasting plasma glucose by 20 mg/dL (1.1 mmol/L) and 2-hour postprandial glucose by 36 mg/dL (2.0 mmol/L) relative to PBO at Week 24. Similar results were observed in the G alone and G+MF strata. HOMA-β was also signficantly (p<0.05) improved with SITA relative to PBO. For the entire cohort, there was a higher incidence of overall adverse experiences (AEs) (60 vs 47%) and drug-related AEs (15 vs 7%) with SITA vs. PBO, with a higher incidence of hypoglycemia AEs (12 vs 2%, respectively) contributing to these differences. At Week 24, body weight was modestly increased with SITA compared with PBO (LS mean change from baseline +0.8 vs -0.4 kg, respectively; p<0.001). In this study, dual or triple therapy with SITA added to G or G+MF improved glycemic control in the fasting and postprandial states. Since co-administration of SITA with MF has an additive effect on active GLP-1 levels (Migoya et al., ADA 2007 submitted), this may have contributed to the greater A1C efficacy observed with triple therapy (SITA with G+MF) compared to dual therapy (SITA with G). The addition of SITA was generally well tolerated; the higher rate of hypoglycemia was consistent with the degree of glycemic improvement and comparable to findings from other add-on to sulfonylurea studies. [ABSTRACT FROM AUTHOR]

Provides information on several studies about signal transduction in transcriptional regulation to be presented at the 65th Scientific Sessions of the American Diabetes Association at the San Diego Convention Center in California from June 10 to 14, 2005. Participation of iPLA2β inhibitor in the glucose-induced insulin secretion signal transduction pathway; Principle mechanism of short term regulation; Effect of palmitic acid on cyclic adenosine monophosphate responsive element binding protein.