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Introduction Given an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.Research design and methods We registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.Results Of the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (>90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups.Conclusions Alogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting.

Cardiovascular disease is a serious complication in diabetic patients. To elucidate the precise mechanisms of atherosclerosis in diabetic patients, the effects of high glucose concentration (25 mM) on apoptosis regulation and bcl-2 family protein expression in human coronary artery smooth muscle cells (CASMC) were examined. Treatment with a high level of glucose (25 mM) caused a significant decrease in apoptosis in CASMC compared with the same cells treated with a physiologically normal glucose concentration (5.5 mM) (23.9 [+ or -] 2.4% vs. 16.5 [+ or -] 1.8%; P < 0.01). With respect to apoptosis regulation, treatment of CASMC with high glucose concentration markedly increased mRNA expressions of bcl-xL and bfl-1/A1 compared with cells treated with normal glucose. High glucose induced phosphorylation of phosphatidylinositol 3-kinase (PI 3-K) and extracellular signal-regulated kinase (ERK)1/2 along with bcl-xL and bfl-1/A1 upregulation. These results suggest that high glucose suppresses apoptosis via upregulation of bcl-xL and bfl-1/A1 levels through PI 3-K and ERK1/2 pathways in CASMC. High glucose-induced increase in the expression of antiapoptotic proteins may be important in the development of atherosclerosis in diabetic patients. diabetes mellitus; atherosclerosis; apoptosis; vascular smooth muscle cells

Genetic variation in the gene encoding the cysteine protease calpain-10 modifies risk of type 2 diabetes. Studies in mice have shown that calpain-10 deficient mice (Capn10[sup -/-]) are significantly more insulin sensitive than wild-type (Capn10[sup +/+]) littermates especially when fed a high fat diet (HFD). There is a 1.7-fold increase in muscle insulin receptor (IR)-beta subunit level in Capn10[sup -/-] mice on a HFD suggesting that Capn10 modulates IR levels. To further examine the molecular basis for Capn10's effect on IR levels and insulin sensitivity, we have studied insulin action in mouse embryo fibroblast cell lines (MEFs) from Capn10[sup -/-] and wild-type mice. The expression and activation of insulin signaling proteins were examined by immunoblotting using specific antibodies. The basal levels of IR-beta and IRS-1 were increased 1.7- and 1.5-fold in Capn10[sup -/-] MEFs. Insulin-stimulated phosphorylation of Akt (Ser 473) was increased 1.8-fold. Insulin-induced degradation of IR-beta and IRS-1 were suppressed in Capn10[sup -/-] MEFs. These results suggest that Capn10 regulates turnover of IR and IRS-1 and increased levels of these key proteins leads to increased insulin sensitivity. [ABSTRACT FROM AUTHOR]

Glucose concentration may be an important factor in breast cancer cell proliferation, and the prevalence of breast cancer is high in diabetic patients. Leptin may also be an important factor since plasma levels of leptin correlated with TNM staging for breast cancer patients. The effects of glucose and leptin on breast cancer cell proliferation were evaluated by examining cell doubling time, DNA synthesis, levels of cell cycle related proteins, protein kinase C (PKC) isozyme expression, and peroxisome proliferator-activated receptor (PPAR) subtypes were determined following glucose exposure at normal (5.5 mM) and high (25 mM) concentrations with/without leptin in MCF-7 human breast cancer cells. In MCF-7 cells, leptin and high glucose stimulated cell proliferation as demonstrated by the increases in DNA synthesis and expression of cdk2 and cyclin D1. PKC-alpha, PPARgamma, and PPARalpha protein levels were up-regulated following leptin and high glucose treatment in drug-sensitive MCF-7 cells. However, there was no significant effect of leptin and high glucose on cell proliferation, DNA synthesis, levels of cell cycle proteins, PKC isozymes, or PPAR subtypes in multidrug-resistant human breast cancer NCI/ADR-RES cells. These results suggested that hyperglycemia and hyperleptinemia increase breast cancer cell proliferation through accelerated cell cycle progression with up-regulation of cdk2 and cyclin D1 levels. This suggests the involvement of PKC-alpha, PPARalpha, and PPARgamma.