Type 2 diabetes mellitus has become an epidemic, and virtually no physician is without patients who have the disease. Whereas insulin insensitivity is an early phenomenon partly related to obesity, pancreas ␤-cell function declines gradually over time already before the onset of clinical hyperglycaemia. Several mechanisms have been proposed, including increased non-esterified fatty acids, inflammatory cytokines, adipokines, and mitochondrial dysfunction for insulin resistance, and glucotoxicity, lipotoxicity, and amyloid formation for ␤-cell dysfunction. Moreover, the disease has a strong genetic component, but only a handful of genes have been identified so far: genes for calpain 10, potassium inward-rectifier 6·2, peroxisome proliferator-activated receptor ␥, insulin receptor substrate-1, and others. Management includes not only diet and exercise, but also combinations of antihyperglycaemic drug treatment with lipid-lowering, antihypertensive, and anti platelet therapy. Glucose concentration in venous plasma (mmol/L) Diabetes mellitusFasting у7·0 or 2-h post-glucose load у11·1 Impaired glucose tolerance Fasting (if measured) Ͻ7·0 and 2-h post-glucose load у7·8 and Ͻ11·1 Impaired fasting glucose Fasting у6·1 and Ͻ7·0 and 2 h post-glucose load (if measured) Ͻ7·8Glucose load=75 g glucose orally. 10

Background-Inflammatory mediators that originate in vascular and extravascular tissues promote coronary lesion formation. Adipose tissue may function as an endocrine organ that contributes to an inflammatory burden in patients at risk of cardiovascular complications. In this study, we sought to compare expression of inflammatory mediators in epicardial and subcutaneous adipose stores in patients with critical CAD. Methods and Results-Paired samples of epicardial and subcutaneous adipose tissues were harvested at the outset of elective CABG surgery (nϭ42; age 65Ϯ10 years).

Since the discovery of insulin nearly 70 years ago, there has been no problem more fundamental to diabetes research than understanding how insulin works at the cellular level. Insulin binds to the alpha subunit of the insulin receptor which activates the tyrosine kinase in the beta subunit, but the molecular events linking the receptor kinase to insulin-sensitive enzymes and transport processes are unknown. Our discovery that insulin stimulates tyrosine phosphorylation of a protein of relative molecular mass between 165,000 and 185,000, collectively called pp185, showed that the insulin receptor kinase has specific cellular substrates. The pp185 is a minor cytoplasmic phosphoprotein found in most cells and tissues; its phosphorylation is decreased in cells expressing mutant receptors defective in signalling. We have now cloned IRS-1, which encodes a component of the pp185 band. IRS-1 contains over ten potential tyrosine phosphorylation sites, six of which are in Tyr-Met-X-Met motifs. During insulin stimulation, the IRS-1 protein undergoes tyrosine phosphorylation and binds phosphatidylinositol 3-kinase, suggesting that IRS-1 acts as a multisite 'docking' protein to bind signal-transducing molecules containing Src-homology 2 and Src-homology-3 domains. Thus IRS-1 may link the insulin receptor kinase and enzymes regulating cellular growth and metabolism.

Increased albuminuria is associated with obesity and diabetes and is a risk factor for cardiovascular and renal disease. However, the link between early albuminuria and adiposity remains unclear. To determine whether adiponectin, an adipocyte-derived hormone, is a communication signal between adipocytes and the kidney, we performed studies in a cohort of patients at high risk for diabetes and kidney disease as well as in adiponectin-knockout (Ad -/-) mice. Albuminuria had a negative correlation with plasma adiponectin in obese patients, and Ad -/-mice exhibited increased albuminuria and fusion of podocyte foot processes. In cultured podocytes, adiponectin administration was associated with increased activity of AMPK, and both adiponectin and AMPK activation reduced podocyte permeability to albumin and podocyte dysfunction, as evidenced by zona occludens-1 translocation to the membrane. These effects seemed to be caused by reduction of oxidative stress, as adiponectin and AMPK activation both reduced protein levels of the NADPH oxidase Nox4 in podocytes. Ad -/-mice treated with adiponectin exhibited normalization of albuminuria, improvement of podocyte foot process effacement, increased glomerular AMPK activation, and reduced urinary and glomerular markers of oxidant stress. These results suggest that adiponectin is a key regulator of albuminuria, likely acting through the AMPK pathway to modulate oxidant stress in podocytes.

OBJECTIVE—To assess the efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes and inadequate glycemic control on diet and exercise. RESEARCH DESIGN AND METHODS—In a 24-week, randomized, double-blind, placebo-controlled, parallel-group study, 1,091 patients with type 2 diabetes and A1C 7.5–11% were randomized to one of six daily treatments: sitagliptin 100 mg/metformin 1,000 mg (S100/M1000 group), sitagliptin 100 mg/metformin 2,000 mg (S100/M2000 group), metformin 1,000 mg (M1000 group), metformin 2,000 mg (M2000 group) (all as divided doses administered twice daily [b.i.d.]), sitagliptin 100 mg q.d. (S100 group), or placebo. Patients who had an A1C >11% or a fasting glucose value >280 mg/dl after the run-in period were not eligible to be randomized; these patients could participate in an open-label substudy and were treated with S100/M2000 for 24 weeks. RESULTS—The mean baseline A1C was 8.8% in the randomized patients. The placebo-subtracted A1C change from baseline was −2.07% (S100/M2000), −1.57% (S100/M1000), −1.30% (M2000), −0.99% (M1000), and −0.83% (S100) (P < 0.001 for comparisons versus placebo and for coadministration versus respective monotherapies). The proportion of patients achieving an A1C <7% and <6.5% was 66 and 44%, respectively, in the S100/M2000 group (P < 0.001 vs. S100 or M2000). For the open-label cohort (n = 117; baseline A1C 11.2%) treated with S100/M2000, the within-group mean A1C change from baseline was −2.9%. The incidence of hypoglycemia was low (0.5–2.2%) across active treatment groups and not significantly different from that in the placebo group (0.6%). The incidence of gastrointestinal adverse experiences was similar for coadministration therapies compared with their respective metformin monotherapy. CONCLUSIONS—The initial combination of sitagliptin and metformin provided substantial and additive glycemic improvement and was generally well tolerated in patients with type 2 diabetes.