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Background: Glucagon-like peptide 1 agonists differ in chemical structure, duration of action and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. Methods: We randomly assigned patients with type 2 diabetes and cardiovascular disease to the addition of once-weekly subcutaneous injection of albiglutide (30 mg to 50 mg) or matching placebo to standard care. We hypothesized that albiglutide would be noninferior to placebo for the primary outcome of first occurrence of cardiovascular death, myocardial infarction, or stroke. If noninferiority was confirmed by an upper limit of the 95% confidence interval for the hazard ratio of less than 1.30, closed-testing for superiority was prespecified. Findings: Overall, 9463 participants were followed for a median of 1.6 years. The primary composite outcome occurred in 338 of 4731 patients (7.1%; 4.6 events per 100 person-years) in the albiglutide group and in 428 of 4732 patients (9.0%; 5.9 events per 100 person-years) in the placebo group (hazard ratio, 0.78; 95% confidence interval [CI ], 0.68 to 0.90), indicating that albiglutide, was superior to placebo (P<0.0001 for noninferiority, P=0.0006 for superiority). The incidence of acute pancreatitis (albiglutide 10 patients and placebo 7 patients), pancreatic cancer (6 and 5), medullary thyroid carcinoma (0 and 0), and other serious adverse events did not differ significantly between the two groups. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. (Funded by GlaxoSmithKline; Harmony Outcomes ClinicalTrials.gov number, NCT02465515.) noninferiority; P = 0.06 for superiority). There seems to be variation in the results of existing trials with GLP-1 receptor agonists, which if correct, might reflect drug structure or duration of action, patients studied, duration of follow-up or other factors.

Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are intermediate states in glucose metabolism that exist between normal glucose tolerance and overt diabetes. Epidemiological studies demonstrate that the two categories describe distinct populations with only partial overlap, suggesting that different metabolic abnormalities characterize IGT and IFG. Insulin resistance and impaired ␤-cell function, the primary defects observed in type 2 diabetes, both can be detected in subjects with IGT and IFG. However, clinical studies suggest that the site of insulin resistance varies between the two disorders. While subjects with IGT have marked muscle insulin resistance with only mild hepatic insulin resistance, subjects with IFG have severe hepatic insulin resistance with normal or near-normal muscle insulin sensitivity. Both IFG and IGT are characterized by a reduction in early-phase insulin secretion, while subjects with IGT also have impaired late-phase insulin secretion. The distinct metabolic features present in subjects with IFG and IGT may require different therapeutic interventions to prevent their progression to type 2 diabetes. Diabetes Care 29:1130 -1139, 2006G lucose is the principal fuel used by humans and is the sole source of energy for the brain. Not surprisingly, glucose homeostasis is tightly controlled, and the fasting plasma glucose concentration is maintained within a very narrow range (70 -90 mg/dl) (1). In type 2 diabetes, both insulin secretion and action are impaired (2-4), and chronic hyperglycemia is a characteristic feature of this common metabolic disorder. Unlike type 1 diabetes, where the disease onset is relatively acute, the course of type 2 diabetes is slow and the metabolic abnormalities that lead to hyperglycemia are established long before overt diabetes (as defined by World Health Organization/ American Diabetes Association criteria [5,6]) develops (7-9). This state, where abnormalities in glucose metabolism are present but elevation in glucose is below the cutoff point for establishing the diagnosis of type 2 diabetes, is referred to as pre-diabetes (10). Defining cut points for pre-diabetes and diabetes has generated much debate among the medical community (11,12), and these cut off points have been subject to revision over time (5,6,13,14). Pre-diabetes includes subjects with high fasting plasma glucose (FPG) concentration and normal response to a glucose load (IFG), subjects with abnormal postprandial glucose excursion but normal FPG concentration (IGT), and combination of IGT plus IFG (14).In 1979, an international workgroup defined type 2 diabetes as an FPG Ն140 mg/dl (7.8 mmol/l) or 2-h plasma glucose Ն200 mg/dl (11.1 mmol/l) following 75-g oral glucose load (14). It also created a new category, IGT, defined as a 2-h plasma glucose of 140 -199 mg/dl (7.8 -11.0 mmol/l) with normal FPG. IGT was meant to replace the terms "borderline" and "chemical" diabetes. In 1997, the American Diabetes Association revised its diagnostic criteria for diabetes (6), lowering the...

As compared with placebo, pioglitazone reduced the risk of conversion of impaired glucose tolerance to type 2 diabetes mellitus by 72% but was associated with significant weight gain and edema. (Funded by Takeda Pharmaceuticals and others; ClinicalTrials.gov number, NCT00220961.).

Chronic hyperglycemia impairs insulin action, resulting in glucotoxicity, which can be ameliorated in animal models by inducing glucosuria with renal glucose transport inhibitors. Here, we examined whether reduction of plasma glucose with a sodium-glucose cotransporter 2 (SGLT2) inhibitor could improve insulin-mediated tissue glucose disposal in patients with type 2 diabetes. Eighteen diabetic men were randomized to receive either dapagliflozin (n = 12) or placebo (n = 6) for 2 weeks. We measured insulin-mediated whole body glucose uptake and endogenous glucose production (EGP) at baseline and 2 weeks after treatment using the euglycemic hyperinsulinemic clamp technique. Dapagliflozin treatment induced glucosuria and markedly lowered fasting plasma glucose. Insulin-mediated tissue glucose disposal increased by approximately 18% after 2 weeks of dapagliflozin treatment, while placebo-treated subjects had no change in insulin sensitivity. Surprisingly, following dapagliflozin treatment, EGP increased substantially and was accompanied by an increase in fasting plasma glucagon concentration. Together, our data indicate that reduction of plasma glucose with an agent that works specifically on the kidney to induce glucosuria improves muscle insulin sensitivity. However, glucosuria induction following SGLT2 inhibition is associated with a paradoxical increase in EGP. These results provide support for the glucotoxicity hypothesis, which suggests that chronic hyperglycemia impairs insulin action in individuals with type 2 diabetes.

This study was conducted to observe changes in insulin secretion and insulin action in subjects with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). A total of 319 subjects were studied with an oral glucose tolerance test (OGTT). Fasting plasma glucose and insulin concentrations were measured at baseline and every 30 min during the OGTT. Fifty-eight subjects also received a euglycemic-hyperinsulinemic clamp. Insulin sensitivity was calculated as the total glucose disposal (TGD) during the last 30 min of the clamp. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated from fasting plasma glucose and insulin concentrations. Subjects with IFG had TGD similar to normal glucose-tolerant subjects, while subjects with IGT and combined IFG/IGT had significantly reduced TGD. HOMA-IR in subjects with IFG was similar to that in subjects with combined IFG/IGT and significantly higher than HOMA-IR in subjects with IGT or NGT. Insulin secretion, measured by the insulinogenic index (⌬I 0 -30 /⌬G 0 -30 ) and by the ratio of the incremental area under the curve (AUC) of insulin to the incremental AUC of glucose (0 -120 min), was reduced to the same extent in all three glucoseintolerant groups. When both measurements of ␤-cell function were adjusted for severity of insulin resistance, subjects with IGT and combined IFG/IGT had a significantly greater reduction in insulin secretion than subjects with IFG. Subjects with IGT and IFG have different metabolic characteristics. Differences in insulin sensitivity and insulin secretion may predict different rates of progression to type 2 diabetes and varying susceptibility to cardiovascular disease.

To test the possible acute proinflammatory effects of fatty acids, we induced an increase in plasma free fatty acid (FFA) concentrations after a lipid and heparin infusion for 4 h in 10 healthy subjects. We determined the nuclear factor-B (NF-B) binding activity in mononuclear cells (MNCs), the p65 subunit of NF-B, reactive oxygen species (ROS) generation by MNC, and polymorphonuclear leukocytes (PMN). Brachial artery reactivity, using postischemic flow-mediated dilation, was also measured. NF-B binding activity in the MNC nuclear extracts increased to 163 ؎ 17% and 144 ؎ 14% as compared with basal levels at 2 and 4 h (P < 0.005) and remained elevated (P < 0.05) at 6 h (2 h after cessation of lipid infusion). NF-B p65 subunit protein expression in MNC homogenates also increased at 2, 4, and 6 h (P < 0.05). ROS generation by PMNs increased significantly at 2 and 4 h (P < 0.005), whereas that by MNCs increased at 4 h (P < 0.05). Plasma macrophage migration inhibitory factor increased at 2 (P < 0.05) and 4 h (P < 0.005), respectively, and declined to baseline at 6 h. The postischemic flow-mediated dilation of brachial artery decreased from 6.3 ؎ 1.1% at baseline to 4.3 ؎ 1.9% and 2.7 ؎ 2.1% (P < 0.01) at 2, 4, and 6 h, respectively. We conclude that an increase in FFA concentration induces oxidative stress and has a proinflammatory effect; it also impairs postischemic flowmediated vasodilation of the brachial artery. Diabetes

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