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Phosphoinositide 3-kinase (PI3K) p85[alpha]-deficient mice exhibit hypoglycemia as a result of increased insulin sensitivity and glucose uptake in peripheral tissues. Although PI3K is central to the metabolic actions of insulin, its mechanism of action in liver is not well understood. In the present study, we investigated hepatic insulin signaling and glucose homeostasis in p85[alpha]-deficient and wild-type mice. In the livers of p85[alpha]-deficient mice, p50[alpha] played a compensatory role in insulin-stimulated PI3K activation by binding to insulin receptor substrate (IRS)-1/2. In p85[alpha]-deficient mice, the ratio of p50[alpha] over p110 catalytic subunit of PI3K in the liver was higher than in the muscles. PI3K activity associated with IRS-1/2 was not affected by the lack of p85[alpha] in the liver. Insulin-stimulated Akt and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) activities in the liver were similar in p85[alpha]-deficient and wild-type mice. A hyperinsulinemic-euglycemic clamp study revealed that the glucose infusion rate and the rate of disappearance were higher in p85[alpha]-deficient mice than in wild-type mice but that endogenous glucose production tended to be higher in p85[alpha]-deficient mice than in wild-type mice. Consistent with this finding, the expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase in livers after fasting was higher in p85[alpha]-deficient mice than in wild-type mice. After mice were fasted, the intrahepatic glucose-6-phosphate level was almost completely depleted in p85[alpha]-deficient mice. The glycogen content fell to nearly zero as a result of glycogenolysis shortly after the initiation of fasting in p85[alpha]-deficient mice. The absence of an increase in insulin-stimulated PI3K activation in the liver of p85[alpha]-deficient mice, unlike the muscles, may be associated with the molecular balance between the regulatory subunit and the catalytic subunit of PI3K. Gluconeogenesis was rather elevated in p85[alpha]-deficient mice, compared with in wild-type mice, and the liver seemed to partially compensate for the increase in glucose uptake in peripheral tissues. phosphoinositide 3-kinase; regulatory subunit; catalytic subunit

Abstract: Aims/Introduction: The present phase 3, randomized, double‐blind 24‐week study with extension to 1 year assessed the efficacy and safety of albiglutide compared with placebo in Japanese patients with type 2 diabetes mellitus inadequately controlled by diet and exercise with or without a single oral antidiabetic drug. Materials and Methods: Patients received weekly albiglutide 30 mg (n = 160), albiglutide 50 mg (n = 150) or a placebo switched to albiglutide 30 mg after 24 weeks (n = 77). Open‐label daily liraglutide 0.9 mg (n = 103) was included as a reference. Oral antidiabetic drug use was discontinued before baseline. The primary end‐point was 24‐week change from baseline in glycated hemoglobin (HbA1c). Secondary end‐points included fasting plasma glucose, bodyweight and adverse events. Results: At 24 weeks, mean HbA1c changes from baseline were −1.10, −1.30, and 0.25% for albiglutide 30, 50 mg and placebo, respectively (P vs placebo <0.0001 for both albiglutide doses), −1.19% for liraglutide. Decreases in HbA1c with albiglutide were sustained through the study. Mean fasting plasma glucose decreased by ≥20 mg/dL, and the mean change in bodyweight was ≤0.5 kg through 1 year across groups. Most commonly reported adverse events were nasopharyngitis, constipation and nausea. The incidence of adverse events was higher in active treatment groups than in the placebo group. Few hypoglycemia events were reported; no patient withdrew as a result of hypoglycemia. No new safety signals were detected. Conclusions: Albiglutide monotherapy achieved clinically significant decreases in HbA1c and fasting plasma glucose with good tolerability in Japanese patients with type 2 diabetes mellitus inadequately controlled by diet and exercise with or without a single oral antidiabetic drug. [ABSTRACT FROM AUTHOR]

Objective:To evaluate the safety and efficacy of once weekly albiglutide added to a single oral antidiabetic drug (OAD) in Japanese patients with inadequately controlled type 2 diabetes mellitus (T2DM). Research design and methods:In this phase 3, 1 year study (NCT01777282), patients (N = 374) received albiglutide 30 mg plus a single OAD (sulfonylurea [n = 120], biguanide [n = 67)], glinide [n = 65], thiazolidinedione [n = 61], or α-glucosidase inhibitor [n = 61]). Albiglutide could be increased to 50 mg after Week 4, based on glycemic criteria. Primary endpoints were the incidence of adverse events (AEs) and hypoglycemia; secondary endpoints were changes from baseline at Week 52 in HbA1cand fasting plasma glucose (FPG), proportion of patients achieving HbA1c≤7.0%, and withdrawals due to hyperglycemia. Results:On-therapy AEs occurred in 78.6% of patients and serious AEs in 2.1%. Common AEs were nasopharyngitis (32.6%), constipation (7.2%), and diabetic retinopathy (5.3%). No serious AEs occurred more than once or were reported in >1 patient. Hypoglycemia occurred in 6.4% of patients, mostly in the albiglutide + sulfonylurea (14.2%) and the albiglutide + glinide (6.2%) groups. Albiglutide was uptitrated in 53.2% of patients. Mean baseline HbA1cwas 8.1%. Mean decreases from baseline in HbA1cwere observed with the addition of albiglutide to thiazolidinediones (−1.42%), α-glucosidase inhibitors (−1.39%), sulfonylureas (−1.04%), glinides (−0.95%), and biguanides (−0.94%). HbA1cof <7% in >50% of patients and mean reductions in FPG were achieved in all groups. Mean changes from baseline in body weight ranged from +0.52 kg (albiglutide + thiazolidinedione) to −0.33 kg (albiglutide + biguanide). Limitations of the study included open label treatment that was not randomized. Conclusions:When combined with a single OAD in Japanese patients with inadequately controlled T2DM, albiglutide led to favorable changes in all glycemic parameters, with minor changes in body weight depending on the background OAD. No new safety concerns were noted. [ABSTRACT FROM PUBLISHER]