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OBJECTIVE--Diabetic hyperglycemia results from insulin resistance of peripheral tissues and glucose overproduction due to increased gluconeogenesis (GNG). Thiazolidinediones (TZDs) improve peripheral insulin sensitivity, but the effect on the liver is [...]

OBJECTIVE--1) To evaluate the effect of a single oral dose of hexyl-insulin monoconjugate 2 (HIM2) on the rate of whole-body glucose disposal ([R.sub.d]) and endogenous glucose production (EGP) in healthy [...]

Thiazolidinediones (TZDs) improve glycemic control and insulin sensitivity in patients with type 2 diabetes. To determine whether the TZD-induced improvement in glycemic control is associated with enhanced insulin receptor signaling in skeletal muscle, 20 type 2 diabetic patients received a 75-g oral glucose tolerance test (OGTT) and euglycemic insulin (80 mU * [m.sup.-2] * [min.sup.-1]) clamp with [3-³H]glucose/indirect calorimetry/vastus lateralis muscle biopsies before and after 16 weeks of rosiglitazone treatment. Six age-matched nondiabetic subjects served as control subjects. RSG improved fasting plasma glucose (185 ± 8 to 139 ± 5 mg/dl), mean plasma glucose during the OGTT (290 ± 9 to 225 ± 6 mg/dl), Hb[A.sub.1c] (8.5 ± 0.3 to 7.1 ± 0.3%), insulin-mediated total-body glucose disposal (TGD) (6.9 ± 0.7 to 9.2 ± 0.8 mg. * [kg.sup.-1] fat-free mass * [min.sup.-1]) (all P < 0.001), and decreased fasting plasma free fatty acid (FFA) (789 ± 59 to 656 ± 50 µEq/l) and mean FFA during the OGTT (644 ± 41 to 471 ± 35 µEq/l) (both P < 0.01). Before RSG treatment, insulin infusion did not significantly increase insulin receptor tyrosine phosphorylation (0.95 ± 0.10 to 1.08 ± 0.13 density units; NS) but had a small stimulatory effect on insulin receptor substrate (IRS)-1 tyrosine phosphorylation (1.05 ± 0.10 to 1.21 ± 0.12 density units; P < 0.01) and the association of p85 with IRS-1 (0.94 ± 0.06 to 1.08 ± 0.06 activity units; P < 0.01). RSG therapy had no effect on basal or insulin-stimulated insulin receptor tyrosine phosphorylation but increased insulin stimulation of IRS-1 tyrosine phosphorylation (1.13 ± 0.11 to 1.56 ± 0.17 density units; P < 0.01 vs. prerosiglitazone) and p85 association with IRS-1 (1.00 ± 0.06 to 1.27 ± 0.07 activity units; P < 0.05 vs. prerosiglitazone). In control and type 2 diabetic subjects, TGD/nonoxidative glucose disposal correlated positively with the insulin-stimulated increments in IRS-1 tyrosine phosphorylation (r = 0.52/r = 0.57, P < 0.01) and inversely with the plasma FFA concentration during the insulin clamp (r = -0.55 r = -0.53, P < 0.01). However, no significant association between plasma FFA concentrations during the insulin clamp and the increment in either IRS-1 tyrosine phosphorylation or the association of p85 with IRS-1 was observed. In conclusion, in type 2 diabetic patients, rosiglitazone treatment enhances downstream insulin receptor signaling in muscle and decreases plasma FFA concentration while improving glycemic control., Insulin resistance in skeletal muscle, the tissue responsible for 70-80% of insulin-stimulated glucose disposal during euglycemic-hyperinsulinemic clamp studies, is a characteristic feature of individuals with type 2 diabetes (1-3). A [...]

The effect of pioglitazone on splanchnic glucose uptake (SGU), endogenous glucose production (EGP), and hepatic fat content was studied in 14 type 2 diabetic patients (age 50 ± 2 years, BMI 29.4 ± 1.1 kg/[m.sup.2], Hb[A.sub.1c] 7.8 ± 0.4%). Hepatic fat content (magnetic resonance spectroscopy) and SGU (oral glucose load-insulin clamp technique) were quantitated before and after pioglitazone (45 mg/day) therapy for 16 weeks. Subjects received a 7-h euglycemic insulin (100 mU x [m.sup.-2] * [min.sup.-1]) clamp, and a 75-g oral glucose load was ingested 3 h after starting the insulin clamp. Following glucose ingestion, the steady-state glucose infusion rate during the insulin clamp was decreased appropriately to maintain euglycemia. SGU was calculated by subtracting the integrated decrease in glucose infusion rate during the 4 h after glucose ingestion from the ingested glucose load. 3-[³H]glucose was infused during the initial 3 h of the insulin clamp to determine rates of EGP and glucose disappearance ([R.sub.d]). Pioglitazone reduced fasting plasma glucose (10.0 ± 0.7 to 7.5 ± 0.6 mmol/l, P < 0.001) and Hb[A.sub.1c] (7.8 ± 0.4 to 6.7 ± 0.3%, P < 0.001) despite increased body weight (83 ± 3 to 86 ± 3 kg, P < 0.001). During the 3-h insulin clamp period before glucose ingestion, pioglitazone improved [R.sub.d] (6.9 ± 0.5 vs. 5.2 ± 0.5 mg. [kg.sup.-1] x [min.sup.-1], P < 0.001) and insulin-mediated suppression of EGP (0.21 ± 0.04 to 0.06 ± 0.02 mg x [kg.sup.-1] * [min.sup.-1], P < 0.01). Following pioglitazone treatment, hepatic fat content decreased from 19.6 ± 3.6 to 10.4 ± 2.1%, (P < 0.005), and SGU increased from 33.0 ± 2.8 to 46.2 [+ or-] 5.1% (P < 0.005). Pioglitazone treatment in type 2 diabetes 1) decreases hepatic fat content and improves insulin-mediated suppression of EGP and 2) augments splanchnic and peripheral tissue glucose uptake. Improved splanchnic/peripheral glucose uptake and enhanced suppression of EGP contribute to the improvement in glycemic control in patients with type 2 diabetes., The splanchnic tissues play a pivotal role in the maintenance of normal glucose homeostasis (1). Hyperglycemia, plasma free fatty acid (FFA) concentration, and route of glucose administration all exert independent [...]

OBJECTIVE -- To investigate the dose-response effects of pioglitazone on glycemic control, insulin sensitivity, and insulin secretion in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS -- A total [...]

OBJECTIVE -- To elucidate the effects of pioglitazone treatment on glucose and lipid metabolism in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS -- A total of 23 diabetic [...]

A novel approach to the treatment of type 2 diabetes OBJECTIVE -- In vertebrates, body fat stores and insulin action are controlled by the temporal interaction of circadian neuroendocrine oscillations. [...]

We examined the effect of pioglitazone on abdominal fat distribution to elucidate the mechanisms via which pioglitazone improves insulin resistance in T2DM patients. 13 patients with T2DM (MF=9/4, age=52 [+ [...]

The present study was designed to examine the mechanisms via which pioglitazone improves glucose metabolism in patients with type 2 diabetes mellitus (T2DM). Twenty-three patients with T2DM (age=54 [+ or [...]

Pioglitazone is a newly approved insulin sensitizing thiazolidinedione, for the treatment of Type 2 Diabetes Mellitus (T2DM). The aim of the present study was to elucidate the mechanism(s) responsible for [...]