OBJECTIVE- Tall-like receptor (TLR)4 has been implicated in the pathogenesis of free fatty acid (FFA)-induced insulin resistance by activating inflammatory pathways, including inhibitor kappaB (IkappaB)/nuclear factor (NFkappaB). However, it is not known whether insulin-resistant subjects have abnormal TLR4 signaling. We examined expression and TLR4-driven (IkappaB/NFkappaB) signaling skeletal muscle. RESEARCH DESIGN AND METHODS- gene protein content were measured muscle biopsies 7 lean, 8...

The effect of pioglitazone (PIO) on plasma adiponectin concentration, endogenous glucose production (EGP), and hepatic fat content (HFC) was studied in 11 type 2 diabetic patients (age, 52 ± yr; body mass index, 29.6 1.1 kg/m2; HbA1c, 7.8 0.4%). HFC (magnetic resonance spectroscopy) basal concentration were quantitated before after PIO (45 mg/d) for 16 wk. Subjects received a 3-h euglycemic insulin (100 mU/m2·min) clamp combined with 3-[3H] infusion to determine rates EGP tissue...

Activation of AMP-activated protein kinase (AMPK) by exercise induces several cellular processes in muscle. Exercise activation AMPK is unaffected lean (BMI ∼25 kg/m2) subjects with type 2 diabetes. However, most diabetic are obese >30 kg/m2), and stimulation blunted rodents. We examined whether have impaired AMPK, at different signaling levels, spanning from the upstream kinase, LKB1, to putative targets, AS160 peroxisome proliferator–activated receptor coactivator (PGC)-1α, involved...

The effect of pioglitazone on splanchnic glucose uptake (SGU), endogenous production (EGP), and hepatic fat content was studied in 14 type 2 diabetic patients (age 50 ± years, BMI 29.4 1.1 kg/m2, HbA1c 7.8 0.4%). Hepatic (magnetic resonance spectroscopy) SGU (oral load- insulin clamp technique) were quantitated before after (45 mg/day) therapy for 16 weeks. Subjects received a 7-h euglycemic (100 mU · m−2 min−1) clamp, 75-g oral load ingested 3 h starting the clamp. Following ingestion,...

To test our hypothesis that initiating therapy with a combination of agents known to improve insulin secretion and sensitivity in subjects new-onset diabetes would produce greater, more durable reduction glycated haemoglobin (HbA1c) levels, while avoiding hypoglycaemia weight gain, compared sequential addition lower plasma glucose but do not correct established pathophysiological abnormalities.Drug-naïve, recently diagnosed type 2 mellitus (T2DM) were randomized an open-fashion design...

We examined the contributions of insulin secretion, glucagon suppression, splanchnic and peripheral glucose metabolism, delayed gastric emptying to attenuation postprandial hyperglycemia during intravenous exenatide administration. Twelve subjects with type 2 diabetes (3 F/9 M, 44 +/- yr, BMI 34 4 kg/m2, Hb A(1c) 7.5 1.5%) participated in three meal-tolerance tests performed double tracer technique (iv [3-3H]glucose oral [1-14C]glucose): 1) iv saline (CON), 2) (EXE), 3) plus (E+G)....

Abstract Objective To examine whether lowering plasma glucose concentration with the sodium-glucose transporter-2 inhibitor empagliflozin improves β-cell function in patients type 2 diabetes mellitus (T2DM). Methods Patients T2DM (N = 15) received (25 mg/d) for weeks. β-Cell was measured a nine-step hyperglycemic clamp (each step, 40 mg/dL) before and at 48 hours 14 days after initiating empagliflozin. Results Glucosuria recorded on 1 [mean ± standard error of mean (SEM), 101 10 g 117 11 g,...

Previous studies indicating that postabsorptive renal glucose production is negligible used the net balance technique, which cannot partition simultaneous and glu- cose uptake. 10d after surgical placement of sampling cath- eters in left vein femoral artery a nonobstruc- tive infusion catheter dogs, systemic glycerol kinetics were measured with peripheral infusions 13-3Hjglucose [2-14Cjglycerol.After baseline measurements, animals received 2-h intrarenal either insulin (a = 6) or saline...

The authors investigated insulin secretory capacity and action in 11 preoperative patients with pancreatic carcinoma 15 age-matched weight-matched healthy subjects (C). Five were classified as diabetic (D), two impaired glucose tolerant (IGT), four nondiabetic (ND). Postabsorptive serum levels (mean ± SE, uU/ml) D (12 2), IGT (17 7), ND (10 2) comparable. After administration of 100 g oral glucose, peak achieved (60 11) was lower than (101 26) (83 20), whereas significantly (P < 0.05) higher...

Elevated plasma FFA cause beta-cell lipotoxicity and impair insulin secretion in nondiabetic subjects predisposed to type 2 diabetes mellitus [T2DM; i.e., with a strong family history of T2DM (FH+)] but not without T2DM. To determine whether lowering acipimox, an antilipolytic nicotinic acid derivative, may enhance secretion, nine FH+ volunteers were admitted twice received random order either acipimox or placebo (double-blind) for 48 h. Plasma glucose/insulin/C-peptide concentrations...

Glucagon‐like peptide 1 (GLP‐1) receptor agonists (GLP‐1‐RAs) act on multiple tissues, in addition to the pancreas. Recent studies suggest that GLP‐1‐RAs liver and adipose tissue reduce insulin resistance (IR). Thus, we evaluated acute effects of exenatide (EX) hepatic (Hep‐IR) (Adipo‐IR) glucose uptake. Fifteen male subjects (age = 56 ± 8 years; body mass index 29 kg/m 2 ; A1c 5.7 0.1%) were studied two occasions, with a double‐blind subcutaneous injection EX (5 μg) or placebo (PLC) 30...

In Brief Impaired insulin secretion, increased hepatic glucose production, and decreased peripheral utilization are the core defects responsible for development progression of type 2 diabetes. However, pathophysiology this disease also includes adipocyte resistance (increased lipolysis), reduced incretin secretion/sensitivity, glucagon enhanced renal reabsorption, brain resistance/neurotransmitter dysfunction. Although current diabetes management focuses on lowering blood glucose, goal...

To examine metabolic factors that influence ketone production after sodium-glucose cotransport inhibitor (SGLT2) administration.Fasting plasma glucose (FPG), insulin, glucagon, free fatty acid and concentrations were measured in 15 type 2 diabetes mellitus (T2DM) 16 non-diabetic subjects before at day 1 14 treatment with empagliflozin.Empagliflozin caused a 38 mg/dL reduction FPG concentration T2DM patients. However, it only small but significant (7 mg/dL) the impaired fasting (IFG) did not...

Peripheral edema, mild weight gain, and anemia are often observed in type II diabetic patients treated with thiazolidinediones (TZDs). Small decreases hemoglobin (Hb) hematocrit (Hct) appear to be a class effect of TZDs generally attributed fluid retention, although experimental data lacking. We analyzed 50 diabetes mellitus undergoing either placebo or pioglitazone (PIO, 45 mg/day) for 16 weeks. Before after therapy, we measured Hb/Hct used 3H2O bioimpedance quantitate total body water...

NF-κB is a transcription factor that controls the gene expression of several proinflammatory proteins. Cell culture and animal studies have implicated increased activity in pathogenesis insulin resistance muscle atrophy. However, it unclear whether insulin-resistant human subjects abnormal muscle. The effect exercise has on activity/signaling also not clear. We measured DNA-binding mRNA level putative NF-κB-regulated myokines interleukin (IL)-6 monocyte chemotactic protein-1 (MCP-1) samples...

To assess glucose-lowering mechanisms of sitagliptin (S), metformin (M), and the two combined (M+S).We randomized 16 patients with type 2 diabetes mellitus (T2DM) to four 6-week treatments placebo (P), M, S, M+S. After each period, subjects received a 6-h meal tolerance test (MTT) [(14)C]glucose calculate glucose kinetics. Fasting plasma (FPG), fasting insulin, C-peptide (insulin secretory rate [ISR]), glucagon, bioactive glucagon-like peptide (GLP-1) gastrointestinal insulinotropic (GIP)...

Renal glucose reabsorption was measured with the stepped hyperglycemic clamp in 15 subjects type 2 diabetes mellitus (T2DM) and without after days more chronic (14 days) treatment empagliflozin. Patients T2DM had significantly greater maximal renal transport (TmG) compared at baseline (459 ± 53 vs. 337 25 mg/min; P < 0.05). Empagliflozin for 48 h reduced TmG both individuals by 44 7 6%, respectively (both 0.001). further empagliflozin groups on day 14 (by 65 5 75 3%, respectively). plasma...