Quantitative insulin sensitivity check index is a useful indicator of insulin resistance in Japanese metabolically obese, normal-weight subjects with normal glucose tolerance.

To clarify whether quantitative insulin sensitivity check index (QUICKI) is useful as an indicator of insulin resistance in Japanese metabolically obese, normal-weight (MONW, body mass index (BMI) <25 and visceral fat area (VFA) > or = 100 cm2 by abdominal computed tomography scanning) subjects with normal glucose tolerance (NGT). Insulin resistance was measured by QUICKI and euglycemic hyperinsulinemic clamp study (clamp IR) in 27 MONW and 27 normal subjects (BMI <25 and visceral fat area <100 cm2). QUICKI (P<0.01) and clamp IR (p<0.01) were significantly decreased in MONW subjects compared with normal subjects. QUICKI was significantly associated with VFA [MONW subjects: r = -0.459, p<0.02; all (MONW and normal) subjects: r = -0.506, p<0.0001] and with the serum levels of triglycerides (MONW subjects: r = -0.386, p<0.05; all subjects: r = -0.505, p<0.001) in MONW and all subjects. There were significant correlations between clamp IR and VFA (MONW subjects: r = -0.562, p<0.01; all subjects: r = -0.575, p<0.0001), fasting serum levels of insulin (MONW subjects: r = -0.673, p<0.001; all subjects: r = -0.619, p<0.0001) or serum levels of triglycerides (MONW subjects: r = -0.485, p<0.02; all subjects: r = -0.565, p<0.0001) in MONW and all subjects. QUICKI was significantly correlated with clamp IR in MONW (r = 0.754, p<0.0001) and in all subjects (r = 0.568, p<0.0001). QUICKI may be an useful method for assessing insulin resistance in Japanese MONW subjects with NGT.

Metformin-induced suppression of glucose-6-phosphatase expression is independent of insulin signaling in rat hepatoma cells.

Metformin is thought to decrease blood glucose levels by reducing hepatic glucose output. To elucidate the pharmacological action of metformin on hepatic glucose production, we examined its effect on the gene expression of glucose-6-phosphatase (G6Pase), a key enzyme of gluconeogenesis, in H4IIE rat hepatoma cell line by RT-PCR and quantitative real-time PCR. Metformin suppressed dexamethasone/cAMP-induced expression of G6Pase mRNA in a dose dependent manner, its maximum effect being observed at 2 mM (79.3% inhibition, P<0.05). Pretreatment with the PI3-kinase inhibitor wortmannin, the MEK-1 inhibitor PD98059 or the protein kinase C inhibitor GF109203X had no effect on suppressed G6Pase expression by metformin. Moreover, metformin did not stimulate Akt phosphorylation. In the present study, we demonstrate that metformin suppresses G6Pase mRNA expression by a mechanism that is independent of the activation of PI3-kinase, Akt, MAP kinase and protein kinase C pathway in hepatocytes.

Circulating levels of active ghrelin is associated with abdominal adiposity, hyperinsulinemia and insulin resistance in patients with type 2 diabetes mellitus.

OBJECTIVE: To investigate the relationship between the circulating level of active ghrelin and abdominal adiposity, serum levels of insulin or insulin resistance in patients with type 2 diabetes mellitus. DESIGN: We measured the plasma levels of the active form of ghrelin in 18 obese and 18 nonobese patients with type 2 diabetes mellitus using a radioimmunoassay (RIA) kit. Body fat accumulation was measured by computed tomography (CT) and insulin resistance by the glucose infusion rate (GIR) during an euglycemic hyperinsulinemic clamp study. RESULTS: Plasma levels of ghrelin in obese patients with type 2 diabetes mellitus were significantly decreased compared with nonobese patients. There were significant correlations between the plasma levels of ghrelin and BMI (r=-0.505, P<0.01), visceral (r=-0.444, P<0.01), subcutaneous (r=-0.506, P<0.01) and total (r=-0.534, P<0.01) fat area, serum levels of insulin (r=-0.513, P<0.01) or GIR (r=0.478, P<0.01) in type 2 diabetic patients. The plasma level of ghrelin was significantly associated with serum levels of insulin (F=8.468, P<0.05) or GIR (F=8.522, P<0.05) after adjustment for BMI in patients with type 2 diabetes mellitus. CONCLUSIONS: Decreased plasma levels of active ghrelin are significantly associated with abdominal adiposity, hyperinsulinemia and insulin resistance in type 2 diabetic patients. Hyperinsulinemia associated with insulin resistance may suppress plasma levels of active ghrelin in patients with type 2 diabetes mellitus.

Oxidative stress is associated with adiposity and insulin resistance in men.

To investigate the direct relationship of oxidative stress with obesity and insulin resistance in men, we measured the plasma levels of 8-epi-prostaglandin F2alpha (PGF2alpha) in 14 obese and 17 nonobese men and evaluated their relationship with body mass index; body fat weight; visceral, sc, and total fat areas, measured by computed tomography; and glucose infusion rate during a euglycemic hyperinsulinemic clamp study. Obese men had significantly higher plasma concentrations of 8-epi-PGF2alpha than nonobese men (P < 0.05). The plasma levels of 8-epi-PGF2alpha were significantly correlated with body mass index (r = 0.408; P < 0.05), body fat weight (r = 0.467; P < 0.05), visceral (r = 0.387; P < 0.05) and total fat area (r = 0.359; P < 0.05) in all (obese and nonobese) men. There was also a significant correlation between the plasma levels of 8-epi-PGF2alpha and glucose infusion rate in obese men (r = -0.552; P < 0.05) and all men (r = -0.668; P < 0.01). In all subjects, the plasma levels of 8-epi-PGF2alpha were significantly correlated with fasting serum levels of insulin (r = 0.487; P < 0.01). In brief, these findings showed that the circulating levels of 8-epi-PGF2alpha are related to adiposity and insulin resistance in men. Although correlation does not prove causation, the results of this study suggest that obesity is an important factor for enhanced oxidative stress and that this oxidative stress triggers the development of insulin resistance in men.

Increased visceral fat and serum levels of triglyceride are associated with insulin resistance in Japanese metabolically obese, normal weight subjects with normal glucose tolerance.

OBJECTIVE: The purpose of this study was to investigate the association between visceral adiposity or triglyceride (TG) metabolism and insulin resistance in metabolically obese, normal weight (MONW) Japanese individuals with normal glucose tolerance. RESEARCH DESIGN AND METHODS: We evaluated body fat areas, lipid profiles, and the glucose infusion rate (GIR) during a euglycemic-hyperinsulinemic clamp study in 20 MONW subjects (BMI <25 kg/m(2)and visceral fat areas 100 cm(2)) with normal glucose tolerance. Body fat areas were measured by computed tomography scans. Control data were obtained from 20 normal subjects (BMI <25 kg/m(2) and visceral fat areas <100 cm(2)). RESULTS: MONW subjects showed a significant increase in fasting serum levels of TG (P < 0.01) and a decrease in GIR (P < 0.01) compared with normal subjects. There were significant correlations between visceral fat areas (r = -0.563, P < 0.01) or serum levels of TG (r = -0.474, P < 0.05) and GIR in MONW subjects. Multiple regression analyses showed that visceral fat areas (F = 7.702, P < 0.02) and serum levels of TG (F = 7.114, P < 0.05) were significantly associated with GIR in all (MONW and normal) subjects. CONCLUSIONS: Increased visceral fat and serum levels of TG are associated with insulin resistance in Japanese MONW subjects with normal glucose tolerance. Excess visceral fat and elevated TG levels may play important roles in the development of insulin resistance in Japanese MONW subjects with normal glucose tolerance.

Nitric oxide stimulates glucose transport through insulin-independent GLUT4 translocation in 3T3-L1 adipocytes.

OBJECTIVE: It is well known that nitric oxide synthase (NOS) is expressed and that it modulates glucose transport in skeletal muscles. Recent studies have shown that adipose tIssues also express inducible and endothelial nitric oxide synthase (eNOS). In the present study, we investigated whether nitric oxide (NO) induces glucose uptake in adipocytes, and the signaling pathway involved in the NO-stimulated glucose uptake in 3T3-L1 adipocytes. METHODS: First, we determined the expression of eNOS in 3T3-L1 adipocytes, and then these cells were treated with the NO donor sodium nitroprusside (SNP) and/or insulin, and glucose uptake and phosphorylation of insulin receptor substrate (IRS)-1 and Akt were evaluated. Moreover, we examined the effects of a NO scavenger, a guanylate cyclase inhibitor or dexamethasone on SNP-stimulated glucose uptake and GLUT4 translocation. RESULTS: SNP at a concentration of 50 mmol/l increased 2-deoxyglucose uptake (1.8-fold) without phosphorylation of IRS-1 and Akt. Treatment with the NO scavenger or guanylate cyclase inhibitor decreased SNP-stimulated glucose uptake to the basal level. Dexamethasone reduced both insulin- and SNP-stimulated glucose uptake with impairment of GLUT4 translocation. CONCLUSION: NO is capable of stimulating glucose transport through GLUT4 translocation in 3T3-L1 adipocytes, via a mechanism different from the insulin signaling pathway.

Increased plasma thrombin-activatable fibrinolysis inhibitor levels in normotensive type 2 diabetic patients with microalbuminuria.

Hypofibrinolysis is a common finding in patients with diabetes mellitus and a risk factor for diabetic nephropathy. Recently, a new potent inhibitor of fibrinolysis, the thrombin-activatable fibrinolysis inhibitor (TAFI), has been isolated from human plasma. The possibility that TAFI also participates in the mechanism of hypofibrinolysis has not been appraised in diabetic patients with microalbuminuria. In the present study, we investigated the plasma levels of TAFI and its relation to urinary albumin excretion in normotensive diabetic patients with normo- and microalbuminuria. Thirty-nine normotensive nonobese type 2 diabetic patients (27 with normoalbuminuria, 12 with microalbuminuria) and 20 age-matched normal subjects were enrolled in this study. The plasma level of thrombin-antithrombin complex was significantly increased (22.1 +/- 2.6 vs. 8.3 +/- 1.0 nmol/liter; P < 0.05), whereas the D-dimer/thrombin-antithrombin complex ratio was significantly decreased (15.7 +/- 1.4 vs. 26.5 +/- 2.2; P < 0.05), showing the occurrence of hypercoagulability and hypofibrinolysis in diabetic patients. The plasma level of TAFI in diabetic patients was significantly elevated, compared with normal subjects (147.4 +/- 11.6 vs. 99.5 +/- 4.9%; P < 0.05). The plasma level of TAFI in diabetic patients with microalbuminuria was significantly higher than the level in diabetic patients with normoalbuminuria (194.1 +/- 24.5 vs. 128.8 +/- 12.3%; P < 0.02) or normal subjects (194.1 +/- 24.5 vs. 99.5 +/- 4.9%; P < 0.005). Univariate analysis showed that the plasma TAFI levels are significantly and proportionally correlated with urinary albumin excretion rate (r = 0.58; P < 0.005) and with plasma soluble thrombomodulin level, a marker of endothelial cell damage, in all diabetic patients (r = 0.42; P < 0.01). These data suggest that increased plasma level of TAFI may be involved in the mechanism of vascular endothelial damage in patients with type 2 diabetes mellitus.

Neither homeostasis model assessment nor quantitative insulin sensitivity check index can predict insulin resistance in elderly patients with poorly controlled type 2 diabetes mellitus.

To clarify whether homeostasis model assessment (HOMA IR) and quantitative insulin sensitivity check index (QUICKI) may be indicators of insulin resistance in elderly patients with type 2 diabetes mellitus, their relationship with the glucose infusion rate during the euglycemic hyperinsulinemic clamp study (clamp IR) was assessed. This study comprised 56 Japanese patients with type 2 diabetes mellitus; of these, 28 were 70 yr of age or older (group 1) and 28 were less than 70 yr of age (group 2). Their blood sugars were in poor control (fasting plasma glucose levels: group 1, 9.0 +/- 2.6 mmol/liter; group 2, 8.9 +/- 2.3 mmol/liter; hemoglobin A1c: group 1, 9.5 +/- 2.0%; group 2, 9.2 +/- 1.7%). Log-transformed HOMA IR was significantly correlated with the clamp IR in group 2 patients (r = -0.51, P < 0.01), but not in group 1 patients (r = -0.28, P = 0.15). There was a significant positive correlation between QUICKI and clamp IR in group 2 patients (r = 0.50, P < 0.01). However, no significant correlation was observed between QUICKI and clamp IR in group 1 patients (r = 0.31, P = 0.12). There was a significant correlation between log-transformed HOMA IR (r = -0.37, P < 0.01) or QUICKI (r = 0.37, P < 0.01) and clamp IR when both groups were combined. In conclusion, neither HOMA IR nor QUICKI should be used as an index of insulin resistance in elderly patients with poorly controlled type 2 diabetes mellitus. The results of this study suggest the need for developing a new noninvasive method for evaluating insulin resistance in those patients.

QUICKI is useful for following improvements in insulin sensitivity after therapy in patients with type 2 diabetes mellitus.

To investigate whether quantitative insulin sensitivity check index (QUICKI) would be useful as an index of insulin resistance during the clinical course of type 2 diabetes mellitus, correlation between QUICKI and the index of the euglycemic hyperinsulinemic clamp study [clamp insulin resistance (clamp IR)] was evaluated in 60 patients with type 2 diabetes mellitus before and after treatment. The therapy program consisted of diet (1440-1720 kcal/d) and exercise (walking 10,000 steps daily) for 6 wk. QUICKI and clamp IR were significantly correlated before (r = 0.598, P < 0.0001) and after (r = 0.583, P < 0.0001) treatment. Neither the slope nor the intercept of the linear correlation between QUICKI and clamp IR measured before treatment was significantly different from those measured after treatment (slopes; F = 0.002, P = 0.96, intercepts; F = 2.65, P = 0.11). During treatment, the values of both QUICKI (8% change; P < 0.0001) and clamp IR (38% change; P < 0.0001) significantly increased and their changes were significantly correlated (r = 0.415, P < 0.01). In conclusion, QUICKI may become a useful method for the follow-up of insulin resistance during the treatment of patients with type 2 diabetes mellitus.

Acute hyperinsulinemia is associated with increased circulating levels of adrenomedullin in patients with type 2 diabetes mellitus.

OBJECTIVE: To investigate the effect of acute hyperinsulinemia on the plasma levels of adrenomedullin (AM) in patients with type 2 diabetes mellitus. DESIGN: We measured the plasma levels of AM in 18 patients with type 2 diabetes mellitus and in 19 normal subjects before and during a euglycemic hyperinsulinemic clamp study (the goal was for blood sugar levels of 5.24 mmol/l and insulin levels of 1200 pmol/l). Both plasma AM and serum insulin were measured by immunoradiometric assays. RESULTS: Before the glucose clamp study there was no significant difference in the plasma levels of AM between patients with type 2 diabetes mellitus and normal subjects. During the glucose clamp study, the serum levels of insulin significantly increased (from 33.0+/-3.6 to 1344.6+/-67.8 pmol/ml, P<0.001), as did the plasma levels of AM (from 12.8+/-0.7 to 14.2+/-0.9 fmol/ml, P<0.03) only in patients with type 2 diabetes mellitus. There was a significant correlation between the change in circulating levels of insulin and AM (r=0.755, P<0.01). CONCLUSIONS: Acute hyperinsulinemia induced a significant increase in the plasma levels of AM in patients with type 2 diabetes mellitus. Increased insulin may regulate circulating levels of AM in patients with type 2 diabetes mellitus.