Intake of n-3 polyunsaturated fatty acids and non-alcoholic fatty liver disease: a cross-sectional study in Japanese men and women.

BACKGROUND/OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is a common condition, in which abnormal amounts of triglycerides accumulate in hepatocytes and is closely related to cardiovascular diseases and diabetes. Dietary fats contribute 15% of fat accumulation in the liver and regulate hepatic lipid metabolism. The supplementation of n-3 polyunsaturated fatty acids (n-3 PUFAs) improves NAFLD. The aim of this study is to assess the cross-sectional association between dietary n-3 PUFAs and NAFLD in Japanese men and women. SUBJECTS/METHODS: Participants were middle-aged, apparently healthy, 296 men and 496 women, who did not drink alcohol and who participated in a general health check-up program. Dietary information from the previous month was obtained by the brief-type self-administered diet history questionnaire. NAFLD was diagnosed if abdominal ultrasonography revealed the presence of fatty liver. RESULTS: The prevalence of NAFLD was 45.3% in men and 17.5% in women. In comparison with the first tertile, multivariate adjusted odds ratios (95% confidence intervals) for the presence of NAFLD in the second and third tertiles for men taking eicosapentaenoic acid (EPA) were 0.59 (0.31-1.14) and 0.45 (0.23-0.90), respectively, (P for linear trend=0.024), and the multivariate adjusted odds ratios (95% confidence intervals) for the presence of NAFLD in the second and third tertiles for men taking EPA+docosahexaenoic acid (DHA) were 0.44 (0.23-0.86) and 0.48 (0.24-0.95), respectively, (P for linear trend=0.035). However, there was no significant relation between NAFLD and each of these nutrients in women. CONCLUSIONS: Dietary EPA and EPA+DHA may be independent and preventive nutrients for NAFLD in Japanese men.

Prevalence of non-alcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults.

AIMS: To assess the prevalence of non-alcoholic fatty liver disease (NAFLD) and its association with impaired glucose metabolism in Japanese subjects. METHODS: One thousand, nine hundred and fifty subjects enrolled in a general health examination programme from September 2002 to February 2003 were recruited. NAFLD was diagnosed if a person showed 'fatty liver' on ultrasonography, and his/her alcohol consumption, estimated by questionnaire, was < 40 gram/week. A general linear model was used for the comparison of estimated means of metabolic variables adjusted for age and body mass index (BMI) between subjects with NAFLD and those without fatty liver. Multivariate regression with fasting plasma glucose (FPG) as the dependent variable was performed in 1547 non-diabetic individuals after adjusting for age, gender, BMI and NAFLD. RESULTS: NAFLD was found in 566 of the 1950 health-check examinees (29%). Its prevalence increased with increasing FPG levels: 27% in the subgroup with normal fasting glucose, 43% in impaired fasting glucose and 62% in newly diagnosed diabetes. Adjusted means of FPG, HbA1c, triglyceride, total protein, albumin, AST and ALT were all significantly higher, while adjusted means of HDL cholesterol and AST/ALT ratio were significantly lower in subjects with NAFLD than those without fatty liver. Multivariate regression analysis showed that NAFLD was independently associated with increasing FPG in non-diabetic individuals. CONCLUSIONS: The prevalence of NAFLD was 29% in apparently healthy middle-aged Japanese adults and NAFLD was independently associated with impaired glucose metabolism.

ATP-Sensitive potassium channels modulate glucose transport in cultured human skeletal muscle cells.

Several lines of evidence suggest that ATP-sensitive potassium (KATP) channels are involved in glucose uptake by insulin target tissues. The aim of the present study was to prove directly the effect of KATP channel activity on glucose transport into cultured human skeletal muscle cells. We used potassium channel openers PCO-400 and nicorandil alone or in combination with channel blockers glibenclamide and gliclazide to examine their effects on insulin- or high glucose concentration-induced glucose uptake using 2-deoxy-D-3H-glucose or 3-O-methyl-D-3H-glucose as tracer, respectively. PCO-400 inhibited the basal (non-stimulated) uptake of 2-DG or 3-OMG at the glucose concentration of 5 mM. PCO-400 and nicorandil dose-dependently inhibited insulin-stimulated glucose uptake, and their inhibitory effects were reversed by glibenclamide or gliclazide. In addition, PCO-400 inhibited high glucose concentration-facilitated glucose transport in the absence of insulin, and this effect was also antagonized by both sulfonylurea drugs. Regarding the mechanism by which KATP channels modulate glucose transport, we focused on protein kinase C (PKC), because PKC has been supposed to participate in both insulin- and high glucose concentration-stimulated glucose transport. PMA (phorbol 12-myristate 13-acetate) dose-dependently reversed the PCO-400-induced suppression of insulin-stimulated glucose uptake. On the other hand, PCO-400 at the concentration that inhibited glucose uptake caused no alteration of membrane-associated PKC activity in the presence of insulin or PMA. From these results we conclude that KATP channels modulate the basal and insulin-or high glucose level-stimulated glucose transport in skeletal muscle through a mechanism independent of PKC.

Characterization of an early decline in baseline plasma glucose concentration after acute insulin elevation during euglycemic hyperinsulinemic clamp in patients with type 2 diabetes mellitus.

To investigate the contribution of the liver to whole-body insulin resistance in patients with type 2 diabetes mellitus, we analyzed the early decline (slope "a") in the baseline plasma glucose level following acute hyperinsulinemia in the initial phase of a euglycemic hyperinsulinemic clamp study, rather than using an isotope-dilution method. Slope "a" was comparable among groups of diabetic and non-diabetic subjects, and did not correlate well with glucose infusion rate (GIR), an index of peripheral (primarily skeletal muscle) insulin resistance. In contrast, slope "a" was significantly lower in obese (BMI > 25) type 2 diabetic patients compared with their non-obese counterparts, consistent with the general belief that obesity is a condition of insulin resistance in liver as well as in peripheral tissues. A subset of six insulin-resistant (nearly zero GIR) type 2 diabetic patients (pubertal adolescents) demonstrated a markedly blunted slope "a". Their insulin resistance (GIR) substantially recovered concomitant with an increase in slope "a" after pretreatment with somatostatin analogue in two cases studied, suggesting possible suppression of hepatic glucose production through lowering of plasma glucagon concentrations. Furthermore, slope "a" correlated significantly (r = -0.480, p<0.0001) with HOMA index (FPG x FIRI), the latter being recently regarded as an index of hepatic insulin resistance. These data showed that slope "a" obtained from euglycemic hyperinsulinemic clamp may be a clinically useful index of hepatic insulin resistance rather than an index of peripheral insulin resistance.

[Insulin sensitizer and urate metabolism].

Gout patients often have various characteristics of insulin resistance (IR) syndrome such as glucose intolerance, hyperlipidemia, hypertension and obesity. In addition, epidemiological data suggest that hyperuricemia is associated with higher rates of death due to cardiovascular and cerebrovascular disorders. However, it has not conclusively been shown whether the association between hyperuricemia and increased death rate is secondary to the association between IR and death or hyperuricemia itself is an independent risk of death. It is of interest to examine the effects of insulin sensitizer which was developed recently on serum urate concentration because it may provide a new idea as to the mechanism of the association between IR, hyperuricemia and vascular disorders. In the present paper, we discuss the relevance of IR to hyperuricemia and gout, and show the data of urate and glucose metabolism obtained from control subjects or the patients with hyperuricemia, gout or type 2 diabetes.

Adenosine triphosphate-sensitive potassium channels are involved in insulin-mediated glucose transport in humans.

We investigated the influence of treatment with nicorandil, a K-channel opener currently used for angina, on glucose homeostasis in patients with non-insulin-dependent diabetes mellitus (NIDDM) and coronary artery disease (CAD). Adenosine triphosphate (ATP)-sensitive K (K-ATP) channels are present in various tissues, including pancreatic B cells and skeletal muscle, and are the putative targets of this agent. Nine NIDDM patients with CAD and five healthy subjects participated in the study. Fasting plasma levels (mean+/-SEM) of glucose (144+/-11 to 180+/-22 mg/dL, P<.05) and insulin (5.8+/-1.6 to 7.0+/-1.8 microU/mL, P<.05) and hemoglobin A1c (7.54+/-0.47 to 8.11+/-0.55%, P<.01) increased significantly in nine NIDDM patients after treatment with nicorandil at a dose of 5 mg three times daily for 2 to 8 months. Glucose tolerance as examined by an identical meal test deteriorated (P<.001), but the insulin response did not change significantly. A washout of nicorandil for 1 to 4 months restored glucose tolerance almost to pretreatment levels in four patients. A 5- to 7-day trial of nicorandil (5 mg three times daily) in five healthy subjects resulted in a marginal to twofold increase in fasting plasma insulin, reflecting the progression of insulin resistance. In addition, three healthy subjects showed a substantial reduction in the glucose infusion rate (GIR) required in the euglycemic-hyperinsulinemic clamp study. Since the therapeutic dose of nicorandil did not affect pancreatic B-cell function but caused insulin resistance in both healthy and NIDDM subjects, we conclude that K-ATP channels play a regulatory role in insulin-mediated glucose transport in humans.

Plasma concentration of immunoreactive vascular endothelial growth factor and its relation to smoking.

We determined the plasma concentration of immunoreactive vascular endothelial growth factor (IR-VEGF) and searched for a relationship between it and the degree of microangiopathy. The plasma VEGF level was measured using an enzyme immunoassay in 110 non-insulin-dependent diabetes mellitus (NIDDM) patients with varying degrees of nephropathy or retinopathy (RP) and in 39 healthy controls and 30 nondiabetic patients for comparison. One fourth of the control subjects, 60% of whom were currently smokers, had plasma levels of IR-VEGF higher than the lower limit (15.6 pg/mL) of detection for this assay, whereas this was the case in half of the NIDDM patients. Plasma IR-VEGF was detectable in all patients with cerebral infarction, chronic renal failure, and severe infection, suggesting that tissue hypoxia might be a common cause for the elevation of plasma VEGF in these disorders. The prevalence of measurable plasma IR-VEGF levels increased in parallel with increases in the urinary albumin excretion rate ([UAER] 35.1% for UAER <30 mg/24 h, 54.8% for UAER 30 to 300 mg/24 h, and 61.3% for UAER >300 mg/24 h; P < .05 v UAER <30 mg/24 h). The mean measurable plasma concentration tended to increase with increasing UAER. However, there was no such correlation with the severity of RP. Smoking caused an acute increase of plasma IR-VEGF in only 22.6% (12 of 53) of the patients with a smoking habit. In conclusion, these findings suggest that circulating IR-VEGF may be linked to the progression of nephropathy, and smoking may facilitate this process by causing tissue hypoxia in susceptible patients.

Assessment of insulin resistance in acromegaly associated with diabetes mellitus before and after transsphenoidal adenomectomy.

With a euglycemic hyperinsulinemic clamp method, whole-body insulin resistance was assessed in 6 cases with acromegaly associated with diabetes mellitus before and after transsphenoidal adenomectomy. The glucose infusion rate (GIR) correlated well with the plasma IGF-I level but poorly with that of GH. Further improvement in insulin sensitivity occurred 3-4 months after operation without substantial changes in plasma levels of both GH and IGF-I or glycemic control. These results indicate that GH excess can induce insulin resistance in association with plasma IGF-I and also through undefined secondary effect.

Urinary albumin excretion rate is related to insulin resistance in normotensive subjects with impaired glucose tolerance.

Microalbuminuria has been reported to precede the development of NIDDM and to be a risk marker for cardiovascular disease. Therefore, the present study investigated the relationship between urinary albumin excretion rate (UAER) and the degree of insulin resistance in Japanese subjects with impaired glucose tolerance (IGT). Thirty-three normotensive IGT subjects were divided into three groups and twenty hypertensive IGT subjects were divided into two groups according to the degree of insulin resistance (GIR value) estimated by the euglycemic hyperinsulinemic clamp method. UAER was significantly higher in the lower GIR group in normotensive subjects (highest GIR group, 6.6 +/- 0.9 mg/24 h; intermediate group, 10.5 +/- 3.0 mg/24 h; lowest group, 21.3 +/- 3.8 mg/24 h; P<0.01 between highest and both of the other groups), but not in hypertensive subjects. The lowest GIR was associated with higher fasting plasma insulin, increased insulin response to glucose, higher plasma triglyceride and uric acid, and lower high-density-lipoprotein cholesterol, but not with increased creatinine clearance rate in normotensive subjects. A similar tendency was also found in hypertensive subjects. It is concluded that UAER is related to insulin resistance in normotensive subjects with IGT through a mechanism other than glomerular hyperfiltration.