Takashi Funayama

Effects of sitagliptin on ectopic fat contents and glucose metabolism in type 2 diabetic patients with fatty liver: A pilot study

Recent data have shown that ectopic fat accumulation in the liver worsens hepatic glucose metabolism, suggesting that fatty liver in patients with type 2 diabetes is a therapeutic target. Glucagon‐like peptide (GLP)‐1 improves fatty liver, but the effect of dipeptidyl peptidase‐4 inhibitor on fatty liver is still unclear. The present pilot study determined the effects of 12‐week treatment with sitagliptin, a dipeptidyl peptidase‐4 inhibitor, on liver fat content in type 2 diabetes with fatty liver. We also evaluated intramyocellular lipid (IMCL) and glucose kinetics during oral glucose tolerance test (OGTT) before and after the treatment.

Association Between Expression of FABPpm in Skeletal Muscle and Insulin Sensitivity in Intramyocellular Lipid-Accumulated Nonobese Men

CONTEXT Intramyocellular lipid (IMCL) accumulation is observed in both insulin-resistant subjects and insulin-sensitive endurance athletes (athletes paradox). We hypothesized that the expression pattern of fatty acid transporters may influence oxidative capacity and determine the association between IMCL and insulin resistance. OBJECTIVE The objective of the study was to investigate the muscle expression of fatty acid transporters and their function related to insulin sensitivity in IMCL-accumulated subjects. DESIGN AND SETTING The study subjects were 36 nonobese healthy men. Their IMCL levels were measured by (1)H-magnetic resonance spectroscopy, and their insulin sensitivity was evaluated by steady-state glucose infusion rate (GIR) during a euglycemic-hyperinsulinemic clamp. Gene expression levels in the vastus lateralis were evaluated by quantitative RT-PCR. We compared the clinical phenotypes and the expression levels of genes involved in lipid metabolism in skeletal muscle between IMCL-accumulated high-GIR (H-GIR) subjects (n = 8) and low-GIR subjects (n = 9). The functions of candidate fatty acid transporters were determined by in vitro analyses. RESULTS Compared with the low-GIR group, body fat was lower and maximum oxygen uptake was higher in the H-GIR group. Several lipid oxidation genes in muscle were up-regulated in the H-GIR group, and this was associated with increased expression of higher plasma membrane-associated fatty acid-binding protein (FABPpm) and decreased expression of fatty acid transport protein (FATP)-1. Overexpression of FABPpm in C2C12 myotubes increased fatty acid oxidation coupled with the elevated expression of genes related to fatty acid oxidation. These changes were not observed in FATP1-overexpressed myotubes. CONCLUSIONS Differences in the gene expression of fatty acid transporters may, at least in part, affect insulin sensitivity in IMCL-accumulated nonobese men.

Correlates of insulin clearance in apparently healthy non-obese Japanese men

Hyperinsulinemia observed in obese subject is caused at least in part by low metabolic clearance rate of insulin (MCRI). However, the determinants of MCRI in non-obese subjects are not fully understood. To investigate the correlates of MCRI in healthy non-obese men (BMI <25 kg/m2), we studied 49 non-obese Japanese men free of cardiometabolic risk factors. Using a 2-step hyperinsulinemic euglycemic clamp, we evaluated MCRI and insulin sensitivity. We also calculated the rate of glucose disappearance (Rd) during the clamp and muscle insulin sensitivity was defined as Rd/steady state serum insulin (SSSI) at the second step. Based on the median value of MCRI, the subjects were divided into the low- and high-MCRI groups. Subjects of the low-MCRI group had significant impairment of muscle insulin sensitivity, although Rd levels were comparable between the two groups, probably due to elevated SSSI in the low-MCRI group. Subjects of the low-MCRI group had higher total body fat content and lower VO2peak and showed no deterioration of cardiometabolic risk factors. Our results suggest that low MCRI may be early change to maintain glucose uptake and metabolic status in the face of slight impairment of muscle insulin sensitivity caused by increased adiposity and lower fitness level.

Characteristics of hepatic insulin‐sensitive nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) plays a crucial role in type 2 diabetes and hepatocellular carcinoma. The major underlying pathogenesis is hepatic insulin resistance. The aim of the present study was to characterize patients with NAFLD with paradoxically normal hepatic insulin sensitivity relative to patients with NAFLD with hepatic insulin resistance. We recruited 26 patients with NAFLD and divided them into three groups ranked by the level of hepatic insulin sensitivity (HIS; high‐HIS, mid‐HIS, low‐HIS), as assessed by the hyperinsulinemic‐euglycemic clamp studies using stable isotope. Hepatic insulin sensitivity of the high‐HIS group was identical to that of the non‐NAFLD lean control (clamped percent suppression of endogenous glucose production, 91.1% ± 5.2% versus 91.0% ± 8.5%, respectively) and was significantly higher than that of the low‐HIS group (66.6% ± 7.5%; P < 0.01). Adiposity (subcutaneous, visceral, intrahepatic, and muscular lipid content), hepatic histopathology, and expression levels of various genes by using liver biopsies, muscle, and adipose tissue insulin sensitivity, plasma metabolites by metabolomics analysis, putative biomarkers, and lifestyles were assessed and compared between the high‐HIS and low‐HIS groups. Among these, adipose tissue insulin sensitivity assessed by clamped percent suppression of free fatty acid, serum high molecular weight adiponectin, and plasma tricarboxylic acid cycle metabolites, such as citric acid and cis‐aconitic acid, were significantly higher in the high‐HIS group compared to the low‐HIS group. In contrast, there were no differences in adiposity, including intrahepatic lipid content assessed by proton magnetic resonance spectroscopy (28.3% ± 16.1% versus 20.4% ± 9.9%, respectively), hepatic histopathology, other putative biomarkers, and lifestyles. Conclusion: High levels of adipose tissue insulin sensitivity, serum high molecular weight adiponectin, and plasma tricarboxylic acid cycle metabolites are unique characteristics that define patients with hepatic insulin‐sensitive NAFLD regardless of intrahepatic lipid content. (Hepatology Communications 2017;1:634–647)

Increased intramyocellular lipid/impaired insulin sensitivity is associated with altered lipid metabolic genes in muscle of high responders to a high-fat diet

The accumulation of intramyocellular lipid (IMCL) is recognized as an important determinant of insulin resistance, and is increased by a high-fat diet (HFD). However, the effects of HFD on IMCL and insulin sensitivity are highly variable. The aim of this study was to identify the genes in muscle that are related to this inter-individual variation. Fifty healthy men were recruited for this study. Before and after HFD for 3 days, IMCL levels in the tibialis anterior were measured by (1)H magnetic resonance spectroscopy, and peripheral insulin sensitivity was evaluated by glucose infusion rate (GIR) during the euglycemic-hyperinsulinemic clamp. Subjects who showed a large increase in IMCL and a large decrease in GIR by HFD were classified as high responders (HRs), and subjects who showed a small increase in IMCL and a small decrease in GIR were classified as low responders (LRs). In five subjects from each group, the gene expression profile of the vastus lateralis muscle was analyzed by DNA microarray analysis. Before HFD, gene expression profiles related to lipid metabolism were comparable between the two groups. Gene Set Enrichment Analysis demonstrated that five gene sets related to lipid metabolism were upregulated by HFD in the HR group but not in the LR group. Changes in gene expression patterns were confirmed by qRT-PCR using more samples (LR, n = 9; HR, n = 11). These results suggest that IMCL accumulation/impaired insulin sensitivity after HFD is closely associated with changes in the expression of genes related to lipid metabolism in muscle.

Impaired peripheral insulin sensitivity in non-obese Japanese patients with type 2 diabetes mellitus and fatty liver

Type two diabetes mellitus and fatty liver (FL) are not uncommon in Asians with normal body mass index. Previous studies reported a link between FL and insulin resistance. Thus, FL could coexist with insulin resistance in Asian type two diabetes mellitus patients with a normal body mass index. However, the clinical and metabolic features of such patients have not been characterized yet.

Characteristics of Glucose Metabolism in Underweight Japanese Women

Abstract Context Japanese women have substantially lower body mass index (BMI) than women in other developed countries. The BMI of Japanese women has steadily decreased over time. However, glucose metabolism in underweight Japanese women has not been fully characterized. Objective The aim of this study was to investigate glucose metabolism and the physical characteristics of underweight Japanese women. Design and Participants We recruited 31 young (20 to 29 years of age) and 30 postmenopausal (50 to 65 years of age) underweight women. We also recruited young normal-weight women (n = 13) and postmenopausal normal-weight women (n = 10) to serve as references. We administered an oral glucose tolerance test (OGTT) and evaluated intramyocellular lipid (IMCL) levels and body composition using 1H-magnetic resonance spectroscopy and dual-energy X-ray absorptiometry, respectively. Results Young underweight women had similar glucose tolerance as young normal-weight women. However, postmenopausal underweight women had a higher area under the curve (AUC) for glucose during OGTT than postmenopausal normal-weight women. In postmenopausal underweight women, 2-hour glucose levels during OGTT were negatively correlated with lean body mass (r = −0.55, P < 0.01) and insulinogenic index (r = −0.42, P = 0.02) and were positively correlated with IMCL levels (r = 0.40, P = 0.03). Compared with young underweight women, postmenopausal underweight women had a higher AUC for glucose during OGTT and a lower insulinogenic index and AUC for insulin during OGTT. Conclusions Postmenopausal underweight women had more impaired glucose tolerance than young underweight women. In postmenopausal underweight women, the degree of glucose tolerance impairment was associated with decreased lean body mass, increased IMCL accumulation, and impaired insulin secretion.

Effects of alcohol abstinence on glucose metabolism in Japanese men with elevated fasting glucose: A pilot study

It has been demonstrated that moderate alcohol consumption provides protection against the development of type 2 diabetes. However, several other reports suggested that moderate alcohol intake may increase the risk of type 2 diabetes in non-obese Japanese. The aim of present study was to investigate the effect of 1-week alcohol abstinence on hepatic insulin sensitivity and fasting plasma glucose (FPG) in non-obese Japanese men. We recruited 8 non-obese Japanese men with mildly elevated FPG and drinking habits alcohol (mean frequency; 5.6 ± 2.5 times/week, mean alcohol consumption; 32.1 ± 20.0 g/day). Before and after the 1-week alcohol abstinence, we used the 2-step hyperinsulinemic-euglycemic clamp to measure endogenous glucose production (EGP) and insulin sensitivity (IS) in muscle and liver. One-week alcohol abstinence significantly reduced both FPG by 7% (from 105.5 ± 11.7 to 98.2 ± 7.8 mg/dl, P < 0.01) and fasting EGP by 6% (from 84.1 ± 4.2 to 77.6 ± 1.6 mg/m2 per min, P < 0.01), respectively. Two–step clamp study showed that alcohol abstinence significantly improved hepatic-IS, but not muscle-IS. In conclusion, one week alcohol abstinence improved hepatic IS and FPG in non-obese Japanese men with mildly elevated FPG and drinking habits alcohol.