ALDH2 rs671 Is Associated With Elevated FPG, Reduced Glucose Clearance and Hepatic Insulin Resistance in Japanese Men.

CONTEXT: A recent meta-analysis of genome-wide association studies data from East Asians identified aldehyde dehydrogenase 2 (ALDH2) rs671 as a susceptibility variant for type 2 diabetes in males. OBJECTIVE: To investigate the association between ALDH2 rs671 and metabolic characteristics. METHODS: We studied 94 nonobese, nondiabetic, Japanese men. Using a 2-step hyperinsulinemic-euglycemic clamp, we evaluated insulin sensitivity in muscle and liver. Intrahepatic lipid and fat distribution were measured using 1H-magnetic resonance spectroscopy and magnetic resonance imaging, respectively. We divided participants into a risk-carrying group with ALDH2 rs671 G/G (n = 53) and a nonrisk-carrying group with ALDH2 rs671 G/A or A/A (n = 41). RESULTS: The risk-carrying group had significantly higher levels of alcohol consumption (18.4 [interquartile range, IQR, 10.4-48.9]) vs 12.1 (IQR, 1.3-29.0) g/day; P = .003), elevated fasting plasma glucose (FPG) (97.5 ±â€…7.9 vs 93.5 ±â€…6.2 mg/dL; P = .010), lower hepatic insulin sensitivity (61.7 ±â€…20.5% vs 73.1 ±â€…15.9%; P = .003), and lower fasting glucose clearance (0.84 ±â€…0.8 dL·m-2·min-1 vs 0.87 ±â€…0.09 dL·m-2·min-1; P = .047) than the nonrisk-carrying group, while insulin resistance in muscle and body fat distribution were similar. The single linear correlation analysis revealed significant correlations between alcohol consumption and hepatic insulin sensitivity (r = -0.262, P = .011), fasting glucose clearance (r = -0.370, P < .001), or FPG (r = 0.489, P < .001). The multiple regression analysis revealed that both ALDH2 rs671 G/G genotype and alcohol consumption were significant independent correlates for hepatic insulin sensitivity, whereas only alcohol consumption was a significant independent correlate for fasting glucose clearance. CONCLUSION: Our data suggest that high-alcohol intake-dependent and independent hepatic insulin resistance and reduced fasting glucose clearance due to high alcohol intake could be a relatively upstream metabolic abnormality in ALDH2 rs671 G/G carriers.

Adipose Insulin Resistance and Decreased Adiponectin Are Correlated With Metabolic Abnormalities in Nonobese Men.

CONTEXT: Adipose tissue dysfunction is characterized by decreased adiponectin (AN) levels and impaired adipose tissue insulin sensitivity (ATIS) and is associated with metabolic disorders. While Asians readily develop metabolic disease without obesity, it remains unclear how decreased AN level and impaired ATIS affect metabolic abnormalities in nonobese Asians. DESIGN AND SETTING: To investigate the relationships between decreased AN level, impaired ATIS, and metabolic abnormalities, we studied 94 Japanese men whose body mass index was less than 25 kg/m2. We divided the subjects into 4 groups based on their median AN level and ATIS, the latter calculated as the degree of insulin-mediated suppression of free fatty acids during hyperinsulinemic euglycemic clamp, and compared the metabolic parameters in the 4 groups. RESULTS: The High-ATIS/High-AN group (n = 29) showed similar anthropometric data to the High-ATIS/Low-AN group (n = 18). In contrast, both the Low-ATIS/High-AN (n = 18) and Low-ATIS/Low-AN (n = 29) groups showed significantly lower muscle insulin sensitivity than the High-ATIS groups. The intrahepatic lipid level in the Low-ATIS/Low-AN group was significantly higher than that in the High-ATIS groups. In addition, the Low-ATIS/Low-AN group had a significantly higher fasting serum triglyceride level and significantly lower high-density lipoprotein cholesterol level than the other 3 groups. CONCLUSIONS: In nonobese Japanese men with high ATIS, the AN level was not associated with metabolic characteristics. On the other hand, subjects with low ATIS showed reduced muscle insulin sensitivity, and those with a decreased AN level demonstrated multiple metabolic abnormalities, represented by fatty liver and dyslipidemia.

Endurance Runners with Intramyocellular Lipid Accumulation and High Insulin Sensitivity Have Enhanced Expression of Genes Related to Lipid Metabolism in Muscle.

CONTEXT: Endurance-trained athletes have high oxidative capacities, enhanced insulin sensitivities, and high intracellular lipid accumulation in muscle. These characteristics are likely due to altered gene expression levels in muscle. DESIGN AND SETTING: We compared intramyocellular lipid (IMCL), insulin sensitivity, and gene expression levels of the muscle in eight nonobese healthy men (control group) and seven male endurance athletes (athlete group). Their IMCL levels were measured by proton-magnetic resonance spectroscopy, and their insulin sensitivity was evaluated by glucose infusion rate (GIR) during a euglycemic-hyperinsulinemic clamp. Gene expression levels in the vastus lateralis were evaluated by quantitative RT-PCR (qRT-PCR) and microarray analysis. RESULTS: IMCL levels in the tibialis anterior muscle were approximately 2.5 times higher in the athlete group compared to the control group, while the IMCL levels in the soleus muscle and GIR were comparable. In the microarray hierarchical clustering analysis, gene expression patterns were not clearly divided into control and athlete groups. In a gene set enrichment analysis with Gene Ontology gene sets, "RESPONSE TO LIPID" was significantly upregulated in the athlete group compared with the control group. Indeed, qRT-PCR analysis revealed that, compared to the control group, the athlete group had 2-3 times higher expressions of proliferator-activated receptor gamma coactivator-1 alpha (PGC1A), adiponectin receptors (AdipoRs), and fatty acid transporters including fatty acid transporter-1, plasma membrane-associated fatty acid binding protein, and lipoprotein lipase. CONCLUSIONS: Endurance runners with higher IMCL levels have higher expression levels of genes related to lipid metabolism such as PGC1A, AdipoRs, and fatty acid transporters in muscle.

Decreased Muscle Strength of Knee Flexors is Associated with Impaired Muscle Insulin Sensitivity in Non-Diabetic Middle-Aged Japanese Male Subjects.

INTRODUCTION: Reduced muscle strength is a high risk factor for type 2 diabetes mellitus, and this association is especially strong in non-obese male individuals. However, it remains unclear how reduced muscle strength affects susceptibility to diabetes. We have examined whether lower limb muscle strength is associated with insulin resistance in non-obese Japanese male subjects. METHODS: Measurements from 64 non-diabetic, non-obese, middle-aged Japanese men were analyzed. Insulin sensitivity in muscle was measured using the hyperinsulinemic-euglycemic clamp. Isometric muscle strength of the knee extensor and flexor muscles was evaluated using a dynameter. RESULTS: Lower muscle strength of knee flexors, but not knee extensors, was associated with impaired muscle insulin sensitivity (knee flexor muscles: low, medium, and high strength was 6.6 ± 2.2, 7.3 ± 2.0, and 8.8 ± 2.2 mg/kg per minute, respectively, p for trend < 0.05; knee extensor muscles: low, medium, and high strength was 7.3 ± 2.5, 7.5 ± 2.2, and 7.8 ± 2.3 mg/kg per minute, respectively, p for trend = 0.73). Knee flexor muscle strength was also identified as an independent determinant of insulin sensitivity in the multiple regression analysis (ß = 0.274, p = 0.036). CONCLUSIONS: Diminished strength of knee flexor muscles, but not knee extensor muscles, was associated with muscle insulin sensitivity in non-diabetic, non-obese Japanese male subjects.

Effects of blood flow restriction on muscle size and gene expression in muscle during immobilization: A pilot study.

PURPOSE: Muscle mass is known to rapidly decrease with muscle disuse. Previous reports suggest that repetitive blood flow restriction (BFR) mitigates the reduction of muscle mass with disuse. However, the effects of BFR on muscle atrophy and gene expression levels in muscle during cast immobilization have not been clarified. METHODS: To investigate the effect of BFR on muscle atrophy and gene expression levels during cast immobilization in humans, we recruited 10 healthy males who were randomly divided into the control and BFR treatment groups. All subjects were immobilized with a cast for 14 days. BFR treatment was conducted only in the BFR group. We evaluated cross sectional area (CSA) of thigh muscles by magnetic resonance imaging before and 14 days after cast immobilization. A percutaneous biopsy of the vastus lateralis muscle (VL) was performed before and 1, 7, and 14 days after cast immobilization. Expression of genes related to muscle atrophy and synthesis were evaluated using real-time PCR. RESULTS: The CSA of the VL and the thigh flexor muscles were significantly decreased in both groups; however, percent decrease in CSA was significantly smaller in the BFR group compared with the control group. In two-way repeated ANOVA analysis, the time × treatment interaction in gene expression of the muscle-specific ubiquitin ligases muscle ring finger 1 (MuRF1) was significant, and elevated MURF1 expression level by cast immobilization was seemed to be suppressed by the BFR treatment. CONCLUSION: BFR treatment may prevent reduced VL and thigh flexor muscles and increased MuRF1 expression level during cast immobilization. Further study is required to confirm these results.

Both higher fitness level and higher current physical activity level may be required for intramyocellular lipid accumulation in non-athlete men.

Accumulation of intramyocellular lipid (IMCL) is observed in individuals with insulin resistance as well as insulin-sensitive endurance athletes with high peak oxygen consumption (VO2peak), which is called the athlete's paradox. It remains unclear whether non-athletes with higher fitness levels have IMCL accumulation and higher insulin sensitivity in general. In this study, we investigated the association between IMCL accumulation and muscle insulin sensitivity (M-IS) in subjects with high or low VO2peak. We studied 61 nonobese (BMI, 23 to 25 kg/m2), non-athlete Japanese men. We divided the subjects into four groups based on the median value of VO2peak and IMCL in the soleus muscle. We evaluated M-IS using a two-step hyperinsulinemic-euglycemic clamp. Among subjects with higher VO2peak (n = 32), half of those (n = 16) had lower IMCL levels. Both High-VO2peak groups had higher M-IS than the Low-VO2peak groups. On the other hand, M-IS was comparable between the High-VO2peak/High-IMCL and High-VO2peak/Low-IMCL groups, whereas the High-VO2peak/High-IMCL group had IMCL levels that were twice as high as those in the High-VO2peak/Low-IMCL group. On the other hand, the High-VO2peak/High-IMCL group had significantly higher physical activity levels (approximately 1.8-fold) than the other three groups. In conclusion, in nonobese, non-athlete Japanese men, subjects with higher VO2peak and higher IMCL had higher physical activity levels. IMCL accumulation is not associated with insulin resistance in individuals with higher or lower fitness levels.

Characteristics associated with elevated 1-h plasma glucose levels during a 75-g oral glucose tolerance test in non-obese Japanese men.

Elevated 1-h plasma glucose (1h-PG; ≥155 mg/dL) during an oral glucose tolerance test is a risk factor for type 2 diabetes. However, the metabolic characteristics of non-obese Asians with elevated 1h-PG are unknown. Thus, we studied 59 non-obese Japanese men with normal glucose tolerance. We divided study participants into the Low 1h-PG group (<155 mg/dL) and the High 1h-PG group (≥155 mg/dL). We compared the metabolic characteristics of the groups, including tissue-specific insulin sensitivity measured using a two-step hyperinsulinemic-euglycemic clamp. Insulinogenic index and adiponectin levels were significantly lower in the High 1h-PG group than in the Low 1h-PG group. Other characteristics, including insulin sensitivity, adiposity and ectopic fat accumulation, were similar between the groups. In conclusion, non-obese Japanese men with high 1h-PG have impaired early-phase insulin secretion and lower adiponectin levels. Insulin resistance and abnormal fat distribution were not evident in this population.

Shape of the glucose response curve during an oral glucose tolerance test is associated with insulin clearance and muscle insulin sensitivity in healthy non-obese men.

Individuals with a monophasic glucose response curve (GRC) during a 75-g oral glucose tolerance test have a higher risk for type 2 diabetes than those with a biphasic GRC. However, no studies have addressed the association between GRC type and insulin clearance. Thus, we studied 49 healthy non-obese Japanese men. We divided study participants into the monophasic or biphasic group based on the shape of their GRC. We evaluated tissue-specific insulin sensitivity and insulin clearance using a two-step hyperinsulinemic-euglycemic clamp. The monophasic group had more visceral fat, lower insulin clearance and lower muscle insulin sensitivity than the biphasic group, whereas liver and adipose tissue insulin sensitivity, and insulin secretion were comparable. In conclusion, healthy non-obese men with a monophasic GRC have lower insulin clearance and muscle insulin sensitivity.

Higher C-Peptide Level During Glucose Clamp Is Associated With Muscle Insulin Resistance in Nonobese Japanese Men.

CONTEXT: Circulating C-peptide is generally suppressed by exogenous insulin infusion. However, steady-state serum C-peptide (SSSC) levels during hyperinsulinemic-euglycemic clamp in obese subjects are higher than in healthy subjects, which may contribute to hyperinsulinemia to compensate for insulin resistance. Even in healthy subjects, interindividual variations in SSSC levels are present; however, the characteristics of subjects with high SSSC levels in those populations have not been fully elucidated. OBJECTIVE: To investigate the clinical parameters associated with interindividual variations in SSSC levels in apparently healthy, nonobese Japanese men. DESIGN AND PARTICIPANTS: We studied 49 nonobese (BMI < 25 kg/m2), healthy Japanese men. We evaluated SSSC and insulin sensitivity using hyperinsulinemic-euglycemic clamp with tracer. Intrahepatic lipid (IHL) was measured using proton magnetic resonance spectroscopy. RESULTS: We divided subjects into high and low SSSC groups based on the median SSSC value and compared their clinical parameters. Compared with the low SSSC group, the high SSSC group had IHL accumulation, impaired muscle insulin sensitivity, reduced insulin clearance, and hyperinsulinemia during a 75-g oral glucose tolerance test (OGTT). All of these factors were significantly correlated with SSSC. CONCLUSIONS: In healthy, nonobese men, higher SSSC was associated with impaired muscle insulin sensitivity, IHL accumulation, and hyperinsulinemia during OGTT. These findings suggest that higher endogenous insulin secretion during hyperinsulinemia, along with reduced insulin clearance, may be an early change to maintain metabolic status in the face of moderate muscle insulin resistance, even in healthy, nonobese men.

Fatty Liver Has Stronger Association With Insulin Resistance Than Visceral Fat Accumulation in Nonobese Japanese Men.

CONTEXT: Asians have a high prevalence of insulin resistance, even in the nonobese state. Whereas both visceral fat accumulation (VFA) and fatty liver (FL) have been shown to be associated with insulin resistance, it is still unclear which is a better marker to predict insulin resistance in nonobese Asians. OBJECTIVE: The aim of this study was to investigate the relation between VFA or FL and insulin resistance in nondiabetic nonobese Japanese men who do not have diabetes. DESIGN AND PARTICIPANTS: We studied 87 nonobese (body mass index <25 kg/m2) Japanese men without diabetes. Using a two-step hyperinsulinemic euglycemic clamp, we evaluated insulin sensitivity in adipose tissue, muscle, and liver. Intrahepatic lipid and abdominal visceral fat area were measured by 1H-magnetic resonance spectroscopy and MRI, respectively. Subjects were divided into four groups based on the presence or absence of VFA (visceral fat area ≥100 cm2) and FL (intrahepatic lipid ≥ 5%): control (non-VFA, non-FL; n = 54), VFA only (n = 18), FL only (n = 7), and VFA plus FL (n = 8). RESULTS: Subjects in the FL only and VFA plus FL groups had insulin resistance in adipose tissue and muscle, as well as relatively lower hepatic insulin sensitivity. The specific insulin sensitivities in these organs were comparable in the VFA only and control groups. CONCLUSIONS: In nonobese Japanese men without diabetes, subjects with FL only or VFA plus FL but not VFA only had insulin resistance, suggesting that FL may be a more useful clinical marker than VFA to predict insulin resistance in nonobese Japanese men without diabetes.

Three days of a eucaloric, low-carbohydrate/high-fat diet increases insulin clearance in healthy non-obese Japanese men.

Metabolic clearance rate of insulin (MCRI) is thought to help maintain glucose homeostasis even in healthy subjects. However, the effect of a low carbohydrate/high fat (LCHF) diet on MCRI in healthy subject remains unclear. To investigate the effect of a 3-day eucaloric LCHF diet on MCRI in healthy subjects, we studied 42 healthy non-obese Japanese men. Each subject consumed a eucaloric LCHF diet for 3 days. Before and after the LCHF diet, intramyocellular lipid (IMCL) levels were measured using 1H-magnetic resonance spectroscopy, and glucose infusion rate (GIR) and MCRI were evaluated with a euglycemic hyperinsulinemic clamp. The LCHF diet increased MCRI by 10% and decreased steady state serum insulin (SSSI) and GIR during glucose clamp by 10% and 6%, respectively. To further investigate the role of MCRI, we divided subjects into high-responder (HR) and low-responder (LR) groups based on the median %change in MCRI. The LCHF diet increased IMCL and decreased SSSI during glucose clamp in the HR group, while those were not altered in the LR group. Our results suggested that a 3-day eucaloric LCHF diet increases MCRI in healthy non-obese Japanese men. This change seemed to be beneficial in terms of maintaining euglycemia during low carbohydrate availability.

Clinical Features of Nonobese, Apparently Healthy, Japanese Men With Reduced Adipose Tissue Insulin Sensitivity.

CONTEXT: Adipose tissue insulin resistance has been observed in obese subjects and is considered an early metabolic defect that precedes insulin resistance in muscle and liver. Although Asians can readily develop metabolic disease without obesity, the clinical features of nonobese, apparently healthy, Asians with reduced adipose tissue insulin sensitivity (ATIS) have not been elucidated. OBJECTIVE: To investigate the clinical parameters associated with reduced ATIS in nonobese, apparently healthy (body mass index <25 kg/m2), Japanese men. METHODS: We studied 52 nonobese Japanese men without cardiometabolic risk factors. Using a two-step hyperinsulinemic euglycemic clamp with a glucose tracer, we evaluated the insulin sensitivity in muscle, liver, and adipose tissue. ATIS was calculated as the percentage of free fatty acid (FFA) suppression/insulin concentration during the first step of the glucose clamp. RESULTS: Using the median ATIS value, the subjects were divided into low- and high-FFA suppression groups. The low-FFA suppression group had moderate fat accumulation in the abdominal subcutaneous adipose tissue and liver. Compared with the high-FFA group, they also had a lower fitness level, decreased insulin clearance, impaired insulin sensitivity in muscle, moderately elevated triglycerides, and lowered high-density lipoprotein cholesterol levels. All these factors correlated significantly with ATIS. Hepatic insulin sensitivity was comparable between the two groups. CONCLUSIONS: In nonobese, apparently healthy, Japanese men, reduced ATIS was associated with moderate fat accumulation in subcutaneous fat and liver, lower insulin clearance, muscle insulin resistance, and moderate lipedema. These data suggest that reduced ATIS can occur early in the development of the metabolic syndrome, even in nonobese, apparently healthy, men.

Association Between Visceral Fat Accumulation and Exercise Tolerance in Non-Obese Subjects Without Diabetes.

BACKGROUND: We examined the associations between visceral fat accumulation, presence of the components of metabolic syndrome (MetS), and exercise tolerance in non-obese subjects without diabetes. METHODS: Seventy-four non-obese, non-diabetic Japanese men were enrolled. The subjects were divided into the following two groups: non-obese subjects without any MetS risk factors (n = 38, Group A) and non-obese subjects with one or two MetS risk factors (n = 36, Group B). Anthropometric and metabolic parameters were measured. The response of heart rate (HR) and blood pressure (BP), and exercise tolerance were also evaluated with a cardiopulmonary exercise test using a bicycle ergometer. RESULTS: The body mass index, abdominal circumference, visceral fat area, and homeostasis model assessment-insulin resistance, were significantly higher, while levels of anaerobic threshold and maximal oxygen uptake were significantly lower in Group B than in Group A. The levels of resting HR, resting BP, and BP at maximal exercise were significantly higher in Group B than in Group A. There were no significant differences in the HR at maximal exercise as well as the HR and BP after exercise between the two groups. The visceral fat area was significantly and negatively correlated with exercise tolerance. Multivariate linear regression analyses demonstrated that visceral fat area, but not abdominal circumference, was significantly and independently associated with maximal oxygen uptake. CONCLUSIONS: These data suggest that the visceral fat area is a significant determinant for exercise tolerance even in non-obese subjects without diabetes.

Characteristics of Glucose Metabolism in Underweight Japanese Women.

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.

RELATIONSHIP BETWEEN THE EFFECTIVENESS OF INORGANIC IODINE AND THE SEVERITY OF GRAVES THYROTOXICOSIS: A RETROSPECTIVE STUDY.

OBJECTIVE: Inorganic iodine is often used to treat patients with Graves thyrotoxicosis who do not tolerate thionamides due to adverse effects. However, predictors of continued inorganic iodine efficacy have not been fully elucidated. This study aimed to investigate the factors affecting the continued efficacy of potassium iodide (KI) in patients with Graves thyrotoxicosis. METHODS: In this study, among 1,197 patients with Graves disease who were initially treated with thionamides, we retrospectively studied 24 consecutive Japanese patients whose treatment was changed to KI alone due to the adverse effects of thionamides. We divided these patients into 2 groups: patients who had maintained euthyroid function for at least 180 days (nonrecurrence group, n = 11), and patients who had not maintained euthyroid function for 180 days (recurrence group, n = 13). RESULTS: Free triiodothyronine (FT3) and free thyroxine (FT4) levels on the day of changing from thionamides to KI were statistically higher in the recurrence group than in the nonrecurrence group (FT3, 9.3 [range, 5.2-11.6] vs. 3.7 [3.3-4.8] pg/mL, P = .02 and FT4, 3.6 [1.8-4.5] vs. 1.4 [1.2-1.9] ng/dL, P = .02). FT4 levels on the day of drug change were significantly higher in the recurrence group, even after adjusting for thionamide or KI dose. In the recurrence group, the duration of KI effect was inversed correlated with FT3 and FT4 levels on the day of drug change. CONCLUSION: Continued efficacy of KI after thionamides might be inversely correlated with thyrotoxicosis severity on the day of drug change. ABBREVIATIONS: ANOVA = analysis of variance eTV = estimated thyroid volume FT3 = free triiodothyronine FT4 = free thyroxine IQR = interquartile range KI = potassium iodide MMI = thiamazole PTU = propylthiouracil RAIT = radioactive iodine therapy TRAb = TSH receptor antibody TSH = thyroid stimulating hormone.

Safety and efficacy of metformin up-titration in Japanese patients with type 2 diabetes mellitus treated with vildagliptin and low-dose metformin.

BACKGROUND: This study investigated the safety and efficacy of metformin up-titration in Japanese patients with type 2 diabetes mellitus treated with vildagliptin (100 mg/day) and low-dose metformin (500 or 750 mg/day). RESEARCH DESIGN AND METHODS: Fifty patients were randomly allocated to the control group (maintaining the initial low-dose of metformin) and the dose increase group (up-titrating of metformin to 1,500-2,250 mg/day) for 24 weeks. The primary outcome was change in HbA1c from baseline to 24 weeks. RESULTS: Among the 25 patients allocated to the dose increase group, four patients were not able to complete the study protocol because of gastrointestinal symptoms. HbA1c in the dose increase group was significantly but modestly lower than in the control group (change in HbA1c: 0.22 ± 0.57 vs. -0.15 ± 0.58%, group comparison, P < 0.05). The dose increase group did not gain weight during the study period, and no hypoglycemic events were reported in both groups. The rate of gastrointestinal symptoms in the dose increase group was profoundly higher than in the control group (32 vs. 0%, P < 0.01). CONCLUSIONS: In Japanese patients with type 2 diabetes treated with vildagliptin and low-dose metformin, metformin up-titration significantly but modestly improved glycemic control without hypoglycemia and weight gain.

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

AIMS/INTRODUCTION: 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. MATERIALS AND METHODS: We recruited 29 non-obese (body mass index <25 kg/m2 ) Japanese patients with early type two diabetes mellitus. Based on intrahepatic lipid level measured by H-magnetic resonance spectroscopy, the participants were divided into the FL (intrahepatic lipid ≥5%, n = 7) and non-FL groups (intrahepatic lipid <5%, n = 22). RESULTS: Peripheral insulin sensitivity measured by hyperinsulinemic euglycemic clamp was ~25% lower in the FL group than in the non-FL group, whereas hepatic insulin sensitivity was comparable between the two groups. The subcutaneous fat area was larger, free fatty acid level was higher, C-reactive protein was higher and high molecular weight adiponectin was lower in the FL group than the non-FL group. CONCLUSIONS: The present study showed that the metabolic features of non-obese Japanese type two diabetes patients with FL include impaired peripheral (mainly muscle) insulin sensitivity, fat accumulation and related metabolic disorders, such as elevated free fatty acid, low high molecular weight adiponectin and low-grade inflammation.

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.