Non-obese Japanese Research Articles

The different associations of serum gamma-glutamyl transferase and alanine aminotransferase with insulin secretion, β-cell function, and insulin resistance in non-obese Japanese

The present study investigated the associations of serum gamma-glutamyl transferase (GGT), a marker of fatty liver and oxidative stress, and ALT/AST, a marker of fatty liver, with percentage trunk fat and postload glucose, insulin resistance, and β-cell function in middle-aged Japanese individuals, whose BMI averaged < 23.0 kg/m2. Pancreatic β-cell function was assessed using the disposition index calculated by a product of the insulinogenic index (IGI) and Matsuda insulin sensitivity index, a biomarker of early-phase glucose-stimulated insulin secretion and whole-body insulin sensitivity, respectively. Multivariate linear regression analyses revealed that the disposition index was associated inversely with GGT independently of percentage trunk fat, homeostasis model assessment insulin resistance (HOMA-IR), a marker of insulin resistance, and Matsuda index. When IGI was included instead of the disposition index, IGI (inversely) and HOMA-IR were associated with GGT independently of percentage trunk fat and Matsuda index. When the area under the glucose concentration curve (AUCg) during an oral glucose tolerance test was included instead of the disposition index, AUCg and HOMA-IR emerged as independent determinants of GGT. ALT/AST was associated with HOMA-IR alone. Results suggest a different pathophysiologic basis between GGT and ALT/AST in predicting diabetic risk in non-obese Japanese.

Impact of body composition on patient prognosis after SARS-Cov-2 infection.

Since the first outbreak of coronavirus disease 2019 (COVID-19), it has been reported that several factors, including hypertension, type 2 diabetes mellitus, and obesity, have close relationships with a severe clinical course. However, the relationship between body composition and the prognosis of COVID-19 has not yet been fully studied. The present study enrolled 76 consecutive COVID-19 patients with computed tomography (CT) scans from the chest to the pelvis at admission. The patients who needed intubation and mechanical ventilation were defined as severe cases. Patients were categorized into four groups according to their body mass index (BMI). The degree of hepatic steatosis was estimated by the liver/spleen (L/S) ratio of the CT values. Visceral fat area (VFA), psoas muscle area (PMA), psoas muscle mass index (PMI), and intra-muscular adipose tissue content (IMAC) were measured by CT scan tracing. These parameters were compared between non-severe and severe cases. Severe patients had significantly higher body weight, higher BMI, and greater VFA than non-severe patients. However, these parameters did not have an effect on disease mortality. Furthermore, severe cases had higher IMAC than non-severe cases in the non-obese group. Our data suggest high IMAC can be a useful predictor for severe disease courses of COVID-19 in non-obese Japanese patients, however, it does not predict either disease severity in obese patients or mortality in any obesity grade.

A Short-Term High-Fat Diet Worsens Insulin Sensitivity with Changes in Metabolic Parameters in Non-Obese Japanese Men.

A short-term high-calorie high-fat diet (HCHFD) impairs insulin sensitivity in non-obese South Asian but not Caucasian men; however, the effect of short-term HCHFD on insulin sensitivity in East Asians is unknown. We recruited 21 healthy non-obese Japanese men to evaluate metabolic parameters and gut microbiota before and after 6-day HCHFD consisting of a regular diet plus a 45% energy excess with dairy fat supplementation. We evaluated tissue-specific insulin sensitivity and metabolic clearance rate of insulin (MCRI) using a two-step hyperinsulinemic euglycemic clamp, glucose tolerance using the glucose tolerance test, and measured ectopic fat in muscle and the liver using ¹H-magnetic resonance spectroscopy. The primary outcome of this study was insulin sensitivity measured by the clamp study. The secondary/exploratory outcomes were other metabolic changes. After HCHFD, levels of circulating lipopolysaccharide binding protein (LBP), a marker of endotoxemia, increased by 14%. In addition, intramyocellular lipid levels in the tibialis anterior and soleus and intrahepatic lipid levels increased by 47%, 31%, and 200%, respectively. Insulin sensitivity decreased by 4% in muscle and 8% in liver. However, even with reduced insulin sensitivity, glucose metabolism was maintained by increased serum insulin concentrations due to lower MCRI and higher endogenous insulin secretion during the clamp. Glucose levels during the meal tolerance test were comparable before and after HCHFD. In conclusion, short-term HCHFD impaired insulin sensitivity in the muscle and livers of non-obese Japanese men with increased LBP and ectopic fat accumulation. Elevated insulin levels from modulated insulin secretion and clearance might contribute to the maintenance of normal glucose metabolism during the clamp and meal tolerance test.

Comparative Effects of Metformin and Dipeptidyl Peptidase-4 Inhibitors in Japanese Obese Patients with Type 2 Diabetes: A Claims Database Study.

IntroductionMetformin has demonstrated favorable effects on glycemic control in patients with type 2 diabetes (T2D), regardless of the body mass index (BMI). On the contrary, dipeptidyl peptidase-4 inhibitors (DPP-4is) are reportedly less effective in patients having high BMI values (≥ 25 or ≥ 30). The aim of this study was to compare metformin and DPP-4is as first-line treatment for their effects on glycemic control and improvement of other health outcomes among obese and non-obese Japanese patients with T2D.MethodsA Japanese health insurance claims database that also included annual medical checkup data was used. This database included data on company employees who were members of health insurance societies and their family members. Most patients were aged < 65 years and most were men. Inclusion criteria were: (1) a first T2D diagnosis between May 2010 and June 2017; (2) either metformin or a DPP-4i prescribed as the first-line antidiabetic therapy; and (3) glycated hemoglobin (HbA1c) and BMI data available for the 3-month period immediately preceding the initiation of antidiabetic treatment (baseline). The reduction rate in excessive HbA1c (> 6.5%; primary outcome) and changes in fasting plasma glucose, BMI, triglyceride, cholesterol, and abdominal circumference (secondary outcomes) at 12 months from baseline were compared between treatments.ResultsWhen evaluated relative to the baseline BMI, the mean reduction rate in excessive HbA1c tended to be higher in the metformin group than in the DPP-4i group, especially in patients with BMI ≥ 25. Similarly, significant improvement was observed in most outcomes in obese patients prescribed metformin compared to those prescribed a DPP-4i. In contrast, in patients with BMI < 25, HbA1c reduction was greater in patients prescribed DPP-4i and fewer outcomes showed significant improvement in patients prescribed metformin.ConclusionIn obese Japanese patients with T2D, greater improvements in glycemic control and other outcomes were seen with metformin as first-line treatment for T2D compared with DPP-4is, although some limitations regarding the database information should be considered.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-021-01101-2.

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

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 non-obese Asians. 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 25kg/m 2. We divided the subjects into four 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 four groups. 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 three groups. In non-obese 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.

Oleic acid to stearic acid ratio might be a potential marker for insulin resistance in non-obese Japanese.

Results from a recent study indicate that a higher level of oleic acid/stearic acid ratio was associated with metabolically unhealthy obesity. This was further validated in cross-sectional and interventional studies; however, this was not extensively studied in a non-obese population. We recruited 260 Japanese subjects with serum free fatty acid profiles undergoing anti-aging health examinations. The determinants for oleic acid/stearic acid ratio were investigated using multiple regression analyses. To compare different markers, the subjects were classified based on oleic acid/stearic acid ratio and the combination of oleic acid/stearic acid ratio and triglyceride levels. The oleic acid/stearic acid ratio exhibited a positive correlation with the logmatic transformed triglyceride/high-density lipoprotein cholesterol ratio and the fasting triglycerides-glucose index, both of which were used as markers for insulin resistance. Multiple regression analyses revealed that the triglyceride/high-density lipoprotein cholesterol ratio and fasting triglyceride-glucose index were positively associated with the oleic acid/stearic acid ratio. Most markers were the worst in the highest triglyceride group in both oleic acid/stearic acid groups. In addition, most markers were worse in high oleic acid/stearic acid ratio group than low group. In conclusion, oleic acid/stearic acid ratio might be a useful marker for insulin resistance in non-obese Japanese subjects.

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

IntroductionReduced 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.MethodsMeasurements 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.ResultsLower 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 (β = 0.274, p = 0.036).ConclusionsDiminished strength of knee flexor muscles, but not knee extensor muscles, was associated with muscle insulin sensitivity in non-diabetic, non-obese Japanese male subjects.

Decrease in fasting insulin secretory function correlates with significant liver fibrosis in Japanese non-alcoholic fatty liver disease patients.

Background and AimNon‐alcoholic fatty liver disease (NAFLD) is typically associated with metabolic syndrome and diabetes, and insulin resistance is involved in its pathogenesis. However, the relationship between insulin secretion and NAFLD is unclear. We aimed to characterize the relationship between fasting insulin secretory function (ISF), evaluated using the homeostatic model assessment‐beta cell function (HOMA‐β) and the severity of fibrosis during NAFLD.MethodsA‐β was calculated in 188 patients with biopsy‐confirmed NAFLD, and the correlations between Log HOMA‐β and clinical parameters, including hepatic fibrosis, were calculated.ResultsLog HOMA‐β was significantly lower in NAFLD patients with significant fibrosis (stages 2–4) than in those in the early stages (stages 0–1) (median [interquartile range]) (2.1 [1.9–2.4] vs 2.0 [1.8–2.2], P = 0.04). The prevalence of significant fibrosis decreased with increasing Log HOMA‐β: it was 59.2% in participants with low ISF (Log HOMA‐β < 1.85), 43.6% in those with intermediate ISF (1.85 ≤ Log HOMA‐β < 2.25), and 68.0% in those with high ISF (Log HOMA‐β ≥ 2.25). Patients with lower Log HOMA‐β had lower current body mass index (BMI), BMI at 20 years of age, and peak lifetime BMI than patients with intermediate or high Log HOMA‐β.ConclusionsFasting ISF decreased alongside the development of liver fibrosis in NAFLD, suggesting that an impaired β cell function has a characteristic finding of significant liver fibrosis in relatively nonobese Japanese patients.

Association between non-obesity and health state among young Japanese male university students.

[Purpose] The obesity rate in both males and females has been lower in Japan than in other countries. However, the prevalence of metabolic syndrome-related risk factors is not low when compared with that in Western countries. In this study, we aimed to evaluate the health state of young, non-obese adults in Japan. [Participants and Methods] We recruited 20 young, non-obese Japanese male university students and examined the maximum oxygen consumption, physical activity, and components of metabolic syndrome. We evaluated the physical activity level and dietary habits of the participants through a questionnaire survey. [Results] The questionnaire survey revealed that 70% participants had non-standard dietary habits, 55% did not engage in any regular exercise, and 25% were inactive. On examination, 20% participants had at least one positive risk factor for metabolic syndrome. The homeostatic model assessment of insulin resistance and triglyceride values did not correlate with the body mass index of the participants; however, the values were inversely related to the maximum oxygen consumption levels. [Conclusion] Even participants with normal body mass index had poor dietary habits and a lack of exercise. Our results confirmed that even non-obese Japanese individuals have certain health risks and that having higher maximum oxygen consumption has beneficial effects in preventing the risk factors of severe and life-threatening diseases.

1666-P: Metabolic Characteristic of Elevated One-Hour Plasma Glucose Levels during a 75g Oral Glucose Tolerance Test in the Nonobese Japanese Men

It has been shown that subjects with normal glucose tolerance (NGT) but elevated 1-hour glucose level ≧155 mg/dl during a 75g oral glucose tolerance test (75g OGTT) is an independent risk factor for type 2 diabetes. In Caucasian, subjects with elevated 1-h glucose were characterized by adiposity with lower insulin sensitivity and impaired beta-cell function. While type 2 diabetes in Asians is frequently affected in non-obese (BMI&amp;lt;25 kg/m2) subjects, the characteristics of non-obese Asians with elevated 1-h glucose are totally unknown. Here, we studied 59 non-obese Japanese men with NGT. Based on the level of 1-hour glucose level during 75g OGTT, we divided the subjects into Low-1 hour group (&amp;lt; 155mg/dl) and High-1 hour group (≧155mg/dl). We measured ectopic fat in muscle and liver and subcutaneous and viscera fat areas by 1H-MRS and MRI, respectively. We also measured tissue specific insulin sensitivity by 2 step hyperinsulinemic-euglycemic clamp. Insulinogenic index (0.66±0.30 vs. 1.41±1.21ΔInsulin0-30 min/ΔGlucose 0-30min, p=0.02) was significantly lower and area under the curve of glucose and insulin during 75g OGTT were significantly higher in High-1 hour group than Low-1 hour group (Figure). However, other parameters including insulin sensitivity and ectopic fat in muscle and liver, subcutaneous and viscera fat areas were comparable between the groups. These data suggest that non-obese Japanese men with High-1 hour glucose are characterized by impaired early-phase insulin secretion and subsequent hyperinsulinemia. Insulin resistance and abnormal fat distribution are not evident in this population. Disclosure M. Sato: None. Y. Tamura: None. H. Kaga: None. Y. Someya: None. S. Kakehi: None. N. Yamasaki: None. D. Sugimoto: None. S. Kadowaki: None. R. Suzuki: None. Y. Furukawa: None. K. Takeno: None. T. Funayama: None. R. Kawamori: None. H. Watada: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kissei Pharmaceutical Co., Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Pfizer Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Kowa Pharmaceutical Europe Co. Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Sanwa Chemical Industry Co. Ltd., Takeda Pharmaceutical Company Limited.

1941-P: The Relationship among Intramyocellular Lipid, Peak Oxygen Consumption, and Insulin Resistance in Nonobese Japanese Men

Accumulation of intramyocellular lipid (IMCL) is observed not only in insulin resistant obese subjects with low peak oxygen consumption (VO2peak), but also in insulin sensitive endurance athletes with high VO2peak (athlete’s paradox). While the relationship among intramyocellular lipid, peak oxygen consumption and insulin resistance is variable among the different subjects, its relation within non-obese non-athlete subject has not been elucidated yet. To investigate this relation, we studied 61 non-obese (BMI&amp;lt;25kg/m2) non-athlete Japanese men. We evaluated muscle insulin sensitivity (M-IS) by a 2-step hyperinsulinemic euglycemic clamp. We divided the subjects into 4 groups based on the median value of VO2 peak (31.4 ml/kg per min) and the IMCL in soleus muscles (14.3 s-fat/Cre), then we compared M-IS. Compared with Low-VO2peak/High-IMCL group, M-IS was significantly higher in High-VO2peak/Low-IMCL group and High-VO2peak/High-IMCL group (Fig). On the other hand, M-IS was comparable between High-VO2peak/Low-IMCL group and High-VO2peak/High-IMCL group. These results suggest that in non-obese non-athlete Japanese men, VO2peaklevel is an important determinant of muscle insulin sensitivity in IMCL accumulated subjects. In addition, IMCL accumulation is not an important determinant of muscle insulin sensitivity in subjects with high VO2peak. Disclosure N. Yamasaki: None. Y. Tamura: None. K. Takeno: None. S. Kakehi: None. Y. Someya: None. T. Funayama: None. Y. Furukawa: None. H. Kaga: None. R. Suzuki: None. D. Sugimoto: None. S. Kadowaki: None. M. Sato: None. R. Kawamori: None. H. Watada: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Kissei Pharmaceutical Co., Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Pfizer Inc., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited, Teijin Pharma Limited. Speaker's Bureau; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Sanofi, Takeda Pharmaceutical Company Limited, Terumo Medical Corporation. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Kowa Pharmaceutical Europe Co. Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Sanwa Chemical Industry Co. Ltd., Takeda Pharmaceutical Company Limited.

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

ContextAsians 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.ObjectiveThe 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 ParticipantsWe 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).ResultsSubjects 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.ConclusionsIn 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.

Prevalence of Obstructive Sleep Apnea Determined by the Watchpat in Nonobese Japanese Patients with Poor Glucose Control And Type 2 Diabetes

Diagnosing obstructive sleep apnea (OSA) usually involves high cost, patient inconvenience, and the need for examination at a specialized center. This study employed a portable, wearable, diagnostic device (WatchPAT) to investigate the prevalence of OSA in nonobese Japanese patients with type 2 diabetes. Patients with type 2 diabetes were tested for OSA over one night using the WatchPAT. Logistic regression analysis was used to estimate the odds ratios (ORs) of risk factors for OSA in nonobese subjects. A total of 200 eligible patients with type 2 diabetes were studied (64.5% men; aged 60.1 ± 13.6 years; body mass index [BMI], 26.3 ± 5.2 kg/m2). When OSA was defined as apnea-hypopnea index ≥5/hour, its prevalence was 80.5%. The prevalence of OSA in subjects with a BMI <20 kg/m2, ≥20 and <25 kg/m2, ≥25 and <30 kg/m2, and ≥30 kg/m2 was 38.9%, 73.5%, 86.5%, and 97.5%, respectively. The severity of OSA increased in proportion to BMI, especially when the BMI was >25 kg/m2. The prevalence of OSA was also high (66.3%) in normal-weight subjects (BMI <25 kg/m2). Furthermore, the serum triglyceride level (OR, 1.01; 95% confidence interval, 1.00 to 1.02; P = .042) was significantly related to OSA. A high prevalence of OSA was observed in this nonobese population of Japanese patients with type 2 diabetes. The triglyceride level was associated with OSA among nonobese patients. AHI = apnea-hypopnea Index; BMI = body mass index; CI = confidence interval; ESS = Epworth Sleepiness Scale; HbA1c = glycated hemoglobin; OR = odds ratio; OSA = obstructive sleep apnea; PAT = peripheral arterial tone; T2D = type 2 diabetes; TG = triglyceride.

Ectopic fat, insulin resistance and metabolic disease in non-obese Asians: investigating metabolic gradation.

Although metabolic abnormalities commonly occur in non-obese Asians, their pathogenesis is not fully understood. Proton magnetic resonance spectroscopy has been used to analyze intracellular lipids in humans, and results suggest that ectopic fat accumulation in muscle and liver may induce insulin resistance in each tissue independently of obesity. Thus, measurement of ectopic fat currently plays an important role in the study of insulin resistance in non-obese Asians. In addition, studies using 2-step hyperinsulinemic euglycemic clamp with a glucose tracer may clarify how tissue-specific insulin resistance in muscle, liver, and adipose tissue contributes to the development of metabolic disease in non-obese Japanese. Although numerous studies have elucidated the pathophysiology of insulin resistance in obese subjects, research on "metabolic gradation," defined as the gradual transition from an insulin-sensitive to an insulin-resistant state, is less common, especially in terms of early metabolic changes. This review addresses a simple question: when and how is insulin resistance induced in non-obese East Asians? Several studies revealed that impaired insulin clearance and hyperinsulinemia not only compensated for insulin resistance, but also secondarily facilitated insulin resistance and weight gain. In this regard, we recently found that impaired insulin clearance and hyperinsulinemia could occur in apparently healthy subjects without significant insulin resistance, suggesting that this change may be an initial trigger that drives subsequent insulin resistance and weight gain. Further research is required to clarify the pathogenesis of metabolic gradation in non-obese Asians.

Fatty Liver Is a Better Marker of Muscle Insulin Resistance than Visceral Fat Accumulation in Nonobese Japanese Men

Metabolic diseases easily develop in non-obese Asians. We recently found that insulin resistance (IR) in muscle is closely associated with metabolic abnormalities in non-obese Japanese men and muscle IR is correlated well with both visceral fat accumulation (VFA) and fatty liver (FL). However, VFA and FL are correlated well with each other, thus it is unclear which is a better marker of muscle IR.To clarify this, we studied 87 nondiabetic non-obese middle-aged Japanese men. Using a two-step hyperinsulinemic euglycemic clamp, we evaluated insulin sensitivity (IS) in muscle and liver. Intrahepatic lipid (IHL) and visceral fat area are measured by 1H-MRS and MRI, respectively. According to the generally accepted definition, subject was divided into 4 groups by the presence or absence of VFA (visceral fat area 100cm2) and FL (IHL 5%); control (non-VFA non-FL; n=54), VFA alone (n=18), FL alone (n=7), VFA+FL (n=8). Hepatic-IS was similar among the groups. On the other hand, muscle-IS was significantly lower in groups of FL alone and VFA+FL than the control group. Interestingly, muscle-IS of VFA alone group was comparable to the control group, and it was significantly higher than FL alone group (Figure). These differences were still significant after adjustment for confounders. These data suggested that FL is a better marker than VFA in nondiabetic non-obese men in terms of sensitivity to detect muscle IR. Disclosure S. Kadowaki: None. Y. Tamura: None. Y. Someya: None. K. Takeno: None. T. Funayama: None. Y. Furukawa: None. S. Kakehi: None. H. Kaga: None. R. Suzuki: None. D. Sugimoto: None. R. Kawamori: None. H. Watada: Advisory Panel; Self; AstraZeneca. Consultant; Self; Astellas Pharma US, Inc., AstraZeneca, Boehringer Ingelheim GmbH, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk A/S, Novartis AG, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Takeda Development Center Asia, Pte. Ltd.. Research Support; Self; Abbott, Astellas Pharma US, Inc., AstraZeneca, Bayer AG, Benefit One Health Care Co., Ltd., Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Sumitomo Dainippon Pharma Co., Ltd., Eli Lilly and Company, Kissei Pharmaceutical Co., Ltd., Kowa Pharmaceuticals America, Inc., Kyowa Hakko Kirin Co., Ltd., Johnson &amp; Johnson Diabetes Institute, LLC., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nitto Boseki Co., Ltd., Novartis AG, Novo Nordisk A/S, Ono Pharmaceutical Co., Ltd., Pfizer Inc., Sanofi, Sanwa Kagaku Kenkyusho Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Terumo Medical Corporation.

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

Aims/IntroductionType 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 MethodsWe 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).ResultsPeripheral 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.ConclusionsThe 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.

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.

Correlation between Occupational Stress, Lifestyle, and Hyperglycemia among Obese and Non-Obese Middle-Aged Japanese Male Workers

The aim of this study was to identify the correlation between stress, lifestyle, and hyperglycemia among middle-aged Japanese male workers. We also analyzed the obese (OB) and non-obese (non- OB) groups pertaining to the risk of hyperglycemia. A total of 353 male employees aged between 50 and 59 years taking health checkup sat a company in Japan were examined. The data were collected using validated scales of occupational stress and medical examination. Of the 353 employees, 335 (effective response rate 95%) were analyzed. “Support from colleagues” and “reward from work” reported by the OB group were lower than the non-OB group. The items “eating until satiety” and “having greasy meal often” were significantly more common in the OB group than in the non-OB group. There was a significant correlation between less sleep time and hyperglycemia in the OB group than in the non-OB group. The non-OB group reported more overtime hours than the OB group. Hyperglycemia in the non-OB group was positively correlated with long working hours, “workload,” and “mental workload.” The results indicated that the OB group would benefit from lifestyle interventions, for example, improvement in sleep time and eating habits may prevent hyperglycemia and eventually in obesity. Furthermore, it was suggested that stress in response to “workload” and “mental workload” owing to long working hours leads to hyperglycemia in the non-OB group. Therefore, the improvement of the workplace environment, reducing the number of hours at work, and stress management are required to prevent hyperglycemia in the non-OB group.