Pneumococcal vaccination reduces in-hospital mortality, length of stay and medical expenditure in hospitalized elderly patients.

Pneumococcal vaccination has been shown to reduce occurrence of invasive pneumococcal diseases in elderly patients. In this study, we investigated the real-world efficacy of pneumococcal vaccination implemented in elderly individuals in Japan. We reviewed the in-patient database of Juntendo University Hospital and selected elderly patients (≥65 years-old) who had received in-patient care in the general medicine department during 2014-2018. A total of 1355 patients were retrospectively enrolled and comprised of 1045 unvaccinated and 315 vaccinated elderly individuals. Prior vaccination was found associated with all-cause shorter hospital stays (adjusted RR = 0.66, 95% CI = 0.57 to 0.76) and less medical expenditure (adjusted RR = 0.76, 95% CI = 0.66 to 0.87) compared with no vaccination, as well as protection for all-cause in-hospital mortality (adjusted OR = 0.42, 95% CI = 0.22 to 0.83). The association of shorter hospital stays and less medical expenditure with vaccination was also observed in the context of pneumonia, although no altered risk in mortality was observed. In conclusion, this study is one of the first reporting real-world data after the initiation of pneumococcal vaccination program in 2014 in Japan. The national PPV23 vaccination program contributed to the reduction of all-cause in-patient days, mortality, and medical expenses in the elderly aged ≥65 years. Further data is warranted to evaluate the contribution from influenza vaccination and protein-conjugate based pneumococcal vaccine.

The estimated impact of the 5-year national vaccination program on the trend of 23-valent pneumococcal polysaccharide vaccine vaccination rates in the elderly in Japan, 2009-2018.

Pneumonia is the third most common cause of death in Japan. Low vaccination rates are thought to be related to low levels of public subsidy. Since 2014, the Japanese government has offered subsidies through a 5-year national routine vaccination program of the 23-valent pneumococcal polysaccharide vaccine (PPV23) for older adults at age ≥65 years with 5-year age intervals. We previously reported that, 2 years into the 5-year program, the estimated vaccination rate was 40.6% at the end of 2015, a significant increase compared with periods before the program introduced. Here, we present an update on the estimated vaccination coverage of the 5-year national routine vaccination program at the end of 2018. The PPV23 vaccination rates were calculated by dividing the cumulative amount shipped to each municipality by the population aged ≥65 years. At the end of 2018, the completion of the 5-year national immunization program, the estimated cumulative vaccination rate was 74%. Stepwise regression analysis revealed that the annual PPV23 vaccination rate significantly increased after 2014 (from 2 to 5% prior to 2014, to 10-11% after 2014), and remained steady for 2014-2018. Our findings suggest that the 5-year national routine vaccination subsidy program was successful in achieving a steady and higher vaccination rate of PPV23 in Japan.

Type 2 Diabetes and Bacteremia.

BACKGROUND: A high proportion of type 2 diabetes cases are associated with host genetic and environmental factors. During the past decade, microorganisms that inhabit the gut have emerged as contributors to the pathogenesis of obesity and type 2 diabetes. Therefore, manipulation of the human gut microbiota will provide essential clues regarding new therapeutic targets for diabetes. SUMMARY: Several studies have established the presence of gut dysbiosis in patients with type 2 diabetes mellitus, even though there are some differences among the studies that could be explained by differences in ethnicity, diet, and methodology. Gut dysbiosis affects the quality and quantity of short-chain fatty acids and secondary bile acids that act as signaling molecules in energy, glucose, and lipid metabolism. In addition, gut dysbiosis affect intestinal permeability. In particular, a high-fat diet can lead to changes in the gut microbiota that strongly reduce intestinal permeability due to the malfunction of tight junction proteins, such as occludin and ZO-1 [1]. The formation of leaky gut results in increased plasma levels of lipopolysaccharide, which activate Toll-like receptor 4 and result in innate and adaptive immune responses [2]. Key messages: Gut dysbiosis play an important role in the pathogenesis of obesity and diabetes, for example, via chronic low-grade inflammation. Normalizing gut dysbiosis could be a new approach to overcome diseases of insulin resistance, such as diabetes mellitus.

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.

Relationship between dietary patterns and risk factors for cardiovascular disease in patients with type 2 diabetes mellitus: a cross-sectional study.

BACKGROUND: While some dietary patterns are associated with the incidence of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD), the relationship between dietary pattern and risk factors for CVD in patients with T2DM remains to be clarified. The aim of this study was to identify dietary patterns and investigate the relationship between dietary patterns and potential risk factors for CVD in patients with T2DM. METHODS: The study participants comprised 726 Japanese T2DM outpatients free of history of CVD. Life styles were analyzed using self-reported questionnaires. The relationship between dietary patterns, identified by factor analysis, and potential risk factors for CVD was investigated by linear and logistic regression analyses. RESULTS: Six dietary patterns were identified by factor analysis. Especially, three dietary patterns were associated with risk factors for CVD. The "Seaweeds, Vegetables, Soy products and Mushrooms" pattern, characterized by high consumption of seaweeds, soy products and mushrooms, was associated with lower use of diabetes medication and healthier lifestyles. The "Noodle and Soup" pattern, characterized by high consumption of noodle and soup was associated with higher body mass index, alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transpeptidase and triglyceride levels. The "Fruit, Dairy products and Sweets" pattern was associated with lower γ-glutamyl transpeptidase levels, blood pressure, albuminuria and brachial-ankle pulse wave velocity. CONCLUSIONS: The findings suggested that dietary patterns correlated with risk factors for CVD in T2DM patients.

Poor sleep quality is associated with increased arterial stiffness in Japanese patients with type 2 diabetes mellitus.

BACKGROUND: While poor sleep quality can worsen cardiovascular risk factors such as glucose and lipid profiles in patients with type 2 diabetes mellitus (T2DM), the relationship between sleep quality and atherosclerosis remains largely unknown. The aim of this study was to examine this relationship. METHODS: The study participants comprised 724 Japanese T2DM outpatients free of history of cardiovascular diseases. The relationships between sleep quality (assessed by the Pittsburgh Sleep Quality Index (PSQI)) and various clinical and laboratory parameters were investigated. RESULTS: The mean PSQI was 5.1 ± 3.0 (±SD). Patients were divided into three groups based on the total PSQI score; subjects with good sleep quality (n = 462), average sleep quality (n = 185), and poor sleep quality (n = 77). In the age/gender-adjusted model, patients with poor sleep quality tended to be obese, evening type and depressed. However, other lifestyles showed no significant trends. Alanine aminotransferase, fasting blood glucose, HbA1c, systolic blood pressure, urinary albumin excretion, and brachial-ankle pulse wave velocity (baPWV) tended to be higher in patients with poor sleep quality. High baPWV was the only parameter that correlated with poor sleep in a model adjusted for several other lifestyle factors. CONCLUSIONS: Our study indicates that poor sleep quality in T2DM patients correlates with increased arterial wall stiffness, a marker of atherosclerosis and a risk factor for cardiovascular diseases.

Beneficial effects of vildagliptin combined with miglitol on glucose tolerance and islet morphology in diet-controlled db/db mice.

Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes primarily by increasing plasma active glucagon-like peptide-1 (GLP-1) levels. While various combination therapies based on DPP-4 inhibitors have been proposed for treatment of type 2 diabetes, the effects of combination therapy of DPP-4 inhibitors and alpha-glucosidase inhibitors on ß-cell function are less characterized. We evaluated the effects of long-term treatment with vildagliptin, a DPP-4 inhibitor, on metabolic parameters and ß-cell function, in combination with miglitol, an alpha-glucosidase inhibitor, in diet-controlled db/db mice. In this study, 6-week-old male db/db mice were provided with standard chow twice a day for 6 weeks. Meal tolerance tests and glucose tolerance tests showed that the combination therapy of vildagliptin with miglitol, but not each alone, suppressed postprandial glycemic excursion, enhanced postprandial active GLP-1 levels and prevented deterioration of glucose tolerance in the db/db mice. The combination treatment did not alter ß-cell mass, but resulted in preserved expression of glucose transporter 2, Zinc transporter 8 and MafA and reduced the number of α cells. These results suggest that the combination of vildagliptin and miglitol prevents the development of overt diabetes in diet-controlled pre-diabetic db/db mice by normalizing postprandial glucose and incretin response, and by preserving ß-cell structure and the expression of factors essential for ß-cell function.

Exercise-induced enhancement of insulin sensitivity is associated with accumulation of M2-polarized macrophages in mouse skeletal muscle.

Exercise enhances insulin sensitivity in skeletal muscle, but the underlying mechanism remains obscure. Recent data suggest that alternatively activated M2 macrophages enhance insulin sensitivity in insulin target organs such as adipose tissue and liver. Therefore, the aim of this study was to determine the role of anti-inflammatory M2 macrophages in exercise-induced enhancement of insulin sensitivity in skeletal muscle. C57BL6J mice underwent a single bout of treadmill running (20 m/min, 90 min). Twenty-four hours later, ex vivo insulin-stimulated 2-deoxy glucose uptake was found to be increased in plantaris muscle. This change was associated with increased number of CD163-expressing macrophages (i.e. M2-polarized macrophages) in skeletal muscle. Systemic depletion of macrophages by pretreatment of mice with clodronate-containing liposome abrogated both CD163-positive macrophage accumulation in skeletal muscle as well as the enhancement of insulin sensitivity after exercise, without affecting insulin-induced phosphorylation of Akt and AS160 or exercise-induced GLUT4 expression. These results suggest that accumulation of M2-polarized macrophages is involved in exercise-induced enhancement of insulin sensitivity in mouse skeletal muscle, independently of the phosphorylation of Akt and AS160 and expression of GLUT4.

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.

Evaluation of a Medical Interview-Assistance System Using Artificial Intelligence for Resident Physicians Interviewing Simulated Patients: A Crossover, Randomized, Controlled Trial.

Medical interviews are expected to undergo a major transformation through the use of artificial intelligence. However, artificial intelligence-based systems that support medical interviews are not yet widespread in Japan, and their usefulness is unclear. A randomized, controlled trial to determine the usefulness of a commercial medical interview support system using a question flow chart-type application based on a Bayesian model was conducted. Ten resident physicians were allocated to two groups with or without information from an artificial intelligence-based support system. The rate of correct diagnoses, amount of time to complete the interviews, and number of questions they asked were compared between the two groups. Two trials were conducted on different dates, with a total of 20 resident physicians participating. Data for 192 differential diagnoses were obtained. There was a significant difference in the rate of correct diagnosis between the two groups for two cases and for overall cases (0.561 vs. 0.393; p = 0.02). There was a significant difference in the time required between the two groups for overall cases (370 s (352-387) vs. 390 s (373-406), p = 0.04). Artificial intelligence-assisted medical interviews helped resident physicians make more accurate diagnoses and reduced consultation time. The widespread use of artificial intelligence systems in clinical settings could contribute to improving the quality of medical care.

Association of gut microbiota and inflammatory markers in obese patients with type 2 diabetes mellitus: post hoc analysis of a synbiotic interventional study.

Chronic inflammation caused by gut dysbiosis is associated with the pathophysiology of metabolic disease. Synbiotics are useful for ameliorating gut dysbiosis; however, it remains unclear what types of bacteria act as key markers for synbiotic-driven improvement of chronic inflammation. Here, we performed a post hoc analysis of a 24-week randomized controlled study using synbiotics to investigate the association between gut microbiota and inflammatory markers. We characterized the responders who showed lower interleukin-6 (IL-6) levels in response to synbiotic supplementation among 86 obese patients with type 2 diabetes mellitus. In our baseline analysis, the relative abundances of Bifidobacterium adolescentis and Alistipes onderdonkii correlated positively with IL-6, lipopolysaccharide binding protein (LBP), and high-sensitivity C-reactive protein (Hs-CRP) levels. The relative abundance of Eubacterium rectale correlated positively with LBP and Hs-CRP levels, and that of Bacteroides thetaiotaomicron correlated positively with LBP levels. Based on our responder analysis, patients with higher body mass indices (over 30 kg/m2 on average), low abundances of Bacteroides caccae and Parabacteroides merdae at baseline and 24 weeks, and minimal changes in the relative abundance of E. rectale and Shannon index from baseline showed decreased IL-6 levels compared with baseline. However, glycemic control in responders was unchanged. In conclusion, we identified four bacterial species (B. adolescentis, A. onderdonkii, E. rectale, and B. thetaiotaomicron) related to chronic inflammation and predictive markers (B. caccae, P. merdae, and severity of obesity) in responders to synbiotic supplementation among obese patients with type 2 diabetes.

Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces intimal thickening after vascular injury.

Glucagon-like peptide-1 is a hormone secreted by L cells of the small intestine and stimulates glucose-dependent insulin response. Glucagon-like peptide-1 receptor agonists such as exendin-4 are currently used in type 2 diabetes, and considered to have beneficial effects on the cardiovascular system. To further elucidate the effect of glucagon-like peptide-1 receptor agonists on cardiovascular diseases, we investigated the effects of exendin-4 on intimal thickening after endothelial injury. Under continuous infusion of exendin-4 at 24 nmol/kg/day, C57BL/6 mice were subjected to endothelial denudation injury of the femoral artery. Treatment of mice with exendin-4 reduced neointimal formation at 4weeks after arterial injury without altering body weight or various metabolic parameters. In addition, in vitro studies of isolated murine, rat and human aortic vascular smooth muscle cells showed the expression of GLP-1 receptor. The addition of 10nM exendin-4 to cultured smooth muscle cells significantly reduced their proliferation induced by platelet-derived growth factor. Our results suggested that exendin-4 reduced intimal thickening after vascular injury at least in part by the suppression of platelet-derived growth factor-induced smooth muscle cells proliferation.

Effects of Synbiotic Supplementation on Chronic Inflammation and the Gut Microbiota in Obese Patients with Type 2 Diabetes Mellitus: A Randomized Controlled Study.

The aim of this study was to investigate the effects of 24-week synbiotic supplementation on chronic inflammation and the gut microbiota in obese patients with type 2 diabetes. We randomized 88 obese patients with type 2 diabetes to one of two groups for 24 weeks: control or synbiotic (Lacticaseibacillus paracasei strain Shirota (previously Lactobacillus casei strain Shirota) and Bifidobacterium breve strain Yakult, and galactooligosaccharides). The primary endpoint was the change in interleukin-6 from baseline to 24 weeks. Secondary endpoints were evaluation of the gut microbiota in feces and blood, fecal organic acids, high-sensitivity C-reactive protein, lipopolysaccharide-binding protein, and glycemic control. Synbiotic administration for 24 weeks did not significantly affect changes in interleukin-6 from baseline to 24 weeks (0.35 ± 1.99 vs. -0.24 ± 1.75 pg/mL, respectively). Relative to baseline, however, at 24 weeks after synbiotic administration there were positive changes in the counts of Bifidobacterium and total lactobacilli, the relative abundances of Bifidobacterium species such as Bifidobacterium adolescentis and Bifidobacterium pseudocatenulatum, and the concentrations of acetic and butyric acids in feces. No significant changes in inflammatory markers were found in the synbiotic group compared to the control group. However, synbiotic administration at least partially improved the gut environment in obese patients with type 2 diabetes.

A Pilot Study of Intervention With a Mobile Application Visualizing the Macronutrient Content for Type 2 Diabetes at a Japanese Center.

BACKGROUND: Estimating the nutritional content of food is essential for self-management in people with type 2 diabetes mellitus, but it is a difficult skill to learn. The aim of this study was to investigate how diabetes management was impacted by the ability of patients to search for items they ate from a database of 26,300 different foods, and to visualize nutritional intake using the Japanese mobile application (app) "Calomeal." METHODS: This was a single-arm, single-center, pilot study. Eighteen outpatients with type 2 diabetes mellitus used the "Calomeal" app for 3 months. The primary endpoint was change in hemoglobin A1c (HbA1c). Secondary endpoints were changes in body weight (BW), lipid parameters, and quality of life scores. RESULTS: The baseline characteristics of the study subjects were as follows: age: 53.4 ± 7.8 years; male/female ratio: 11/7; HbA1c: 7.9 (7.58 - 8.23)%; and body mass index (BMI): 25.17 (21.63 - 28.59) kg/m2. Significant reductions in HbA1c and BMI were observed over 3 months (HbA1c: 7.9 (7.58 - 8.23)% to 7.6 (7.3 - 8.23)%, P = 0.0410; BMI: 25.17 (21.63 - 28.59) to 24.54 (21.57 - 27.81) kg/m2, P = 0.0057). Reductions in HbA1c and BMI both correlated with decreased carbohydrate intake estimated by the mobile app. CONCLUSIONS: Japanese patients who used their smartphones to visualize their nutritional intake using the "Calomeal" app demonstrated improved short-term glycemic control and BMI. Although the validity of the results should be tested in future randomized controlled trials, this approach may be a clinical option for improving self-management in Japanese patients with type 2 diabetes mellitus.

Aldose reductase inhibitor, epalrestat, reduces lipid hydroperoxides in type 2 diabetes.

The increased flux of polyol pathway induced by hyperglycemia is implicated in the pathogenesis of various complications associated with diabetic, which results in increased oxidative stress. Because oxidative stress causes tissue damage in patients with diabetes, searching for an effective strategy to reduce oxidative stress in clinical setting is important in order to prevent diabetic complications. The aim of this study was to evaluate the effects of aldose reductase inhibition on oxidative stress in patients with type 2 diabetes mellitus. The subjects of this study were 21 patients with type 2 diabetes. We compared the levels of various oxidative stress markers and antioxidants including plasma thiobarbituric acid-reactive substances, malondialdehyde-modified low-density lipoprotein, vitamin E, beta-carotene and lipid hydroperoxides in erythrocytes at baseline with those measured after a 3-month course of epalrestat (150 mg/day), an aldose reductase inhibitor. While administration of epalrestat did not result in significant changes in plasma thiobarbituric acid-reactive substances, malondialdehyde-modified low-density lipoprotein, vitamin E, or beta-carotene, it significantly reduced lipid hydroperoxides in erythrocytes. Given the importance of measuring lipid hydroperoxides in erythrocytes as an index of oxidative stress, these results highlight the potential usefulness of epalrestat in reducing oxidative stress in type 2 diabetes mellitus.

Dramatic improvement of blood glucose control after pioglitazone treatment in poorly controlled over-weight diabetic patients with myotonic dystrophy.

Insulin resistance is mainly present in skeletal muscle in non-obese patients with myotonic dystrophy. Thiazolidinediones are reported to reduce insulin resistance in these patients. However, the effects of pioglitazone in overweight patients with myotonic dystrophy and type 2 diabetes mellitus have not been established. Here, we evaluated the effect of pioglitazone in two poorly-controlled over-weight diabetic patients with myotonic dystrophy. Case 1 was a 41- year-old women (BMI 27.8 kg/m(2)) with myotonic dystrophy and type 2 diabetes had been treated with 3 mg/day glimepiride and 500 mg/day metformin, but the treatment failed to achieve good glycemic control (HbA(1C) 11.8 %). Following admission to the hospital, she was treated with low-dose insulin and 30 mg/day pioglitazone. At 10 days after initiation of therapy, glycemic control was improved, serum IL-6 and hs-CRP decreased, and adiponectin level increased rapidly. Case 2 was a 47-year-old women (BMI 29.2 kg/m(2)) with myotonic dystrophy and type 2 diabetes mellitus had been treated with insulin without successful glycemic control (HbA(1C) 10.3 %). After admission, she was treated with 15 mg/day pioglitazone. This improved glycemic control, reduced daily insulin requirement, decreased IL-6 and hs-CRP levels rapidly and increased adiponectin level at 10 days after initiation of therapy. In both cases, pioglitazone rapidly improved glycemic control, enhanced adiponectin production, and reduced inflammatory cytokines. These results suggest that pioglitazone may be suitable for these patients.

Clinical factors associated with bacterial translocation in Japanese patients with type 2 diabetes: A retrospective study.

OBJECTIVE: To explore clinical factors associated with bacterial translocation in Japanese patients with type 2 diabetes mellitus (T2DM). METHODS: The data of 118 patients with T2DM were obtained from two previous clinical studies, and were retrospectively analyzed regarding the clinical parameters associated with bacterial translocation defined as detection of bacteremia and levels of plasma lipopolysaccharide binding protein (LBP), the latter of which is thought to reflect inflammation caused by endotoxemia. RESULTS: LBP level was not significantly different between patients with and without bacteremia. No clinical factors were significantly correlated with the detection of bacteremia. On the other hand, plasma LBP level was significantly correlated with HbA1c (r = 0.312), fasting blood glucose (r = 0.279), fasting C-peptide (r = 0.265), body mass index (r = 0.371), high-density lipoprotein cholesterol (r = -0.241), and inflammatory markers (high-sensitivity C-reactive protein, r = 0.543; and interleukin-6, r = 0.456). Multiple regression analysis identified body mass index, HbA1c, high-sensitivity C-reactive protein, and interleukin-6 as independent determinants of plasma LBP level. CONCLUSION: The plasma LBP level was similar in patients with and without bacteremia. While both bacteremia and LBP are theoretically associated with bacterial translocation, the detection of bacteremia was not associated with LBP level in T2DM.

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.

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.