A low serum IGF-1 is correlated with sarcopenia in subjects with type 1 diabetes mellitus: Findings from a post-hoc analysis of the iDIAMOND study.

AIM: Our previous study revealed that sarcopenia was frequently observed in subjects with type 1 diabetes mellitus (T1DM). However, the factors associated with sarcopenia that are related to T1DM have not yet been clarified. Insulin-like growth factor-1 (IGF-1) has been shown to play a role in skeletal muscle growth, differentiation, and regeneration. The present study, therefore, investigated the association between the serum IGF-1 level and sarcopenia and low skeletal muscle mass in subjects with T1DM. METHODS: This cross-sectional study enrolled subjects with T1DM (n = 168) and without diabetes (n = 59) who had had their clinical data on serum IGF-1 collected in the iDIAMOND study. RESULTS: The z-score of serum IGF-1 was significantly lower in the subjects with T1DM than that in those without diabetes (p < 0.001). Among subjects with T1DM, the z-score of serum IGF-1 was significantly lower in sarcopenic subjects than in non-sarcopenic subjects. The multivariable logistic regression analysis showed that the serum IGF-1 z-score was an independent determinant of sarcopenia and a low skeletal muscle mass index, but not low grip strength nor slow gait speed in subjects with T1DM. CONCLUSIONS: A low serum IGF-1 level is correlated with sarcopenia and low skeletal muscle mass in subjects with T1DM.

High prevalence and clinical impact of dynapenia and sarcopenia in Japanese patients with type 1 and type 2 diabetes: Findings from the Impact of Diabetes Mellitus on Dynapenia study.

AIMS/INTRODUCTION: The present study aimed to clarify the prevalence and clinical characteristics of sarcopenia and dynapenia, which are muscle weakness with and without low muscle mass, respectively, in Japanese patients with type 1 diabetes mellitus and type 2 diabetes mellitus. MATERIALS AND METHODS: This cross-sectional study enrolled 1,328 participants with type 1 diabetes (n = 177), type 2 diabetes (n = 645) and without diabetes (n = 506). Sarcopenia was defined as a low grip strength and slow gait speed with low skeletal muscle mass index, whereas dynapenia was defined as low strengths of grip and knee extension with a normal skeletal muscle mass index. Participants without sarcopenia and dynapenia were defined as robust. RESULTS: Among participants aged ≥65 years, sarcopenia and dynapenia were observed in 12.2% and 0.5% of individuals without diabetes, 42.9% and 11.4% of type 1 diabetes patients, and 20.9% and 13.9% of type 2 diabetes patients. In both type 1 diabetes and type 2 diabetes patients, sarcopenic patients were significantly older and thinner, and showed a significantly higher rate of diabetic neuropathy than robust patients. In patients with type 1 diabetes and type 2 diabetes, dynapenic patients were older, and showed a higher rate of diabetic neuropathy and lower estimated glomerular filtration rate than robust patients. Patients complicated with sarcopenia and dynapenia showed a significantly lower physical quality of life and higher rate of incidental falls than robust patients. CONCLUSIONS: Sarcopenia and dynapenia were more frequent in patients with type 1 diabetes and type 2 diabetes than in individuals without diabetes, which might contribute to their impaired quality of life and incidental falls.

The usefulness of a cholesterol absorption inhibitor in Japanese type 2 diabetes patients with dyslipidemia.

AIM: Cholesterol absorption has been suggested to be an independent risk factor for cerebral and cardiovascular events. We studied the clinical efficacy of ezetimibe in Japanese patients with type 2 diabetes mellitus complicated by dyslipidemia, in whom increased cholesterol absorption had been reported. SUBJECTS AND METHODS: Ninety-six patients with type 2 diabetes complicated by dyslipidemia received ezetimibe at 10 mg/day for 12 weeks. The lipid profile, a cholesterol synthesis marker (lathosterol), and cholesterol absorption markers (cholestanol, sitosterol, and campesterol) were measured before and after the therapy to evaluate the clinical efficacy of ezetimibe. RESULTS: Serum low-density lipoprotein-cholesterol (LDL-C) levels were positively associated with cholesterol absorption markers but not associated with a cholesterol synthesis marker, suggesting that serum LDL-C levels are more strongly related to cholesterol absorption than synthesis. During the 12-week ezetimibe treatment period, cholesterol absorption markers significantly decreased, and serum lipid profiles, including LDL-C levels, significantly improved. The LDL-C-lowering rate was greater in those patients who had been receiving statin therapy and were newly started on ezetimibe additionally than in the ezetimibe monotherapy group (-31.4% vs. -18.4%; P<0.001). CONCLUSIONS: It is suggested that ezetimibe improves the lipid profile in Japanese type 2 diabetes patients with dyslipidemia through the substantial reduction of cholesterol absorption.

Vitamin D deficiency is significantly associated with retinopathy in young Japanese type 1 diabetic patients.

The aim of this study was to examine the possible association of vitamin D deficiency with diabetic retinopathy in 75 young Japanese type 1 diabetic patients. A multivariate regression analysis, duration of diabetes and vitamin D deficiency were independent determinants of diabetic retinopathy.

Plasma pentraxin 3 levels are associated with carotid IMT in type 1 diabetic patients.

AIMS: Pentraxin3 (PTX3), a recently discovered inflammatory mediator, is produced abundantly in various cells in atherosclerotic lesions, and therefore, its plasma level could reflect local inflammation at the site of atherosclerotic lesion. The present study evaluated whether plasma PTX3 levels are associated with subclinical atherosclerosis in young subjects with type 1 diabetes. METHODS: Plasma PTX3 levels, urinary albumin excretion, diabetic retinopathy, and carotid intima-media thickness (IMT) were examined in 78 Japanese type 1 diabetic patients (30 men and 48 women, aged 28.5 ± 5.3 years (±SD), duration of diabetes 19.7 ± 6.5 years). RESULTS: There was statistically significant association between plasma PTX3 levels and Max-IMT (r=0.363, p=0.001). A stepwise multivariate regression analysis including conventional coronary risk factors as independent variables revealed that plasma PTX3 levels (ß=0.389, p<0.001), duration of diabetes (ß=0.256, p=0.035), and serum triglyceride levels (ß=0.371, p<0.001) were independent determinants of Max-IMT. In addition, plasma PTX3 levels was an independent determinant of urinary albumin excretion, an indicator of diabetic nephropathy (ß=0.258, p=0.018). However, there was no significant association between plasma PTX3 levels and diabetic retinopathy. CONCLUSIONS: Increased levels of plasma PTX3 are associated with accelerated atherosclerotic change and increased albuminuria in young patients with type 1 diabetes.

Usefulness of a novel system for measuring glucose area under the curve while screening for glucose intolerance in outpatients.

AIMS/INTRODUCTION: To realize the effectiveness of a novel system for measuring glucose area under the curve (AUC) using minimally invasive interstitial fluid extraction technology (MIET), outpatients undergoing oral glucose tolerance tests (OGTT) were investigated for the efficacy of screening for glucose intolerance using this system. MATERIALS AND METHODS: Fifty outpatients scheduled to undergo a 75-g OGTT for medical reasons were recruited to the study. An area of skin on the forearm was pretreated with microneedle arrays before the application of hydrogels for interstitial fluid extraction. Plasma glucose (PG) levels were measured every 30 min for 2 h to calculate reference (actual) AUC. The AUC was predicted by MIET on the basis of glucose extracted by the hydrogel using sodium ion levels as the internal standard. RESULTS: Good correlation between MIET-predicted and reference AUCs obtained using PG levels was confirmed for a wide AUC range. By introducing a threshold level for AUC to separate glucose intolerance with peak glucose ≥180 mg/dL from normal glucose tolerance, the system was demonstrated to provide better screening accuracy compared with conventional methods that use HbA1c and fasting PG levels. The results of a questionnaire-based survey administered to the subjects suggested that this system was readily accepted by the majority as a painless monitoring method. CONCLUSIONS: The findings suggest that our glucose AUC measurement system using MIET would be useful for screening of glucose intolerance. In the future, this system may prove to be a useful aid as a screen for glucose intolerance before performing an OGTT for diagnosis.

Ultrasonic tissue characterization of carotid plaque improves the prediction of cardiovascular events in diabetic patients: a pilot study.

OBJECTIVE: The aim of this study is to evaluate whether noninvasive ultrasonic tissue characterization of carotid plaque using integrated backscatter (IBS) analysis can be a predictor of future cardiovascular events (CVE) in asymptomatic type 2 diabetic patients. RESEARCH DESIGN AND METHODS: We prospectively evaluated the association between Calibrated-IBS value, an ultrasonic marker for tissue characteristics of carotid plaque, and CVE in 85 asymptomatic type 2 diabetic patients with carotid plaque. RESULTS: The median follow-up period was 7.9 years, and there were 20 new CVE. The risk of CVE was significantly higher in the subjects with low Calibrated-IBS values (<-17.1 dB; n = 42) as compared with those with high values (≥-17.1 dB; n = 43) (P = 0.004, log-rank test). Cox proportional hazards regression analysis revealed that both Calibrated-IBS value (hazard ratio [HR] 0.802 [95% CI 0.710-0.906]; P < 0.0001) and plaque thickness (1.938 [1.170-3.213]; P = 0.010) were independently associated with CVE, even after adjustment for the 10-year risk for a general cardiovascular disease estimated by Framingham risk scoring (FRS). Time-dependent receiver operating characteristic curve analysis for CVE at 10 years after the baseline examinations revealed that area under the curve for Calibrated-IBS was 0.76 (0.60-0.90) and substantially higher than those for plaque thickness (0.60 [0.45-0.79]) and FRS (0.60 [0.40-0.78]). These analyses also revealed that the addition of both plaque thickness and Calibrated-IBS value to conventional risk factors significantly improved the event prediction. CONCLUSIONS: Calibrated-IBS value could improve the risk prediction of CVE in asymptomatic type 2 diabetic patients with carotid plaque.

Pioglitazone reduces ER stress in the liver: direct monitoring of in vivo ER stress using ER stress-activated indicator transgenic mice.

It is known that endoplasmic reticulum (ER) stress is provoked under diabetic conditions and is possibly involved in the development of insulin resistance. In this study, using ER stress-activated indicator (ERAI) transgenic mice which express green fluorescent protein under ER stress conditions, we directly evaluated the effects of a diabetic agent pioglitazone on in vivo ER stress under diabetic conditions. In high fat and high sucrose diet-induced diabetic ERAI transgenic mice, 8 weeks of pioglitazone treatment reduced the accumulation of fat droplets in the liver and attenuated the development of insulin resistance. In the liver of the ERAI transgenic mice, ERAI fluorescence activity was clearly reduced as early as after 4 weeks of pioglitazone treatment, preceding the improvement of insulin resistance. In addition, after the pioglitazone treatment, serum free fatty acid and triglyceride levels were decreased, and serum adiponectin levels were increased. These data indicate that pioglitazone treatment suppresses ER stress in the liver which may explain, at least in part, the pharmacological effects of pioglitazone to reduce insulin resistance.

Role of copper ion in the pathogenesis of type 2 diabetes.

Reactive oxygen species (ROS) are induced under diabetic conditions and are likely associated with the development of type 2 diabetes. It is also known that ROS production is facilitated in the presence of copper ion through the Fenton reaction. The aim of this study was to examine the involvement of copper ion in the pathogenesis of type 2 diabetes and to evaluate the potential usefulness of a copper chelating agent for the treatment of type 2 diabetes. First, both serum copper ion and ROS levels in diabetic C57BL/KsJ-db/db mice were significantly higher compared to those in nondiabetic mice. Second, we treated diabetic db/db mice with a copper chelating agent tetrathiomolybdate and examined the effects on the development of type 2 diabetes. As the results, both serum copper ion and ROS levels were significantly decreased by the treatment, which were equivalent to those in non-diabetic mice. Consequently, the treatment with a copper chelating agent reduced insulin resistance and ameliorated glucose intolerance in diabetic db/db mice. In addition, serum triglyceride levels were also decreased by the treatment. In conclusion, our present results suggest that copper ion is involved in the development of type 2 diabetes and thereby a potential therapeutic target for diabetes.

Glycated albumin is a better indicator for glucose excursion than glycated hemoglobin in type 1 and type 2 diabetes.

To determine the impact of blood glucose profile, involving fluctuation and excursion of blood glucose levels, on glycated proteins, we evaluated the association among the daily profile of blood glucose, and glycated albumin (GA) and HbA1c levels in patients with type 1 diabetes (n = 93) and type 2 diabetes (n = 75). GA levels were strongly correlated with HbA1c levels in type 1 (r = 0.85, P<0.0001) and type 2 diabetes (r = 0.61, P<0.0001), respectively. HbA1c levels were similar between patients with type 1 and type 2 diabetes, while GA levels were significantly higher in type 1 diabetes. Thus the ratio of GA levels to HbA1c levels was significantly higher in type 1 diabetes than that in type 2 diabetes (3.32 0.36 vs. 2.89 0.44, p<0.001). The degrees of GA levels and HbA1c levels correlated with maximum and mean blood glucose levels in patients with type 1 and type 2 diabetes. Stepwise multivariate analysis revealed that GA levels independently correlated with maximum blood glucose levels in type 1 diabetes (F = 43.34, P<0.001) and type 2 diabetes (F = 41.57, P<0.001). HbA1c levels also independently correlated with maximum blood glucose levels in type 1 diabetes (F = 34.78, P<0.001), as well as being correlated with mean blood glucose levels in type 2 diabetes (F = 11.28, P<0.001). In summary, GA could be a better marker for glycemic control than glycated hemoglobin in diabetic patients, especially for evaluating glycemic excursion, which is considered to be a major cause of diabetic angiopathy.

Direct monitoring of in vivo ER stress during the development of insulin resistance with ER stress-activated indicator transgenic mice.

Type 2 diabetes is one of the most prevalent and serious metabolic diseases in the world, and insulin resistance and pancreatic beta-cell dysfunction are the hallmarks of the disease. It has been suggested that endoplasmic reticulum (ER) stress is provoked under diabetic conditions and is possibly involved in the development of insulin resistance. In this study, using ER stress-activated indicator (ERAI) transgenic mice which express green fluorescent protein (GFP) under ER stress conditions, we directly monitored in vivo ER stress in various insulin target tissues such as liver, fat, and muscle in diabetic mice with insulin resistance induced by high fat and high sucrose (HF/HS) diet treatment. In the liver of the ERAI transgenic mice, ERAI fluorescence activity was clearly observed as early as after 4 weeks of HF/HS diet treatment, whereas it was not detected at all in the fat and muscle even after 12 weeks of HF/HS diet treatment. These results suggest that induction of ER stress is associated with the development of insulin resistance and that ER stress in the liver may facilitate the development of insulin resistance in the whole body. This is the first report to directly monitor in vivo ER stress in various insulin target tissues during the development of insulin resistance. In addition, our present results suggest that ERAI transgenic mice are very useful for evaluating in vivo ER stress, especially in the liver, during the development of insulin resistance.

Oxidative stress and the JNK pathway are involved in the development of type 1 and type 2 diabetes.

Failure of pancreatic beta-cells is the common characteristic of type 1 and type 2 diabetes. Type 1 diabetes mellitus is induced by destruction of pancreatic beta-cells which is mediated by an autoimmune mechanism and consequent inflammatory process. Various inflammatory cytokines and oxidative stress are produced during this process, which has been proposed to play an important role in mediating beta-cell destruction. The JNK pathway is also activated by such cytokines and oxidative stress, and is involved in beta-cell destruction. Type 2 diabetes is the most prevalent and serious metabolic disease, and beta-cell dysfunction and insulin resistance are the hallmark of type 2 diabetes. Under diabetic conditions, chronic hyperglycemia gradually deteriorates beta-cell function and aggravates insulin resistance. This process is called "glucose toxicity". Under such conditions, oxidative stress is provoked and the JNK pathway is activated, which is likely involved in pancreatic beta-cells dysfunction and insulin resistance. In addition, oxidative stress and activation of the JNK pathway are also involved in the progression of atherosclerosis which is often observed under diabetic conditions. Taken together, it is likely that oxidative stress and subsequent activation of the JNK pathway are involved in the pathogenesis of type 1 and type 2 diabetes.

Beneficial effects of nateglinide on insulin resistance in type 2 diabetes.

Nateglinide, a rapid insulin secretagogue, is known to facilitate the early phase of insulin secretion and has been used for the treatment of type 2 diabetic patients with postprandial hyperglycemia. The aim of this study is to evaluate the effect of nateglinide on insulin resistance as well as insulin secretory defects in type 2 diabetic patients. Insulin secretion ability was evaluated by the hyperglycemic clamp test, and insulin sensitivity was evaluated by the euglycemic hyperinsulinemic clamp test, using an artificial pancreas. The hyperglycemic clamp test showed that a 7-day treatment with nateglinide significantly increased insulin secretion in response to high glucose. Interestingly, although nateglinide is known to facilitate insulin secretion, daily urinary C-peptide excretion was decreased after nateglinide treatment. Moreover, in the euglycemic hyperinsulinemic clamp test, glucose infusion rate was significantly increased by nateglinide treatment, indicating that nateglinide functions to decrease insulin resistance. Nateglinide ameliorates insulin resistance as well as insulin secretory defects in type 2 diabetic patients.

Hepatic insulin resistance induced by chronic hindlimb ischemia.

Peripheral vascular disease (PVD) has been reported to cause deterioration in insulin sensitivity. The precise mechanism of insulin resistance induced by PVD has not been clarified. To elucidate the mechanism causing impaired insulin action and glucose metabolism under peripheral ischemic conditions, we determined glucose turnover and glucose tolerance in hindlimb-ischemic (FAL) rats. The right femoral artery was ligated in hindlimb-ischemic (FAL) rats, while the artery was only exposed in the Sham operated (Sham) rats used as a control. Two weeks after the ligation, glucose tolerance was impaired and plasma insulin levels were significantly increased in FAL rats compared with Sham rats after intraperitoneal glucose loading (2 g kg(-1)). Under euglycemic hyperinsulinemic clamp conditions, the glucose infusion rate was significantly lower in FAL rats compared with Sham rats, but there was no significant difference in the glucose disappearance rate between the two groups. Hyperinsulinemia suppressed endogenous glucose production by 50% in Sham rats, while the suppression was 20% in FAL rats, indicating hepatic insulin resistance in FAL rats. mRNA analysis of isolated liver after the clamp experiment revealed that glucokinase mRNA, but not PEPCK and glucose-6-phosphatase mRNA, was significantly lower in FAL rats compared with Sham rats. In conclusion, chronic hindlimb ischemia impaired glucose tolerance associated with insulin resistance in the liver rather than the peripheral tissues.

Possible novel index determined by the glucose clamp test for selection of a suitable therapy for each type 2 diabetic patient.

The hallmark of type 2 diabetes is insulin resistance and insufficient insulin secretion, and appropriate therapy should be selected for each patient. In this study, to establish some index to select suitable therapy for each patient, we evaluated insulin sensitivity and insulin secretion with euglycemic hyperinsulinemic clamp and hyperglycemic clamp tests, respectively, and found that specific GIR index (GIRxIRI (90)) could be a useful marker to select suitable therapy for each type 2 diabetic patient (GIR: glucose infusion rate in euglycemic hyperinsulinemic clamp test; IRI (90): plasma insulin level 90 min after starting the hyperglycemic clamp test).

Involvement of endoplasmic reticulum stress in insulin resistance and diabetes.

Type 2 diabetes is one of the most prevalent and serious metabolic diseases in the world, and insulin resistance and pancreatic beta-cell dysfunction are the hallmarks of the disease. In this study, we have shown that endoplasmic reticulum (ER) stress, which is provoked under diabetic conditions, plays a crucial role in the insulin resistance found in diabetes by modifying the expression of oxygen-regulated protein 150 (ORP150), a molecular chaperone that protects cells from ER stress. Sense ORP overexpression in the liver of obese diabetic mice significantly improved insulin resistance and markedly ameliorated glucose tolerance. Conversely, expression of antisense ORP150 in the liver of normal mice decreased insulin sensitivity. The phosphorylation state of IRS-1 and Akt, which are key molecules for insulin signaling, and the expression levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, key enzymes of gluconeogenesis, were also altered by ORP150 overexpression. This is the first report showing that ER stress plays a crucial role in the insulin resistance found in diabetes and thus could be a potential therapeutic target for diabetes.