Proteasome inhibition in skeletal muscle cells unmasks metabolic derangements in type 2 diabetes

2014 ◽  
Vol 307 (9) ◽  
pp. C774-C787 ◽  
Author(s):  
Lubna Al-Khalili ◽  
Thais de Castro Barbosa ◽  
Jörgen Östling ◽  
Julie Massart ◽  
Pablo Garrido Cuesta ◽  
...  
Keyword(s):  
Metabolic Disease ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Proteome Analysis ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Insulin Resistant ◽  
Type 2 Diabetic

Two-dimensional difference gel electrophoresis (2-D DIGE)-based proteome analysis has revealed intrinsic insulin resistance in myotubes derived from type 2 diabetic patients. Using 2-D DIGE-based proteome analysis, we identified a subset of insulin-resistant proteins involved in protein turnover in skeletal muscle of type 2 diabetic patients, suggesting aberrant regulation of the protein homeostasis maintenance system underlying metabolic disease. We then validated the role of the ubiquitin-proteasome system (UPS) in myotubes to investigate whether impaired proteasome function may lead to metabolic arrest or insulin resistance. Myotubes derived from muscle biopsies obtained from people with normal glucose tolerance (NGT) or type 2 diabetes were exposed to the proteasome inhibitor bortezomib (BZ; Velcade) without or with insulin. BZ exposure increased protein carbonylation and lactate production yet impaired protein synthesis and UPS function in myotubes from type 2 diabetic patients, marking the existence of an insulin-resistant signature that was retained in cultured myotubes. In conclusion, BZ treatment further exacerbates insulin resistance and unmasks intrinsic features of metabolic disease in myotubes derived from type 2 diabetic patients. Our results highlight the existence of a confounding inherent abnormality in cellular protein dynamics in metabolic disease, which is uncovered through concurrent inhibition of the proteasome system.

scholarly journals Apelin and APJ regulation in adipose tissue and skeletal muscle of type 2 diabetic mice and humans

2010 ◽  
Vol 298 (6) ◽  
pp. E1161-E1169 ◽  
Author(s):  
Cédric Dray ◽  
Cyrille Debard ◽  
Jennifer Jager ◽  
Emmanuel Disse ◽  
Danièle Daviaud ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Receptor Expression ◽  
Diabetic Patients ◽  
Mrna Levels ◽  
Type 2 Diabetic Patients ◽  
Insulin Resistant ◽  
Type 2 Diabetic

Apelin, an adipocyte-secreted factor upregulated by insulin, is increased in adipose tissue (AT) and plasma with obesity. Apelin was recently identified as a new player in the control of glucose homeostasis. However, the regulation of apelin and APJ (apelin receptor) expression in skeletal muscle in relation to insulin resistance or type 2 diabetes is not known. Thus we studied apelin and APJ expression in AT and muscle in different mice models of obesity and in type 2 diabetic patients. In insulin-resistant high-fat (HF)-fed mice, apelin and APJ expression were increased in AT compared with control. This was not the case in AT of highly insulin-resistant db/ db mice. In skeletal muscle, apelin expression was similar in control and HF-fed mice and decreased in db/ db mice. APJ expression was decreased in both HF-fed and db/ db mice. Control subjects and type 2 diabetic patients were subjected to a hyperinsulinemic-euglycemic clamp, and tissues biopsies were obtained before and at the end of the clamp. There was no significant difference in basal apelin and APJ expression in AT and muscle between control and diabetic patients. However, apelin plasma levels were significantly increased in diabetic patients. During the clamp, hyperinsulinemia increased apelin and APJ expression in AT of control but not in diabetic subjects. In muscle, only APJ mRNA levels were increased in control but also in diabetic patients. Taken together, these data show that apelin and APJ expression in mice and humans is regulated in a tissue-dependent manner and according to the severity of insulin resistance.

Increased collagen content in insulin-resistant skeletal muscle

2006 ◽  
Vol 290 (3) ◽  
pp. E560-E565 ◽  
Author(s):  
Rachele Berria ◽  
Lishan Wang ◽  
Dawn K. Richardson ◽  
Jean Finlayson ◽  
Renata Belfort ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Extracellular Matrix ◽  
Collagen Content ◽  
Matrix Composition ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Insulin Resistant ◽  
Obese Subjects ◽  
Type 2 Diabetic

Oversupply and underutilization of lipid fuels are widely recognized to be strongly associated with insulin resistance in skeletal muscle. Recent attention has focused on the mechanisms underlying this effect, and defects in mitochondrial function have emerged as a potential player in this scheme. Because evidence indicates that lipid oversupply can produce abnormalities in extracellular matrix composition and matrix changes can affect the function of mitochondria, the present study was undertaken to determine whether muscle from insulin-resistant, nondiabetic obese subjects and patients with type 2 diabetes mellitus had increased collagen content. Compared with lean control subjects, obese and type 2 diabetic subjects had reduced muscle glucose uptake ( P < 0.01) and decreased insulin stimulation of tyrosine phosphorylation of insulin receptor substrate-1 and its ability to associate with phosphatidylinositol 3-kinase ( P < 0.01 and P < 0.05). Because it was assayed by total hydroxyproline content, collagen abundance was increased in muscle from not only type 2 diabetic patients but also nondiabetic obese subjects (0.26 ± 0.05, 0.57 ± 0.18, and 0.67 ± 0.20 μg/mg muscle wet wt, lean controls, obese nondiabetics, and type 2 diabetics, respectively), indicating that hyperglycemia itself could not be responsible for this effect. Immunofluorescence staining of muscle biopsies indicated that there was increased abundance of types I and III collagen. We conclude that changes in the composition of the extracellular matrix are a general characteristic of insulin-resistant muscle.

scholarly journals Hypoadiponectinemia is associated with increased insulin resistance, dyslipidemia and presence of type 2 diabetes in non obese central Indian population

2018 ◽  
Vol 7 (1) ◽  
pp. 106
Author(s):  
Anil B. Choudhury ◽  
Shankar M. Pawar ◽  
Purnima Dey Sarkar ◽  
Keerti Gopi
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Waist Circumference ◽  
Adiponectin Level ◽  
Diabetic Group ◽  
Diabetic Patients ◽  
Inverse Association ◽  
Type 2 Diabetic Patients ◽  
Type 2 Diabetic

Background: Accumulating evidence suggests that adiponectin, a major adipocyte secretory protein, has insulin-sensitizing and anti-atherogenic properties and protects against later development of type 2 diabetes. We investigated the association of adiponectin with insulin resistance, blood lipids and type 2 diabetes in non obese central Indian population.Methods: Anthropometric and biochemical parameters were measured in 149 (81 male and 68 female) newly diagnosed non obese type 2 diabetic patients and 157 (85 male and 72 female) age and body mass index (BMI) matched controls.Results: Adiponectin level (p<0.0001) was significantly lower in the diabetic group than in non diabetic control. In an age, gender and BMI adjusted model, adiponectin level was significantly negatively correlated with waist circumference, waist to hip ratio, systolic blood pressure, fasting insulin, homeostasis model assessment-insulin resistance (HOMA-IR) (p= 0.0034), HbA1C, total cholesterol, LDL-cholesterol, and triglycerides (p<0.0001) and positively correlated with HDL-cholesterol (p =0.0014) in non obese type 2 diabetic group. However, there was no significant correlation between adiponectin and glucose in this study. In stepwise linear regression analysis, adjusted for potential confounder, significant inverse association was observed between serum adiponectin level and HOMA-IR (p = 0.0001). In multivariate logistic regression model, adjusted for age, gender, BMI, waist circumference, and waist-hip ratio, lower adiponectin was independently associated with the presence of type 2 diabetes (p<0.0001).Conclusions: Lower adiponectin levels in non obese type 2 diabetic patients were significantly related to the increased insulin resistance, dyslipidemia, and presence of type 2 diabetes, independently of overall and abdominal adiposity, thereby suggesting a direct link between adiponectin and carbohydrate and lipid metabolism in human.

Skeletal muscle capillary density and microvascular function are compromised with aging and type 2 diabetes

2014 ◽  
Vol 116 (8) ◽  
pp. 998-1005 ◽  
Author(s):  
Bart B. L. Groen ◽  
Henrike M. Hamer ◽  
Tim Snijders ◽  
Janneau van Kranenburg ◽  
Dionne Frijns ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Fiber Type ◽  
Capillary Density ◽  
Boundary Region ◽  
Whole Body ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Type 2 Diabetic

Adequate muscle perfusion is required for the maintenance of skeletal muscle mass. Impairments in microvascular structure and/or function with aging and type 2 diabetes have been associated with the progressive loss of skeletal muscle mass. Our objective was to compare muscle fiber type specific capillary density and endothelial function between healthy young men, healthy older men, and age-matched type 2 diabetes patients. Fifteen healthy young men (24 ± 1 yr), 15 healthy older men (70 ± 2 yr), and 15 age-matched type 2 diabetes patients (70 ± 1 yr) were selected to participate in the present study. Whole body insulin sensitivity, muscle fiber type specific capillary density, sublingual microvascular density, and dimension of the erythrocyte-perfused boundary region were assessed to evaluate the impact of aging and/or type 2 diabetes on microvascular structure and function. Whole body insulin sensitivity was significantly lower at a more advanced age, with lowest values reported in the type 2 diabetic patients. In line, skeletal muscle capillary contacts were much lower in the older and older type 2 diabetic patients when compared with the young. Sidestream darkfield imaging showed a significantly greater thickness of the erythrocyte perfused boundary region in the type 2 diabetic patients compared with the young. Skeletal muscle capillary density is reduced with aging and type 2 diabetes and accompanied by impairments in endothelial glycocalyx function, which is indicative of compromised vascular function.

Insulin-sensitive and insulin-resistant variants in nonobese Japanese type 2 diabetic patients. The role of triglycerides in insulin resistance

Diabetes Care ◽  
1999 ◽  
Vol 22 (12) ◽  
pp. 2100-2101 ◽  
Author(s):  
A. Taniguchi ◽  
M. Fukushima ◽  
M. Sakai ◽  
K. Kataoka ◽  
K. Miwa ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Insulin Resistant ◽  
Type 2 Diabetic

scholarly journals Evidence of increased visceral obesity and reduced physical fitness in healthy insulin-resistant first-degree relatives of type 2 diabetic patients

2004 ◽  
pp. 207-214 ◽  
Author(s):  
B Nyholm ◽  
MF Nielsen ◽  
K Kristensen ◽  
S Nielsen ◽  
T Ostergard ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Visceral Obesity ◽  
Visceral Adiposity ◽  
Diabetic Patients ◽  
Vo2 Max ◽  
Type 2 Diabetic Patients ◽  
Insulin Resistant ◽  
History Of ◽  
Type 2 Diabetic

OBJECTIVE: First-degree relatives (FDR) of type 2 diabetic patients are often insulin resistant. Visceral obesity is closely linked to both insulin resistance and type 2 diabetes. We therefore hypothesized that the inheritance of an increased tendency to store fat in visceral fat depots may be a characteristic phenotypic feature in FDR contributing to their insulin resistance. DESIGN AND METHODS: We measured fat distribution in 20 FDR and 14 age-, gender- and body mass index (BMI)-matched controls employing dual energy X-ray absorbtiometry (DEXA)- and computed tomography (CT)-scanning. Insulin-stimulated glucose uptake (ISGU) was determined by a hyperinsulinemic clamp and maximal aerobic work capacity (VO2 max) by a bicycle ergometer test. Baseline lipolysis was measured using [3H]palmitate. The activity level of the hypothalamic-pituitary-adrenal axis was assessed as the 24 h urinary (u)-cortisol/creatinine ratio. RESULTS: All subjects had a normal oral glucose tolerance test (OGTT), but FDR were insulin resistant (ISGU: 6.64+/-0.48 vs 9.12+/-0.98 mg/kg ffm/min, P=0.01). Despite similar BMI (25.2+/-0.5 vs 24.8+/-0.7 kg/m2, P=0.61) and overall fat mass (26.4+/-1.6 vs 24.2+/-2.1%, P=0.41) in FDR vs controls, the amount of visceral adipose tissue was substantially increased (65.9+/-10.0 vs 40.1+/-11.3 cm2, P<0.05) and VO2 max was reduced (52.2+/-3.1 vs 63.3+/-3.9 ml/kg ffm/min, P<0.05) in FDR. Visceral adiposity was inversely correlated with ISGU (FDR: r=-0.52, P<0.05; controls: r=-0.65, P<0.01) and in multiple regression analysis visceral adiposity (P<0.01), VO2 max (P<0.001) and a family history of type 2 diabetes (P<0.05) (r2=0.64) all significantly and independently contributed to the level of ISGU. Baseline palmitate appearance (145+/-10 vs 139+/-15 micromol/min, P=0.74) and the 24 h u-cortisol/creatinine ratio ((24.9+/-1.3 vs 27.4+/-2.0).10(-6), P=0.28) were both comparable in the two groups. CONCLUSION: Healthy but insulin-resistant FDR have enhanced visceral obesity and reduced VO2 max compared with people without a family history of diabetes, despite similar BMI and overall fat mass. Both the visceral adiposity and reduced aerobic fitness are strongly associated with and may contribute to their insulin resistance.

Metabolic differences in healthy first-degree female relatives of type 2 diabetic patients

2013 ◽  
Vol 154 (44) ◽  
pp. 1747-1753
Author(s):  
Györgyi Kovács ◽  
Barbara Buday ◽  
Attila Fék ◽  
Botond Literáti-Nagy ◽  
József Pauer ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Hepatic Insulin Resistance ◽  
High Density Lipoproteins ◽  
Oral Glucose ◽  
Diabetic Patients ◽  
Type 2 Diabetic Patients ◽  
Prediabetic State ◽  
Type 2 Diabetic

Introduction: Today the prevalence of type 2 diabetes reached an epidemic level. It is known that type 2 diabetes could only be prevented before the manifestation, during the “prediabetic” state, urging the development of diagnostic tests to recognize the group at risk in time. Aim: The authors explored metabolic differences between healthy, normal glucose tolerant, normal insulin resistant females having first degree relatives with and without type 2 diabetes. Method: Healthy, normal insulin sensitive females without (n = 26) and with (n = 18) type 2 diabetic relatives were investigated. Results: Healthy females with first degree diabetic relatives had lower low density lipoproteins and higher high density lipoproteins as well as higher glucose and insulin levels at the 120 min of oral glucose test as compared to those without first degree diabetic relatives. Conclusions: These results suggest that the appearance of insulin resistance is preceded by hepatic insulin resistance and impaired lipid metabolism in the symptom-free prediabetic period of genetically suceptible females. Orv. Hetil., 154 (44), 1747–1753.

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