Insulin signal transduction in human skeletal muscle: identifying the defects in Type II diabetes

2005 ◽  
Vol 33 (2) ◽  
pp. 354-357 ◽  
Author(s):  
M. Björnholm ◽  
J.R. Zierath
Keyword(s):  
Skeletal Muscle ◽  
Type Ii Diabetes ◽  
Insulin Action ◽  
Glucose Transporter ◽  
Whole Body ◽  
Diabetic Patients ◽  
Type Ii ◽  
Peripheral Tissues ◽  
Glucose Homoeostasis ◽  
Insulin Receptor Signalling

Type II diabetes is characterized by defects in insulin action on peripheral tissues, such as skeletal muscle, adipose tissue and liver and pancreatic β-cell defects. Since the skeletal muscle accounts for approx. 75% of whole body insulin-stimulated glucose uptake, defects in this tissue play a major role in the impaired glucose homoeostasis in Type II diabetic patients. Thus identifying defective steps in this process may reveal attractive targets for drug development to combat insulin resistance and Type II diabetes. This review will describe the effects of insulin on glucose transport and other metabolic events in skeletal muscle that are mediated by intracellular signalling cascades. Evidence for impaired activation of the insulin receptor signalling cascade and defective glucose transporter 4 translocation in the skeletal muscle from Type II diabetic patients will be presented. Through the identification of the intracellular defects in insulin action that control glucose homoeostasis, a better understanding of the disease pathogenesis can be gained and strategies for intervention may be developed.

Increments in insulin sensitivity during intensive treatment are closely correlated with decrements in glucocorticoid receptor mRNA in skeletal muscle from patients with Type II diabetes

2001 ◽  
Vol 101 (5) ◽  
pp. 533-540 ◽  
Author(s):  
Henrik VESTERGAARD ◽  
Palle BRATHOLM ◽  
Niels Juel CHRISTENSEN
Keyword(s):  
Skeletal Muscle ◽  
Type Ii Diabetes ◽  
Intensive Treatment ◽  
Whole Body ◽  
Glucose Disposal ◽  
Diabetic Patients ◽  
Mrna Levels ◽  
Type Ii ◽  
Total Rna ◽  
Glucose Disposal Rate

To test the hypothesis that changes in the expression of the glucocorticoid receptor (GCR) and the β2-adrenoceptor (β2-AR) contribute significantly to the abnormal glucose metabolism in skeletal muscle from patients with Type II diabetes, we have examined (1) the levels of total GCR (α+β isoforms), the α/α2 isoform of GCR and β2-AR mRNAs in skeletal muscle from insulin-resistant patients with Type II diabetes (n = 10) and healthy controls (n = 15), and (2) the effects of 8 weeks of intensive treatment on the whole-body glucose disposal rate and on total GCR, α/α2 GCR and β2-AR mRNA levels in diabetic patients. The total glucose disposal rate was measured by the euglycaemic hyperinsulinaemic (2m-unitsċmin-1ċkg-1) clamp technique, and mRNA levels were assessed by reverse transcriptase-PCR and HPLC for separation of standard and unknown and quantification. Mean levels of total GCR and α/α2 GCR mRNAs were increased in patients with Type II diabetes when compared with control subjects [total GCR, 2.06±0.30 and 1.47±0.10 amol/μg of total RNA respectively (P = 0.09); α/α2 GCR mRNA, 1.69±0.31and 0.92±0.09amol/μg of total RNA respectively (P = 0.02)], whereas mRNA levels of the β isoform of GCR (total GCR minus α/α2 GCR) were decreased (P = 0.006). β2-AR mRNA levels were comparable in diabetic patients and control subjects (0.53±0.05 and 0.45±0.02amol/μg of total RNA respectively; P = 0.2). Intensive treatment for 8 weeks was associated with improved glycaemic control (P = 0.019), and during the clamp a 75% (P = 0.001) increase in the whole-body insulin-stimulated glucose disposal rate was demonstrated. Total GCR (P = 0.005), α/α2 GCR (P = 0.005) and β2-AR (P = 0.03) mRNA levels all decreased significantly after intensive insulin treatment. A close correlation was found between increments in glucose uptake during intensive treatment and decrements in skeletal muscle total GCR mRNA (r = 0.95, P<0.001; multiple regression analysis), and between glucose uptake and α/α2 GCRm RNA levels (r = 0.88, P<0.001; simple correlation). In conclusion, the abnormal regulation of GCR mRNA is likely to play a significant role in the insulin resistance observed in obese patients with Type II diabetes.

Effects of Type II diabetes on capillary hemodynamics in skeletal muscle

2006 ◽  
Vol 291 (5) ◽  
pp. H2439-H2444 ◽  
Author(s):  
Danielle J. Padilla ◽  
Paul McDonough ◽  
Brad J. Behnke ◽  
Yutaka Kano ◽  
K. Sue Hageman ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Blood Glucose ◽  
Type Ii Diabetes ◽  
Capillary Tube ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Diabetic Patients ◽  
Type I ◽  
Type Ii ◽  
Gk Rats

Microcirculatory red blood cell (RBC) hemodynamics are impaired within skeletal muscle of Type I diabetic rats (Kindig CA, Sexton WL, Fedde MR, and Poole DC. Respir Physiol 111: 163–175, 1998). Whether muscle microcirculatory dysfunction occurs in Type II diabetes, the more prevalent form of the disease, is unknown. We hypothesized that Type II diabetes would reduce the proportion of capillaries supporting continuous RBC flow and RBC hemodynamics within the spinotrapezius muscle of the Goto-Kakizaki Type II diabetic rat (GK). With the use of intravital microscopy, muscle capillary diameter ( dc), capillary lineal density, capillary tube hematocrit (Hctcap), RBC flux ( FRBC), and velocity ( VRBC) were measured in healthy male Wistar (control: n = 5, blood glucose, 105 ± 5 mg/dl) and male GK ( n = 7, blood glucose, 263 ± 34 mg/dl) rats under resting conditions. Mean arterial pressure did not differ between groups ( P > 0.05). Sarcomere length was set to a physiological length (∼2.7 μm) to ensure that muscle stretching did not alter capillary hemodynamics; dc was not different between control and GK rats ( P > 0.05), but the percentage of RBC-perfused capillaries (control: 93 ± 3; GK: 66 ± 5 %), Hctcap, VRBC, FRBC, and O2 delivery per unit of muscle were all decreased in GK rats ( P < 0.05). This study indicates that Type II diabetes reduces both convective O2 delivery and diffusive O2 transport properties within muscle microcirculation. If these microcirculatory deficits are present during exercise, it may provide a basis for the reduced O2 exchange characteristic of Type II diabetic patients.

scholarly journals Loss of CHIP Expression Perturbs Glucose Homeostasis and Leads to Type II Diabetes through Defects in Microtubule Polymerization and Glucose Transporter Localization

2017 ◽  
Author(s):  
Holly McDonough ◽  
Kaitlin C. Lenhart ◽  
Sarah M. Ronnebaum ◽  
Chunlian Zhang ◽  
Jie An ◽  
...  
Keyword(s):  
Glucose Homeostasis ◽  
Protein Trafficking ◽  
Type Ii Diabetes ◽  
Glucose Transporter ◽  
Protein A ◽  
Whole Body ◽  
Type Ii ◽  
Interacting Protein ◽  
Microtubule Polymerization ◽  
Dependent Protein

ABSTRACTRecent evidence has implicated CHIP (carboxyl terminus of Hsc/Hsp70-interacting protein), a co-chaperone and ubiquitin ligase, in the functional support of several metabolism-related proteins, including AMPK and SirT6. In addition to previously reported aging and stress intolerance phenotypes, we find that CHIP -/- mice also demonstrate a Type II diabetes-like phenotype, including poor glucose tolerance, decreased sensitivity to insulin, and decreased insulin-stimulated glucose uptake in isolated skeletal muscle, characteristic of insulin resistance. In CHIP-deficient cells, glucose stimulation fails to induce translocation of Glut4 to the plasma membrane. This impairment in Glut4 translocation in CHIP-deficient cells is accompanied by decreased tubulin polymerization associated with decreased phosphorylation of stathmin, a microtubule-associated protein required for polymerization-dependent protein trafficking within the cell. Together, these data describe a novel role for CHIP in regulating microtubule polymerization that assists in glucose transporter translocation, promoting whole-body glucose homeostasis and sensitivity to insulin.

scholarly journals Troglitazone Effects on Gene Expression in Human Skeletal Muscle of Type II Diabetes Involve Up-Regulation of Peroxisome Proliferator-Activated Receptor-γ1

1998 ◽  
Vol 83 (8) ◽  
pp. 2830-2835 ◽  
Author(s):  
Kyong Soo Park ◽  
Theodore P. Ciaraldi ◽  
Kristin Lindgren ◽  
Leslie Abrams-Carter ◽  
Sunder Mudaliar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Type Ii Diabetes ◽  
Insulin Action ◽  
Peroxisome Proliferator ◽  
Type Ii ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nondiabetic Control ◽  
Muscle Cultures ◽  
Stimulation Of

abstract Troglitazone, besides improving insulin action in insulin-resistant subjects, is also a specific ligand for the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ). To determine whether troglitazone might enhance insulin action by stimulation of PPARγ gene expression in muscle, total PPARγ messenger RNA (mRNA), and protein were determined in skeletal muscle cultures from nondiabetic control and type II diabetic subjects before and after treatment of cultures with troglitazone (4 days ± troglitazone, 11.5μ m). Troglitazone treatment increased PPARγ mRNA levels up to 3-fold in muscle cultures from type II diabetics (277 ± 63 to 630 ± 100 × 103 copies/μg total RNA, P = 0.003) and in nondiabetic control subjects (200 ± 42 to 490 ± 81, P = 0.003). PPARγ protein levels in both diabetic (4.7 ± 1.6 to 13.6± 3.0 AU/10 μg protein, P &lt; 0.02) and nondiabetic cells (7.4 ± 1.0 to 12.7 ± 1.8, P &lt; 0.05) were also up-regulated by troglitazone treatment. Increased PPARγ was associated with stimulation of human adipocyte lipid binding protein (ALBP) and muscle fatty acid binding protein (mFABP) mRNA, without change in the mRNA for glycerol-3-phosphate dehydrogenase, PPARδ, myogenin, uncoupling protein-2, or sarcomeric α-actin protein. In summary, we showed that troglitazone markedly induces PPARγ, ALBP, and mFABP mRNA abundance in muscle cultures from both nondiabetic and type II diabetic subjects. Increased expression of PPARγ protein and other genes involved in glucose and lipid metabolism in skeletal muscle may account, in part, for the insulin sensitizing effects of troglitazone in type II diabetes.

PPARγ-mediated insulin sensitization: the importance of fat versus muscle

2005 ◽  
Vol 288 (2) ◽  
pp. E287-E291 ◽  
Author(s):  
Ulrich Kintscher ◽  
Ronald E. Law
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Nuclear Hormone Receptor ◽  
Whole Body ◽  
Diabetic Patients ◽  
Peroxisome Proliferator ◽  
Type 2 Diabetic Patients ◽  
Peroxisome Proliferator Activated Receptor ◽  
Peripheral Tissues

Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear hormone receptor that functions as a transcriptional regulator in a variety of tissues. PPARγ activation, e.g., through binding of the synthetic glitazones or thiazolidinediones (TZD), results in a marked improvement in type 2 diabetic patients of insulin and glucose parameters resulting from an improvement of whole body insulin sensitivity. The role of different metabolic tissues (fat, skeletal muscle, liver) in mediating PPARγ function in glucose and insulin homeostasis is still unclear. Recently, the function of PPARγ in adipose tissue and skeletal muscle has been intensively characterized by using targeted deletion of PPARγ in those tissues. In those studies, adipose PPARγ has been identified as an essential mediator for the maintainance of whole body insulin sensitivity. Two major mechanisms have been described. 1) Adipose PPARγ protects nonadipose tissue against excessive lipid overload and maintains normal organ function (liver, skeletal muscle); and 2) adipose PPARγ guarantees a balanced and adequate production of secretion from adipose tissue of adipocytokines such as adiponectin and leptin, which are important mediators of insulin action in peripheral tissues. In contrast to studies in adipose-specific PPARγ-deficient mice, the data in muscle-specific PPARγ−/− mice demonstrate that whole body insulin sensitivity is, at least in part, relying on an intact PPARγ system in skeletal muscle. Finally, these early and elegant studies using tissue-specific PPARγ knockout mouse models pinpoint adipose tissue as the major target of TZD-mediated improvement of hyperlipidemia and insulin sensitization.

Relationship between uric acid and creatinine in pre-diabetic and diabetic patients: Vidarbha region of Maharashtra

2020 ◽  
Vol 11 (3) ◽  
pp. 3412-3417
Author(s):  
Ranjit S. Ambad ◽  
Rakesh Kumar Jha ◽  
Lata Kanyal Butola ◽  
Nandkishor Bankar ◽  
Brij Raj Singh ◽  
...  
Keyword(s):  
Uric Acid ◽  
Serum Uric Acid ◽  
Type Ii Diabetes ◽  
Fasting Blood Glucose ◽  
General Medicine ◽  
Control Group ◽  
Diabetic Patients ◽  
Type Ii ◽  
Develop Type ◽  
Low Levels

Prediabetes is a glucose homeostasis condition characterized by decreased absorption to glucose or reduced fasting glucose. Both of these are reversible stages of intermediate hyperglycaemia providing an increased type II DM risk. Pre-diabetes can therefore be viewed as a significant reversible stage which could lead to type II DM, and early detection of prediabetes may contribute to type II DM prevention. Prediabetes patients are at high risk for potential type II diabetes, and 70 percent of them appear to develop Type II diabetes within 10 years. The present study includes total 200 subjects that include 100 Prediabetic patients, 50 T2DM patients and 50 healthy individual. Blood samples were collected from the subjects were obtained for FBS, PPBS, Uric acid and Creatinine estimation, from OPD and General Medicine Wards. Present study showed low levels of Serum Uric Acid in prediabetic and T2DM patients were decreased as compared to control group, while the level of creatinine in prediabetic and diabetic were elevated as compared to control group, were not statically significant. Serum Uric Acid was high in control group and low in prediabetic and diabetic patients. Serum creatinine was declined in control group and increased in prediabetic and diabetic patients with increasing Fasting blood glucose level.

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