Regulation of Glucose Metabolism by MuRF1 and Treatment of Myopathy in Diabetic Mice with Small Molecules Targeting MuRF1

The muscle-specific ubiquitin ligase MuRF1 regulates muscle catabolism during chronic wasting states, although its roles in general metabolism are less-studied. Here, we metabolically profiled MuRF1-deficient knockout mice. We also included knockout mice for MuRF2 as its closely related gene homolog. MuRF1 and MuRF2-KO (knockout) mice have elevated serum glucose, elevated triglycerides, and reduced glucose tolerance. In addition, MuRF2-KO mice have a reduced tolerance to a fat-rich diet. Western blot and enzymatic studies on MuRF1-KO skeletal muscle showed perturbed FoxO-Akt signaling, elevated Akt-Ser-473 activation, and downregulated oxidative mitochondrial metabolism, indicating potential mechanisms for MuRF1,2-dependent glucose and fat metabolism regulation. Consistent with this, the adenoviral re-expression of MuRF1 in KO mice normalized Akt-Ser-473, serum glucose, and triglycerides. Finally, we tested the MuRF1/2 inhibitors MyoMed-205 and MyoMed-946 in a mouse model for type 2 diabetes mellitus (T2DM). After 28 days of treatment, T2DM mice developed progressive muscle weakness detected by wire hang tests, but this was attenuated by the MyoMed-205 treatment. While MyoMed-205 and MyoMed-946 had no significant effects on serum glucose, they did normalize the lymphocyte–granulocyte counts in diabetic sera as indicators of the immune response. Thus, small molecules directed to MuRF1 may be useful in attenuating skeletal muscle strength loss in T2DM conditions.

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Effect of metformin on the expression of SNAER proteins in the skeletal muscle of rats with type 2 diabetes

Journal of Birjand University of Medical Sciences ◽

10.32592/jbirjandunivmedsci.2021.28.3.105 ◽

2021 ◽

pp. 270-278

Keyword(s):

Type 2 Diabetes ◽

Skeletal Muscle ◽

Body Weight ◽

Serum Insulin ◽

Serum Glucose ◽

Snare Complex ◽

Snare Proteins ◽

Glucose Levels ◽

Male Wistar Rats

Background and Aims: SNARE proteins are composed of a combination of SNAP-23, Stx-4, and VAMP-2 isoforms that are significantly expressed in skeletal muscle. These proteins control the transport of GLUT4 to the cell membranes. The modifications in the expression of SNARE proteins can cause Type 2 diabetes. The present study aimed to assess the effect of metformin on the expression of these proteins in rats. Materials and Methods: For the purpose of the study, 40 male Wistar rats were randomly selected. Streptozotocin and Nicotinamide were used for the induction of type 2 diabetes. The animals were assigned to five groups (n=8), including healthy and diabetic groups as control, as well as three experimental groups which were treated with different doses of metformin (100, 150, and 200 mg/kg body weight) for 30 days. The quantitative reverse transcription PCR (RT-qPCR) method was applied to evaluate the expression of SNARE complex proteins.. Results: Based on the results, metformin (100, 150, and 200 mg/kg body weight) decreased serum glucose levels and increased serum insulin levels. This difference in dose of 200 mg/kg body weight was statistically significant (P<0.05). Moreover, all three doses of metformin increased the expression of SNAP- 23, syntaxin-4, and VAMP-2 proteins in skeletal muscle tissue. Metformin at a dose of 200 mg/kg body weight demonstrated the most significant effects (P<0.05). Conclusion: As evidenced by the results of the current study, another anti-diabetic mechanism of metformin is to increase the expression of SNARE proteins, which effectively improves insulin resistance and lowers blood glucose.

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Abstract 209: Dimethylarginine Dimethylaminohydrolase 1 and Insulin Resistance

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.34.suppl_1.209 ◽

2014 ◽

Vol 34 (suppl_1) ◽

Author(s):

Sophie E Piper ◽

James M Leiper

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Plasma Glucose ◽

Knockout Mice ◽

Physiological Role ◽

Causal Link ◽

Chow Diet ◽

Dimethylarginine Dimethylaminohydrolase

Type 2 diabetes is a prevalent metabolic condition and is the result of an impaired response to insulin. Insulin resistance and type 2 diabetes are clearly associated with obesity and the secondary cardiovascular complications of this condition are serious and life threatening. Asymemetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases and increased levels are seen in multiple pathologies. Increased plasma levels of ADMA have been associated with patients with type 2 diabetes, insulin resistance and obesity, although a causal link between ADMA and diabetes has not been established. Dimethylarginine dimethylaminohydrolase (DDAH) is the enzyme that catalyses the metabolism of ADMA. There are two isoforms of the enzyme which are both involved in the control of ADMA and NO. The interplay of insulin with NO release is well established but the initial causes for the onset of insulin resistance are not well defined. Elevated levels of ADMA are linked to insulin resistance and transgenic mice that over-express ddah1 show increased insulin sensitivity. Of note is that metformin, an insulin sensitising drug that is widely used in the treatment of insulin resistance, reduces plasma glucose and ADMA concentrations. In order to elucidate the physiological role of DDAH1 in glucose homeostasis we investigated the glucose handling in a ddah1 global knockout model. Intra-peritoneal glucose tolerance tests in ddah1 global knockout mice demonstrate insulin resistance. Baseline plasma glucose levels were 25% higher in ddah1 knockouts and peak levels were 53% higher in ddah1 knockouts. The kinetics of plasma glucose accumulation and clearance in ddah1 knockout mice suggests dysfunction in both the liver and skeletal muscle. On a normal chow diet, hepatocyte specific ddah1 knockout mice and skeletal muscle specific ddah1 knockout mice show no insulin resistance. On a high fat diet however the hepatocyte specific ddah1 knockout mice show significant insulin resistance and lower metabolic rate than their fat fed wild-type counterparts. These studies demonstrate for the first time a causal link between ADMA accumulation and insulin resistance. Furthermore these data establish DDAH1 activity is a significant regulator of insulin resistance.

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Premature senescence in primary muscle cultures of myotonic dystrophy type 2 is not associated with p16 induction

European Journal of Histochemistry ◽

10.4081/ejh.2014.2444 ◽

2014 ◽

Cited By ~ 11

Author(s):

L.V. Renna ◽

R. Cardani ◽

A. Botta ◽

G. Rossi ◽

B. Fossati ◽

...

Keyword(s):

Skeletal Muscle ◽

Myotonic Dystrophy ◽

Muscle Weakness ◽

Premature Senescence ◽

Myotonic Dystrophy Type ◽

Myotonic Dystrophy Type 2 ◽

Histopathological Features ◽

Progressive Muscle Weakness

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are multisystemic disorders linked to two different genetic loci and characterized by several features including myotonia, muscle weakness and atrophy, cardiac dysfunctions, cataracts and insulin-resistance. In both forms, expanded nucleotide sequences cause the accumulation of mutant transcripts in the nucleus deregulating the activity of some RNAbinding proteins and providing an explanation for the multisystemic phenotype of DM patients. However this pathogenetic mechanism does not explain some histopathological features of DM skeletal muscle like muscle atrophy. It has been observed that DM muscle shares similarities with the ageing muscle, where the progressive muscle weakness and atrophy is accompanied by a lower regenerative capacity possibly due to the failure in satellite cells activation. The aim of our study is to investigate if DM2 satellite cell derived myoblasts exhibit a premature senescence as reported for DM1 and if alterations in their proliferation potential and differentiation capabilities might contribute to some of the histopathological features observed in DM2 muscles. Our results indicate that DM myoblasts have lower proliferative capability than control myoblasts and reach in vitro senescence earlier than controls. Differentely from DM1, the p16 pathway is not responsible for the premature growth arrest observed in DM2 myoblasts which stop dividing with telomeres shorter than controls. During in vitro senescence, a progressive decrease in fusion index is observable in both DM and control myotubes with no significant differences between groups. Moreover, myotubes obtained from senescent myoblasts appear to be smaller than those from young myoblasts. Taken together, our data indicate a possible role of DM2 premature myoblast senescence in skeletal muscle histopathological alterations i.e., dystrophic changes and type 2 fibre atrophy.

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Hyperglycaemic hyperosmolar state in an obese prepubertal girl with type 2 diabetes: case report and critical approach to diagnosis and therapy

Italian Journal of Pediatrics ◽

10.1186/s13052-021-00983-z ◽

2021 ◽

Vol 47 (1) ◽

Author(s):

Angelika Mohn ◽

Nella Polidori ◽

Valeria Castorani ◽

Laura Comegna ◽

Cosimo Giannini ◽

...

Keyword(s):

Type 2 Diabetes ◽

Elevated Serum ◽

Serum Glucose ◽

Critical Approach ◽

Obese Adults ◽

Case Presentation ◽

Threatening Condition ◽

Life Threatening

Abstract Introduction Isolated Hyperosmolar Hyperglycaemic Syndrome (HHS) is a life-threatening condition characterized by elevated serum glucose concentrations and hyperosmolality without significant ketosis. It is often described in obese adults with unknown Type 2 Diabetes (T2D), rarely in youth. In childhood the most common cause of metabolic glucose related derangement is Diabetic Ketoacidosis (DKA) in Type 1 Diabetes (T1D). Interestingly, both components can be combined with each other, thus the prevalent condition needs to be recognised implying a different therapeutic approach. Case presentation In this case, we report a prepubertal Caucasian obese girl admitted for two episodes of combined HHS/DKA in order to elucidate her clinical course taking into account the current pediatric recommendations based on adult guidelines for HHS. Conclusions The treatment of HHS and even more of HHS/DKA in youth is still controversial as no specific guidelines for children are available especially during the prepubertal age. The description of our case might be helpful and offer relevant points for future consensus.

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Abstract 39: Statin Use is Associated with Elevated Serum Glucose and Incidence of Type 2 Diabetes in US Veterans

Circulation ◽

10.1161/circ.135.suppl_1.39 ◽

2017 ◽

Vol 135 (suppl_1) ◽

Author(s):

Luc Djousse ◽

Brittany Deane ◽

Brian Charest ◽

Constance Nelson ◽

Kelly Cho ◽

...

Keyword(s):

Type 2 Diabetes ◽

Propensity Score ◽

Cox Regression ◽

Elevated Serum ◽

Serum Glucose ◽

Hypoglycemic Agents ◽

Us Veterans ◽

Adjusted Model ◽

Statin Use

Background: While some but not all trial data have suggested a slightly elevated risk of type 2 diabetes (T2D), limited data are available on the relation of statin use with glycemia among US veterans. Objective: To test the hypothesis that treatment with a statin is associated with elevated serum glucose and a higher risk of T2D among US veterans. Methods: We studied 549,143 US veterans with electronic health records from 1998 to 2016. We used the VA Corporate Data Warehouse to obtain information on glucose (fasting and non-fasting). Statin use was captured using the pharmacy database. T2D was defined as having at least one inpatient diagnosis or at least 2 outpatient diagnoses of T2D using ICD 9 codes 250.xx, or the use of hypoglycemic agents. We addressed confounding by indication using propensity score (included 444 variables/interactions) for receiving statin and inverse probability weighting in the Cox regression. Results: The mean age was 60±12.8 y; 94.3% were men; 77.1% were white; and 15.4% were black. In this cohort, simvastatin was the most prescribed statin (84%) followed by lovastatin (7%). During a median follow-up of 4.4 years, 130,819 new cases of T2D occurred. Among 418,847 veterans receiving statin, we observed a 2 mg/dl increase in serum glucose when comparing serum glucose measured at the time of statin initiation and short-term <1 y as well as long-term glucose values (all p <0.01). In crude analysis, statin use was associated with a 53% higher risk of T2D compared with non-users of statin [HR=1.53 (95% CI: 1.51-1.54)]. In a multivariable adjusted model, hazard ratio (95% CI) for T2D was 1.25 (95% CI: 1.24-1.26) after adjustment for propensity score for being on statin. There was a borderline statistically significant interaction between statin and triglycerides on T2D risk (p=0.09): HR=1.15 (95% CI: 1.14-1.16) for people with triglecerides below 150 mg/dl and HR=1.36 (95% CI: 1.35-1.38) for people with triglycerides of at least 150 mg/dl in the adjusted model. We did not have enough data to stratify by type of statin given the predominance of simvastatin in this population. Conclusions: Our data show a positive association between statin use and increase in both serum glucose and incidence of T2D among US veterans. If confirmed by others, this suggests closer monitoring of patients at risk of T2D when statin therapy is initiated.

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Evaluation of Effects of Chinese Prescription Kangen-karyu on Diabetes-Induced Alterations such as Oxidative Stress and Apoptosis in the Liver of Type 2 Diabeticdb/dbMice

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/143489 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 2

Author(s):

Chan Hum Park ◽

Jeong Sook Noh ◽

Takuya Okamoto ◽

Jong Cheol Park ◽

Takako Yokozawa

Keyword(s):

Oxidative Stress ◽

Elevated Serum ◽

Nicotinamide Adenine Dinucleotide Phosphate ◽

Serum Glucose ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Hepatocellular Damage ◽

Ameliorative Effect ◽

Oxide Synthase

The present study was conducted to examine whether Kangen-karyu has an ameliorative effect on diabetes-induced alterations such as oxidative stress and apoptosis in the liver of type 2 diabeticdb/dbmice. Kangen-karyu (100 or 200 mg/kg body weight/day, p.o.) was administered every day for 18 weeks todb/dbmice and its effect was compared with vehicle-treateddb/dbandm/mmice. The administration of Kangen-karyu decreased the elevated serum glucose and leptin concentrations indb/dbmice, and reduced the increased oxidative biomarkers including the generation of reactive oxygen species and lipid peroxidation in the liver. Thedb/dbmice exhibited the upregulation of nicotinamide adenine dinucleotide phosphate oxidase subunits, NF-E2-related factor 2, heme oxygenase-1, nuclear factor-kappa B, cyclooxygenase-2, and inducible nitric oxide synthase levels in the liver; however, Kangen-karyu treatment significantly reduced those expressions. Moreover, the augmented expressions of apoptosis-related proteins, Bax, cytochromec, c-Jun N-terminal kinase (JNK), phosphor-JNK, AP-1, and caspase-3, were downregulated by Kangen-karyu administration. Hematoxylin-eosin staining showed that the increased hepatocellular damage in the liver ofdb/dbmice improved by Kangen-karyu administration. Our findings support the therapeutic evidence for Kangen-karyu ameliorating the development of diabetic hepatic complicationsviaregulating oxidative stress and apoptosis.

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Skeletal Muscle Ratio: A Complete Mediator of Physical Activity and HbA1C in Type 2 Diabetes

Biological Research For Nursing ◽

10.1177/1099800420942884 ◽

2020 ◽

Vol 22 (4) ◽

pp. 536-543

Author(s):

Sen-Te Wang ◽

Yen-Kuang Lin ◽

Shuen-Fu Weng ◽

Chen-Ling Huang ◽

Hui-Chuan Huang ◽

...

Keyword(s):

Physical Activity ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Visceral Fat ◽

Serum Glucose ◽

Activity Level ◽

Visceral Fat Area ◽

The Relationship

Background: An increase in the physical activity level reduces body weight, decreases body fat, increases skeletal muscle mass, and improves serum glucose; however, the influence of body composition parameters on the relationship between physical activity and serum glucose remains unclear. Objective: This study investigated whether skeletal muscle and visceral fat affect the relationship between high physical activity and long-term serum glucose goals. Method: This cross-sectional study recruited patients with type 2 diabetes. The Chinese version of the International Physical Activity Questionnaire was used for estimating the physical activity level, and a bioimpedance device was used to measure the skeletal muscle ratio (skeletal muscle mass/total body weight, %) and visceral fat area (cm2). Hierarchical logistic regression models and mediation tests were conducted according to Hayes’ procedures. Results: Of the total 543 Chinese individuals with type 2 diabetes enrolled, HbA1C levels of fewer than half (n = 243, 44.8%) met the target of ≤7.0%. The skeletal muscle ratio was found to be a complete mediator (OR = 0.920, 95% CI: 0.848 to 0.998; indirect effect: −0.238, 95% CI: −0.525 to −0.020) of the relationship between high physical activity and the target HbA1C level after controlling for visceral fat area (indirect effect: −0.013, 95% CI: −0.183 to 0.156), age, time since diabetes diagnosis, and rice intake. Conclusion: Nurses should include an increase in the skeletal muscle ratio as an objective in physical activity interventions for patients with type 2 diabetes to help them achieve their long-term serum glucose goals.

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