Skeletal muscle dysfunction in the db/db mouse model of type 2 diabetes

Type 2 diabetes mellitus is a major health problem and a societal burden. Individuals with prediabetes are at increased risk of type 2 diabetes mellitus. Catalpol, an iridoid glycoside, has been reported to exert a hypoglycaemic effect in db/db mice, but its effect on the progression of prediabetes is unclear. In this study, we established a mouse model of prediabetes and examined the hypoglycaemic effect, and the mechanism of any such effect, of catalpol. Catalpol (200 mg/(kg·day)) had no effect on glucose tolerance or the serum lipid level in a mouse model of impaired glucose tolerance-stage prediabetes. However, catalpol (200 mg/(kg·day)) increased insulin sensitivity and decreased the fasting glucose level in a mouse model of impaired fasting glucose/impaired glucose tolerance-stage prediabetes. Moreover, catalpol increased the mitochondrial membrane potential (1.52-fold) and adenosine triphosphate content (1.87-fold) in skeletal muscle and improved skeletal muscle function. These effects were mediated by activation of the insulin receptor-1/glucose transporter type 4 (IRS-1/GLUT4) signalling pathway in skeletal muscle. Our findings will facilitate the development of a novel approach to suppressing the progression of diabetes at an early stage. Novelty Catalpol prevents the progression of prediabetes in a mouse model of prediabetes. Catalpol improves insulin sensitivity in skeletal muscle. The effects of catalpol are mediated by activation of the IRS-1/GLUT4 signalling pathway.

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1-Deoxysphingolipids, Early Predictors of Type 2 Diabetes, Compromise the Functionality of Skeletal Myoblasts

Frontiers in Endocrinology ◽

10.3389/fendo.2021.772925 ◽

2021 ◽

Vol 12 ◽

Author(s):

Duyen Tran ◽

Stephen Myers ◽

Courtney McGowan ◽

Darren Henstridge ◽

Rajaraman Eri ◽

...

Keyword(s):

Type 2 Diabetes ◽

Skeletal Muscle ◽

Glucose Uptake ◽

Muscle Cells ◽

Skeletal Muscle Cells ◽

Muscle Dysfunction ◽

Dependent Manner

Metabolic dysfunction, dysregulated differentiation, and atrophy of skeletal muscle occur as part of a cluster of abnormalities associated with the development of Type 2 diabetes mellitus (T2DM). Recent interest has turned to the attention of the role of 1-deoxysphingolipids (1-DSL), atypical class of sphingolipids which are found significantly elevated in patients diagnosed with T2DM but also in the asymptomatic population who later develop T2DM. In vitro studies demonstrated that 1-DSL have cytotoxic properties and compromise the secretion of insulin from pancreatic beta cells. However, the role of 1-DSL on the functionality of skeletal muscle cells in the pathophysiology of T2DM still remains unclear. This study aimed to investigate whether 1-DSL are cytotoxic and disrupt the cellular processes of skeletal muscle precursors (myoblasts) and differentiated cells (myotubes) by performing a battery of in vitro assays including cell viability adenosine triphosphate assay, migration assay, myoblast fusion assay, glucose uptake assay, and immunocytochemistry. Our results demonstrated that 1-DSL significantly reduced the viability of myoblasts in a concentration and time-dependent manner, and induced apoptosis as well as cellular necrosis. Importantly, myoblasts were more sensitive to the cytotoxic effects induced by 1-DSL rather than by saturated fatty acids, such as palmitate, which are critical mediators of skeletal muscle dysfunction in T2DM. Additionally, 1-DSL significantly reduced the migration ability of myoblasts and the differentiation process of myoblasts into myotubes. 1-DSL also triggered autophagy in myoblasts and significantly reduced insulin-stimulated glucose uptake in myotubes. These findings demonstrate that 1-DSL directly compromise the functionality of skeletal muscle cells and suggest that increased levels of 1-DSL observed during the development of T2DM are likely to contribute to the pathophysiology of muscle dysfunction detected in this disease.

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Hyperglycemia, maturity-onset obesity, and insulin resistance in NONcNZO10/LtJ males, a new mouse model of type 2 diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00376.2006 ◽

2007 ◽

Vol 293 (1) ◽

pp. E327-E336 ◽

Cited By ~ 37

Author(s):

You-Ree Cho ◽

Hyo-Jeong Kim ◽

So-Young Park ◽

Hwi Jin Ko ◽

Eun-Gyoung Hong ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Skeletal Muscle ◽

Mouse Model ◽

Lipid Content ◽

Insulin Action ◽

Plasma Insulin ◽

Glut4 Expression ◽

Organ Specific

As a new mouse model of obesity-induced diabetes generated by combining quantitative trait loci from New Zealand Obese (NZO/HlLt) and Nonobese Nondiabetic (NON/LtJ) mice, NONcNZO10/LtJ (RCS10) male mice developed type 2 diabetes characterized by maturity onset obesity, hyperglycemia, and insulin resistance. To metabolically profile the progression to diabetes in preobese and obese states, a 2-h hyperinsulinemic euglycemic clamp was performed and organ-specific changes in insulin action were assessed in awake RCS10 and NON/LtJ (control) males at 8 and 13 wk of age. Prior to development of obesity and attendant increases in hepatic lipid content, 8-wk-old RCS10 mice developed insulin resistance in liver and skeletal muscle due to significant decreases in insulin-stimulated glucose uptake and GLUT4 expression in muscle. Transition to an obese and hyperglycemic state by 13 wk of age exacerbated insulin resistance in skeletal muscle, liver, and heart associated with organ-specific increases in lipid content. Thus, this polygenic mouse model of type 2 diabetes, wherein plasma insulin is only modestly elevated and obesity develops with maturity yet insulin action and glucose metabolism in skeletal muscle and liver are reduced at an early prediabetic age, should provide new insights into the etiology of type 2 diabetes.

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Sulforaphane protects against skeletal muscle dysfunction in spontaneous type 2 diabetic db/db mice

Life Sciences ◽

10.1016/j.lfs.2020.117823 ◽

2020 ◽

Vol 255 ◽

pp. 117823 ◽

Cited By ~ 1

Author(s):

Meili Wang ◽

Die Pu ◽

Yuxing Zhao ◽

Jinliang Chen ◽

Shiyu Zhu ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Dysfunction ◽

Skeletal Muscle Dysfunction ◽

Type 2 Diabetic

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Muscle Contractile Force Dysfunction Concurrently with Intracellular Ca2+ Dysregulation in Skeletal Muscle in a Mouse Model of Type 2 Diabetes

Juntendo Medical Journal ◽

10.14789/jmj.2018.64.jmj18-p44 ◽

2018 ◽

Vol 64 (Suppl.1) ◽

pp. 91-92

Author(s):

HIROAKI ESHIMA ◽

YOSHIFUMI TAMURA ◽

SAORI KAKEHI ◽

RYUZO KAWAMORI ◽

HIROTAKA WATADA

Keyword(s):

Type 2 Diabetes ◽

Skeletal Muscle ◽

Mouse Model ◽

Contractile Force ◽

Intracellular Ca ◽

Muscle Contractile

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Vitamin D deficiency impairs skeletal muscle function in a smoking mouse model

Journal of Endocrinology ◽

10.1530/joe-15-0491 ◽

2016 ◽

Vol 229 (2) ◽

pp. 97-108 ◽

Cited By ~ 5

Author(s):

Nele Cielen ◽

Nele Heulens ◽

Karen Maes ◽

Geert Carmeliet ◽

Chantal Mathieu ◽

...

Keyword(s):

Skeletal Muscle ◽

Vitamin D ◽

Mouse Model ◽

Vitamin D Deficiency ◽

Muscle Mass ◽

Muscle Function ◽

Receptor Expression ◽

Chronic Obstructive ◽

Muscle Dysfunction ◽

Skeletal Muscle Dysfunction

Chronic obstructive pulmonary disease (COPD) is associated with skeletal muscle dysfunction. Vitamin D plays an important role in muscle strength and performance in healthy individuals. Vitamin D deficiency is highly prevalent in COPD, but its role in skeletal muscle dysfunction remains unclear. We examined the time-course effect of vitamin D deficiency on limb muscle function in mice with normal or deficient vitamin D serum levels exposed to air or cigarette smoke for 6, 12 or 18 weeks. The synergy of smoking and vitamin D deficiency increased lung inflammation and lung compliance from 6 weeks on with highest emphysema scores observed at 18 weeks. Smoking reduced body and muscle mass of the soleus and extensor digitorum longus (EDL), but did not affect contractility, despite type II atrophy. Vitamin D deficiency did not alter muscle mass but reduced muscle force over time, downregulated vitamin D receptor expression, and increased muscle lipid peroxidation but did not alter actin and myosin expression, fiber dimensions or twitch relaxation time. The combined effect of smoking and vitamin D deficiency did not further deteriorate muscle function but worsened soleus mass loss and EDL fiber atrophy at 18 weeks. We conclude that the synergy of smoking and vitamin D deficiency in contrast to its effect on lung disease, had different, independent but important noxious effects on skeletal muscles in a mouse model of mild COPD.

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