scholarly journals Trans-Endothelial Insulin Transport is Impaired in Skeletal Muscle Capillaries of Obese Male Mice

2019 ◽  
Author(s):  
Ian M Williams ◽  
P Mason McClatchey ◽  
Deanna P Bracy ◽  
Jeffrey S Bonner ◽  
Francisco A Valenzuela ◽  
...  

ABSTRACTDelivery of insulin to the surface of myocytes is required for skeletal muscle (SkM) insulin action. Previous studies have shown that SkM insulin delivery is reduced in the setting of obesity and insulin resistance (IR). The key variables that control SkM insulin delivery are 1) microvascular perfusion and 2) the rate at which insulin moves across the continuous endothelium of SkM capillaries. Obesity and IR are associated with reduced insulin-stimulated SkM perfusion. Whether an impairment in trans-endothelial insulin transport (EIT) contributes to SkM IR, however, is unknown. We hypothesized that EIT would be delayed in a mouse model of diet-induced obesity (DIO) and IR. Using intravital insulin imaging, we found that DIO male mice have a ~15% reduction in EIT compared to their lean counterparts. This impairment in EIT is associated with a 45% reduction in the density of endothelial vesicles. Despite impaired EIT, hyperinsulinemia sustained delivery of insulin to the interstitial space in DIO male mice. Even with maintained interstitial insulin delivery DIO male mice still showed SkM IR, indicating severe myocyellular IR in this model. Interestingly, there was no difference in EIT, endothelial ultrastructure or SkM insulin sensitivity between lean and high fat diet-fed female mice. These results suggest that, in male mice, obesity results in damage to the capillary endothelium which limits the capacity for EIT.

Obesity ◽  
2020 ◽  
Vol 28 (2) ◽  
pp. 303-314 ◽  
Author(s):  
Ian M. Williams ◽  
P. Mason McClatchey ◽  
Deanna P. Bracy ◽  
Jeffrey S. Bonner ◽  
Francisco A. Valenzuela ◽  
...  

Physiology ◽  
2016 ◽  
Vol 31 (5) ◽  
pp. 336-345 ◽  
Author(s):  
Warren L. Lee ◽  
Amira Klip

Most research on insulin resistance has focused on impaired signaling at the level of target tissues like skeletal muscle. Insulin delivery is also important and includes recruitment and perfusion of capillaries bearing insulin, but also the transit of insulin across the capillary endothelium. The mechanisms of this second stage (insulin transcytosis) and whether it contributes to insulin resistance remain uncertain.


2013 ◽  
Author(s):  
Naeyer Helene De ◽  
Inge Everaert ◽  
Spaey Annelies De ◽  
Jean-Marc Kaufman ◽  
Youri Taes ◽  
...  

2003 ◽  
Vol 285 (4) ◽  
pp. E876-E888 ◽  
Author(s):  
Suzanne Reisz-Porszasz ◽  
Shalender Bhasin ◽  
Jorge N. Artaza ◽  
Ruoqing Shen ◽  
Indrani Sinha-Hikim ◽  
...  

Mutations in the myostatin gene are associated with hypermuscularity, suggesting that myostatin inhibits skeletal muscle growth. We postulated that increased tissue-specific expression of myostatin protein in skeletal muscle would induce muscle loss. To investigate this hypothesis, we generated transgenic mice that overexpress myostatin protein selectively in the skeletal muscle, with or without ancillary expression in the heart, utilizing cDNA constructs in which a wild-type (MCK/Mst) or mutated muscle creatine kinase (MCK-3E/Mst) promoter was placed upstream of mouse myostatin cDNA. Transgenic mice harboring these MCK promoters linked to enhanced green fluorescent protein (EGFP) expressed the reporter protein only in skeletal and cardiac muscles (MCK) or in skeletal muscle alone (MCK-3E). Seven-week-old animals were genotyped by PCR of tail DNA or by Southern blot analysis of liver DNA. Myostatin mRNA and protein, measured by RT-PCR and Western blot, respectively, were significantly higher in gastrocnemius, quadriceps, and tibialis anterior of MCK/Mst-transgenic mice compared with wild-type mice. Male MCK/Mst-transgenic mice had 18–24% lower hind- and forelimb muscle weight and 18% reduction in quadriceps and gastrocnemius fiber cross-sectional area and myonuclear number (immunohistochemistry) than wild-type male mice. Male transgenic mice with mutated MCK-3E promoter showed similar effects on muscle mass. However, female transgenic mice with either type of MCK promoter did not differ from wild-type controls in either body weight or skeletal muscle mass. In conclusion, increased expression of myostatin in skeletal muscle is associated with lower muscle mass and decreased fiber size and myonuclear number, decreased cardiac muscle mass, and increased fat mass in male mice, consistent with its role as an inhibitor of skeletal muscle mass. The mechanism of gender specificity remains to be clarified.


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