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Skeletal muscle microvascular insulin resistance in type 2 diabetes is not improved by eight weeks of regular walking.

ABSTRACT: We aimed to examine whether individuals with type 2 diabetes (T2D) exhibit suppressed leg vascular conductance and skeletal muscle capillary perfusion in response to a hyperinsulinemic-euglycemic clamp and to test whether these two variables are positively correlated. Subsequently, we examined whether T2D-associated skeletal muscle microvascular insulin resistance, as well as overall vascular dysfunction, would be ameliorated by an 8-wk walking intervention (45 min at 60% of heart rate reserve, 5 sessions/week). We report that, relative to healthy subjects, overweight and obese individuals with T2D exhibit depressed insulin-stimulated increases in leg vascular conductance, skeletal muscle capillary perfusion, and Akt phosphorylation. Notably, we found that within individuals with T2D, those with lesser increases in leg vascular conductance in response to insulin exhibited the lowest increases in muscle capillary perfusion, suggesting that limited muscle capillary perfusion may be, in part, linked to the impaired ability of the upstream resistance vessels to dilate in response to insulin. Furthermore, we show that the 8-wk walking intervention, which did not evoke weight loss, was insufficient to ameliorate skeletal muscle microvascular insulin resistance in previously sedentary, overweight/obese subjects with T2D, despite high adherence and tolerance. However, the walking intervention did improve (P < 0.05) popliteal artery flow-mediated dilation (+4.52%) and reduced HbA1c (-0.75%). It is possible that physical activity interventions that are longer in duration, engage large muscle groups with recruitment of the maximum number of muscle fibers, and lead to a robust reduction in metabolic risk factors may be required to overhaul microvascular insulin resistance in T2D.NEW & NOTEWORTHY This report provides evidence that in sedentary subjects with type 2 diabetes diminished insulin-stimulated increases in leg vascular conductance and ensuing blunted capillary perfusion in skeletal muscle are not restorable by increased walking alone. More innovative physical activity interventions that ultimately result in a robust mitigation of metabolic risk factors may be vital for reestablishing skeletal muscle microvascular insulin sensitivity in type 2 diabetes.

SUBMITTER: Park LK

PROVIDER: S-EPMC7473951 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AimsAngiotensin II (AngII) is a potent vasoconstrictor implicated in both hypertension and insulin resistance. Insulin dilates the vasculature in skeletal muscle to increase microvascular blood flow and enhance glucose disposal. In the present study, we investigated whether acute AngII infusion interferes with insulin's microvascular and metabolic actions in skeletal muscle.Methods and resultsAdult, male Sprague-Dawley rats received a systemic infusion of either saline, AngII, insulin (hyperinsulinaemic euglycaemic clamp), or insulin (hyperinsulinaemic euglycaemic clamp) plus AngII. A final, separate group of rats received an acute local infusion of AngII into a single hindleg during systemic insulin (hyperinsulinaemic euglycaemic clamp) infusion. In all animals' systemic metabolic effects, central haemodynamics, femoral artery blood flow, microvascular blood flow, and skeletal muscle glucose uptake (isotopic glucose) were monitored. Systemic AngII infusion increased blood pressure, decreased heart rate, and markedly increased circulating glucose and insulin concentrations. Systemic infusion of AngII during hyperinsulinaemic euglycaemic clamp inhibited insulin-mediated suppression of hepatic glucose output and insulin-stimulated microvascular blood flow in skeletal muscle but did not alter insulin's effects on the femoral artery or muscle glucose uptake. Local AngII infusion did not alter blood pressure, heart rate, or circulating glucose and insulin. However, local AngII inhibited insulin-stimulated microvascular blood flow, and this was accompanied by reduced skeletal muscle glucose uptake.ConclusionsAcute infusion of AngII significantly alters basal haemodynamic and metabolic homeostasis in rats. Both local and systemic AngII infusion attenuated insulin's microvascular actions in skeletal muscle, but only local AngII infusion led to reduced insulin-stimulated muscle glucose uptake. While increased local, tissue production of AngII may be a factor that couples microvascular insulin resistance and hypertension, additional studies are needed to determine the molecular mechanisms responsible for these vascular defects.

Project description:AIMS:The aims of this study were to determine the effects of four weeks of intermittent exposure to a moderate hypoxia environment (15% oxygen), and compare with the effects of exercise in normoxia or hypoxia, on glucose homeostasis, insulin sensitivity, GLUT4 translocation, insulin receptor phosphorylation, Akt-dependent GSK3 phosphorylation and Akt activity in skeletal muscle of obese mice with type 2 diabetes. METHODS:C57BL/6J mice that developed type 2 diabetes with a high-fat-diet (55% fat) (fasting blood glucose, FBG = 13.9 ± 0.69 (SD) mmol/L) were randomly allocated into diabetic control (DC), rest in hypoxia (DH), exercise in normoxia (DE), and exercise in hypoxia (DHE) groups (n = 7, each), together with a normal-diet (4% fat) control group (NC, FBG = 9.1 ± 1.11 (SD) mmol/L). The exercise groups ran on a treadmill at intensities of 75-90% VO2max. The interventions were applied one hour per day, six days per week for four weeks. Venous blood samples were analysed for FBG, insulin (FBI) and insulin sensitivity (QUICKI) pre and post the intervention period. The quadriceps muscle samples were collected 72 hours post the last intervention session for analysis of GLUT4 translocation, insulin receptor phosphorylation, Akt expression and phosphorylated GSK3 fusion protein by western blot. Akt activity was determined by the ratio of the phosphorylated GSK3 fusion protein to the total Akt protein. RESULTS:The FBG of the DH, DE and DHE groups returned to normal level (FBG = 9.4 ± 1.50, 8.86 ± 0.94 and 9.0 ± 1.13 (SD) mmol/L for DH, DE and DHE respectively, P < 0.05), with improved insulin sensitivity compared to DC (P < 0.05), after the four weeks treatment, while the NC and DC showed no significant changes, as analysed by general linear model with repeated measures. All three interventions resulted in a significant increase of GLUT4 translocation to cell membrane compared to the DC group (P < 0.05). The DE and DH showed a similar level of insulin receptor phosphorylation compared with NC that was significantly lower than the DC (P < 0.05) post intervention. The DH and DHE groups showed a significantly higher Akt activity compared to the DE, DC and NC (P < 0.05) post intervention, as analysed by one-way ANOVA. CONCLUSIONS:This study produced new evidence that intermittent exposure to mild hypoxia (0.15 FiO2) for four weeks resulted in normalisation of FBG, improvement in whole body insulin sensitivity, and a significant increase of GLUT4 translocation in the skeletal muscle, that were similar to the effects of exercise intervention during the same time period, in mice with diet-induced type 2 diabetes. However, exercise in hypoxia for four weeks did not have additive effects on these responses. The outcomes of the research may contribute to the development of effective, alternative and complementary interventions for management of hyperglycaemia and type 2 diabetes, particularly for individuals with limitations in participation of physical activity.

Project description:BACKGROUND:Altering the temporal distribution of energy intake (EI) and introducing periods of intermittent fasting (IF) exert important metabolic effects. Restricting EI to earlier in the day [early time-restricted feeding (eTRF)] is a novel type of IF. OBJECTIVES:We assessed the chronic effects of eTRF compared with an energy-matched control on whole-body and skeletal muscle insulin and anabolic sensitivity. METHODS:Sixteen healthy males (aged 23 ± 1 y; BMI 24.0 ± 0.6 kg·m-2) were assigned to 2 groups that underwent either 2 wk of eTRF (n = 8) or control/caloric restriction (CON:CR; n = 8) diet. The eTRF diet was consumed ad libitum and the intervention was conducted before the CON:CR, in which the diet was provided to match the reduction in EI and body weight observed in eTRF. During eTRF, daily EI was restricted to between 08:00 and 16:00, which prolonged the overnight fast by ?5 h. The metabolic responses to a carbohydrate/protein drink were assessed pre- and post-interventions following a 12-h overnight fast. RESULTS:When compared with CON:CR, eTRF improved whole-body insulin sensitivity [between-group difference (95% CI): 1.89 (0.18, 3.60); P = 0.03; ?2p = 0.29] and skeletal muscle uptake of glucose [between-group difference (95% CI): 4266 (261, 8270) ?mol·min-1·kg-1·180 min; P = 0.04; ?2p = 0.31] and branched-chain amino acids (BCAAs) [between-group difference (95% CI): 266 (77, 455) nmol·min-1·kg-1·180 min; P = 0.01; ?2p = 0.44]. eTRF caused a reduction in EI (?400 kcal·d-1) and weight loss (-1.04 ± 0.25 kg; P = 0.01) that was matched in CON:CR (-1.24 ± 0.35 kg; P = 0.01). CONCLUSIONS:Under free-living conditions, eTRF improves whole-body insulin sensitivity and increases skeletal muscle glucose and BCAA uptake. The metabolic benefits of eTRF are independent of its effects on weight loss and represent chronic adaptations rather than the effect of the last bout of overnight fast. This trial was registered at clinicaltrials.gov as NCT03969745.

Project description:Diabetic 'lipotoxicity' theory suggests that fat-induced skeletal muscle insulin resistance (FISMIR) in obesity induced by a high-fat diet (HFD), which leads to ectopic lipid accumulation in insulin-sensitive tissues, may play a pivotal role in the pathogenesis of type 2 diabetes. However, the changes in gene expression and the molecular mechanisms associated with the pathogenesis of FISMIR have not yet been fully elucidated. In the present study the changes in skeletal muscle gene expression were examined in FISMIR in obese insulin-resistant and diabetic hamster models induced by HFD with or without low-dose streptozotocin-treatment. Microarray technology and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to explore the potential underlying molecular mechanisms. The pathophysiological and metabolic features of obesity and type 2 diabetes in humans are closely resembled by these hamster models. The results of microarray analysis showed that the differentially expressed genes associated with metabolism were mostly related to the abnormal regulation and changes in the gene expression of liver X receptor (LXR), peroxisome proliferator-activated receptor (PPAR) and sterol regulatory element-binding protein (SREBP) transcriptional programs in the skeletal muscle from insulin-resistant and diabetic hamsters. The microarray findings confirmed by RT-qPCR indicated that the increased expression of SREBPs and LXRβ and the decreased expression of LXRα and PPARs were involved in the molecular mechanisms of FISMIR pathogenesis in insulin-resistant and diabetic hamsters. A significant difference in the abnormal expression of skeletal muscle LXRs, PPARs and SREBPs was found between insulin-resistant and diabetic hamsters. It may be concluded that the combined abnormal expression of LXR, PPAR and SREBP transcriptional programs may contribute to the development of FISMIR mediated by skeletal muscle lipid accumulation resulting from abnormal skeletal muscle glucose and lipid metabolism in these HFD- and streptozotocin injection-induced insulin-resistant and diabetic hamsters.

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Skeletal muscle microvascular insulin resistance in type 2 diabetes is not improved by eight weeks of regular walking.

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