Insulin-mediated Glucose Uptake In Skeletal Muscle Research Articles

Skeletal Muscle Health in Polycystic Ovary Syndrome: Protective Effect of Hyperandrogenism or Detrimental Effect of Insulin Resistance? A Systematic Review and Meta-Analysis

Women with polycystic ovary syndrome (PCOS) exhibit reduced skeletal muscle insulin-mediated glucose uptake. Altered muscle mass may affect insulin resistance (IR) and inflammation, thereby potentially aggravating reproductive status including ovulatory cyclicity and fertility potential. However, the relationship between PCOS and skeletal muscle mass is elusive given conflicting reports on protective or detrimental influence of PCOS endocrine derangements (hyperandrogenism, IR) on muscle. We evaluated whether muscle mass and function are affected by PCOS in response to a call to elucidate musculoskeletal alterations in the International Evidence-based Guideline for the Assessment and Management of PCOS. Databases of MEDLINE, Web of Science, and Scopus were searched (January 1990 to September 2020) to identify observational studies on skeletal muscle mass (lean tissue mass) and function (strength) in PCOS and control groups. The primary outcome was total lean body mass (LBM) or fat-free mass (FFM). Data were pooled by random-effects models and expressed as weighted mean differences and 95% confidence intervals. Forty-five studies (n = 3,676 [1,854, PCOS; 1,822, controls]) were eligible. Forty-one evaluated lean tissue mass and five strength. PCOS groups had increased total (0.83 [0.08, 1.58] kg; P=0.03; I2 = 72.0%) yet comparable trunk (0.84 [-0.37, 2.05] kg; P = 0.15; I2 = 73.0%) LBM/FFM. There were no associations between mean differences of groups in total testosterone (TT) or homeostatic model assessment of IR (HOMA-IR) and total/trunk LBM/FFM (All: P ≥ 0.75) by meta-regressions. However, mean differences of groups in body mass index (BMI) were associated with total (0.65 [0.23, 1.06] kg; P < 0.01; I2 = 56.9%) and trunk (0.56 [0.11, 1.01] kg; P = 0.02; I2 = 42.8%) LBM/FFM. Accordingly, PCOS sub-group with overweight/obesity (BMI ≥ 25 kg/m2) exhibited greater total LBM/FFM than controls (1.58 [0.82, 2.34] kg; P < 0.01; I2 = 64.0%) unlike a lean (BMI < 25 kg/m2) sub-group (-0.45 [-1.94, 1.05] kg; P = 0.53; I2 = 69.5%). Some study results were contradictory (i.e., increased appendicular mass or strength in PCOS group or comparable findings between groups) and study methodology varied; thus, inclusion in meta-analyses was not possible. PCOS cohorts have a tendency for increased total and trunk lean tissue mass likely attributed to obesity. However, most critically, whether PCOS influences other lean tissue areas (appendicular), morphology, and function is unclear. Our observations do not support any protective/detrimental influence of hyperandrogenism (TT) or IR (HOMA-IR) on lean mass. Heterogeneity among studies warrants research to address any contributions of lifestyle, healthcare, and biological factors to observed differences for future guideline recommendations to improve PCOS musculoskeletal and reproductive health (www.crd.york.ac.uk/PROSPERO ID, CRD42020203490).

Adipose tissue and skeletal muscle insulin-mediated glucose uptake in insulin resistance: role of blood flow and diabetes

Adipose tissue glucose uptake is impaired in insulin-resistant states, but ex vivo studies of human adipose tissue have yielded heterogeneous results. This discrepancy may be due to different regulation of blood supply. The aim of this study was to test the flow dependency of in vivo insulin-mediated glucose uptake in fat tissues, and to contrast it with that of skeletal muscle. We reanalyzed data from 159 individuals in which adipose tissue depots-subcutaneous abdominal and femoral, and intraperitoneal-and femoral skeletal muscle were identified by MRI, and insulin-stimulated glucose uptake ([18F]-fluoro-2-deoxyglucose) and blood flow ([15O]-H2O) were measured simultaneously by positron emission tomography scanning. Individuals in the bottom tertile of whole-body glucose uptake [median (IQR) 36 (17) µmol. kg fat-free mass (kgFFM)-1 . min-1 .nM-1] displayed all features of insulin resistance compared with the rest of the group [median (IQR) 97 (71) µmol . kgFFM-1 .min-1 . nM-1]. Rates of glucose uptake were directly related to the degree of insulin resistance in all fat depots as well as in skeletal muscle. However, blood flow was inversely related to insulin sensitivity in each fat depot (all P≤0.03), whereas femoral muscle blood flow was not significantly different between insulin-resistant and insulin-sensitive subjects, and was not related to insulin sensitivity. Furthermore, in subjects performing one-leg exercise, blood flow increased 5- to 6-fold in femoral muscle but not in the overlying adipose tissue. The presence of diabetes was associated with a modest increase in fat and muscle glucose uptake independent of insulin resistance. Reduced blood supply is an important factor for the impairment of in vivo insulin-mediated glucose uptake in both subcutaneous and visceral fat. In contrast, the insulin resistance of glucose uptake in resting skeletal muscle is predominantly a cellular defect. Diabetes provides a modest compensatory increase in fat and muscle glucose uptake that is independent of insulin resistance.

SIRT2 is required for in vivo tissue‐specific and whole body insulin action in mice

High fat (HF) feeding impairs insulin action and, subsequently glucose homeostasis. A reduction in insulin‐mediated skeletal muscle glucose uptake (MGU) in response to HF feeding is a key contributor to dysregulated glucose homeostasis in the insulin resistant state. Increased skeletal muscle lysine acetylation, a post‐translational modification, has been reported to mediate insulin resistance in response to HF feeding. Indeed, skeletal muscle mitochondrial protein hyperacetylation precipitates insulin resistance. However, the impact of hyperacetylation in the cytosolic compartment is unknown.Hyperinsulinemic‐euglycemic (insulin) clamps combined with isotopic tracers were completed to assess the role of cytosolic hyperacetylation on insulin‐stimulated skeletal muscle glucose utilization in the conscious, unrestrained mouse. Genetic and dietary means were used to increase skeletal muscle cytosolic acetylation. Specifically, mice with a whole‐body knockout (KO) of the predominant cytosolic NAD+‐dependent deacetylase, Sirtuin 2 (SIRT2), and wildtype (WT) littermates were fed a low fat (LF) or HF diet. The hypothesis tested was that loss of SIRT2 would induce cytosolic hyperacetylation leading to impaired MGU in the presence of high‐physiological circulating insulin. It was also hypothesized that this impairment in insulin action would be worsened with a HF diet.LF SIRT2 KO mice exhibited higher skeletal muscle protein acetylation compared to LF WT mice, but similar to levels observed in HF WT mice. Skeletal muscle acetylation was increased in HF WT mice compared to LF WT mice, but not HF SIRT2 KO mice in relation to either LF SIRT2 KO or HF WT mice. LF SIRT2 KO mice exhibited a 27% reduction in insulin‐stimulated MGU compared to LF WT mice (gastrocnemius; p&lt;0.05, n=7–9). This impairment was exacerbated in HF SIRT2 KO mice compared to HF‐WT type mice as gastrocnemius glucose uptake was reduced by 43% (p&lt;0.001, n=12–13). While our experiments were designed to probe muscle glucose metabolism, our in vivo approach allowed us to uncover an additional contributor to insulin resistance in HF SIRT2 KO mice. The ability of insulin to suppress endogenous glucose production was significantly impaired in the HF SIRT2 KO mice (n=7–13). This suggests liver glucose formation is not effectively attenuated by insulin in HF SIRT2 KO mice.In summary, the increased lysine acetylation induced by HF feeding has been implicated in promoting insulin resistance. Extensive study has linked mitochondrial hyperacetylation to impaired insulin action. Here we show that increased acetylation in the cytosol compartment profoundly reduces insulin‐stimulated MGU. Furthermore, our in vivo approach identified a regulatory role for cytosolic hyperacetylation in the control of liver glucose production.Support or Funding InformationNIH DK054902, DK050277This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of ovariectomy and intrinsic aerobic capacity on tissue-specific insulin sensitivity.

High-capacity running (HCR) rats are protected against the early (i.e., ∼ 11 wk postsurgery) development of ovariectomy (OVX)-induced insulin resistance (IR) compared with low-capacity running (LCR) rats. The purpose of this study was to utilize the hyperinsulinemic euglycemic clamp to determine whether 1) HCR rats remain protected from OVX-induced IR when the time following OVX is extended to 27 wk and 2) tissue-specific glucose uptake differences are responsible for the protection in HCR rats under sedentary conditions. Female HCR and LCR rats (n = 40; aged ∼ 22 wk) randomly received either OVX or sham (SHM) surgeries and then underwent the clamp 27 wk following surgeries. [3-(3)H]glucose was used to determine glucose clearance, whereas 2-[(14)C]deoxyglucose (2-DG) was used to assess glucose uptake in skeletal muscle, brown adipose tissue (BAT), subcutaneous white adipose tissue (WAT), and visceral WAT. OVX decreased the glucose infusion rate and glucose clearance in both lines, but HCR had better insulin sensitivity than LCR (P < 0.05). In both lines, OVX significantly reduced glucose uptake in soleus and gastrocnemius muscles; however, HCR showed ∼ 40% greater gastrocnemius glucose uptake compared with LCR (P < 0.05). HCR also exhibited greater glucose uptake in BAT and visceral WAT compared with LCR (P < 0.05), yet these tissues were not affected by OVX in either line. In conclusion, OVX impairs insulin sensitivity in both HCR and LCR rats, likely driven by impairments in insulin-mediated skeletal muscle glucose uptake. HCR rats have greater skeletal muscle, BAT, and WAT insulin-mediated glucose uptake, which may aid in protection against OVX-associated insulin resistance.

Differential effects of glucagon-like peptide-1 on microvascular recruitment and glucose metabolism in short- and long-term insulin resistance.

Acute glucagon-like peptide-1 (GLP-1) infusion reversed the high fat diet-induced microvascular insulin resistance that occurred after both 5days and 8weeks of a high fat diet intervention. When GLP-1 was co-infused with insulin it had overt effects on whole body insulin sensitivity as well as insulin-mediated skeletal muscle glucose uptake after 5days of a high fat diet, but not after 8weeks of high fat diet intervention. Acute GLP-1 infusion did not have an additive effect to that of insulin on microvascular recruitment or skeletal muscle glucose uptake in the control group. Here we demonstrate that GLP-1 potently increases the microvascular recruitment in rat skeletal muscle but does not increase glucose uptake in the fasting state. Thus, like insulin, GLP-1 increased the microvascular recruitment but unlike insulin, GLP-1 had no direct effect on skeletal muscle glucose uptake. Acute infusion of glucagon-like peptide-1 (GLP-1) has potent effects on blood flow distribution through the microcirculation in healthy humans and rats. A high fat diet induces impairments in insulin-mediated microvascular recruitment (MVR) and muscle glucose uptake, and here we examined whether this could be reversed by GLP-1. Using contrast-enhanced ultrasound, microvascular recruitment was assessed by continuous real-time imaging of gas-filled microbubbles in the microcirculation after acute (5days) and prolonged (8weeks) high fat diet (HF)-induced insulin resistance in rats. A euglycaemic hyperinsulinaemic clamp (3mUmin(-1) kg(-1) ), with or without a co-infusion of GLP-1 (100pmoll(-1) ), was performed in anaesthetized rats. Consumption of HF attenuated the insulin-mediated MVR in both 5day and 8week HF interventions which was associated with a 50% reduction in insulin-mediated glucose uptake compared to controls. Acute administration of GLP-1 restored the normal microvascular response by increasing the MVR after both 5days and 8weeks of HF intervention (P<0.05). This effect of GLP-1 was associated with a restoration of both whole body insulin sensitivity and increased insulin-mediated glucose uptake in skeletal muscle by 90% (P<0.05) after 5days of HF but not after 8weeks of HF. The present study demonstrates that GLP-1 increases MVR in rat skeletal muscle and can reverse early stages of high fat diet-induced insulin resistance in vivo.

Early Microvascular Recruitment Modulates Subsequent Insulin-Mediated Skeletal Muscle Glucose Metabolism During Lipid Infusion

OBJECTIVETo test whether early, insulin-mediated microvascular recruitment in skeletal muscle predicts steady-state glucose metabolism in the setting of physiological elevation of free fatty acid concentrations.RESEARCH DESIGN AND METHODSWe measured insulin’s microvascular and metabolic effects in 14 healthy young adults during a 2-h euglycemic insulin clamp. Plasma free fatty acid concentrations were raised (Intralipid and heparin infusion) for 3 h before the clamp and maintained at postprandial concentrations during the clamp. Microvascular blood volume (MBV) was measured by contrast-enhanced ultrasound (CEU) continuously from baseline through the first 30 min of the insulin clamp. Muscle glucose and insulin uptake were measured by the forearm balance method.RESULTSThe glucose infusion rate (GIR) necessary to maintain euglycemia during the clamp varied by fivefold across subjects (2.5–12.5 mg/min/kg). The early MBV responses to insulin, as indicated by CEU video intensity, ranged widely, from a 39% decline to a 69% increase. During the clamp, steady state forearm muscle glucose uptake and GIR each correlated significantly with the change in forearm MBV (P < 0.01). To explore the basis for the wide range of vascular and metabolic insulin sensitivity observed, we also measured Vo2max in a subset of eight subjects. Fitness (Vo2max) correlated significantly with the GIR, the forearm glucose uptake, and the percentage change in MBV during the insulin clamp (P < 0.05 for each).CONCLUSIONSEarly microvascular responses to insulin strongly associate with steady state skeletal muscle insulin-mediated glucose uptake. Physical fitness predicts both metabolic and vascular insulin responsiveness.

Peroxisome proliferator-activated receptor-gamma in the renal mesangium.

The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that are expressed in a variety of tissues, including the liver (PPARalpha), adipose tissue, vascular smooth muscle, the heart, skeletal muscle, and the kidney (PPARgamma). PPARdelta is expressed ubiquitously. The receptors function as transcription factors to regulate the expression of genes involved in lipid metabolism, cell growth and migration as well as insulin-mediated skeletal muscle glucose uptake. Although the mechanisms by which all these actions occur have not been completely worked out, ligands to these receptors function to improve lipid metabolism, insulin sensitivity, endothelial dysfunction and urinary albumin excretion in patients with diabetes. Thus PPARs appear to have enormous implications for the management of cardiovascular disease.

Effect of perfusion rate on the time course of insulin-mediated skeletal muscle glucose uptake.

To better define the time course of skeletal muscle glucose uptake and its modulation by changes in perfusion, we performed systemic euglycemic-hyperinsulinemic clamps (40 mU.m-2.min-1) for a 90-min period in a group of lean, insulin-sensitive subjects (n = 9) on two occasions (approximately 4 wk apart) with insulin-mediated vasodilation intact or inhibited. Insulin-mediated vasodilation was inhibited by an intrafemoral artery infusion of NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of nitric oxide synthase. During the study, leg blood flow (LBF) and arteriovenous glucose difference (AVG delta) were measured every 10 min; leg glucose uptake (LGU) was calculated as LGU = LBF x AVG delta. The systemic insulin infusion caused a time-dependent increase in LBF from 0.194 +/- 0.024 to 0.349 +/- 0.046 l/min (P < 0.01). The intrafemoral artery infusion of L-NMMA completely inhibited this increase in LBF. AVG delta, LGU, and whole body glucose disposal rates increased in a time-dependent manner in both studies. The maximum AVG delta was lower with insulin-mediated vasodilation intact than when inhibited (25.9 +/- 2.5 vs. 35.0 +/- 1.6 mg/dl, P < 0.001). The time to achieve half-maximal (T1/2) AVG delta was somewhat longer with insulin-mediated vasodilation intact compared with inhibited (35.6 +/- 4.1 vs. 29.7 +/- 1.6 min, P < 0.01). Maximal LGU was 93.9 +/- 26.8 and 57.2 +/- 11.6 mg/min (P < 0.005), and the T1/2 LGU was 50.2 +/- 16.0 and 36.3 +/- 8.8 min (P = 0.1) during intact and inhibited insulin-mediated vasodilation, respectively. Thus insulin-mediated vasodilation has a modest effect in slowing the time course at which insulin stimulates glucose uptake but has a marked effect in augmenting the maximal rate of insulin-stimulated glucose uptake in skeletal muscle. Impaired insulin-mediated vasodilation, as observed in patients with essential hypertension, may explain, at least in part, the insulin resistance observed in these patients.

Pyruvate dehydrogenase inactivity is not responsible for sepsis-induced insulin resistance

To determine whether activation of pyruvate dehydrogenase with dichloroacetate can reverse sepsis-induced insulin resistance in humans or rats. Prospective, controlled study. Intensive care unit (ICU) and laboratory at a university medical center. Nine patients were admitted to the ICU with Gram-negative sepsis, confirmed by cultures. In addition, chronically instrumented, Sprague-Dawley rats, either controls or with live Escherichia coli-induced sepsis. Hyperinsulinemic euglycemic clamp, with or without coadministration of dichloroacetate. In humans, a primed, constant infusion of [6,6-2H2]glucose was used to determine endogenous glucose production and whole-body glucose disposal. Septic humans exhibited impaired maximal insulin-stimulated glucose utilization (39.5 +/- 2.7 mumol/kg/min), despite complete suppression of endogenous glucose production. In rats, a primed, constant infusion of [3-3H]glucose was used to determine endogenous glucose production and whole-body glucose disposal. Tissue glucose uptake in vivo was determined by [14C]-2-deoxyglucose uptake. Maximal, whole-body, insulin-stimulated glucose utilization was 205 +/- 11 and 146 +/- 9 mumol/kg/min in control and septic rats, respectively. The defect was specific to skeletal muscle and heart. Stimulation of pyruvate dehydrogenase with dichloroacetate caused a 50% decrease in plasma lactate concentration but failed to improve whole-body insulin-stimulated glucose utilization in either the septic human or rat. Dichloroacetate reversed the impairment of insulin-stimulated myocardial glucose uptake in septic rats, but did not influence skeletal muscle glucose uptake either under basal conditions or during insulin stimulation. Activation of pyruvate dehydrogenase with dichloroacetate does not ameliorate the impairment of whole-body, insulin-stimulated glucose uptake in septic humans or rats, or reverse the specific defect in insulin-mediated skeletal muscle glucose uptake by septic rats. Therefore, the decreased pyruvate dehydrogenase activity associated with sepsis does not appear to mediate sepsis-induced insulin resistance during insulin-stimulated glucose uptake at either the whole-body or tissue level.

Decreased effect of insulin to stimulate skeletal muscle blood flow in obese man. A novel mechanism for insulin resistance.

Obesity is characterized by decreased rates of skeletal muscle insulin-mediated glucose uptake (IMGU). Since IMGU equals the product of the arteriovenous glucose difference (AVGd) across muscle and blood flow into muscle, reduced blood flow and/or tissue activity (AVGd) can lead to decreased IMGU. To examine this issue, we studied six lean (weight 68 +/- 3 kg, mean +/- SEM) and six obese (94 +/- 3 kg) men. The insulin dose-response curves for whole body and leg IMGU were constructed using the euglycemic clamp and leg balance techniques over a large range of serum insulin concentrations. In lean and obese subjects, whole body IMGU, AVGd, blood flow, and leg IMGU increased in a dose dependent fashion and maximal rates of all parameters were reduced in obese subjects compared to lean subjects. The dose-response curves for whole body IMGU, leg IMGU, and AVGd were right-shifted in obese subjects with an ED50 two- to threefold higher than that of lean subjects for each parameter. Leg blood flow increased approximately twofold from basal 2.7 +/- 0.2 to 4.4 +/- 0.2 dl/min in lean, P less than 0.01, and from 2.5 +/- 0.3 to 4.4 +/- 0.4 dl/min in obese subjects, P less than 0.01. The ED50 for insulin's effect to increase leg blood flow was about fourfold higher for obese (957 pmol/liter) than lean subjects (266 pmol/liter), P less than 0.01. Therefore, decreased insulin sensitivity in human obesity is not only due to lower glucose extraction in insulin-sensitive tissues but also to lower blood flow to these tissues. Thus, in vivo insulin resistance can be due to a defect in insulin action at the tissue level and/or a defect in insulin's hemodynamic action to increase blood flow to insulin sensitive tissues.

Rates and tissue sites of non-insulin- and insulin-mediated glucose uptake in humans.

In vivo glucose uptake can occur via two mechanisms, namely, insulin-mediated glucose uptake (IMGU) and non-insulin-mediated glucose uptake (NIMGU). Although the principal tissue sites for IMGU are skeletal muscle, the tissue sites for NIMGU at a given serum glucose concentration are not known. To examine this issue, rates of whole body glucose uptake (Rd) were measured at basal and during glucose clamp studies performed at euglycemia (approximately 90 mg/dl) and hyperglycemia (approximately 220 mg/dl) in six lean healthy men. Studies were performed during hyperinsulinemia (approximately 70 microU/ml) and during somatostatin-induced insulinopenia to measure IMGU and NIMGU, respectively. During each study, leg glucose balance (arteriovenous catheter technique) was also measured. With this approach, rates of whole body skeletal muscle IMGU and NIMGU can be estimated, and the difference between overall Rd and skeletal muscle glucose uptake represents non-skeletal muscle Rd. The results indicate that approximately 20% of basal Rd is into skeletal muscle. During insulinopenia approximately 86% of body NIMGU occurs in non-skeletal muscle tissues at euglycemia. When hyperglycemia was created, whole body NIMGU increased from 128 +/- 6 to 213 +/- 18 mg/min (P less than 0.01); NIMGU into non-skeletal muscle tissues was 134 +/- 11 and 111 +/- 6 mg/min at hyperglycemia and euglycemia, respectively, P = NS. Therefore, virtually all the hyperglycemia induced increment in NIMGU occurred in skeletal muscle. During hyperinsulinemia, IMGU in skeletal muscle represented 75 and 95% of body Rd, at euglycemia and hyperglycemia, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)