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BackgroundInsulin resistance (IR) in skeletal muscle is a key feature of the pre-diabetic state, hypertension, dyslipidemia, cardiovascular diseases and also predicts type 2 diabetes. However, the underlying molecular mechanisms are still poorly understood.MethodsTo explore these mechanisms, we related global skeletal muscle gene expression profiling of 38 non-diabetic men to a surrogate measure of insulin sensitivity,i.e.homeostatic model assessment of insulin resistance (HOMA-IR).ResultsWe identified 70 genes positively and 110 genes inversely correlated with insulin sensitivity in human skeletal muscle, identifying autophagy-related genes as positively correlated with insulin sensitivity. Replication in an independent study of 9 non-diabetic men resulted in 10 overlapping genes that strongly correlated with insulin sensitivity, includingSIRT2, involved in lipid metabolism, andFBXW5that regulates mammalian target-of-rapamycin (mTOR) and autophagy. The expressions ofSIRT2andFBXW5were also positively correlated with the expression of key genes promoting the phenotype of an insulin sensitive myocytee.g.PPARGC1A.ConclusionsThe muscle expression of 180 genes were correlated with insulin sensitivity. These data suggest that activation of genes involved in lipid metabolism,e.g.SIRT2, and genes regulating autophagy and mTOR signaling,e.g.FBXW5, are associated with increased insulin sensitivity in human skeletal muscle, reflecting a highly flexible nutrient sensing.

Aims We investigated whether physical inactivity could unmask defects in insulin and AMPK signaling in low birth weight (LBW) subjects. Methods Twenty LBW and 20 normal birth weight (NBW) subjects were investigated using the euglycemic–hyperinsulinemic clamp with excision of skeletal muscle biopsies pre and post 9 days of bed rest. Employing Western blotting, we investigated skeletal muscle Akt, AS160, GLUT4, and AMPK signaling. Results Peripheral insulin action was similar in the two groups and was decreased to the same extent post bed rest. Insulin and AMPK signaling was unaffected by bed rest in NBW individuals. LBW subjects showed decreased insulin-stimulated Akt phosphorylation and increased AMPK α1 and γ3 protein expression post bed rest. Insulin response of AS160 phosphorylation was lower in LBW subjects both pre and post bed rest. Conclusions Bed rest-induced insulin resistance is not explained by impaired muscle insulin or AMPK signaling in subjects with or without LBW. Lower muscle insulin signaling in LBW subjects post bed rest despite similar degree of insulin resistance as seen in controls may to some extent support the idea that LBW subjects are at higher risk of developing type 2 diabetes when being physically inactive.

Objective: The molecular mechanisms linking physical inactivity and muscle insulin resistance in humans have been suggested to include increased muscle inflammation, possibly associated with impaired oxidative metabolism. We employed a human bed rest study including 20 young males with normal birth weight (NBW) and 20 with low birth weight (LBW) and increased risk of diabetes. Methodology: The subjects were studied before and after 9 days of bed rest using the euglycemic– hyperinsulinemic clamp and muscle biopsy excision. Muscle inflammatory status was assessed as nuclear factor-kB (NF-kB) activity and mRNA expression of the pro-inflammatory MCP1 (CCL2) and IL6 and the macrophage marker CD68. Furthermore, mRNA expression of genes central to oxidative phosphorylation (OXPHOS) was measured including ATP5O, COX7A1, NDUFB6, and UQCRB. Results: At baseline, muscle inflammatory status was similar in NBW and LBW individuals. After bed rest, CD68 expression was increased in LBW (PZ0.03) but not in NBW individuals. Furthermore, expression levels of all OXPHOS genes were reduced after bed rest in LBW (P%0.05) but not in NBW subjects and were negatively correlated with CD68 expression in LBW subjects (P%0.03 for all correlations). MCP1 expression and NF-kB activity were unaffected by bed rest, and IL6 expression was too low for accurate measurements. None of the inflammatory markers correlated with insulin sensitivity. Conclusions: Although LBW subjects exhibit disproportionately elevated CD68 mRNA expression suggesting macrophage infiltration and reduced OXPHOS gene expression when exposed to bed rest, our data altogether do not support the notion that bed rest-induced (9 days) insulin resistance is caused by increased muscle inflammation.

OBJECTIVE First-degree relatives (FDRs) of patients with type 2 diabetes may exhibit a disproportionately elevated risk of developing insulin resistance, obesity, and type 2 diabetes when exposed to physical inactivity, which to some unknown extent may involve low-grade inflammation. We investigated whether subjects who are nonobese FDRs show signs of low-grade inflammation before or after exposure to short-term physical inactivity. RESEARCH DESIGN AND METHODS We studied 13 healthy FDR subjects and 20 control (CON) subjects matched for age, sex, and BMI before and after 10 days of bed rest (BR). Insulin sensitivity was measured by the hyperinsulinemic euglycemic clamp. Key low-grade inflammation mediators were measured in arterial blood and microdialysate from subcutaneous abdominal (SCAAT) and femoral adipose tissue. Adipokine mRNA expression was determined in SCAAT. RESULTS Before BR, FDR subjects displayed insulin resistance, elevated plasma C-reactive protein, leptin, and monocyte chemoattractant protein (MCP)-1, high interleukin (IL)-6, and MCP-1 expressions, as well as low adiponectin and leptin expressions. FDR subjects responded to BR by decreasing plasma adiponectin and IL-10 expression and increasing plasma expression of IL-10 and tumor necrosis factor-α. In contrast, CON subjects responded to BR by increasing plasma adiponectin and adiponectin expression and by decreasing SCAAT microdialysate leptin. CONCLUSIONS Young and nonobese FDR of patients with type 2 diabetes exhibit low-grade inflammation, which is further and disproportionately aggravated when exposed to physical inactivity. The study provides support for the notion that people at increased risk of type 2 diabetes should avoid even short periods of physical inactivity.

Physical inactivity is a risk factor for insulin resistance. We examined the effect of 9 days of bed rest on basal and insulin-stimulated expression of genes potentially involved in insulin action by applying hypothesis-generating microarray in parallel with candidate gene real-time PCR approaches in 20 healthy young men. Furthermore, we investigated whether bed rest affected DNA methylation in the promoter region of the peroxisome proliferator-activated receptor-γ coactivator-1α ( PPARGC1A) gene. Subjects were reexamined after 4 wk of retraining. We found that bed rest induced insulin resistance and altered the expression of more than 4,500 genes. These changes were only partly normalized after 4 wk of retraining. Pathway analyses revealed significant downregulation of 34 pathways, predominantly those of genes associated with mitochondrial function, including PPARGC1A. Despite induction of insulin resistance, bed rest resulted in a paradoxically increased response to acute insulin stimulation in the general expression of genes, particularly those involved in inflammation and endoplasmatic reticulum (ER) stress. Furthermore, bed rest changed gene expressions of several insulin resistance and diabetes candidate genes. We also observed a trend toward increased PPARGC1A DNA methylation after bed rest. We conclude that impaired expression of PPARGC1A and other genes involved in mitochondrial function as well as a paradoxically increased response to insulin of genes involved in inflammation and ER stress may contribute to the development of insulin resistance induced by bed rest. Lack of complete normalization of changes after 4 wk of retraining underscores the importance of maintaining a minimum of daily physical activity.

OBJECTIVE The aim of this study was to determine whether the type 2 diabetes–associated T-allele of transcription factor 7-like 2 (TCF7L2) rs7903146 associates with impaired insulin secretion to compensate for insulin resistance induced by bed rest. RESEARCH DESIGN AND METHODS A total of 38 healthy young Caucasian men were studied before and after bed rest using the hyperinsulinemic-euglycemic clamp technique combined with indirect calorimetry preceded by an intravenous glucose tolerance test. The TCF7L2 rs7903146 was genotyped using allelic discrimination performed with an ABI 7900 system. The genetic analyses were done assuming a dominant model of inheritance. RESULTS The first-phase insulin response (FPIR) was significantly lower in carriers of the T-allele compared with carriers of the CC genotype before bed rest, with and without correction for insulin resistance. The incremental rise of FPIR in response to insulin resistance induced by bed rest was lower in carriers of the T-allele (P < 0.001). Fasting plasma glucagon levels were significantly lower in carriers of the T-allele before and after bed rest. While carriers of the CC genotype developed increased hepatic insulin resistance, the TCF7L2 rs7903146 did not influence peripheral insulin action or the rate of lipolysis before or after bed rest. CONCLUSIONS Healthy carriers of the T-allele of TCF7L2 rs7903146 exhibit a diminished increase of insulin secretion in response to intravenous glucose to compensate for insulin resistance as induced by bed rest. Reduced paracrine glucagon stimulation may contribute to the impairment of β-cell function in the carriers TCF7L2 rs7903146 T-allele associated with increased risk of type 2 diabetes.

OBJECTIVE The aim of this study was to investigate the impact of 9 days of bed rest on insulin secretion, insulin action, and whole-body glucose and fat metabolism in first-degree relative (FDR) and matched control (CON) subjects. RESEARCH DESIGN AND METHODS A total of 13 FDR and 20 CON subjects participated in the study. All were studied before and after 9 days of bed rest using the clamp technique combined with indirect calorimetry preceded by an intravenous glucose tolerance test. Glucose and glycerol turnover rates were studied using stable isotope kinetics. RESULTS Bed rest caused a significant decrease in whole-body insulin sensitivity in both groups. Hepatic insulin resistance was elevated in FDR subjects prior to bed rest and was significantly augmented by bed rest in FDR (P < 0.01) but not in CON (P = NS) subjects. The rate of whole-body lipolysis decreased during bed rest in both FDR and CON subjects, with no significant differences between the groups. Insulin resistance induced by bed rest was fully accounted for by the impairment of nonoxidative glucose metabolism in both groups (overall P < 0.001). CONCLUSIONS Whole-body insulin action in both insulin-resistant FDR and healthy CON subjects deteriorates with 9 days of bed rest, converging toward similar degrees of whole-body insulin resistance. FDR subjects exhibit hepatic insulin resistance (HIR), which, in contrast to CON subjects, deteriorates in response to physical inactivity. FDR subjects exhibit reduced insulin secretion when seen in relation to their degree of HIR but not peripheral insulin resistance.

Adipokines play important regulatory roles in the pathophysiology of obesity and insulin resistance. We measured plasma and interstitial concentrations of the adipokines adiponectin, resistin, leptin, monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) and interleukin-8 (IL-8) in subcutaneous, abdominal and femoral adipose tissue using calibrated, large-pore microdialysis technique in 8 healthy, lean men on 2 experimental days. The interstitial leptin concentration was 2.5-fold higher in subcutaneous, femoral than abdominal adipose tissue (P0.05), but no regional differences were found for the remaining adipokines (P0.05). Adiponectin and leptin concentrations were higher in plasma than subcutaneous adipose tissue (approximately 25-fold and approximately 2-fold, respectively, P0.05), whereas MCP-1, IL-6 and IL-8 concentrations were higher in subcutaneous adipose tissue than plasma (approximately 100-fold, approximately 200-fold and approximately 1000-fold, respectively, P0.05). Resistin concentrations did not differ significantly between compartments. Adipose tissue blood flow (ATBF) showed no regional difference (P0.05). The intra- and inter-subject variations of all investigated adipokines as well as of ATBF were substantial (coefficient of variation: 4-177%). In conclusion, interstitial leptin concentrations are approximately 2.5-fold higher in subcutaneous, femoral than abdominal adipose tissue, which might be a potential mechanism behind the health-benefits of "pear-shape". Furthermore, subcutaneous adipose tissue has a marked production of pro-inflammatory adipokines.

OBJECTIVE Genetic susceptibility, low birth weight (LBW), and aging are key etiological factors in the development of type 2 diabetes. LBW is common among twins. It is unknown whether twin status per se is associated with risk of type 2 diabetes, and valid concordance rates of type 2 diabetes in twins on a lifetime perspective are lacking. RESEARCH DESIGN AND METHODS A clinical study was done on a population-based cohort of same-sex elderly monozygotic (MZ) and dizygotic (DZ) twins (n = 297) and singleton control subjects (C) (n = 71) including measures of anthropometry and glucose tolerance. In addition, type 2 diabetes incidence cases in twins (n = 626) and singletons (n = 553) were identified through the National Diabetes Register. RESULTS Twins were more abdominally obese, insulin resistant, and glucose intolerant, as evidenced by a higher A1C (%) (means ± SD) (MZ: 6.0 ± 1.0, DZ: 5.8 ± 0.7, C: 5.6 ± 0.3, P = 0.004) and 120-min post–oral glucose tolerance test plasma glucose levels (in mmol/l) (MZ: 8.6 ± 4.6, DZ: 8.4 ± 3.9, C: 6.8 ± 2.4, P = 0.003) compared with singletons. Importantly, twins had a higher prevalence of type 2 diabetes (MZ: 17.5% [95% CI 14.4–20.6], DZ: 15.7% [13.1–18.3], C: 5.6% [3.0–8.2], P = 0.03) together with a 60% higher incidence rate of type 2 diabetes compared with singletons. Cumulative concordance rates of type 2 diabetes to the age of 84 years were similar among elderly MZ (0.76 [0.68–0.84]) and DZ (0.71 [0.63–0.78]) twins. CONCLUSIONS Twin status per se is associated with abdominal obesity, insulin resistance, and increased prevalence of type 2 diabetes in elderly twins. The data support a quantitatively significant impact of the fetal environment as opposed to genetics on risk of type 2 diabetes.

Numerous studies have shown an association between low weight at birth and being born small for gestational age (SGA) on the one hand and risk of developing insulin resistance and type 2 diabetes on the other. Our studies in twins have indicated a non-genetic age-dependent origin of insulin resistance and type 2 diabetes associated with being born SGA. In order to gain insight into the molecular metabolic defects and mechanisms linking SGA with insulin resistance and type 2 diabetes, we performed a series of experiments in young and elderly twins, and, in particular, in young men (aged 19–23 years) with a weight at birth at term in the lowest 10th percentile with no family history of diabetes. The control group included age-matched men with birth weights at term in the upper normal range. While body mass index and waist-to-hip ratios were similar in the individuals born SGA and controls, dual-energy X-ray absorptiometry studies documented a higher degree of abdominal obesity in the men who had a low weight at birth. Using the gold standard hyperinsulinaemic-euglycaemic clamp technique combined with glucose tracers and studies of forearm glucose uptake, we found an impairment of insulin-stimulated glycolytic flux and reduced forearm (muscle) glucose uptake in the face of normal whole-body glucose uptake. In addition, we found a significantly decreased insulin secretion rate during oral glucose ingestion after correction for insulin action (disposition index), a paradoxical enhanced insulin suppression of hepatic glucose production and lower fasting plasma glycerol levels, suggesting impaired lipolysis. Finally, analysis of skeletal muscle biopsies showed reduced muscle expression of several key proteins involved in insulin signalling and glucose transport, including protein kinase C-ζ, the two subunits of phosphoinositol 3-kinase (i.e., p85α and p110β) and the insulin-sensitive glucose transporter, Glut-4, in individuals of low birth weight. In conclusion, being born SGA and of low birth weight is associated with type 2 diabetes in a non-genetic manner, and programming of muscle insulin action and signalling represents an early mechanism responsible for this association.

Intrauterine growth retardation (IUGR) is associated with a central fat distribution and risk of developing type 2 diabetes in adults when exposed to a sedentary Western lifestyle. Increased lipolysis is an early defect of metabolism in IUGR subjects, but the sites and molecular mechanisms involved are unknown. Twenty IUGR and 20 control (CON) subjects, aged 20–30 years, were studied before and after 10 days of bed rest using the glucose clamp technique combined with measurements of in vivo metabolism by microdialysis technique and blood flow by 133Xe washout technique in subcutaneous abdominal (SCAAT) and femoral (SCFAT) adipose tissue. Additionally, mRNA expression of lipases was evaluated in biopsies from SCAAT. Lipolysis in SCAAT was substantially higher in IUGR than in CON subjects despite markedly lower mRNA expression of lipases. Blood flow was higher in IUGR compared with CON in both SCAAT and SCFAT. Whole body insulin sensitivity did not differ between groups and decreased after bed rest. After bed rest, SCAAT lipolysis remained higher in IUGR compared with CON, and SCFAT lipolysis decreased in CON but not in IUGR. Prior to the development of whole body insulin resistance, young men with IUGR are characterized by increased in vivo adipose tissue lipolysis and blood flow with a paradoxically decreased expression of lipases compared with CON, and 10 days of physical inactivity underlined the baseline findings. Subjects with IUGR exhibit primary defects in adipose tissue metabolism.

Physical inactivity is a known risk factor for type 2 diabetes. We studied whole body and forearm insulin sensitivity in subjects at increased risk for type 2 diabetes [persons with low birth weight (LBW group; n = 20) and first-degree relatives to type 2 diabetic patients (FDR group; n = 13)] as well as a control (CON) group ( n = 20) matched for body mass index, age, and physical activity levels before and after 10 days of bedrest. Subjects were studied by hyperinsulinemic isoglycemic clamp combined with arterial and deep venous catheterization of the forearm. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. All groups responded with a decrease in whole body insulin sensitivity in response to bedrest [CON group: 6.8 ± 0.5 to 4.3 ± 0.3 mg·min−1·kg−1( P < 0.0001), LBW group: 6.2 ± 0.5 to 4.3 ± 0.3 mg·min−1·kg−1( P < 0.0001), and FDR group: 4.3 ± 0.7 to 3.1 ± 0.3 mg·min−1·kg−1( P = 0.068)]. The percent decrease was significantly greater in the CON group compared with the FDR group (CON group: 34 ± 4%, LBW group: 27 ± 4%, and FDR group: 10 ± 13%). Forearm insulin-stimulated glucose clearance decreased significantly in the CON and LBW groups in response to bedrest; in the FDR group, clearance was very low before bedrest and no change was observed. Before bedrest, the CON and LBW groups demonstrated a significant increase in FBF during hyperinsulinemia; after bedrest, an increase in FBF was observed only in the CON group. In conclusion, bedrest induced a pronounced reduction in whole body, skeletal muscle, and vascular insulin sensitivity in the CON and LBW groups. The changes were most pronounced in the CON group. In the FDR group, insulin resistance was already present before bedrest, but even this group displayed a high sensitivity to changes in daily physical activity.

The assessment of pancreatic beta cell function in humans is challenging because of a complex interplay between insulin secretion, insulin sensitivity and hepatic insulin extraction. Simplified, the relationship between insulin secretion and insulin sensitivity can be described by an approximate hyperbola with the product of the two variables being constant for individuals with the same degree of glucose tolerance (the disposition index). Strengths and limitations of the disposition index have been widely debated in the literature. In this review we will focus on another and until recently unrecognized dimension of the disposition index, namely the issue of adjusting insulin secretion for hepatic versus peripheral insulin sensitivity. An underlying assumption of this issue is that the liver as compared to muscle plays a different role in the regulation of in vivo insulin secretion.

Individuals born with low birth weight (LBW) are at risk of developing type 2 diabetes mellitus (T2D), which may be precipitated by physical inactivity. Twenty-two LBW subjects and twenty-three controls were studied before and after bed rest by the hyperinsulinemic euglycemic clamp combined with indirect calorimetry and infusion of stable isotope tracers and preceded by an intravenous glucose tolerance test. LBW subjects had a similar body mass index but elevated abdominal obesity compared with controls. The basal rate of whole body lipolysis (WBL) was elevated in LBW subjects with and without correction for abdominal obesity before and after bed rest (all P = 0.01). Skeletal muscle hormone-sensitive lipase (HSL) protein expression and phosphorylation at Ser565 were similar in the two groups. Bed rest resulted in a decrease in WBL and an increased skeletal muscle HSL Ser565 phosphorylation indicating a decreased HSL activity in both groups. All subjects developed peripheral insulin resistance in response to bed rest (all P < 0.0001) with no differences between groups. LBW subjects developed hepatic insulin resistance in response to bed rest. In conclusion, increased WBL may contribute to the development of hepatic insulin resistance when exposed to bed rest in LBW subjects. Nine days of bed rest causes severe peripheral insulin resistance and reduced WBL and skeletal muscle HSL activity, as well as a compensatory increased insulin secretion, with no differences in LBW subjects and controls.

Background: Low birth weight (LBW) is associated with increased risk of type 2 diabetes and cardiovascular disease. We studied endothelial function and insulin sensitivity in young men with LBW (n = 22) and controls (n = 22). Methods: Insulin sensitivity and endothelial function was studied with venous occlusion plethysmography and intra-arterial infusions of adenosine and acetylcholine, before and during a hyperinsulinemic isoglycemic clamp. Results: Forearm blood flow response to systemic hyperinsulinemia was diminished in LBW compared to controls (p < 0.05). Fractional arteriovenous glucose extraction was similar, and consequently insulin-stimulated forearm glucose clearance was diminished in LBW compared with controls (0.8 ± 0.09 vs. 1.4 ± 0.36 ml·100 ml–1·min–1, respectively, p < 0.05). Forearm blood flow response to adenosine and acetylcholine with or without insulin stimulation did not differ between groups. Whole-body glucose uptake was lower in LBW than controls (8.7 ± 0.5 and 9.1 ± 0.6 mg·min–1·kg–1 lean body mass); however, this was not significant. Conclusions: Forearm blood flow response to insulin is impaired in LBW, whereas the response to adenosine and acetylcholine is preserved. The impaired insulin-mediated increase in bulk flow in LBW may be due to an impairment of insulin-mediated capillary recruitment independent of – or preceding – whole-body insulin resistance in LBW subjects.

Objective: Low birth weight (LBW) is an independent risk factor of insulin resistance and type 2 diabetes. Recent studies suggest that mitochondrial dysfunction and impaired expression of genes involved in oxidative phosphorylation (OXPHOS) may play a key role in the pathogenesis of insulin resistance in aging and type 2 diabetes. The aim of this study was to determine whether LBW in humans is associated with mitochondrial dysfunction in skeletal muscle. Methods: Mitochondrial capacity for ATP synthesis was assessed by 31phosphorus magnetic resonance spectroscopy in forearm and leg muscles in 20 young, lean men with LBW and 26 matched controls. On a separate day, a hyperinsulinemic euglycemic clamp with excision of muscle biopsies and dual-energy x-ray absorptiometry scanning was performed. Muscle gene expression of selected OXPHOS genes was determined by quantitative real-time PCR. Results: The LBW subjects displayed a variety of metabolic and prediabetic abnormalities, including elevated fasting blood glucose and plasma insulin levels, reduced insulin-stimulated glycolytic flux, and hepatic insulin resistance. Nevertheless, in vivo mitochondrial function was normal in LBW subjects, as was the expression of OXPHOS genes. Conclusions: These data support and expand previous findings of abnormal glucose metabolism in young men with LBW. In addition, we found that the young, healthy men with LBW exhibited hepatic insulin resistance. However, the study does not support the hypothesis that muscle mitochondrial dysfunction per se is the underlying key metabolic defect that explains or precedes whole body insulin resistance in LBW subjects at risk for developing type 2 diabetes.

First-degree relatives (FDR) of patients with type 2 diabetes mellitus are at increased risk of developing type 2 diabetes mellitus. We studied if endothelial dysfunction of the resistance vessels is present and may coexist with metabolic insulin resistance in FDR. Male FDR (n = 13; 26 +/- 1 years; body mass index, 25 +/- 1 kg m(2) [mean +/- SEM]) and matched control subjects (CON) (n = 22; 25 +/- 1 years; body mass index, 24 +/- 1 kg m(2)) were studied by hyperinsulinemic (40 mU min(-1)m(-2)) isoglycemic clamp combined with brachial arterial and deep venous catheterization of the forearm. Forearm blood flow (FBF) was measured by venous occlusion plethysmography upon stimulation with systemic hyperinsulinemia (291 +/- 11 pmol/L, pooled data from both groups) and upon intraarterial infusion of adenosine (ADN) and acetylcholine (ACH) +/- hyperinsulinemia. Forearm blood flow response to ADN and ACH was less in FDR vs CON (P.05); systemic hyperinsulinemia added to the FBF effect of ADN in CON (P.05) but not in FDR. In addition, FDR demonstrated impaired FBF to hyperinsulinemia (2.1 +/- 0.2 vs 4.0 +/- 0.6 mL 100 mL(-1) min(-1)) in FDR and CON, respectively (P.05). Both M-value (5.0 +/- 0.7 vs 7.0 +/- 0.5 mg min(-1) kg(-1)) and forearm glucose clearance (0.6 +/- 0.1 vs 1.4 +/- 0.4 mL 100 mL(-1)min(-1)) were diminished in FDR compared with CON (all P.05). FDR demonstrated endothelial dysfunction of the resistance vessels in addition to impaired insulin-stimulated increase in bulk flow. Moreover, FDR demonstrated whole-body insulin resistance as well as decreased basal and insulin-stimulated forearm glucose uptake. It remains to be established whether FDR also demonstrate impaired insulin-stimulated microvascular function.

The term “endothelial dysfunction” refers to the inability or attenuated effect of the endothelial cells in participating in the relaxation of the adjacent smooth muscle, thus causing less vasodilation. Although endothelial dysfunction is often seen in patients with type 2 diabetes, it does not necessarily follow that insulin resistance and (or) hyperglycemia is causing the inability to respond properly to vasodilatory stimuli. Rather, this could be related to the impact of concomitant cardiovascular risk factors that are almost invariably present in patients with type 2 diabetes. The impact of physical training — or the opposite, inactivity — on endothelial function is not fully elucidated. Some studies have shown positive effects of physical training, whereas others have not. In general, physical training can improve endothelial function when this is impaired. However, physical training does not seem to have any effect on endothelial function when this is normal.