Insulin Resistance In First-degree Relatives Research Articles

Correlation of markers of inflammation with hormonal, metabolic parameters, insulin resistance and adiposity indices in first-degree relatives of patient with polycystic ovary syndrome.

<b>Background:</b> Polycystic ovary syndrome (PCOS) is a state of chronic low-grade inflammation. Low-grade inflammation has been linked to the development of cardiovascular disease (CVD). There is evidence of clustering for metabolic syndrome, hypertension, dyslipidaemia in type 2 diabetes mellitus and insulin resistance (IR) in mothers, fathers, sisters and brothers of women with PCOS. <b>Aims:</b> The aim is to study the levels of inflammatory markers and IR in first-degree relatives of patients with PCOS and find any correlation with hormonal parameters, metabolic parameters and adiposity indices in them. <b>Settings and Design:</b> A total of 66 first-degree relatives of a patient with PCOS were included in this cross-sectional study. <b>Materials and Methods:</b> All participants underwent detailed clinical evaluation and biochemical investigations, including high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), luteinising hormone (LH), follicle-stimulating hormone (FSH) and total testosterone (only in females). Homeostasis model assessment of IR (HOMA-IR), lipid accumulation product and visceral adiposity index were calculated using standard equations. Visceral adipose tissue thickness and subcutaneous adipose tissue thickness were assessed using ultrasonography. <b>Statistical Analysis Used:</b> Spearman's and Pearson's correlation coefficients were used to analyse the correlation between different non-parametric and parametric data, respectively. Multiple linear regression was used to correlate multiple dependent factors. <b>Results:</b> The mean hs-CRP level was 2.4 ± 1.1 mg/L, which is greater than the cut-off of 2 mg/L and hs-CRP >2 mg/L was found in 62% (<i>n</i> = 41) participants. The mean IL-6 (3.5 ± 1.1 pg/ml) and total white blood cell count (7244 ± 2190/mm³) were in the normal range. The mean HOMA-IR was 2.35 ± 0.76, which is elevated, considering HOMA IR >2 as a predictor of IR and metabolic syndrome. HOMA IR >2 was found in 64% (<i>n</i> = 42) of the participants. Inflammatory markers were significantly correlated with LH and HOMA IR, even after multiple linear regression was fitted for each marker individually. <b><b>Conclusion:</b></b> Apparently, healthy first-degree relatives of PCOS patients had evidence of chronic low-grade inflammation. The chronic inflammation in them correlated well with HOMA-IR and LH but was independent of body mass index. This low-grade inflammation may predispose the first-degree relatives of PCOS to CVD.

Correlation of markers of inflammation with hormonal, metabolic parameters, insulin resistance and adiposity indices in first-degree relatives of patient with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a state of chronic low-grade inflammation. Low-grade inflammation has been linked to the development of cardiovascular disease (CVD). There is evidence of clustering for metabolic syndrome, hypertension, dyslipidaemia in type 2 diabetes mellitus and insulin resistance (IR) in mothers, fathers, sisters and brothers of women with PCOS. The aim is to study the levels of inflammatory markers and IR in first-degree relatives of patients with PCOS and find any correlation with hormonal parameters, metabolic parameters and adiposity indices in them. A total of 66 first-degree relatives of a patient with PCOS were included in this cross-sectional study. All participants underwent detailed clinical evaluation and biochemical investigations, including high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), luteinising hormone (LH), follicle-stimulating hormone (FSH) and total testosterone (only in females). Homeostasis model assessment of IR (HOMA-IR), lipid accumulation product and visceral adiposity index were calculated using standard equations. Visceral adipose tissue thickness and subcutaneous adipose tissue thickness were assessed using ultrasonography. Spearman's and Pearson's correlation coefficients were used to analyse the correlation between different non-parametric and parametric data, respectively. Multiple linear regression was used to correlate multiple dependent factors. The mean hs-CRP level was 2.4 ± 1.1 mg/L, which is greater than the cut-off of 2 mg/L and hs-CRP >2 mg/L was found in 62% (n = 41) participants. The mean IL-6 (3.5 ± 1.1 pg/ml) and total white blood cell count (7244 ± 2190/mm3) were in the normal range. The mean HOMA-IR was 2.35 ± 0.76, which is elevated, considering HOMA IR >2 as a predictor of IR and metabolic syndrome. HOMA IR >2 was found in 64% (n = 42) of the participants. Inflammatory markers were significantly correlated with LH and HOMA IR, even after multiple linear regression was fitted for each marker individually. Apparently, healthy first-degree relatives of PCOS patients had evidence of chronic low-grade inflammation. The chronic inflammation in them correlated well with HOMA-IR and LH but was independent of body mass index. This low-grade inflammation may predispose the first-degree relatives of PCOS to CVD.

Serum ferritin, an early marker of cardiovascular risk: a study in Chinese men of first-degree relatives with family history of type 2 diabetes

BackgroundFerritin is one of the key proteins that regulate iron homeostasis and is widely available clinical biomarker of iron status. This study aimed to discuss the influence of serum ferritin (SF) on cardiovascular risk factors in the first-degree relatives with family history of type 2 diabetes (FHD).MethodsThis cross-sectional study included 232 men. Anthropometric measurements and blood samples were analyzed. The people were divided into four groups according to median SF (102.8 ng/ml) and people with or without FHD. Group A (FHD–and low SF), group B (FHD–and high SF), group C (FHD+ and low SF), and group D (FHD+ and high SF).ResultsThe subjects in different categories of SF concentrations showed significant differences in BMI (SF main effect: P = 0.010), WC (P = 0.030), SBP (P < 0.001), FPG (P < 0.001), PPG-2 h (P < 0.001), FINS (P < 0.001), and HOMA-IR (P = 0.015; all: 2-way ANOVA). There was a significant difference in SBP (FHD main effect: P = 0.003), DBP (P = 0.006), and FINS (P = 0.013, all: 2-way ANOVA) between the groups with or without FHD. The interaction term between SF and FHD was significant for SBP (P = 0.011), DBP (P = 0.012), and PPG-2 h (P = 0.022). Logistic analysis showed that accumulation of CVD risk factors, which were ≥ 2 items and ≥ 3 items in group D were 7.546 and 3.343 times higher compared with group A (P < 0.05).ConclusionsThe increased SF levels increased the risk of cardiovascular risk factors and the occurrence of insulin resistance in first-degree relatives with FHD.

The effects of vitamin D supplementation on adiponectin level and insulin resistance in first-degree relatives of subjects with type 2 diabetes: a randomized double-blinded controlled trial.

BackgroundDespite the certain role of both vitamin D and adiponectin in the regulation of insulin sensitivity, the interaction between these two agents has remained uncertain.ObjectiveThe present study aimed to determine whether vitamin D is able to change plasma adiponectin and affect glucose homeostasis and insulin sensitivity in first-degree relatives of subjects with type 2 diabetes.MethodsThis randomized clinical trial was conducted at Clinic of Shahid Sadoughi Hospital in Yazd, Iran, from January 25, 2012 to December 25, 2014. In this randomized, double-blinded controlled trial, 64 first-degree relatives of type 2 diabetic patients were assigned randomly to receive either vitamin D supplement (50000 IU vitamin D tablet weekly) plus lifestyle change as the intervention group (n = 32) or placebo plus lifestyle change as the control group (n = 32) for twelve weeks (three months).ResultsFifty-three patients (28 in the intervention group and 25 in the control group) completed the study. Serum levels of vitamin D increased while insulin level and consequently insulin resistance (calculated by HOMA formula) significantly decreased in the case group (p-value <0.001 for all variables). Although the values of these three biomarkers showed a slight increase in control group, the changes were not statistically significant. The levels of the changes in other markers including adiponectin, Fasting Blood Sugar (FBS), triglyceride, and total cholesterol remained insignificant in both study groups after completing interventions compared with before interventions.ConclusionThis study showed that decreased insulin resistance is expected by administrating vitamin D supplement in first-degree relatives of the patients with diabetes mellitus.Trial RegistrationThe trial was registered at the Iranian Registry of Clinical Trials (http://www.irct.ir) with the IRCT ID: 201105176430N1.FundingThe authors received no financial support for the research or publication of this article.

Do mitochondria care about insulin resistance?

Do mitochondria care about insulin resistance?

Grape Polyphenols Prevent Fructose-Induced Oxidative Stress and Insulin Resistance in First-Degree Relatives of Type 2 Diabetic Patients

OBJECTIVETo assess the clinical efficacy of nutritional amounts of grape polyphenols (PPs) in counteracting the metabolic alterations of high-fructose diet, including oxidative stress and insulin resistance (IR), in healthy volunteers with high metabolic risk.RESEARCH DESIGN AND METHODSThirty-eight healthy overweight/obese first-degree relatives of type 2 diabetic patients (18 men and 20 women) were randomized in a double-blind controlled trial between a grape PP (2 g/day) and a placebo (PCB) group. Subjects were investigated at baseline and after 8 and 9 weeks of supplementation, the last 6 days of which they all received 3 g/kg fat-free mass/day of fructose. The primary end point was the protective effect of grape PPs on fructose-induced IR.RESULTSIn the PCB group, fructose induced 1) a 20% decrease in hepatic insulin sensitivity index (P < 0.05) and an 11% decrease in glucose infusion rate (P < 0.05) as evaluated during a two-step hyperinsulinemic-euglycemic clamp, 2) an increase in systemic (urinary F2-isoprostanes) and muscle (thiobarbituric acid–reactive substances and protein carbonylation) oxidative stress (P < 0.05), and 3) a downregulation of mitochondrial genes and decreased mitochondrial respiration (P < 0.05). All the deleterious effects of fructose were fully blunted by grape PP supplementation. Antioxidative defenses, inflammatory markers, and main adipokines were affected neither by fructose nor by grape PPs.CONCLUSIONSA natural mixture of grape PPs at nutritional doses efficiently prevents fructose-induced oxidative stress and IR. The current interest in grape PP ingredients and products by the global food and nutrition industries could well make them a stepping-stone of preventive nutrition.

The Size of Large Adipose Cells Is a Predictor of Insulin Resistance in First‐Degree Relatives of Type 2 Diabetic Patients

Early studies reported that the size of adipose cells correlates with insulin resistance. However, a recent study comparing moderately obese, sensitive and resistant subjects, with comparable BMI (~30), did not detect any significant difference in the size of the large cells, but rather a smaller proportion of large cells in the resistant subjects, suggesting impaired adipogenesis. We hypothesize that a decreased proportion, rather than the size, of large adipose cells is also associated with insulin resistance in first-degree relatives of type 2 diabetic patients. Thirty-five leaner (BMI 18-34) subjects who were relatively healthy were recruited. Insulin sensitivity was measured by the euglycemic, hyperinsulinemic clamp. Needle biopsies of abdominal subcutaneous fat were assayed for adipose cell size by fitting the cell size distribution with two exponentials and a Gaussian function. The fraction of large cells was defined as the area of the Gaussian peak and the size of the large cells was defined as its center (c(p)). Glucose infusion rate (GIR) and c(p) were negatively correlated, but insulin sensitivity and the proportion of large cells were not correlated. BMI and c(p) were also strongly correlated, but a relationship of modest correlation between the cell size and insulin resistance was still significant after correcting for BMI. In contrast to moderately obese subjects, in the first-degree relatives of type 2 diabetic patients both BMI and the size of the large adipose cells predict the degree of insulin resistance; no correlation is found between the proportion of large adipose cells and insulin resistance.

Immunological characteristics and pancreatic β-cell function in first-degree relatives of type 1 diabetes mellitus

Oral glucose tolerance test(OGTT)was performed in 419 first-degree relatives(FDRs)of type 1 diabetes mellitus. GADA, IA-2A, and IAA were determined by radioligand assay, and the positive rates were 7.16%, 1.43%, and 1.26%, respectively. Intravenous glucose tolerance test(IVGTT)and nateglinide-OGTT were performed in 39 controls, 11 first-degree relatives with positive autoantibody(Ab+group), 14 ones with negative autoantibody(Ab-group)during 5-7 days.The first-phase insulin release(FPIR), area under insulin release during 0-10 min [AUC0-10] of IVGTT and the value of(ΔI30/ΔG30)of nateglinide-OGTT in Ab+group were lower than those of control and(2.75±0.37 vs 3.61±1.05)mU/mmol, all P＜0.05]. The 1st min insulin release in Ab+group was lower than that of Ab-group [(3.80±0.30 vs 4.52±0.70)mU/L, P＜0.05]. The HOMA-IR was higher in Ab-group than that in control group(2.92±1.04 vs 1.96±1.22, P＜0.05). The results suggest that the positivity rates of autoantibodies in FDRs of type 1 diabetes mellitus are very close to those of Caucasian. There exist insulin secretion defects in FDRs with positive autoantibody while insulin resistance in FDRs with negative autoantibody. Key words: Dabetes mellitus, type 1; First-degree relatives; Islet autoantibodies; Islet β-cell function; Nateglinide

The Effect of Age on Insulin Sensitivity and Insulin Secretion in First-Degree Relatives of Type 1 Diabetic Patients: A Population Analysis

Understanding the role of insulin resistance in type 1 diabetes may lead to new prevention strategies. Estimates of insulin resistance in first-degree relatives of those with type 1 diabetes may be obtained using the minimal model of glucose kinetics incorporating a population approach. The objective of the study was to explore parameters contributing to glucose homeostasis in a cross-sectional study of first-degree relatives across a wide age range. Insulin sensitivity (SI) was assessed using the minimal model of glucose kinetics after an oral glucose tolerance test combined with nonlinear mixed-effects modeling. Beta-cell function was measured from the insulinogenic index at 30 min (IGI(30)). Disposition index (DI) was estimated as the product of SI and IGI(30). The study was conducted at an academic center. Subjects included 1241 first-degree relatives (aged 2-75 yr). SI was found to be negatively correlated with age, whereas IGI(30) increased until young adulthood. The increase IGI(30) was apparently insufficient to compensate for the insulin resistance because DI decreased linearly at the rate of 0.035 (10(-2) min(-1) mmol(-1) liter per year) after young adulthood. Both IGI(30) and DI were significantly lower in those with vs. without autoantibodies, whereas there was no difference between these groups with respect to SI. Beta-cell function, adjusted for age-related insulin resistance, decreases throughout life in first-degree relatives. This deterioration may be exacerbated in the presence of autoantibodies. Oral glucose tolerance test data combined with a nonlinear mixed-effect modeling population approach may be a useful technique to evaluate SI and secretion in a population.

Impaired endothelial function and insulin action in first-degree relatives of patients with type 2 diabetes mellitus

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.

Diabetes mellitus as a prothrombotic condition

Diabetes mellitus (DM) is characterized by fasting hyperglycaemia and a high risk of atherothrombotic disorders affecting the coronary, cerebral and peripheral arterial trees. The risk of myocardial infarction (MI) is 3-5 fold higher in Type 2 DM and a DM subject with no history of MI has the same risk as a non-DM subject with a past history of MI. In total around 70% of deaths are vascular with poorer outcomes to both acute events and cardiological interventions. It was proposed that clustering of vascular risk factors (hyperinsulinaemia, dysglycaemia, dyslipidaemia and hypertension) around insulin resistance (IR) accounted for the increase in risk with Type 2 DM. The importance of this became apparent with the recognition that risk clustering occurs in normoglycaemic and impaired glucose tolerance (IGT) subjects with IR, in total around 25% of the population in addition to long-standing Type 1 subjects with renal disease. Evidence indicates that thrombotic risk clustering also occurs in association with IR, suppression of fibrinolysis due to elevated concentrations of the fibrinolytic inhibitor, plasminogen activator inhibitor-1 (PAI-1) is invariable with IR and there is evidence that this is regulated by the effects of triglyceride on the PAI-1 gene promoter. Other studies indicated that prothrombotic risk (coagulation factors VII, XII and fibrinogen) also associates with the IR syndrome. The development of endothelial cell dysfunction with suppression of nitric oxide and prostacyclin synthesis, combined with platelet resistance to the anti-aggregatory effects of these hormones leads to loss of control over platelet activation. In addition, hyperglycaemia and glycation have marked effects on fibrin structure function, generating a clot which has a denser structure, resistant to fibrinolysis. The combination of increased circulating coagulation zymogens, inhibition of fibrinolysis, changes in fibrin structure/function and alterations in platelet reactivity creates a thrombotic risk clustering which underpins the development of cardiovascular disease.

Endothelial function and biochemical vascular markers in first-degree relatives of type 2 diabetic patients: the effect of exercise training

Endothelial dysfunction (ED) is associated with the presence of atherosclerosis. However, ED is also considered a sign of the early vascular changes preceding atherosclerosis. By measuring flow-mediated vasodilation (FMD) and circulating markers of endothelial function we sought to explore whether impaired endothelial function is already present in healthy subjects at increased risk of developing type 2 diabetes mellitus. Furthermore, we aimed to assess the impact of short-term lifestyle intervention (10 weeks endurance exercise) on the potentially primary defects of endothelial function. Twenty-nine healthy but insulin-resistant first-degree relatives of patients diagnosed with type 2 diabetes mellitus (33 ± 5 years; body mass index, 26.3 ± 1.6 kg/m 2) were compared with 19 control subjects without a family history of diabetes mellitus (31 ± 5 years; body mass index, 25.8 ± 3.0 kg/m 2). At baseline the von Willebrand factor was significantly increased in the relatives ( P < .05). Furthermore, mannose-binding lectin ( P = .06), soluble intercellular adhesion molecule 1 ( P = .08), and osteoprotegerin ( P = .08) tended to be increased in relatives. The following markers of endothelial function were comparable at baseline: FMD, C-reactive protein, plasminogen activator inhibitor 1, and soluble vascular cell adhesion molecule 1. Exercise training resulted in a decrease in mannose-binding lectin ( P = .02) and osteoprotegerin ( P < .01) in relatives only, whereas other biochemical markers were unaffected in both groups. Moreover, the relatively high-intensity exercise training tended weakly to reduce FMD in the relatives ( P = .15). In conclusion, healthy subjects predisposed for type 2 diabetes mellitus show only minor signs of endothelial dysfunction. Under these almost normal vascular conditions, exercise training has little effect on endothelial function.

Low serum PYY is linked to insulin resistance in first-degree relatives of subjects with type 2 diabetes

Low circulating peptide YY (PYY) levels are reported in obese and type II diabetic subjects and results from PYY knockout animals suggests that PYY deficiency may have a causative role in the etiology of obesity and type 2 diabetes. Here, our aims were to determine whether people with a genetic predisposition to developing type 2 diabetes and obesity differ from otherwise similar subjects without such family history, in fasting or meal-related PYY levels, fasting insulin, insulin secretion (HOMA-B) and insulin sensitivity. We also investigated whether PYY ablation affects the intrinsic ability of islets to secrete insulin, which may be a contributing factor to the hyperinsulinemia observed in PYY knockout mice. Healthy female first-degree relatives of people with type 2 diabetes were matched for age, gender and BMI to control subjects but had significantly lower insulin sensitivity (p<0.05). Relatives also had significantly lower fasting serum PYY levels than controls (p<0.05), but their PYY response to a high fat meal (4250 kJ, 73% fat) was not significantly different. Fasting PYY level correlated positively with glucose infusion rate (r=0.713, p=0.002) and fasting adiponectin (r=0.5, p=0.02). Islets of Langerhans from PYY knockout mice were found to hypersecrete insulin in response to 25 mM glucose (p<0.05). These data demonstrate that lack of PYY enhances insulin secretion from the Islets of Langerhans and that low fasting PYY levels are associated with insulin resistance in humans. Together, these findings suggest that low circulating levels of PYY could contribute to hyperinsulinemia and insulin resistance, and possibly contribute to subsequent development of obesity and type 2 diabetes.

Familial Aggregation of Insulin Resistance in First-Degree Relatives of Patients With Nonalcoholic Fatty Liver Disease

An association between nonalcoholic fatty liver disease (NAFLD) and the insulin resistance (IR) syndrome exists. Familial clustering of IR may support a genetic predisposition to NAFLD or cryptogenic cirrhosis (CC). Patients with NAFLD (n = 20) and healthy controls (n = 20) matched for age, sex, and body mass index with at least 4 living relatives and 2 generations of lineage participated in a familial aggregation study. A medical history was obtained from each subject and confirmed with first-degree family members. NAFLD patients were more likely to have cirrhosis (odds ratio [OR] = 12.0), cardiac disease (OR, 3.0), hyperlipidemia (OR, 12.1), diabetes mellitus (DM) (OR, 9.1), renal stones (OR, 4.1), and arthritis (OR, 6.1). IR (P = .042) (the primary dependent variable) and DM (P = .013) were noted in their first-degree relatives. A trend for familial clustering of NAFLD or CC (P = .059) with a maternal linkage for disease expression also may exist. Cholelithiasis (P = .047), presumed NAFLD and/or CC (P = .049), and a trend toward IR (P = .07) were noted in the mothers, but not the fathers, of patients with NAFLD. An increased risk of DM (OR, 4.2; 95% confidence interval, 1.26-18.7; P = .013), IR (OR, 2.86; 95% confidence interval, 1.02-9.38; P = .042), and smoking (OR, 3.41; 95% confidence interval, 1.43-9.07; P = .003) was observed in first-degree relatives of NAFLD patients. No significant survival difference was observed between family cohorts. Familial clustering and a potential maternal linkage for IR support a genetic predisposition for NAFLD. Alternatively, the presence of suppressor genes modifying the expression of IR in paternal lineage warrants further investigation.

Intramyocellular Lipid Is Not Significantly Increased in Healthy Young Insulin Resistant First-Degree Relatives of Diabetic Subjects

Insulin resistance is an early phenotypic feature of nondiabetic first-degree relatives of type 2 diabetic subjects (FDR) (1,2). While intramyocellular lipid (IMCL) is a marker of insulin resistance (3), how it develops is not completely understood. To study early defects accompanying insulin resistance, we characterized a population at high risk of type 2 diabetes (4,5). We studied young, healthy, sedentary, nonsmoking (age <45 years, BMI <36 kg/m2), normolipidemic, and normal glucose tolerant subjects. At-risk FDR subjects (14 female and 5 male) were compared with control subjects without family history of diabetes (12 female and 10 male). To test the lipid supply hypothesis, we extended previous investigations in …

Evidence of impaired adipogenesis in insulin resistance

To elucidate the roles of adipose tissue and skeletal muscle in the early development of insulin resistance, we characterized gene expression profiles of isolated adipose cells and skeletal muscle of non-diabetic insulin-resistant first-degree relatives of type 2 diabetic patients using oligonucleotide microarrays. About 600 genes and expressed sequence tags, which displayed a gene expression pattern of cell proliferation, were differentially expressed in the adipose cells. The differentially expressed genes in the skeletal muscle were mostly related to the cellular signal transduction and transcriptional regulation. To verify the microarray findings, we studied expression of genes participating in adipogenesis. The expression of Wnt signaling genes, WNT1, FZD1, DVL1, GSK3β, β-catenin, and TCF1, and adipogenic transcription factors, C/EBPα and β and δ, PPARγ, and SREBP-1, was reduced in the adipose tissue. The expression of adipose-specific proteins related to terminal differentiation, such as adiponectin and aP2, was reduced both in the adipose tissue and in the adipose cells isolated from portions of the biopsies. The adipose cells were enlarged in the insulin-resistant relatives and the cell size inversely correlated with the expression of the Wnt signaling genes, adiponectin, and aP2. Our findings suggest that insulin resistance is associated with an impaired adipogenesis.

The insulin resistance syndrome and coronary artery disease.

Insulin resistance is an increasingly common metabolic abnormality characterized by an impaired physiological response to insulin. The constellation of insulin resistance and several other metabolic and vascular disorders is known as the insulin resistance syndrome. The characteristic features of the insulin resistance syndrome include central obesity, hypertension, dyslipidemia, glucose intolerance and specific abnormalities of both endothelial cell and vascular function. Although insulin resistance can arise in response to aging, obesity and inactivity, there is a clear genetic component. Insulin resistance is not generally attributable to a single genetic defect. Indeed, it is very likely to be a polygenic disorder in most individuals. A genetic predisposition is suggested to be the demonstration of increased insulin resistance in first-degree relatives of patients with diabetes and by a high incidence of insulin resistance in specific populations. Epidemiological data have demonstrated a strong association between a clustering of specific factors and the risk of cardiovascular disease. The diagnosis of the insulin resistance syndrome remains a significant clinical challenge. At present, clinicians are faced with establishing a clinical diagnosis despite varying definitions of the disorder and controversy regarding how many components presage clinical events. A proposed approach to the management of patients with the insulin resistance syndrome is discussed.

Prandial glucose effectiveness and fasting gluconeogenesis in insulin-resistant first-degree relatives of patients with type 2 diabetes.

Impaired glucose effectiveness (i.e., a diminished ability of glucose per se to facilitate its own metabolism), increased gluconeogenesis, and endogenous glucose release are, together with insulin resistance and beta-cell abnormalities, established features of type 2 diabetes. To explore aspects of the pathophysiology behind type 2 diabetes, we assessed in a group of healthy people prone to develop type 2 diabetes (n = 23), namely first-degree relatives of type 2 diabetic patients (FDR), 1) endogenous glucose release and fasting gluconeogenesis measured using the 2H2O technique and 2) glucose effectiveness. The FDR group was insulin resistant when compared with an age-, sex-, and BMI-matched control group without a family history of type 2 diabetes (n = 14) (M value, clamp: 6.07 +/- 0.48 vs. 8.06 +/- 0.69 mg x kg(-1) lean body weight (lbw) x min(-1); P = 0.02). Fasting rates of gluconeogenesis (1.28 +/- 0.06 vs. 1.41 +/- 0.07 mg x kg(-1) lbw x min(-1); FDR vs. control subjects, P = 0.18) did not differ in the two groups and accounted for 53 +/- 2 and 60 +/- 3% of total endogenous glucose release. Glucose effectiveness was examined using a combined somatostatin and insulin infusion (0.17 vs. 0.14 mU x kg(-1) x min(-1), FDR vs. control subjects), the latter replacing serum insulin at near baseline levels. In addition, a 360-min labeled glucose infusion was given to simulate a prandial glucose profile. After glucose infusion, the integrated plasma glucose response above baseline (1,817 +/- 94 vs. 1,789 +/- 141 mmol/l per 6 h), the ability of glucose to simulate its own uptake (1.50 +/- 0.13 vs. 1.32 +/- 0.16 ml x kg(-1) lbw x min(-1)), and the ability of glucose per se to suppress endogenous glucose release did not differ between the FDR and control group. In conclusion, in contrast to overt type 2 diabetic patients, healthy people at high risk of developing type 2 diabetes are characterized by normal glucose effectiveness at near-basal insulinemia and normal fasting rates of gluconeogenesis.

Endothelial dysfunction is detectable in young normotensive first-degree relatives of subjects with type 2 diabetes in association with insulin resistance.

Endothelial dysfunction (ED) is regarded as an early step in the development of atherosclerosis. Among the pathogenetic factors leading to atherosclerosis, the role of insulin resistance and hyperinsulinemia as independent risk factors is still under debate. In this study, we examined the association between ED and insulin resistance in normotensive and normoglycemic first-degree relatives (FDRs) of patients with type 2 diabetes mellitus (DM). Endothelium-dependent and -independent vasodilation of the brachial artery was measured with high-resolution ultrasound (13 MHz) in 53 normotensive FDRs (21 men, 32 women; mean age, 35 years) with normal oral glucose tolerance, 10 age- and sex-matched normal control subjects, and 25 DM patients (mean age, 57 years). According to the tertiles of the clamp-derived glucose metabolic clearance rate (MCR), the FDRs were further classified as insulin resistant with an MCR <or =5.8 mL. kg(-1). min(-1), insulin sensitive (IS) with an MCR > or =7.8 mL. kg(-1). min(-1), and borderline with an MCR of 5.9 to 7.7 mL. kg(-1). min(-1). Flow-associated dilation was 4.1+/-0.9% in insulin-resistant FDRs, 6.7+/-1.1% in borderline FDRs, 9.0+/-1.2% in insulin-sensitive FDRs (P=0.002), 7.7+/-2.9% in control subjects (P=NS versus FDRs), and 3.8+/-1.0% in DM patients (P=0.03). In multiple regression analysis, low MCR was significantly correlated with ED independent of age, sex, smoking, body mass index, percent body fat, serum insulin, and lipids. There is a significant association between ED and insulin resistance in young FDRs of DM subjects independent of the classic cardiovascular risk factors.

Intracellular skeletal muscle glucose metabolism is differentially altered by dexamethasone treatment of normoglycemic relatives of type 2 diabetic patients.

Young first-degree relatives of type 2 diabetic patients are insulin-resistant, with the insulin resistance mainly located in skeletal muscle due to decreased insulin-induced nonoxidative glucose metabolism and muscle glycogen synthase activation. We investigated whether the mechanism differs for dexamethasone (dex)-induced insulin resistance in first-degree relatives of type 2 diabetics versus healthy control subjects by quantifying intracellular glucose processing in muscle biopsies taken before and after 5 days of dex treatment (4 mg/d) in 20 normal glucose-tolerant relatives of type 2 diabetic patients and 20 matched controls (age, 29.4 +/- 1.7 v 29.4 +/- 1.6 years; body mass index, 25.1 +/- 1.0 v 25.1 +/- 0.9 kg/m2). In addition, an intravenous glucose tolerance test (IVGTT) combined with continuous indirect calorimetry was performed. Following 5 days of dex treatment, glucose tolerance deteriorated in both the relatives and the control subjects. Fasting dry-weight muscle glucose and fasting intracellular muscle glucose concentrations increased in response to dex only in the relatives (2.43 +/- 0.21 v 2.97 +/- 0.26 mmol/kg dry weight, P < .05; 0.28 +/- 0.07 v 0.45 +/- 0.08 mmol/L intracellular water, P < .05); no increases were observed in the control subjects. Fasting dry-weight muscle lactate also increased post-dex only in the relatives (7.37 +/- 0.40 v 10.77 +/- 1.22 mmol/kg dry weight, P < .001). Both basal muscle glucose and lactate concentrations from the IVGTT study correlated with the 2-hour post-dex glucose value obtained during the OGTT study in the relatives (R = .76 and R = .74, respectively, both P < .0001) but not in the control subjects. Basal intramuscular glycogen synthase activity decreased approximately 25% in both the relatives and control subjects post-dex; the decrement was significant (P < .01) only in control subjects. Indirect calorimetry during the post-dex IVGTT demonstrated increased glucose oxidation (P < .03) and reduced lipid oxidation (P < .03) in the relatives only. We postulate that the insulin resistance induced by dex in first-degree relatives of type 2 diabetic patients is associated with a preferential channeling of glucose into the glycolytic pathway (increased glucose oxidation and lactate production), probably associated with a preexisting downregulation of the glycosen synthase pathway.