Insulin Resistance In Non-diabetic Individuals Research Articles

Silymarin Reduced Insulin Resistance in Non-Diabetic Women with Obesity.

Silymarin has ameliorated obesity, type 2 diabetes (T2DM), and insulin resistance (IR) in combination with standard therapy, diet, or exercise in recent studies. Obesity and IR are the main risk factors for developing T2DM and other metabolic disorders. Today, there is a need for new strategies to target IR in patients with these metabolic diseases. In the present longitudinal study, a group of non-diabetic insulin-resistant women with type 1 and type 2 obesity were given silymarin for 12 weeks, with no change in habitual diet and physical activity. We used the Homeostatic Model Assessment for Insulin Resistance Index (HOMA-IR) to determine IR at baseline and after silymarin treatment (t = 12 weeks). We obtained five timepoint oral glucose tolerance tests, and other biochemical and clinical parameters were analyzed before and after treatment. Treatment with silymarin alone significantly reduced mean fasting plasma glucose (FPG) and HOMA-IR levels at 12 weeks compared to baseline values (p < 0.05). Mean fasting plasma insulin (FPI), total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (Tg), indirect bilirubin, and C-reactive protein (CRP) levels decreased compared to baseline values, although changes were non-significant. The overall results suggest that silymarin may offer a therapeutic alternative to improve IR in non-diabetic individuals with obesity. Further clinical trials are needed in this type of patient to strengthen the results of this study.

Abstract 09: Trajectories of Insulin Resistance, Incident Heart Failure and All-Cause Death in Nondiabetics: The Atherosclerosis Risk in Communities Study

Introduction: Previous studies have suggested an association between insulin resistance (IR) trajectories and adverse changes in cardiac structure and function in nondiabetic populations. We studied the associations between IR trajectories and incident heart failure (HF) and all-cause death in nondiabetic participants of the Atherosclerosis Risk in Communities (ARIC) study. We hypothesized that long-term moderate and high IR levels would increase the risk of incident HF and all-cause death. Methods: We included 7,835 participants (3,505 men and 4,330 women) aged 45-64 from the ARIC study without diabetes mellitus at any visit, and no history of prevalent HF, myocardial infarction, stroke, arterial or coronary surgery, or cancer at baseline. We estimated IR using Homeostatic Model Assessment-Insulin Resistance (HOMA-IR), triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C), triglyceride glucose (TyG) index and metabolic score for IR (METS-IR). Serum insulin was not available at visits 2 and 3, so HOMA-IR was calculated for visits 1, 4, and 5. Latent class analysis identified two HOMA-IR trajectories, low-increasing and high-increasing, and three trajectories for TG/HDL-C, TyG index, and METS-IR: low-increasing, moderate-stable, and high-decreasing. We employed Cox proportional-hazards models to examine the associations of IR trajectories with incident HF and all-cause death adjusting for potential confounders. Results: Compared to participants in the low-increasing group, those in the high-increasing group of HOMA-IR were more likely to have incident HF and all-cause death (Table 1). For TG/HDL-C, TyG index and METS-IR, we found an increased risk of incident HF in the moderate-stable and high-decreasing groups relative to the low-increasing group. For all-cause death, consistent associations were found only in women (Table 1). Conclusions: Reduction of insulin resistance in nondiabetic individuals may be a suitable target for prevention strategies to reduce cardiovascular disease.

Serum CD14 concentration is associated with obesity and insulin resistance in non-diabetic individuals.

ObjectiveCD14 is a lipopolysaccharide-binding protein that serves as a marker of monocytes. The role of circulating CD14 in patients with obesity without diabetes remains unknown. Here, we characterized the relationships between serum CD14 concentration and metabolic parameters related to diabetes and obesity.MethodsWe performed an observational, prospective case–control study. Eighty participants were evaluated: 26 drug-naïve patients with type 2 diabetes mellitus and 54 healthy individuals. We compared the circulating CD14 concentration and metabolic parameters of the participants with and without diabetes.ResultsThe circulating CD14 concentration did not significantly differ between the two groups, but was lower in participants with obesity than in lean controls. No significant associations existed between CD14 concentration and metabolic parameters in the participants with diabetes, but in those without diabetes, the circulating CD14 concentration significantly negatively correlated with body mass index; waist circumference; the concentrations of fasting insulin, 2-hour post-load glucose, 2-h post-load insulin, and low-density lipoprotein-cholesterol; homeostasis model of assessment (HOMA) of insulin resistance; and HOMA beta-cell function.ConclusionsThis is the first study to show associations of serum CD14 concentration with metabolic parameters in non-diabetic individuals. Circulating CD14 may represent a useful biomarker of metabolic dysfunction in non-diabetic individuals.

Metabolic signatures of insulin resistance in non-diabetic individuals

BackgroundInsulin resistance (IR) evolved from excessive energy intake and poor energy expenditure, affecting the patient's quality of life. Amino acid and acylcarnitine metabolomic profiles have identified consistent patterns associated with metabolic disease and insulin sensitivity. Here, we have measured a wide array of metabolites (30 acylcarnitines and 20 amino acids) with the MS/MS and investigated the association of metabolic profile with insulin resistance.MethodsThe study population (n = 403) was randomly chosen from non-diabetic participants of the Surveillance of Risk Factors of NCDs in Iran Study (STEPS 2016). STEPS 2016 is a population-based cross-sectional study conducted periodically on adults aged 18–75 years in 30 provinces of Iran. Participants were divided into two groups according to the optimal cut-off point determined by the Youden index of HOMA-IR for the diagnosis of metabolic syndrome. Associations were investigated using regression models adjusted for age, sex, and body mass index (BMI).ResultsPeople with high IR were significantly younger, and had higher education level, BMI, waist circumference, FPG, HbA1c, ALT, triglyceride, cholesterol, non-HDL cholesterol, uric acid, and a lower HDL-C level. We observed a strong positive association of serum BCAA (valine and leucine), AAA (tyrosine, tryptophan, and phenylalanine), alanine, and C0 (free carnitine) with IR (HOMA-IR); while C18:1 (oleoyl L-carnitine) was inversely correlated with IR.ConclusionsIn the present study, we identified specific metabolites linked to HOMA-IR that improved IR prediction. In summary, our study adds more evidence that a particular metabolomic profile perturbation is associated with metabolic disease and reemphasizes the significance of understanding the biochemistry and physiology which lead to these associations.

The Association of Serum Uric Acid with Beta-Cell Function and Insulin Resistance in Nondiabetic Individuals: A Cross-Sectional Study.

PurposeHigher serum levels of uric acid (SUA) are associated with an increased risk of developing type 2 diabetes. Meanwhile, insulin resistance and beta-cell dysfunction are critical factors that mediate the progression from normal glucose tolerance to impaired fasting glucose (IFG) and type 2 diabetes. We aimed to investigate the association between SUA levels and insulin resistance and beta-cell dysfunction in individuals without diabetes, thus explicating the role of uric acid in the early stage of the natural history of type 2 diabetes.Patients and MethodsWe used cross-sectional data from the China Health and Nutrition Survey to examine the association. Insulin resistance and beta-cell dysfunction were estimated using the homeostasis model assessment of insulin resistance (HOMA-IR) index and homeostasis model assessment of beta-cell function (HOMA-beta) index, respectively. The associations were analyzed by using partial correlation analysis and multivariate logistic regressionl analysis.ResultsSUA levels were positively associated with fasting glucose, fasting insulin, HOMA-IR in the total population. After adjustment for age, drinking, smoking, living area, daily dietary nutrient intake, body mass index (BMI), estimated glomerular filtration rate (eGFR), hypertension, and dyslipidemia, compared with participants in the lowest quartile of SUA, the adjusted odds ratios for the fourth quartiles were 1.56(1.09-2.24) for IFG, 1.51(1.27-1.78) for insulin resistance, and 1.06(0.88-1.27) for beta-cell dysfunction. In the subgroup analysis, no interactions were found between serum uric acid and age, drinking status, smoking status, BMI, hypertension, or dyslipidemia (all p for interaction>0.05).ConclusionIn nondiabetic individuals, SUA levels are independently associated with IFG and insulin resistance, while no significant association exists between SUA and beta-cell dysfunction.

OBSTRUCTIVE SLEEP APNEA AS A RISK FACTOR OF INSULIN RESISTANCE IN NONDIABETIC PATIENTS

Objective: Obstructive sleep apnea (OSA) is a common sleep-breathing disorder characterised by collapsing of upper airway during sleep. The aim of this research was to assess relationship beetwen prevalence and severity of OSA and insulin resistance in nondiabetic individuals among patients with increased risk of OSA without diabetes mellitus. Design and method: Our study group estimated 102 individuals with suspected OSA, 71 men and 31 women, mean age 53.02 SD ± 12.37. We excluded individuals with diabetes mellitus and taking hypoglycemic drugs. All patients underwent standardized full night polysomnography in sleep laboratory to diagnose OSA. The Epworth Sleepiness Scale was used to assess daytime sleepiness. Serum insulin and glucose levels were analyzed by Laboratory. The HOMA index was calculated. Results: OSA was diagnosed in 85 patients. Mean AHI in whole study group was 25.78 ± 24.84, mean AHI in group with diagnosed OSA amount to 30.49 ± 24.64, mean AHI in nonapneic patients stands up to 2.23 ± 1.49. The difference was statistically significant p &lt; 0.001. The oxygen desaturation index (ODI) in our study sample estimated about 25 (24.99 ± 23.25), the difference between group with OSA (mean ODI 29.31 ± 23.14) and group without OSA (mean ODI 3.38 ± 2.42) was statistically relevant p &lt; 0.001. The statistically significant differences have occured between patients with (AHI = 15 or AHI &gt; 15) and AHI &lt; 15 taking into account level of insulin and the Homa index p &lt; 0.05, but no statistically significant difference was observed between patients with (ESS = 9 or ESS &gt; 9) and ESS &lt; 9. Conclusions: Individuals with moderate to severe obstructive sleep apnea without diabetes mellitus have higher insulin resistance estimated with HOMA- IR index. This study revealed that there is no evidence if the evaluation of daytime sleepiness using Epworth Sleepiness Scale is a predicting factor of developing IR. Higher AHI and ODI levels beyond individuals from our study sample are independent risk factors for higher fasting insulin levels and higher HOMA index. Increased duration of desaturation time below 90% is an independent risk factor for higher fasting glucose levels.

Insulin Resistance Exacerbates Genetic Predisposition to Nonalcoholic Fatty Liver Disease in Individuals Without Diabetes.

The accumulation of excess fat in the liver (hepatic steatosis) in the absence of heavy alcohol consumption causes nonalcoholic fatty liver disease (NAFLD), which has become a global epidemic. Identifying metabolic risk factors that interact with the genetic risk of NAFLD is important for reducing disease burden. We tested whether serum glucose, insulin, insulin resistance, triglyceride (TG), low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, body mass index (BMI), and waist‐to‐hip ratio adjusted for BMI interact with genetic variants in or near the patatin‐like phospholipase domain containing 3 (PNPLA3) gene, the glucokinase regulatory protein (GCKR) gene, the neurocan/transmembrane 6 superfamily member 2 (NCAN/TM6SF2) gene, and the lysophospholipase‐like 1 (LYPLAL1) gene to exacerbate hepatic steatosis, estimated by liver attenuation. We performed association analyses in 10 population‐based cohorts separately and then meta‐analyzed results in up to 14,751 individuals (11,870 of European ancestry and 2,881 of African ancestry). We found that PNPLA3‐rs738409 significantly interacted with insulin, insulin resistance, BMI, glucose, and TG to increase hepatic steatosis in nondiabetic individuals carrying the G allele. Additionally, GCKR‐rs780094 significantly interacted with insulin, insulin resistance, and TG. Conditional analyses using the two largest European ancestry cohorts in the study showed that insulin levels accounted for most of the interaction of PNPLA3‐rs738409 with BMI, glucose, and TG in nondiabetic individuals. Insulin, PNPLA3‐rs738409, and their interaction accounted for at least 8% of the variance in hepatic steatosis in these two cohorts. Conclusion: Insulin resistance, either directly or through the resultant elevated insulin levels, more than other metabolic traits, appears to amplify the PNPLA3‐rs738409‐G genetic risk for hepatic steatosis. Improving insulin resistance in nondiabetic individuals carrying PNPLA3‐rs738409‐G may preferentially decrease hepatic steatosis.

Low total and free triiodothyronine levels are associated with insulin resistance in non-diabetic individuals

This study examined associations of thyroid hormone levels and insulin resistance (IR) in non-diabetic individuals. Using a cross-sectional design, 2007–2008 data from the National Health and Nutrition Examination Survey (NHANES) were analyzed. NHANES participants ≥20 years of age with complete data of interest were included. The homeostatic model assessment (HOMA) was used to quantify IR, and treated as a continuous variable. Self-reported diabetes or a fasting glucose ≥7 mmol/L were used as criteria to exclude diabetic subjects. Race, liver function, obesity, hypertension, dyslipidemia, smoking, physical activity, vigorous recreational activity, 2-hour glucose, hemoglobin A1C (HbA1C), high-density lipoprotein, triglyceride, vitamin D and C-reactive protein were covariates significantly associated with HOMA-IR. A total of 1,560 non-diabetic subjects were included in the analysis. When adjusted for all factors significant in the univariate analysis (race, liver function, obesity, hypertension, dyslipidemia, smoking, physical activity, vigorous recreational activity, 2-hour glucose, HbA1C, high-density lipoprotein, triglyceride, vitamin D, and CRP) low total triiodothyronine (TT3) and low free T3 (FT3) were significantly associated with decreased HOMA-IR (adjusted coefficient = −0.486, 95% confidence interval [CI]: −0.936, −0.036; adjusted coefficient = −1.151, 95% CI: −1.952, −0.350, respectively). Insulin resistance is associated with low thyroid hormone levels in non-diabetic individuals.

Impact of Insulin Resistance on Acetylcholine-Induced Coronary Artery Spasm in Non-Diabetic Patients.

PurposeCoronary artery spasm (CAS) and diabetes mellitus (DM) are implicated in endothelial dysfunction, and insulin resistance (IR) is a major etiological cause of type 2 DM. However, the association between CAS and IR in non-diabetic individuals has not been elucidated. The aim of the present study was to evaluate the impact of IR on CAS in patients without DM.Materials and MethodsA total of 330 eligible patients without DM and coronary artery disease who underwent acetylcholine (Ach) provocation test were enrolled in this study. Inclusion criteria included both hemoglobin A1c <6.0% and fasting glucose level <110 mg/dL without type 2 DM. Patients were divided into quartile groups according the level of homeostasis model assessment of insulin resistance (HOMA-IR): 1Q (n=82; HOMA-IR<1.35), 2Q (n=82; 1.35≤HOMA-IR<1.93), 3Q (n=83; 1.93≤HOMA-IR< 2.73), and 4Q (n=83; HOMA-IR≥2.73).ResultsIn the present study, the higher HOMA-IR group (3Q and 4Q) was older and had higher body mass index, fasting blood glucose, serum insulin, hemoglobin A1c, total cholesterol, and triglyceride levels than the lower HOMA-IR group (1Q). Also, poor IR (3Q and 4Q) was considerably associated with frequent CAS. Compared with Q1, the hazard ratios for Q3 and Q4 were 3.55 (95% CI: 1.79–7.03, p<0.001) and 2.12 (95% CI: 1.07–4.21, p=0.031), respectively, after adjustment of baseline risk confounders. Also, diffuse spasm and accompanying chest pain during Ach test were more strongly associated with IR patients with CAS.ConclusionHOMA-IR was significantly negatively correlated with reference diameter measured after nitroglycerin and significantly positively correlated with diffuse spasm and chest pain.

Associations of lipid profiles with insulin resistance and β cell function in adults with normal glucose tolerance and different categories of impaired glucose regulation.

AimsTo investigate the associations of dyslipidemia with insulin resistance and β cell function in individuals with normal glucose tolerance (NGT) and different categories of impaired glucose regulation (IGR).Methods544 subjects (365 with dyslipidemia and/or IGR and 179 with normal lipid and glucose tolerance) were enrolled in the study. All subjects underwent oral glucose tolerance test (OGTT). HOMA-IR was used to evaluate insulin sensitivity. Disposition index (DI) was used to evaluate β cell function. Multiple linear regression analysis was performed to assess correlations among lipid profiles, insulin resistance and β cell function.ResultsAmong subjects with NGT, those with dyslipidemia had higher level of HOMA-IR but lower level of DI. While among subjects with different categories of IGR, those with dyslipidemia and CGI had significantly decreased DI. No obvious differences of insulin resistance or β cell function were found in IFG or IGT subjects with or without dyslipidemia. TG and HDL-C were correlated with HOMA-IR (β = 0.79, p <0.001; β = -0.38, p = 0.027, respectively, compared with subjects in the low level groups). Moreover, TG and TC were negatively correlated with DI (β = -2.17, p = 0.013; β = -2.01, p = 0.034 respectively, compared with subjects in the low level groups) after adjusting for confounding parameters.ConclusionsDyslipidemia induces insulin resistance and impaired β cell response to insulin resistance in individuals with NGT. Furthermore, dyslipidemia diminishes β cell function in subjects with CGI. TG and HDL-C were correlated with insulin resistance, and TG, TC were negatively correlated with β cell response to insulin resistance in non-diabetic individuals.

Lipid accumulation product is a powerful index for recognizing insulin resistance in non-diabetic individuals

Lipid accumulation product (LAP) is an index, which combines waist circumference (WC) and triglyceride (TG) reflecting lipid accumulation. The aims of the study were to explore the relationship between LAP and insulin resistance (IR) and to assess whether LAP was superior to WC and body mass index (BMI) in identifying IR. The study was cross-sectional and included 2524 non-diabetic subjects from China. The blood pressure (BP), anthropometric measurements, glucose levels, insulin levels and a fasting lipid profile were measured. BMI, the homeostasis model assessment of IR (HOMA-IR) and LAP were calculated. In both sexes, BP, BMI, total cholesterol (TC), non high-density lipoprotein cholesterol (non-HDL-C), HOMA-IR, fasting and postprandial glucose levels increased across LAP quartiles (P<0.001), while HDL cholesterol (HDL-C) levels decreased across LAP quartiles (P<0.001). Pearson's correlation analysis demonstrated that HOMA-IR was correlated with LAP, BMI, WC, TG, HDL-C and non-HDL-C in both sexes (P<0.001). Multivariate analysis demonstrated that LAP had a greater impact on HOMA-IR than BMI and WC. LAP is closely associated with HOMA-IR and is a powerful index that outperforms BMI and WC in identifying IR in non-diabetic individuals.

Relationship of adipokines and non-esterified fatty acid to the insulin resistance in non-diabetic individuals

Altered secretion of adipokines and non-esterified fatty acid (NEFA) seems to play a pivotal role in the abdominal obesity-related insulin resistance (IR). To determine semi-quantitatively the impact of serum NEFA, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), leptin, adiponectin, and resistin levels on IR measured by homeostasis model assessment (HOMA-IR). MATERIAL/SUBJECTS: Seventy-four Caucasian subjects forming 3 age-, and sex-matched groups were included into the study [Group 1 and 2: non-diabetic obese patients, no.= 25, body mass index (BMI): 28-39.9 kg/m(2), no.=25, BMI≥40 kg/m(2), respectively, and Group 3: 24 healthy, normal weight control subjects]. Serum levels of NEFA and adipokines as well as other metabolic variables including HOMA-IR were measured. HOMA-IR was associated positively with BMI, waist circumference, serum NEFA, leptin, IL-6, and TNF-α levels, negatively with adiponectin, with no significant relation to resistin. In multiple regression analyses, of these factors leptin was a strong, IL-6 and adiponectin were weak independent predictors of HOMA-IR, while the others were not significant determinants of HOMA-IR. However, even together, they explained only 35-36% of variance of HOMAIR. Although IR has associations with many of the investigated parameters, of these, only serum level of leptin, and in lesser degree IL-6 and adiponectin are independent determinants of the severity of IR. Moreover, even together they explain only a minority of variance IR.

Impact of Nonalcoholic Fatty Liver Disease on Insulin Resistance in Relation to HbA1c Levels in Nondiabetic Subjects

A cross-sectional analysis was conducted in healthy, nondiabetic Korean adults to assess the prevalence of nonalcoholic fatty liver disease (NAFLD), to compare the prevalence of NAFLD across different glycemic ranges as assessed by glycosylated hemoglobin (HbA1c), and to examine the impact of NAFLD on insulin resistance in relation to HbA1c levels. After rigorous exclusion criteria, the final number of subjects who participated in a comprehensive health status checkup program was 99,969. All subjects were classified into four categories with respect to HbA1c level (≤4.9, 5.0-5.4, 5.5-5.9, and 6.0-6.4%). We estimated the odds ratio (OR) for prevalence of NAFLD according to the categorized level of HbA1C and evaluated the association of NAFLD with the homeostatic model assessment of insulin resistance (HOMA-IR) in relation to the HbA1c level. Twenty-eight percent (n=28,130, 40.2% of the men, 10.3% of the women) of the study subjects had NAFLD. Men had a 5.83-fold (95% confidence interval 5.63-6.05) increased risk for having NAFLD than did women. The risk for NAFLD increased with increasing level of HbA1c (OR 1.44, 2.62, and 7.18) when compared with the lowest quartile (HbA1C≤4.9%). HOMA-IR increased in the NAFLD subjects as the level of HbA1c increased. The magnitude of association of HOMA-IR with HbA1c level was greater in NAFLD subjects than in non-NAFLD subjects (P<0.001 for interaction). These associations were consistent even after adjustment for body mass index and other metabolic components. NAFLD had an association with HbA1c level and insulin resistance in nondiabetic individuals, and these associations were independent of obesity and other metabolic components.

A Prospective Analysis of Elevated Fasting Glucose Levels and Cognitive Function in Older People

OBJECTIVETo investigate the relationship between fasting glucose levels, insulin resistance, and cognitive impairment in old age. Diabetes is associated with cognitive impairment in older people. However, the link between elevated fasting glucose levels and insulin resistance in nondiabetic individuals, and the risk of cognitive impairment is unclear.RESEARCH DESIGN AND METHODSWe analyzed data from, in total, 8,447 participants in two independent prospective studies: the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), 5,019 participants, aged 69–84 years, and the Rotterdam Study, 3,428 participants, aged 61–97 years. Fasting glucose levels were assessed at baseline in both studies; fasting insulin levels were assessed in the Rotterdam Study only. Cognitive function was assessed in both studies at baseline and during follow-up.RESULTSSubjects with diabetes had impaired cognitive function at baseline. In contrast, in people without a history of diabetes, there was no clear association between baseline fasting glucose levels and executive function and memory, nor was there a consistent relationship between elevated baseline fasting glucose levels and the rate of cognitive decline in either cohort. Insulin resistance (homeostasis model assessment index) was also unrelated to cognitive function and decline.CONCLUSIONSElevated fasting glucose levels and insulin resistance are not associated with worse cognitive function in older people without a history of diabetes. These data suggest either that there is a threshold for effects of dysglycemia on cognitive function or that factors other than hyperglycemia contribute to cognitive impairment in individuals with frank diabetes.

Correlation of the leptin:adiponectin ratio with measures of insulin resistance in non-diabetic individuals.

Aims/hypothesisObesity is the dominant cause of insulin resistance. In adult humans it is characterised by a combination of adipocyte hypertrophy and, to a lesser extent, adipocyte hyperplasia. As hypertrophic adipocytes secrete more leptin and less adiponectin, the plasma leptin:adiponectin ratio (LAR) has been proposed as a potentially useful measure of insulin resistance and vascular risk. We sought to assess the usefulness of the LAR as a measure of insulin resistance in non-diabetic white adults.MethodsLeptin and adiponectin levels were measured in 2,097 non-diabetic individuals from the Ely and European Group for the Study of Insulin Resistance (EGIR) Relationship between Insulin Sensitivity and Cardiovascular Risk (RISC) study cohorts. LAR was compared with fasting insulin and HOMA-derived insulin sensitivity (HOMA-S) in all individuals and with the insulin sensitivity index (M/I) from hyperinsulinaemic–euglycaemic clamp studies in 1,226 EGIR RISC participants.ResultsThe LAR was highly correlated with HOMA-S in men (r = −0.58, p = 4.5 × 10−33 and r = −0.65, p = 1.1 × 10−66 within the Ely and EGIR RISC study cohorts, respectively) and in women (r = −0.51, p = 2.8 × 10−36 and r = −0.61, p = 2.5 × 10−73). The LAR was also strongly correlated with the clamp M/I value (r = −0.52, p = 4.5 × 10−38 and r = −0.47, p = 6.6 × 10−40 in men and women, respectively), similar to correlations between HOMA-S and the M/I value.Conclusions/interpretationThe leptin:adiponectin ratio is a useful measure of insulin resistance in non-diabetic white adults. These data highlight the central role of adipocyte dysfunction in the pathogenesis of insulin resistance. Given that variations between fasting and postprandial leptin and adiponectin levels tend to be small, the leptin to adiponectin ratio might also have potential value in assessing insulin sensitivity in the non-fasted state.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-009-1508-3) contains supplementary material, which is available to authorized users.

Sex hormone-binding globulin and testosterone in individuals with childhood diabetes.

Insulin downregulates hepatic production of sex hormone-binding globulin (SHBG), which in turn influences sex hormone bioavailability. The effects of childhood-onset diabetes and insulin resistance in nondiabetic individuals on SHBG and testosterone in children and young adults are poorly understood. Individuals with diabetes diagnosed at <18 years of age (n = 48) and their siblings without diabetes (n = 47) were recruited for the Chicago Childhood Diabetes Registry Family Study. SHBG and total and free testosterone were measured. Participants ranged in age from 10 to 32 years; 39% were non-Hispanic white. The majority of individuals with diabetes had the classic type 1 phenotype (75%), while the remainder exhibited features of type 2 or mixed diabetes; 96% were treated with insulin. SHBG and total testosterone were higher in male subjects with diabetes compared with those in male siblings. Elevated SHBG was associated with the absence of endogenous insulin independent of sex; elevated total testosterone was similarly associated with the absence of C-peptide for male subjects only. Diabetes type and treatment were unrelated. In those without diabetes, greater insulin resistance had a small, nonsignificant association with lower SHBG and higher free testosterone. SHBG and total testosterone appear to be higher in male children and young adults with diabetes compared with nondiabetic male siblings, which is apparently related to the absence of endogenous insulin. This may have implications for sex hormone-dependent processes across the lifespan in male individuals diagnosed with diabetes as children.

Fat cell enlargement is an independent marker of insulin resistance and ‘hyperleptinaemia’

The aim of this study was to explore whether fat cell size in human subcutaneous and omental adipose tissue is independently related to insulin action and adipokine levels. Fat cells were prepared from abdominal subcutaneous biopsies obtained from 49 type 2 diabetic and 83 non-diabetic subjects and from omental biopsies obtained from 37 non-diabetic subjects. Cell size and insulin action on glucose uptake capacity in vitro were assessed in isolated fat cells. Insulin sensitivity in vivo was assessed with euglycaemic-hyperinsulinaemic clamps. Fasting blood samples were collected and adipokines and NEFA were measured. Negative correlations were found between subcutaneous fat cell size and insulin sensitivity assessed as M-value during clamp and as insulin action on glucose uptake in fat cells in vitro. This was seen in non-diabetic subjects after including age, sex and BMI in the analyses. No such relationship was found in type 2 diabetic subjects. In both groups, subcutaneous fat cell size correlated positively and independently with plasma levels of leptin but not to any of the other assessed adipokines. In non-diabetic subjects, omental fat cell size was independently and negatively correlated with insulin action in subcutaneous, but not omental, fat cells in vitro. Fat cell enlargement is associated with insulin resistance in non-diabetic individuals independently of BMI. This was not seen in type 2 diabetic subjects, suggesting that after development of type 2 diabetes other factors, not related to fat cell size, become more important for the modulation of insulin resistance.

LightCycler assay in the analysis of haplotypes of the type 2 diabetes susceptibility gene CAPN10.

CAPN10 , a gene that encodes a nonlysosomal cysteine protease, has been recently proposed as a type 2 diabetes susceptibility gene in the non-insulin-dependent diabetes mellitus 1 (NIDDM1) region. Numerous single nucleotide polymorphisms (SNPs) in CAPN10 were identified, but only haplotypes based on four SNPs have been associated with type 2 diabetes in Mexican Americans and two Northern-European populations (from Botnia, Finland and Dresden, Germany) (1). Two major haplotypes in CAPN10 show an association with altered mRNA expression, increased risk of type 2 diabetes in multiple ethnic groups, and findings of insulin resistance in nondiabetic individuals (1)(2)(3). Studies investigating genetic variations in CAPN10 in different populations have yielded variable results. Some studies confirmed the association of the at-risk haplotype of CAPN10 112/121 with type 2 diabetes in Caucasian populations (3)(4). Further support of the concept that genetic variation in CAPN10 is involved in type 2 diabetes has recently been found in Caucasian populations in which an association of the homozygous 121 (5) and 111/221 haplotype combination with type 2 diabetes has been reported (6). Additional studies have found associations between the homozygosity of the G-allele of UCSNP-43 and, respectively, higher fasting plasma glucose and lower glucose turnover during a low-insulin euglycemic clamp in Pima Indians (2), type 2 diabetes in African-Americans (7), and increased free fatty acid levels in Caucasians (4). In other studies, the population frequency of the 112/121 risk haplotype of CAPN10 was low, so that demonstrating significant associations between the CAPN10 variants and type 2 diabetes in Chinese (8), Samoans(9 …

Hyperinsulinemia, risk factors, and coronary heart disease. The Zutphen Elderly Study.

We investigated the association between fasting insulin concentration--an indicator of insulin resistance in nondiabetic individuals--cardiovascular risk factors, and coronary heart disease in a study of 390 men in the town of Zutphen. In 1990, an extensive examination was carried out on the participating men (aged 70 to 89 years). Fasting insulin levels were determined and a number of other risk factors measured. Known and newly diagnosed diabetics were excluded from the data analyses. Fasting insulin concentration was significantly associated with levels of glucose, triglycerides, uric acid, serum albumin, creatinine, and fibrinogen as well as resting heart rate. Inverse associations with high-density lipoprotein cholesterol and factor VII activity were observed. These results were independent of confounding factors such as age, body mass index, ratio of subscapular to triceps skinfold thicknesses, cigarette smoking, physical activity, and alcohol consumption. Men with a fasting insulin level higher than 80 pmol/L (highest quartile of the distribution) had a significantly higher prevalence of coronary heart disease and especially of myocardial infarction. This result was independent of potential confounding variables as well as of possible intermediates (total and high-density lipoprotein cholesterol, hypertension, serum triglycerides, fasting glucose, and other risk factors related to fasting insulin) (odds ratio, 2.2; 95% confidence interval, 1.2-4.0). No association between fasting insulin level and hypertension or blood pressure was observed. These results show that fasting insulin is an important indicator of coronary heart disease in elderly men. Clotting factors, resting heart rate, uric acid, serum albumin, and creatinine may also play a role in this metabolic syndrome.