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Background: The risks of heart disease, resistance of insulin, and diabetes mellitus type II are increased in individuals diagnosed with metabolic syndrome. Furthermore, there is an increase in the vascular and neurological effects. This study aimed to assess the isolated independent impact of hepatitis C virus (HCV) on metabolic syndrome, excluding obesity and diabetes mellitus as common risks, this impact was assessed using the metabolic syndrome Severity Z-score (MetS Z-Score) which was initially designed to assess metabolic disease severity itself. Fifty-one HCV patients non-obese and non-diabetic who visited the Tropical Medicine Department from July 2023 to June 2024 were included in our prospective cross sectional study. Results: After calculation of MetS Z-Score, strong correlations were observed between MetS Z-score and the following data: HDL, fasting insulin, fasting blood sugar, HOMA-IR and hypertension (P value < 0.05). Moreover, The MetS Z-Score was found to have higher values in hypertensive patients. Jaundice shows a near to significance correlation with the MetS Z-Score. Anemia, hypoalbuminemia and thrombocytopenia were observed in the included HCV patients. Low density lipoprotein, alanine aminotransferase, aspartate aminotransferase, cholesterol and triglycerides have shown higher levels than normal in the included HCV patients. Conclusion: The MetS Z-score can be used for determining the severity of metabolic abnormalities in HCV patients who are neither diabetic nor obese. [ABSTRACT FROM AUTHOR]

Dietary intake of live microbes may benefit human health, but less is known about the role in insulin resistance. This study was developed with the goal of evaluating potential relationships between IR and dietary live microbes. The National Health and Nutrition Examination Survey (NHANES) dataset was leveraged to collect data from 6,333 subjects 18 + years of age. The Sanders system for the classification of dietary live microbe intake (containing Low (< 104 CFU/g), Medium (104–107 CFU/g), or High (> 107 CFU/g) levels of live microbes) was then used to separate these patients into three groups (low, medium, or high). Fasting blood glucose and insulin levels were used to approximate IR based on the homeostasis model of insulin resistance (HOMA-IR). Weighted linear regressions were used to assess the relationship between IR and live microbe intake. After fully adjusting for confounding factors, subjects in the groups exhibiting medium and high levels of live microbe intake exhibited HOMA-IR scores that were below those of subjects in the low group. The relationship between live microbe intake and HOMA-IR scores was also potentially impacted by ethnicity. In summary, a negative correlation was detected between dietary live microbe intake and HOMA-IR values. [ABSTRACT FROM AUTHOR]

Background: This study examined the effects of a single all-out bout of 30-s sprint-cycle performed daily for 5 consecutive days per week for 6 weeks, on aerobic fitness, muscle strength and metabolic-health markers in physically active young males and females. Methods: Healthy, physically active 20–28 year olds, were randomly assigned to either experimental (EXP, N = 11) or non-training control (CON, N = 8) group. With supervision, the EXP group performed one bout of 30-s sprint-cycle daily, Mondays to Fridays over 6 weeks, while CON group continued with their usual lifestyle. The followings were measured at pre- and post-intervention: maximal aerobic power, peak torque of knee extensors and flexors at velocities 30° s−1 and 300° s−1, resting heart rate, resting blood pressure, body fat percentage, fasting lipid profile, fasting blood glucose, and fasting insulin levels. Results: There were no significant improvements in the EXP group for all the measured variables (all P > 0.05); except for significant interaction effects in peak torque of knee extensors at 30° s−1 (P = 0.044) and low-density lipoprotein-cholesterol (P = 0.046). Post hoc test indicate that CON group showed decline in their low-density lipo-proteins levels (P = 0.024). Conclusion: Six weeks of one all-out bout of 30-s sprint-cycle per day, for 5 consecutive days per week, was ineffective in improving cardiovascular fitness, maximal strength, and most health markers in physically active young adults. The present results when combined with the previous literature suggest that there is a possibility of a minimum threshold for a number of sprint-cycle bouts needed to be performed before any form of cardio-metabolic-health benefit is accrued. [ABSTRACT FROM AUTHOR]

Aims: Type 2 diabetes is a major public health problem for the global community. Having a family history of diabetes significantly increases risk for diabetes development and understanding how family history contributes to diabetes risk could lead to more effective prevention efforts for at-risk individuals. In a previous study, we showed family history of diabetes is a significant predictor of fasting insulin in healthy weight children. The present study aimed to use the National Health and Nutrition Examination Survey (NHANES 2017) to apply similar multiple regression models to a population of healthy weight adults to determine if family history is a significant predictor of fasting glucose and fasting insulin. Methods: Fasting glucose (mg/dL) and fasting insulin (pmol/L) were used as dependent variables in each model, respectively, with family history of diabetes as the independent variable. Covariates for each model included age, gender, race/ethnicity, waist circumference, and macronutrient intake. Results: The model significantly predicted the variance of fasting glucose [(F(11,364) = 34.80, p < 0.001, R2 = 0.2342] and fasting insulin [F(11,343) = 17.58, p < 0.001, R2 = 0.1162]. After adjusting for covariates, family history was a significant predicator of fasting glucose (p = 0.0193) as well as age, gender, non-Hispanic black ethnicity, waist circumference, and fat intake. Significant predictors of fasting insulin included gender and waist circumference, but not family history (p = 0.8264). In addition, fasting glucose was higher in individuals with a family history of diabetes (p = 0.033). Conclusions: These results add to the understanding of how family history influences the biomarkers that contribute to diabetes development. Knowledge of how family history of diabetes relates to fasting insulin and fasting glucose activity in healthy weight individuals can be used to design personalized screening and early prevention strategies. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Our aim was to explore metabolic pathways linking overnutrition in utero to development of adiposity in normal-weight children. Methods: We included 312 normal-weight youth exposed or unexposed to overnutrition in utero (maternal BMI ≥25 kg/m2 or gestational diabetes). Fasting insulin, glucose and body composition were measured at age ~10 years (baseline) and ~16 years (follow-up). We examined associations of overnutrition in utero with baseline fasting insulin, followed by associations of baseline fasting insulin with adiposity (BMI z score [BMIZ], subcutaneous adipose tissue [SAT], visceral adipose tissue [VAT]), insulin resistance (HOMA-IR) and fasting glucose during follow-up. Results: >All participants were normal weight at baseline (BMIZ −0.32 ± 0.88), with no difference in BMIZ for exposed vs unexposed youth (p = 0.14). Of the study population, 47.8% were female sex and 47.4% were of white ethnicity. Overnutrition in utero corresponded with 14% higher baseline fasting insulin (geometric mean ratio 1.14 [95% CI 1.01, 1.29]), even after controlling for VAT/SAT ratio. Higher baseline fasting insulin corresponded with higher BMIZ (0.41 [95% CI 0.26, 0.55]), SAT (13.9 [95% CI 2.4, 25.4] mm2), VAT (2.0 [95% CI 0.1, 3.8] mm2), HOMA-IR (0.87 [95% CI 0.68, 1.07]) and fasting glucose (0.23 [95% CI 0.09, 0.38] SD). Conclusions/interpretation: Overnutrition in utero may result in hyperinsulinaemia during childhood, preceding development of adiposity. However, our study started at age 10 years, so earlier metabolic changes in response to overnutrition were not taken into account. Longitudinal studies in normal-weight youth starting earlier in life, and with repeated measurements of body weight, fat distribution, insulin sensitivity, beta cell function and blood glucose levels, are needed to clarify the sequence of metabolic changes linking early-life exposures to adiposity and dysglycaemia. [ABSTRACT FROM AUTHOR]

Summary: We performed a cross-sectional study using the National Health Examination and Nutrition Survey (NHANES) data and a Mendelian randomisation (MR) study using the GWAS summary statistics from European populations. The T2D-related indices (fasting plasma glucose (FPG), fasting insulin (FI), and insulin resistance (IR)) were found to associate with elevated bone mineral density (BMD). Introduction: The known associations amongst FPG, FI, IR, and BMD remain inconsistent. This study aims to explore the abovementioned associations by using cross-sectional and MR designs. Methods: Data from adults aged ≥ 20 years (n = 7170) in four rounds of the U.S. NHANES (2005–2010 and 2013–2014) were analysed in this cross-sectional study. Multiple linear and logistic regression models were used for statistical analyses. A two-sample MR study was performed using the genome-wide association study summary statistics obtained from the Meta-analyses of Glucose and Insulin-related traits Consortium (n = 108,557) and Genetic Factors for Osteoporosis Consortium (n = 32,735) to examine the causality of the FI–BMD association. Results: Multiple linear regression revealed that FPG was positively associated with the BMDs at the hip, femur neck, and 1st lumbar spine (L1). Multiple logistic regressions revealed that FPG levels were associated with elevated BMDs at the hip and L1, and FI and IR levels were associated with elevated BMD at the hip. Patients with type 2 diabetes had higher hip BMD than those without diabetes. In the MR study, the lumbar spine BMD increased by 0.49 g/cm2 (95% confidence interval: 0.01, 0.97) in response to per unit increase in log-transformed FI. Conclusion: Findings from our cross-sectional and MR studies revealed the associations between the studied diabetic indices and BMD measurements in the US and European adults. [ABSTRACT FROM AUTHOR]

Background: Steroids induced diabetes (SID), may be due to either insulin resistance (IR) or beta cell dysfunction or combination of both. Several studies have established that these effects of steroids may be mediated by an osteoblast derived protein called osteocalcin (OC). However, this effect has been described only in diabetic patients and has not been studied in SID patients. Aim and study design: A prospective observational cohort study was designed to evaluate the correlation between serum OC level and blood glucose profile, in patients on steroids. Results: Out of a total of 88 subjects who were on steroid therapy, 42(47.7%) subjects had their blood sugar levels in the diabetic range. Based on the glycemic status, subjects were divided into three groups, namely, normoglycemic, pre-diabetes and diabetes. The patients who developed SID were older than normoglycemic (mean age 43.15 vs 39.27years). The age (r=-0.105 p=0.5), BMI (r=-0.3 p= 0.07) and abdominal obesity (r=-0.32 p=0.04) were negatively correlated with serum osteocalcin in diabetes group. Serum osteocalcin level decreased as dose of steroid increased in all three groups (normogylcemic r=-0.701 p=0.004 prediabetes r=-0.3 p=0.07 diabetes -0.362 p=0.04). Fasting plasma glucose (r=-0.319 p=0.04), Fasting insulin (r=-0.10 p=0.5) and IR (r=-0.194 p=0.212) were increased with decrease in OC in patients in diabetes group. Conclusion: Decrease in serum osteocalcin level with increase in glycemic parameters in steroid induced diabetes group, point to have a new role in mechanism of steroid induced diabetes. This may be a novel target to discover drugs that can maintain the OC levels so that the effect of steroids on blood sugar level can be minimised. [ABSTRACT FROM AUTHOR]

Aims: To explore the association of marijuana use with mean plasma fasting insulin levels and homeostasis model assessment of insulin resistance (HOMA-IR) score in obese adults with different HOMA-IR. Methods: The National Health and Nutrition Examination Survey (NHANES) is a survey research program designed to assess the health and nutrition status of individuals in the United States and to track changes over time. We abstracted data from NHANES 2009–2016. We estimated the minimal lifetime marijuana use (MLU) using the duration of regular exposure and the frequency of use. We assessed the association of MLU and both plasma fasting insulin and HOMA-IR score using log-linear regression models. Results: A total of 65,209 obese individuals aged 18 to 59 years were included. In obese individuals who never used marijuana (reference), the mean value (± standard deviation) was 19.0 (± 12.8) μU/mL for plasma fasting insulin and 4.78 (± 3.49) for HOMA-IR. In individuals with HOMA-IR < 2.13 or ≥ 5.72, we found no association of marijuana use with HOMA-IR. In those with HOMA-IR < 5.72, the highest tertile of MLU (i.e., ≥ 1799 times) was associated with 12% decrease (95% confidence intervals, 4–19%) in the fasting insulin and 10% decrease in HOMA-IR (95% CI 1–19%), as compared with their counterparts who never used marijuana. In those with HOMA-IR ≥ 2.13, we found a marked impact of marijuana use only in adults who used marijuana ≥ 1799 times, with 13% decrease (95% CI 5–19%) in fasting insulin and 10% decrease (95% CI 3–18%) in HOMA-IR score. Conclusions: Marijuana use is associated with reduced fasting insulin levels and HOMA-IR score in US obese adults with HOMA-IR ≥ 2.13, but not in those with HOMA-IR < 2.13 or ≥ 5.72. The impact of marijuana use is the greatest after long-term exposure and is independent of BMI. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Glycaemic markers and fasting insulin are frequently measured outcomes of intervention studies. To extrapolate accurately the impact of interventions on the risk of diabetes incidence, we investigated the size and shape of the associations of fasting plasma glucose (FPG), 2 h post-load glucose (2hPG), HbA, fasting insulin and HOMA-IR with incident type 2 diabetes mellitus. Methods: The study population included 1349 participants aged 50-75 years without diabetes at baseline (1989) from a population-based cohort in Hoorn, the Netherlands. Incident type 2 diabetes was defined by the WHO 2011 criteria or known diabetes at follow-up. Logistic regression models were used to determine the associations of the glycaemic markers, fasting insulin and HOMA-IR with incident type 2 diabetes. Restricted cubic spline logistic regressions were conducted to investigate the shape of the associations. Results: After a mean follow-up duration of 6.4 (SD 0.5) years, 152 participants developed diabetes (11.3%); the majority were screen detected by high FPG. In multivariate adjusted models, ORs (95% CI) for incident type 2 diabetes for the highest quintile in comparison with the lowest quintile were 9.0 (4.4, 18.5) for FPG, 6.1 (2.9, 12.7) for 2hPG, 3.8 (2.0, 7.2) for HbA, 1.9 (0.9, 3.6) for fasting insulin and 2.8 (1.4, 5.6) for HOMA-IR. The associations of FPG and HbA with incident diabetes were non-linear, rising more steeply at higher values. Conclusions/interpretation: FPG was most strongly associated with incident diabetes, followed by 2hPG, HbA, HOMA-IR and fasting insulin. The strong association with FPG is probably because FPG is the most frequent marker for diabetes diagnosis. Non-linearity of associations between glycaemic markers and incident type 2 diabetes should be taken into account when estimating future risk of type 2 diabetes based on glycaemic markers. [ABSTRACT FROM AUTHOR]

Background: Weight regain and type-2 diabetes relapse has been reported in a significant proportion of vertical sleeve gastrectomy (VSG) patients in some studies, but definitive conclusions regarding the long-term comparative effectiveness of VSG and Roux-en-Y gastric bypass (RYGB) surgery are lacking both in humans and rodent models. This study's objective was to compare the effects of murine models of VSG and RYGB surgery on body weight, body composition, food intake, energy expenditure, and glycemic control. Methods: VSG, RYGB, and sham surgery was performed in high-fat diet-induced obese mice, and the effects on body weight and glycemic control were observed for a period of 12 weeks. Results: After the initial weight loss, VSG mice regained significant amounts of body weight and fat mass that were only marginally lower than in sham-operated mice. In contrast, RYGB produced sustained loss of body weight and fat mass up to 12 weeks and drastically improved fasting insulin and HOMA-IR compared with sham-operated mice. Using weight-matched control groups, we also found that the adaptive hypometabolic response to weight loss was blunted by both VSG and RYGB, and that despite large weight/fat regain, fasting insulin and HOMA-IR were markedly improved, but not reversed, in VSG mice. Conclusions: VSG is less effective to lastingly suppress body weight and improve glycemic control compared with RYGB in mice. Given similar observations in many human studies, the run towards replacing RYGB with VSG is premature and should await carefully controlled randomized long-term trials with VSG and RYGB. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: South Asian individuals have an increased prevalence of type 2 diabetes, but little is known about the development of glycaemic traits in this ethnic group. We compared age-related changes in glycaemic traits between non-diabetic South Asian and white participants. Methods: In a prospective British occupational cohort with 5-yearly clinical examinations ( n = 230/5,749 South Asian/white participants, age 39-79 years at baseline), age-related trajectories of fasting glucose (FG) and 2 h post-load glucose (PLG), log-transformed fasting insulin (FINS) and 2 h post-load insulin (PLINS), HOMA insulin sensitivity (HOMA2-%S) and HOMA insulin secretion (HOMA2-%B) were fitted for South Asian and white individuals who remained free of diabetes between 1991 and 2009. Results: In sex-adjusted multilevel models, FG was stable in white participants but increased with age in South Asians (0.12 [SE = 0.04] mmol/l per decade). PLG, FINS and PLINS levels were lower among white participants (by 0.271 [SE = 0.092] mmol/l, 0.306 [SE = 0.046] log pmol/l, 0.707 [SE = 0.059] log pmol/l at age 50, respectively) compared with South Asians, although their age-related trajectories were parallel. HOMA2-%S was higher (0.226 [SE = 0.038] at age 50) and HOMA2-%B lower (by 0.189 [SE = 0.026] at age 50) among white than South Asian participants. The age-related decline in HOMA2-%S was similar in these groups, but the age-related increase in HOMA2-%B was greater in white participants (0.04 [SE = 0.02] per decade). This difference was explained by obesity, lifestyle and social status. Conclusions/interpretation: Findings from a diabetes-free population suggest an inadequate pancreatic beta cell reserve in South Asians, as a significantly steeper age-related increase in FG was observed in this ethnic group compared with white individuals. [ABSTRACT FROM AUTHOR]

Over the past 8 years, the genetics of complex traits have benefited from an unprecedented advancement in the identification of common variant loci for diseases such as type 2 diabetes (T2D). The ability to undertake genome-wide association studies in large population-based samples for quantitative glycaemic traits has permitted us to explore the hypothesis that models arising from studies in non-diabetic individuals may reflect mechanisms involved in the pathogenesis of diabetes. Amongst 88 T2D risk and 72 glycaemic trait loci, only 29 are shared and show disproportionate magnitudes of phenotypic effects. Important mechanistic insights have been gained regarding the physiological role of T2D loci in disease predisposition through the elucidation of their contribution to glycaemic trait variability. Further investigation is warranted to define causal variants within these loci, including functional characterisation of associated variants, to dissect their role in disease mechanisms and to enable clinical translation. [ABSTRACT FROM AUTHOR]

Insulin-mediated glucose disposal varies severalfold in apparently healthy individuals, and approximately one-third of the most insulin resistant of these individuals is at increased risk to develop various adverse clinical syndromes. Since direct measurements of insulin sensitivity are not practical in a clinical setting, several surrogate estimates of insulin action have been proposed, including fasting plasma insulin (FPI) concentration and the homeostasis model assessment of insulin resistance (HOMA-IR) calculated by a formula employing fasting plasma glucose (FPG) and FPI concentrations. The objective of this study was to compare FPI as an estimate of insulin-mediated glucose disposal with values generated by HOMA-IR in 758 apparently healthy nondiabetic individuals. Measurements were made of FPG, FPI, triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C) concentrations, and insulin-mediated glucose uptake was quantified by determining steady-state plasma glucose (SSPG) concentration during the insulin suppression test. FPI and HOMA-IR were highly correlated ( r = 0.98, P < 0.001). The SSPG concentration also correlated to a similar degree ( P < 0.001) with FPI ( r = 0.60) and HOMA-IR ( r = 0.64). Furthermore, the relationship between FPI and TG ( r = 0.35) and HDL-C ( r = −0.40) was comparable to that between HOMA-IR and TG ( r = 0.39) and HDL-C ( r = −0.41). In conclusion, FPI and HOMA-IR are highly correlated in nondiabetic individuals, with each estimate accounting for ~40 % of the variability (variance) in a direct measure of insulin-mediated glucose disposal. Calculation of HOMA-IR does not provide a better surrogate estimate of insulin action, or of its associated dyslipidemia, than measurement of FPI. [ABSTRACT FROM AUTHOR]

Klotho (KL) gene has been involved in severe alterations of physiological biochemical parameters leading to premature aging-like phenotypes and strikingly shortening lifespan. KL participates to the regulation of a number of intracellular biochemical pathways, including lipid profile and glucose metabolism. Aim of this study was to investigate the possible association between KL locus and biological parameters commonly accepted as indicators of the clinical status in hospitalized older patients. We genotyped the single-nucleotide polymorphisms (SNPs) rs9536314, rs1207568, and rs564481 at the KL locus in 594 hospitalized older patients (65-99 years), consecutively attending a geriatric ward, and tested the association of these KL variants with biological quantitative traits using analyses of covariance and genetic risk score models. Significant associations of rs9536314 with serum levels of hemoglobin, albumin, and high-density lipoprotein cholesterol (HDL-C) as well as significant associations of rs564481 with serum levels of hemoglobin, fasting insulin, and fasting glucose were observed. Gender-segregated analyses confirmed these associations, and suggested that the associations of KL genotypes with HDL-C, fasting glucose and fasting insulin levels may be driven by the female gender, while the association with serum levels of hemoglobin may be driven by the male gender. The association of KL genotypes with creatinine levels was found only in females, while the association with insulin-like growth factor-1 (IGF-1) and lymphocytes count (LC) was found only in males. The genetic risk score (GRS) models further confirmed significant associations among KL SNPs and hemoglobin, total cholesterol, and HDL-C. Gender-segregated analyses with the GRS-tagged approach confirmed the associations with HDL-C, fasting glucose, and fasting insulin levels in females, and with hemoglobin and LC in males. Our findings suggested that KL locus may influence quantitative traits such as serum levels of lipid, fasting glucose, albumin and hemoglobin in hospitalized older patients, with some gender differences suggested for creatinine, IGF-1 levels, and LC, thus being one of the genetic factors possibly contributing to age-related diseases and longevity. [ABSTRACT FROM AUTHOR]

The relationship between the expression of resistin in polycystic ovary syndrome (PCOS) and insulin resistance was investigated. The plasma resistin concentrations in 35 patients with PCOS and 40 controls were measured by ELISA. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), and fasting insulin (FIN) were tested by radioimmunoassay. Insulin resistance index (HOMA-IR) was calculated. Fasting plasma glucose (FPG) was determined by oxidase test. Western blot and reverse transcriptase PCR (RT-PCR) methods were used to detect the expression of resistin in adipose tissues. The levels of plasma resistin, LH, LH/FSH and FIN and HOMA-IR in patients with PCOS were significantly higher than those in control group (all P<0.05). Plasma resistin was correlated positively with FPG, FIN, HOMA-IR, LH and LH/FSH ( r=0.56, 0.60, 0.65, 0.48, and 0.42 respectively). Resistin protein and mRNA expression levels in patients with PCOS were significantly higher than those in normal tissues (all P<0.01). It was concluded that resistin might be involved in the pathogenesis of insulin resistance of PCOS. [ABSTRACT FROM AUTHOR]

Background/Objectives:Most dietary interventions have metabolic effects in the short term, but long-term effects may require dietary fat changes to influence body composition and insulin action. This study assessed the effect of sustained high polyunsaturated fatty acids (PUFA) intake through walnut consumption on metabolic outcomes in type II diabetes.Subjects/Methods:Fifty overweight adults with non-insulin-treated diabetes (mean age 54±8.7 years) were randomized to receive low-fat dietary advice ±30 g per day walnuts targeting weight maintenance (around 2000 kcal, 30% fat) for 1 year. Differences between groups were assessed by changes in anthropometric values (body weight, body fat, visceral adipose tissue) and clinical indicators of diabetes over treatment time using the general linear model.Results:The walnut group consumed significantly more PUFA than the control (P=0.035), an outcome attributed to walnut consumption (contributing 67% dietary PUFA at 12 months). Most of the effects were seen in the first 3 months. Despite being on weight maintenance diets, both groups sustained a 1–2 kg weight loss, with no difference between groups (P=0.680). Both groups showed improvements in all clinical parameters with significant time effects (P<0.004), bar triacylglycerol levels, but these were just above normal to begin with. The walnut group produced significantly greater reductions in fasting insulin levels (P=0.046), an effect seen largely in the first 3 months.Conclusions:Dietary fat can be manipulated with whole foods such as walnuts, producing reductions in fasting insulin levels. Long-term effects are also apparent but subject to fluctuations in dietary intake if not of the disease process.European Journal of Clinical Nutrition (2009) 63, 1008–1015; doi:10.1038/ejcn.2009.19; published online 8 April 2009 [ABSTRACT FROM AUTHOR]

A recent meta-analysis on three genome-wide association (GWA) scans identified six loci (NOTCH2, THADA, ADAMTS9, JAZF1, CDC123/CAMKID and TSPAN8/LGRS) highly associated with type II diabetes (T2D) in Caucasians. This investigation seeks to confirm this association with diabetes and related metabolic traits in Khatri Sikh diabetics of North India. We genotyped highly significant variants from each locus in a case–control cohort consisting of 680 T2D cases and 637 normoglycemic (NG) controls. Only CDC123/CAMKID (rs12779790) replicated earlier evidence of association with T2D under a dominant model (odds ratio (OR): 1.27; 95% confidence interval (CI): 1.02–1.57; P=0.031) during initial testing. However, we could not confirm this association using multiple testing corrections. In a multiple linear-regression analysis, the same variant in the CDC123/CAMKID revealed a marked decrease in fasting insulin levels among ‘G’ (risk) allele carriers independently in NG controls (P=0.030) and in T2D cases (P=0.009), as well as in the combined sample (P=0.003) after adjusting for covariates. Evidence of impaired β-cell function was also observed among ‘G’ (risk) allele carriers in T2D cases (P=0.008) and in a combined cohort (P=0.026). Our data could not confirm the role of the remaining variants with risk either for T2D or quantitative phenotypes measuring insulin secretion or insulin resistance. These findings suggest that CDC123/CAMKID could be a major risk factor for the development of T2D in Sikhs by affecting β-cell function. To our knowledge, this is the first study reporting the role of recently emerging loci in this high-risk population from the South Asian subcontinent.Journal of Human Genetics (2009) 54, 162–168; doi:10.1038/jhg.2009.7; published online 27 February 2009 [ABSTRACT FROM AUTHOR]