Diabetes-free Individuals Research Articles

Association of pro-inflammatory cytokines, adipokines and hepatokine with incident diabetes in India: a nested case-control study within CARRS cohort.

To study the association of pro-inflammatory markers with incident diabetes in India. We did a nested case-control study within the CARRS (Centre for ArdiometabolicRiskReduction inSouth Asia) cohort. Of the 5739 diabetes-free individuals at the baseline, 216 participants with incident diabetes and 432 age-, gender- and city-matched controls at 2-year follow-up were included. We measured high sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 ( MCP-1), adiponectin, leptin and fetuin-A in the stored baseline blood samples. We did multivariate conditional logistic regression to estimate association of inflammatory markers (as quartiles) and incident diabetes. Covariates were baseline fasting plasma glucose (FPG) and lipids, body mass index (BMI), family history of diabetes, smoking and alcohol use. Baseline hsCRP and TNF-α were higher, and IL-6 and adiponectin were lower among cases vs. controls. In multivariate conditional logistic regression models, only quartile-3 (odds ratio [OR]: 2.96 [95% CI:1.39, 6.30]) and quartile-4 (OR: 2.58 [95% CI:1.15, 5.79]) of TNF-α and quartile-4 of MCP-1 (OR: 2.55 [95% CI:1.06, 6.16]) were positively associated with diabetes after adjusting for baseline FPG and BMI. These associations did not remain after adjusting for family history. High level (quartile-4) of IL-6 was negatively associated with diabetes after adjusting for all factors (OR: 0.18 [95% CI:0.06, 0.55]). Higher TNF-α and MCP-1 levels and lower IL-6 were associated with higher risk of developing diabetes. Better understanding and potential methods of addressing these biomarkers, especially in relation to family history, are needed to address diabetes in South Asians.

Genetic Risk, Healthy Lifestyle Adherence, and Risk of Developing Diabetes in the Japanese Population.

This study examined the relationship between genetic risk, healthy lifestyle, and risk of developing diabetes. This prospective cohort study included 11,014 diabetes-free individuals ≥ 20 years old from the Tohoku Medical Megabank Community-based cohort study. Lifestyle scores, including the body mass index, smoking, physical activity, and gamma-glutamyl transferase (marker of alcohol consumption), were assigned, and participants were categorized into ideal, intermediate, and poor lifestyles. A polygenic risk score (PRS) was constructed based on the type 2 diabetes loci from the BioBank Japan study. A multiple logistic regression model was used to estimate the association between genetic risk, healthy lifestyle, and diabetes incidence and to calculate the area under the receiver operating characteristic curve (AUROC). Of the 11,014 adults included (67.8% women; mean age [standard deviation], 59.1 [11.3] years old), 297 (2.7%) developed diabetes during a mean 4.3 (0.8) years of follow-up. Genetic and lifestyle score is independently associated with the development of diabetes. Compared with the low genetic risk and ideal lifestyle groups, the odds ratio was 3.31 for the low genetic risk and poor lifestyle group. When the PRS was integrated into a model including the lifestyle and family history, the AUROC significantly improved to 0.719 (95% confidence interval [95% CI]: 0.692-0.747) compared to a model including only the lifestyle and family history (0.703 [95% CI, 0.674-0.732]). Our findings indicate that adherence to a healthy lifestyle is important for preventing diabetes, regardless of genetic risk. In addition, genetic risk might provide information beyond lifestyle and family history to stratify individuals at high risk of developing diabetes.

Age and sex dynamics in the incidence of diabetes in Contributory Health Services Scheme beneficiaries: A retrospective cohort study in Mumbai

ABSTRACT Introduction: A comprehensive body of literature addresses self-reported diabetes prevalence, yet a notable gap exists in research investigating the clinically ascertained incidence of diabetes in India through rigorous longitudinal data analysis. This study aimed to determine the incidence of clinically diagnosed diabetes in a nondiabetic cohort. Materials and Methods: The research gathered data from 1669 participants (aged 30 years and above) enrolled in a government hospital’s Contributory Health Services Scheme, utilizing electronic medical records. Clinical diagnosis of diabetes relied on three laboratory tests. A cohort of initially diabetes-free individuals in 2011–2012 was tracked for 10 years to assess diabetes incidence. Age-adjusted incidence rates were determined through survival analysis techniques. Results: Over a decade-long observational period, 552 beneficiaries within the study cohort were clinically diagnosed with diabetes, yielding an age-adjusted incidence rate of 38.9 cases per 1000 person-years (PYs) spanning from 2013 to 2021. Stratifying by gender, age-adjusted incidence rates were notably elevated in males compared to females, with rates of 41.5 versus 38.5 cases per 1000 PYs, respectively. Further analysis revealed the highest incidence rates among males aged 55–59 years (60.5 per 1000 PYs) and females aged 65–69 years (83.4 per 1000 PYs). Conclusion: This extended follow-up investigation transpired in a setting characterized by uniform health-care provision, devoid of discernible access differentials, or inequalities, thereby enhancing the credibility of the ascertained diabetes incidence rates.

A family history of type 2 diabetes as a predictor of fatty liver disease in diabetes-free individuals with excessive body weight

Comprehensive screening for non-alcoholic fatty liver disease (NAFLD) may help prompt clinical management of fatty liver disease. A family history, especially of diabetes, has been little studied as a predictor for NAFLD. We characterized the cross-sectional relationship between a family history of type 2 diabetes (FHT2D) and NAFLD probability in 1185 diabetes-free Apulian (Southern-Italy) subjects aged > 20 years with overweight or obesity not receiving any drug or supplementation. Clinical data and routine biochemistry were analysed. NAFLD probability was defined using the fatty liver index (FLI). A first-degree FHT2D was assessed by interviewing subjects and assigning a score of 0, 1, or 2 if none, only one, or both parents were affected by type 2 diabetes mellitus (T2DM). Our study population featured most females (70.9%, N = 840), and 48.4% (N = 574) of the sample had first-degree FHT2D. After dividing the sample by a FHT2D, we found a higher BMI, Waist Circumference (WC), and diastolic blood pressure shared by FHT2D subjects; they also showed altered key markers of glucose homeostasis, higher triglyceride levels, and worse liver function. FLI scores were significantly lower in subjects without a first-degree FHT2D. After running logistic regression models, a FHT2D was significantly associated with the NAFLD probability, even adjusting for major confounders and stratifying by age (under and over 40 years of age). A FHT2D led to an almost twofold higher probability of NAFLD, regardless of confounding factors (OR 2.17, 95% CI 1.63 to 2.89). A first-degree FHT2D acts as an independent determinant of NAFLD in excess weight phenotypes, regardless of the age group (younger or older than 40 years). A NAFLD risk assessment within multidimensional screening might be useful in excess weight subjects reporting FHT2D even in the absence of diabetes.

Association of Metformin and Abdominal Aortic Aneurysm Repair Outcomes

Metformin is a commonly used drug in diabetes mellitus treatment. Recently it has been suggested that the use of metformin on diabetes mellitus patients may lower the prevalence and slow the progression of AAA (abdominal aortic aneurysm) as well as the risk of rupture related mortality. The aim of this studywas to investigate the impact of metformin treatment on the risk of AAA repair related mortality and surgical complications. In this retrospective study, the clinical data of 306 patients, including 77 patients with diabetes mellitus, who underwent abdominal aortic aneurysm repair has been analyzed. Treatment outcomes have been investigated. The diabetes and metformin prescription status has been obtained from the medical history. Patients were divided into three groups: diabetes-free individuals, diabetics treated with metformin and diabetics treated with other glucose lowering drugs. The association between metformin treatment and AAA diameter, surgical complications and mortality were assessed using chi-square independence test and odds ratio analysis. In order to assess which factors are influencing AAA repair related complications and mortality a multi-variables analysis has been performed. A significant protective effect of metformin treatment towards AAA repair related mortality (P = 0.019) and complications (P = 0.032) among patients suffering from diabetes mellitus was revealed. These findings were statistically insignificant when considering all groups of patients (diabetes-free individuals, diabetics treated with metformin and diabetics treated with other glucose lowering drugs). Metformin may lower the risk of AAA repair related mortality and surgical complications among patients with diabetes.

Relationship between plasma angiogenic growth factors and diabetic foot ulcers

BackgroundAngiogenic growth factors play an important role in wound healing. However, their associations with diabetic foot ulcers (DFUs) in humans have rarely been investigated. We examined the relationships between circulating concentrations of vascular endothelial growth factor (VEGF)-A and placenta growth factor (PlGF), and DFU risk. MethodsWe recruited 447 participants, including 169 DFU patients, 182 diabetes patients without DFUs, and 96 diabetes-free individuals. Plasma VEGF-A and PlGF concentrations were measured using commercial enzyme immunoassay kits. ResultsConcentrations of VEGF-A and PlGF in DFU patients were higher than those in diabetes-free controls (P < 0.05), but lower than those in the diabetic controls (P < 0.05). Increased concentrations of VEGF-A and PlGF were associated with a reduced risk of DFUs. The odds ratios (95% confidence intervals) were 0.93 (0.88, 0.97) for every 10 pg/ml increase in VEGF-A concentrations, and 0.96 (0.94, 0.99) for every 5 pg/ml increase in PlGF concentrations. VEGF-A concentrations were positively related to BMI, glycated hemoglobin (HbA1c), hypertension, and neuropathy, and PlGF was positively correlated to age, HbA1c, and hypertension, among DFU patients. ConclusionVEGF-A and PlGF play important roles in the development of DFU but need to be confirmed in prospective studies.

A Review of the Relationship Between Chronic Periodontitis and Diabetes

Chronic periodontitis (CP) is a common inflammatory disease which is characterized by progressive destruction of the tooth supporting structures and ultimately, potential tooth loss. A relationship between CP and diabetes has been recognized for some time. Both diseases share several collective risk factors, however, recent research has provided greater insight into the relationship with evidence emerging for each disease being a co-factor in the pathogenesis of the other. The aim of this review is to examine recent epidemiological evidence for the impact of diabetes on CP, and in the reverse direction, the impact of CP on diabetes. Based on the available evidence to date, it seems likely that the level of metabolic control influences future periodontal disease risk. In the reverse direction, the presence of CP has the potential to adversely affect glycemic control in both diabetes-affected and diabetes-free individuals. CP may potentially be a risk factor for the development of type 2 diabetes in diabetes-free individuals. Interventional studies show that successful treatment of CP may improve metabolic control in people with diabetes in the short term.

LONG-TERM EFFECTS OF PREDIABETES AND DIABETES ON COGNITIVE TRAJECTORIES IN A POPULATION-BASED COHORT

Although diabetes has been linked to dementia risk, the cognitive trajectories in older adults with diabetes remain unclear. We aimed to investigate the effect of prediabetes and diabetes on cognitive trajectories among cognitively intact older adults in a long-term follow-up study. Within the Swedish Adoption/Twin Study of Aging, 793 cognitively intact older adults aged ≥50 were identified at baseline and followed for up to 23 years. Cognitive domains (verbal, spatial/fluid, memory, perceptual speed) were assessed at baseline and up to seven follow-ups. Prediabetes was defined according to blood glucose levels in diabetes-free participants. Diabetes was ascertained based on self-report, hypoglycemic medication use and blood glucose levels. Data were analyzed with linear mixed-effect models adjusting for potential confounders. At baseline, 68 participants (8.6%) had prediabetes and 45 (5.7%) had diabetes among all participants. Compared to diabetes-free individuals, people with diabetes had lower performance in spatial/fluid abilities (β -2.63; 95% CI -5.36, 0.05; p = 0.058), and an accelerated linear decline over time in verbal abilities (β -0.15; 95% CI -0.29, -0.01; p = 0.041). Prediabetes was associated with an accelerated decline in processing speed (β -0.01; 95% CI -0.02, -0.004; p = 0.041), but with a better maintenance of memory (β 0.23; 95% CI 0.05, 0.42; p = 0.013) over the follow-up. Prediabetes may accelerate processing speed decline, and diabetes is associated with the verbal ability decline, suggesting that diabetes and even prediabetes affect especially the cognitive domains of fluid intelligence at the early stages of cognitive impairment.

Introduction of the DiaGene study: clinical characteristics, pathophysiology and determinants of vascular complications of type 2 diabetes

BackgroundType 2 diabetes is a major healthcare problem. Glucose-, lipid-, and blood pressure-lowering strategies decrease the risk of micro- and macrovascular complications. However, a substantial residual risk remains. To unravel the etiology of type 2 diabetes and its complications, large-scale, well-phenotyped studies with prospective follow-up are needed. This is the goal of the DiaGene study. In this manuscript, we describe the design and baseline characteristics of the study.MethodsThe DiaGene study is a multi-centre, prospective, extensively phenotyped type 2 diabetes cohort study with concurrent inclusion of diabetes-free individuals at baseline as controls in the city of Eindhoven, The Netherlands. We collected anthropometry, laboratory measurements, DNA material, and detailed information on medication usage, family history, lifestyle and past medical history. Furthermore, we assessed the prevalence and incidence of retinopathy, nephropathy, neuropathy, and diabetic feet in cases. Using logistic regression models, we analyzed the association of 11 well known genetic risk variants with type 2 diabetes in our study.ResultsIn total, 1886 patients with type 2 diabetes and 854 controls were included. Cases had worse anthropometric and metabolic profiles than controls. Patients in outpatient clinics had higher prevalence of macrovascular (41.9% vs. 34.8%; P = 0.002) and microvascular disease (63.8% vs. 20.7%) compared to patients from primary care. With the exception of the genetic variant in KCNJ11, all type 2 diabetes susceptibility variants had higher allele frequencies in subjects with type 2 diabetes than in controls.ConclusionsIn our study population, considerable rates of macrovascular and microvascular complications are present despite treatment. These prevalence rates are comparable to other type 2 diabetes populations. While planning genomics, we describe that 11 well-known type 2 diabetes genetic risk variants (in TCF7L2, PPARG-P12A, KCNJ11, FTO, IGF2BP2, DUSP9, CENTD2, THADA, HHEX, CDKAL1, KCNQ1) showed similar associations compared to literature. This study is well-suited for multiple omics analyses to further elucidate disease pathophysiology. Our overall goal is to increase the understanding of the underlying mechanisms of type 2 diabetes and its complications for developing new prediction, prevention, and treatment strategies.

Cognitive Trajectories of Older Adults With Prediabetes and Diabetes: A Population-Based Cohort Study.

Diabetes has been linked to dementia risk; however, the cognitive trajectories in older adults with diabetes remain unclear. We aimed to investigate the effect of prediabetes and diabetes on cognitive trajectories among cognitively intact older adults in a long-term follow-up study. Within the Swedish Adoption/Twin Study of Aging, 793 cognitively intact older adults aged ≥50 were identified at baseline and followed for up to 23 years. Based on standardized scores from 11 cognitive tests, administered at baseline and up to seven follow-ups, four cognitive domains (verbal abilities, spatial/fluid, memory, perceptual speed) were identified by principal-component analysis. Prediabetes was defined according to blood glucose levels in diabetes-free participants. Diabetes was ascertained based on self-report, hypoglycemic medication use and blood glucose levels. Data were analyzed with linear mixed-effect models adjusting for potential confounders. At baseline, 68 participants (8.6%) had prediabetes and 45 (5.7%) had diabetes. Compared to diabetes-free individuals, people with diabetes had a steeper decline over time in perceptual speed and verbal abilities. The annual declines in these domains were greater than the annual decline in memory. Prediabetes was associated with lower performance in memory in middle-age, but also associated with a less steep memory decline over the follow-up. Diabetes is associated with a faster decline in perceptual speed and verbal abilities, while prediabetes is associated with lower memory performance in middle-age. However, the detrimental effects of hyperglycemia seem to not affect memory over time.

CDH13 Genetic Polymorphisms, Adiponectin and Ischemic Stroke: a Chinese Family-based Sib-pair Study

ObjectiveTo understand the relationships between CDH13 (T-cadherin) genetic polymorphisms, adiponectin levels and ischemic stroke, and possible interactions between CDH13 polymorphisms and other risk factors. MethodsWe recruited 342 Chinese ischemic stroke sib pairs. We genotyped rs4783244 and rs7193788 on CDH13 using time-of-flight mass spectrometry genotyping technology and measured total and high-molecular weight (HMW) adiponectin levels. We investigated associations between SNPs and ischemic stroke, and interactions between SNPs and other risk factors using multi-level mixed-effects regression model. ResultsIn individuals without ischemic stroke, CDH13 rs4783244 was associated with total adiponectin levels (per T: Coef = −0.257, P = 0.001). CDH13 rs7193788 was associated with total adiponectin levels (per A: Coef = −0.221, P = 0.001) and HMW adiponectin levels (per A: Coef = −0.163, P = 0.003). rs7193788 was significantly associated with ischemic stroke (GA/AA vs. GG: OR = 1.55, 95% CI: 1.07 to 2.24, P = 0.020) after Bonferroni correction (α = 0.025). There was an interaction between rs7193788 and diabetes (P = 0.036). Compared to diabetes-free individuals with rs7193788 GG genotype, diabetes patients with rs7193788 GA/AA genotypes had higher risks for ischemic stroke (OR = 2.64, 95% CI: 1.58-4.40, P < 0.001). ConclusionCDH13 genetic polymorphisms are associated with adiponectin levels and ischemic stroke. An interaction is found between CDH13 SNP and diabetes for ischemic stroke.

Derivation and validation of an HbA1c optimal cutoff for diagnosing prediabetes in a South African mixed ancestry population

IntroductionPrediabetes compromises impaired fasting glucose and impaired glucose tolerance and is a high risk for future diabetes mellitus and cardiovascular disease. Traditional diagnostic methods involve a fasting sample or oral glucose tolerance test, which is cumbersome, time-consuming and inconvenient. An HbA1c-based approach has been incorporated into new guidelines, but cut-offs may vary and have not been defined for all population groups. We derived and validated HbA1c cut-offs to diagnose prediabetes in mixed ancestry South Africans. MethodsParticipants were 667 (derivation sample), 234 (validation sample 1) and 674 (validation sample 2) diabetes-free individuals. They underwent standard 2-hour OGTT with HbA1c test. Receiver–operator characteristic curves were used to determine optimal HbA1c cut-off to predict prediabetes. ResultsA total of 27.7% participants in the derivation sample had prediabetes versus 17.5% (validation sample 1) and 15.4% (validation sample 2). The optimal cut-off was 5.75% in all three cohorts with sensitivity and specificity of 64.8% and 60.4% in combined derivation and validation sample 1, and 59.6% and 69.8% in validation sample 2. ConclusionThe discriminatory capacity of HbA1c for predicting prediabetes in this population is modest at the derived cut-off. The use of HbA1c alone in this setting may result in an inaccurate diagnosis.

Type 1 Diabetes–associated TLR Responsiveness of Oral Epithelial Cells

In type 1 diabetes (T1D), a Toll-like receptor (TLR)-hyper-inflammatory monocytic phenotype has been implicated as a mechanism of exacerbated tissue destruction. Other cells of the periodontium, including oral epithelial cells (OECs), express innate immune receptors, including TLRs. To delineate the TLR responses of OECs derived from T1D participants and to determine effects of the anti-inflammatory agent triclosan on the TLR-hyper-inflammatory phenotype, primary human OECs from individuals with T1D and diabetes-free individuals were stimulated with TLR ligands in the presence and/or absence of triclosan. The expression of pro-inflammatory cytokines and micro-RNAs (miRNAs) was evaluated. While the repertoire of TLRs expressed by OECs is similar to that expressed by macrophages (Mϕ), the relative amounts and ratios are significantly different. OECs demonstrate a TLR-response profile similar to that of Mϕ, yet attenuated. OECs have a unique response to P. gingivalis LPS, where miR146a and miR155 play a regulatory role in responsiveness. OECs from T1D participants are TLR-hyper-responsive, due to dysregulated induction of miR146a and miR155, which is abrogated by pre-treatment with triclosan. The aberrant TLR-activation of OECs in T1D has the potential to contribute to excessive soft- and hard-tissue destruction. Importantly, triclosan’s anti-inflammatory property is effective in abrogating TLR-induced OEC hyperactivity.

Lifestyle factors and mortality risk in individuals with diabetes mellitus: are the associations different from those in individuals without diabetes?

Thus far, it is unclear whether lifestyle recommendations for people with diabetes should be different from those for the general public. We investigated whether the associations between lifestyle factors and mortality risk differ between individuals with and without diabetes. Within the European Prospective Investigation into Cancer and Nutrition (EPIC), a cohort was formed of 6,384 persons with diabetes and 258,911 EPIC participants without known diabetes. Joint Cox proportional hazard regression models of people with and without diabetes were built for the following lifestyle factors in relation to overall mortality risk: BMI, waist/height ratio, 26 food groups, alcohol consumption, leisure-time physical activity, smoking. Likelihood ratio tests for heterogeneity assessed statistical differences in regression coefficients. Multivariable adjusted mortality risk among individuals with diabetes compared with those without was increased, with an HR of 1.62 (95% CI 1.51, 1.75). Intake of fruit, legumes, nuts, seeds, pasta, poultry and vegetable oil was related to a lower mortality risk, and intake of butter and margarine was related to an increased mortality risk. These associations were significantly different in magnitude from those in diabetes-free individuals, but directions were similar. No differences between people with and without diabetes were detected for the other lifestyle factors. Diabetes status did not substantially influence the associations between lifestyle and mortality risk. People with diabetes may benefit more from a healthy diet, but the directions of association were similar. Thus, our study suggests that lifestyle advice with respect to mortality for patients with diabetes should not differ from recommendations for the general population.

Lifestyle Habits of People with Self-reported Diabetes: Changes During a Five-year Period

The aims of our study were to investigate the prevalence of risk factors in persons with previously known diabetes ("old DM"), persons with diabetes developed during the 2003-2008 period ("new DM") and diabetes-free individuals within the CroHort study. Risk factors were defined as physical inactivity, unhealthy nutritional regimen, smoking and excessive alcohol consumption, while diabetes status was self-reported. The most prevalent risk factor in both "old DM" and "new DM" group was physical inactivity (46.7% and 33.7% in 2003; 46.8% and 46.3% in 2008), then smoking (12.1% and 14.6%; 12.7% and 14.4%), unhealthy diet (8.8% and 13.8; 8.2% and 10.0%) and heavy alcohol consumption (11.1% and 6.0%; 7.8% and 13.8%). Diabetes-free individuals had higher rates of smoking and unhealthy diet, and lower rates of alcohol consumption and physical inactivity than both diabetes groups. These results indicate the need for comprehensive actions oriented towards persons with diabetes concerning physical activity.

Acute Pancreatitis in Association With Type 2 Diabetes and Antidiabetic Drugs

OBJECTIVEPrevious observational studies have found an increased risk of acute pancreatitis among type 2 diabetic patients. However, limited information is available on this association and specifically on the role of antidiabetic treatment. Our aim, therefore, was to further assess the risk of acute pancreatitis in adult patients with type 2 diabetes.RESEARCH DESIGN AND METHODSWe performed a population-based case-control analysis nested in a cohort of 85,525 type 2 diabetic patients and 200,000 diabetes-free individuals from the general population using data from The Health Improvement Network database. Subjects were followed up to ascertain incident cases of acute pancreatitis.RESULTSWe identified 419 cases of acute pancreatitis, 243 in the general population and 176 in the diabetes cohort. Incidence rates were 30.1 and 54.0 per 100,000 person-years in the general population and the diabetes cohort, respectively. In the cohort analysis, the adjusted incidence rate ratio of acute pancreatitis in diabetic patients versus that in the general population was 1.77 (95% CI 1.46–2.15). The magnitude of this association decreased with adjustment for multiple factors in the nested case-control analysis (adjusted odds ratio 1.37 [95% CI 0.99–1.89]). Furthermore, we found that the risk of acute pancreatitis was decreased among insulin-treated diabetic patients (0.35 [0.20–0.61]).CONCLUSIONSType 2 diabetes may be associated with a slight increase in the risk of acute pancreatitis. We also found that insulin use in type 2 diabetes might decrease this risk. Further research is warranted to confirm these associations.

Common genetic variation in the melatonin receptor 1B gene (MTNR1B) is associated with decreased early-phase insulin response.

Aims/hypothesisWe investigated whether variation in MTNR1B, which was recently identified as a common genetic determinant of fasting glucose levels in healthy, diabetes-free individuals, is associated with measures of beta cell function and whole-body insulin sensitivity.MethodsWe studied 1,276 healthy individuals of European ancestry at 19 centres of the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study. Whole-body insulin sensitivity was assessed by euglycaemic–hyperinsulinaemic clamp and indices of beta cell function were derived from a 75 g oral glucose tolerance test (including 30 min insulin response and glucose sensitivity). We studied rs10830963 in MTNR1B using additive genetic models, adjusting for age, sex and recruitment centre.ResultsThe minor (G) allele of rs10830963 in MTNR1B (frequency 0.30 in HapMap Centre d’Etude du Polymorphisme [Utah residents with northern and western European ancestry] [CEU]; 0.29 in RISC participants) was associated with higher levels of fasting plasma glucose (standardised beta [95% CI] 0.17 [0.085, 0.25] per G allele, p = 5.8 × 10−5), consistent with recent observations. In addition, the G-allele was significantly associated with lower early insulin response (−0.19 [−0.28, −0.10], p = 1.7 × 10−5), as well as with decreased beta cell glucose sensitivity (−0.11 [−0.20, −0.027], p = 0.010). No associations were observed with clamp-assessed insulin sensitivity (p = 0.15) or different measures of body size (p > 0.7 for all).Conclusions/interpretationGenetic variation in MTNR1B is associated with defective early insulin response and decreased beta cell glucose sensitivity, which may contribute to the higher glucose levels of non-diabetic individuals carrying the minor G allele of rs10830963 in MTNR1B.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-009-1392-x) contains a list of the members of the RISC Consortium, which is available to authorised users.

Metabolic syndrome and its components as predictors of incident type 2 diabetes mellitus in an Aboriginal community

Risk factors for type 2 diabetes remain poorly characterized among Aboriginal Canadians. We aimed to determine the incidence of type 2 diabetes in an Aboriginal community and to evaluate prospective associations with metabolic syndrome and its components. Of 606 participants in the Sandy Lake Health and Diabetes Project from 1993 to 1995 who were free of diabetes at baseline, 540 (89.1%) participated in 10-year follow-up assessments. Baseline anthropometry, blood pressure, fasting insulin and serum lipid levels were measured. Fasting and 2-hour postload glucose levels were obtained at follow-up to determine incident cases of type 2 diabetes. The 10-year cumulative incidence of diabetes was 17.5%. High adiposity, dyslipidemia, hyperglycemia, hyperinsulinemia and hypertension at baseline were associated with an increased risk of diabetes after adjustment for age and sex (all p < or = 0.03). Metabolic syndrome had high specificity (75%-88%) and high negative predictive value (85%-87%) to correctly detect diabetes-free individuals at follow-up. It had low sensitivity (26%-48%) and low positive predictive value (29%-32%) to detect future diabetes. Metabolic syndrome at baseline was associated with incident diabetes after adjustment for age and sex, regardless of whether the syndrome was defined using the National Cholesterol Education Program criteria (odds ratio [OR] 2.03, 95% confidence interval [CI] 1.10-3.75) or the International Diabetes Federation criteria (OR 2.14, 95% CI 1.29-3.55). The association was to the same degree as that for impaired glucose tolerance assessed using the oral glucose tolerance test (OR 2.87, 95% CI 1.52-5.40; p > 0.05 for comparison of C statistics). Metabolic syndrome and its components can be identified with readily available clinical measures. As such, the syndrome may be useful for identifying individuals at risk of type 2 diabetes in remote Aboriginal communities.

Uncontrolled diabetes increases the risk of Alzheimer’s disease: a population-based cohort study

Diabetes has been related to Alzheimer's disease with inconsistent findings. We aimed to clarify the association of diabetes with different dementing disorders taking into account glycaemic control, and to explore the link between glucose dysregulation and neurodegeneration. A dementia-free cohort (n = 1,248) aged >or=75 years was longitudinally examined to detect dementia, Alzheimer's disease and vascular dementia (VaD) cases (Diagnostic and Statistical Manual of Mental Disorders, revised third edition [DSM-III-R] criteria). The Alzheimer's disease diagnoses were subdivided into Alzheimer's disease with stroke and Alzheimer's disease without hypertension, heart disease and stroke. Diabetes was ascertained based on medical history, or hypoglycaemic medication use, or a random blood glucose level >or=11.0 mmol/l, which included undiagnosed diabetes when neither a history of diabetes nor hypoglycaemic drugs use was present. Uncontrolled diabetes was classified as a random blood glucose level >or=11.0 mmol/l in diabetic patients. Borderline diabetes was defined as a random blood glucose level of 7.8-11.0 mmol/l in diabetes-free individuals. Cox models were used to estimate HRs. During the 9 year follow-up, 420 individuals developed dementia, including 47 with VaD and 320 with Alzheimer's disease (of the 320 Alzheimer's disease cases, 78 had previous, temporally unrelated stroke, and 137 had no major vascular comorbidities). Overall diabetes was only related to VaD (HR 3.21, 95% CI 1.20-8.63). Undiagnosed diabetes led to an HR of 3.29 (95% CI 1.20-9.01) for Alzheimer's disease. Diabetic patients with random blood glucose levels <7.8 mmol/l showed no increased dementia risk. Uncontrolled and borderline diabetes were further associated with Alzheimer's disease without vascular comorbidities. Uncontrolled diabetes increases the risk of Alzheimer's disease and VaD. Our findings suggest a direct link between glucose dysregulation and neurodegeneration.

The Effect of Borderline Diabetes on the Risk of Dementia and Alzheimer’s Disease

To verify the hypothesis that borderline diabetes may increase the risk of dementia and Alzheimer's disease, a community-based cohort of 1,173 dementia- and diabetes-free individuals aged >or=75 years was longitudinally examined three times to detect patients with dementia and Alzheimer's disease (Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition criteria). Borderline diabetes was defined as a random plasma glucose level of 7.8-11.0 mmol/l. Data were analyzed using Cox proportional hazards models. During the 9-year follow-up, 397 subjects developed dementia, including 307 Alzheimer's cases. At baseline, 47 subjects were identified with borderline diabetes. Borderline diabetes was associated with adjusted hazard ratios (95% CIs) of 1.67 (1.04-2.67) for dementia and 1.77 (1.06-2.97) for Alzheimer's disease; the significant associations were present after additional adjustment for future development of diabetes. Stratified analysis suggested a significant association between borderline diabetes and Alzheimer's disease only among noncarriers of APOE epsilon4 allele. There was an interaction between borderline diabetes and severe systolic hypertension on the risk of Alzheimer's disease (P = 0.04). We conclude that borderline diabetes is associated with increased risks of dementia and Alzheimer's disease; the risk effect is independent of the future development of diabetes. Borderline diabetes may interact with severe systolic hypertension to multiply the risk of Alzheimer's disease.