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Parental transmission of type 2 diabetes: The Framingham Offspring Study

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Abstract

Study of parental transmission of diabetes provides insight into the relative contributions of underlying maternal and paternal influences. We estimated risk for type 2 diabetes and milder degrees of glucose intolerance associated with parental diabetes among subjects of the population-based Framingham Offspring Study, in which participants are primarily Caucasian and at relatively low risk for diabetes and for which both parental and offspring phenotypes were ascertained by direct examination. Parental diabetes, assessed over 40 years of biennial follow-up, was defined by use of hypoglycemic drug therapy or a casual plasma glucose level > or = 11.1 mmol/l at any examination. Offspring glucose tolerance, assessed over 20 years of quadrennial follow-up, was defined by fasting plasma glucose levels > or = 7.8 mmol/l at any two examinations, use of hypoglycemic drug therapy at any examination, or with a 75-g oral glucose tolerance test (1980 World Health Organization criteria) at the most recent examination. We calculated odds ratios (ORs) and 95% CIs for offspring glucose tolerance status using generalized estimating equations to account for differential correlations within and between families. The 2,527 offspring came from 1,303 nuclear families, of which 77.6% had two or more siblings per family and in which the prevalence of parental diabetes was 24.6%. The mean offspring age was 54 years (range 26-82), 53% were women, 8.6% had diabetes, 11.4% had impaired glucose tolerance, 76.3% had no parental diabetes, 10.5% had maternal diabetes, 11.5% had paternal diabetes, and 1.7% had bilineal diabetes. Relative to individuals without parental diabetes, the age-adjusted ORs (95% CI) for offspring type 2 diabetes or abnormal glucose tolerance (fasting plasma glucose > or = 6.1 mmol/l or 2-h postchallenge glucose tolerance > or = 7.8 mmol/l) among individuals with maternal diabetes were 3.4 (2.3-4.9) and 2.7 (2.0-3.7), respectively; among individuals with paternal diabetes were 3.5 (2.3-5.2) and 1.7 (1.2-2.4), respectively; and among individuals with bilineal diabetes were 6.1 (2.9-13.0) and 5.2 (2.6-10.5), respectively. Although maternal and paternal diabetes conferred equivalent risk for offspring type 2 diabetes, offspring with maternal diabetes were slightly more likely to have abnormal glucose tolerance compared with those with paternal diabetes (OR 1.6, 95% CI 1.1-2.4). Offspring with maternal diabetes and an age of onset of <50 years had marked increased risk for both type 2 diabetes (9.7, 4.3-22.0) and abnormal glucose tolerance (9.0, 4.2-19.7). We conclude that risk ratios for offspring type 2 diabetes are consistent with a simple additive risk model, where risk when both parents are affected equals the sum of risk when either parent is affected. For maternal diabetes to confer excess risk for mild but not overt glucose intolerance, offspring of diabetic fathers may transit abnormal to impaired glucose tolerance relatively quickly, or diabetic mothers may transmit risk for a mild slowly progressive form of abnormal glucose tolerance in addition to overt diabetes. Very high risk for abnormal glucose homeostasis among offspring with young age-of-onset maternal diabetes is consistent with hypotheses that perinatal exposures increase diabetes risk. Given equivalent risk ratios for type 2 diabetes, fathers may transmit unique paternal genetic factors of similar strength to maternal environmental factors.

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... While cultural and environmental factors typical of each ethnicity can explain part of this increased prevalence [12,31], divergent genetic backgrounds are interpreted as a major factor contributing to these differences [12,32]. In addition, the excess risk of T2D is well known to relate to family history of the disease [12,[33][34][35][36][37][38][39]. The lifetime risk for first-degree relatives of a patient with T2D is 3-6 times higher than that of age-and weight-matched subjects without a family history of diabetes [36]. ...
... In addition, the excess risk of T2D is well known to relate to family history of the disease [12,[33][34][35][36][37][38][39]. The lifetime risk for first-degree relatives of a patient with T2D is 3-6 times higher than that of age-and weight-matched subjects without a family history of diabetes [36]. In particular, offspring of T2 diabetics have an increased risk ranging from~40 to 70% depending on whether one (with the affected mother conferring the higher risk) or both parents are affected [37]. ...
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Diabetes is a severe threat to global health. Almost 500 million people live with diabetes worldwide. Most of them have type 2 diabetes (T2D). T2D patients are at risk of developing severe and life-threatening complications, leading to an increased need for medical care and reduced quality of life. Improved care for people with T2D is essential. Actions aiming at identifying undiagnosed diabetes and at preventing diabetes in those at high risk are needed as well. To this end, biomarker discovery and validation of risk assessment for T2D are critical. Alterations of DNA methylation have recently helped to better understand T2D pathophysiology by explaining differences among endophenotypes of diabetic patients in tissues. Recent evidence further suggests that variations of DNA methylation might contribute to the risk of T2D even more significantly than genetic variability and might represent a valuable tool to predict T2D risk. In this review, we focus on recent information on the contribution of DNA methylation to the risk and the pathogenesis of T2D. We discuss the limitations of these studies and provide evidence supporting the potential for clinical application of DNA methylation marks to predict the risk and progression of T2D.
... Based on the genotyping results of all participants, we mainly used GCTA software (GCTA 1. 26.0) to perform principal component analysis (PCA) and construct a kinship matrix to evaluate the genetic relationship between participants in this study [20]. The specific operations are as follows: (1) Plink software (PLINK v1.90b6.12) was used to convert the file format of genotyping data, which is necessary for PCA construction through GCTA software. ...
... We are also grateful to all participants for providing blood samples. 1 ...
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Background Evidence from genetic epidemiology indicates that type 2 diabetes (T2D) has a strong genetic basis. Activated STAT4 has an inflammatory effect, and STAT4 is an important mediator of inflammation in diabetes. Our study aimed to study the association between STAT4 single nucleotide polymorphisms (SNPs) and T2D susceptibility in Chinese Han population. Methods We conducted a 'case–control' study among 500 T2D patients and 501 healthy individuals. 5 candidate STAT4 SNPs were successfully genotyped. The association between SNPs and T2D susceptibility under different genetic models was evaluated by logistic regression analysis. ‘SNP-SNP’ interaction was analyzed and completed by multi-factor dimensionality reduction (MDR). Finally, we evaluated the differences of clinical characteristics under different genotypes by one-factor analysis of variance. Results The overall results showed that STAT4 rs3821236 was associated with increasing T2D risk under allele (OR 1.23, p = 0.020), homozygous (OR 1.51, p = 0.025), dominant (OR 1.36, p = 0.029), and additive models (OR 1.23, p = 0.020). The results of stratified analysis showed that rs3821236, rs11893432, and rs11889341 were risk factors for T2D among participants ≤ 60 years old. Only rs11893432 was associated with increased T2D risk among female participants. There was also a potential association between rs3821236 and T2D with nephropathy risk. STAT4 rs11893432, rs7574865 and rs897200 were significantly associated with lysophosphatidic acid, cystatin C and thyroxine t4, respectively. Conclusion The genetic polymorphisms of STAT4 is potentially associated with T2D susceptibility of Chinese population. In particular, rs3821236 is significantly associated with T2D risk both in the overall and several subgroup analyses. Our study may provide new ideas for T2D individualized diagnosis/protection.
... 3,4 Offspring are at a 3.5-fold increased risk of developing T2D when just one parent has T2D. 5,6 When both parents have T2D, this risk increases sixfold. 5,6 Given the strong link between parental body mass index (BMI, kg/m 2 ) and offspring BMI, 7,8 it is not surprising that child BMI is also an important predictor of insulin resistance (IR), the primary physiological precursor to T2D. [9][10][11] In adults, psychological factors, including anxiety and depression, have been cross-sectionally and prospectively associated with the development of IR and T2D, especially among women. ...
... 5,6 When both parents have T2D, this risk increases sixfold. 5,6 Given the strong link between parental body mass index (BMI, kg/m 2 ) and offspring BMI, 7,8 it is not surprising that child BMI is also an important predictor of insulin resistance (IR), the primary physiological precursor to T2D. [9][10][11] In adults, psychological factors, including anxiety and depression, have been cross-sectionally and prospectively associated with the development of IR and T2D, especially among women. [12][13][14][15] A metaanalysis found that adults with depression or elevated depressive symptoms have a 37% increased risk of developing T2D 16 ; conversely, meta-analytic findings also indicate that adults with T2D have a 24% increased risk of developing depression. ...
Article
Background Children whose parents have type 2 diabetes (T2D) are at high-risk for developing T2D. In youth, negative affect has been shown to predict insulin resistance (IR), and disinhibited-eating behaviors have been linked to IR. It is unknown if youth with a parent with T2D (P-T2D) report greater psychological and behavioral symptoms than those without a P-T2D. Objective To compare youth with and without a P-T2D on symptoms of negative affect and disinhibited-eating. Methods Nine-hundred-thirty-two youth (13.3±2.6 y; BMIz 1.06±1.06; 67.8% female; 53.6% People of Color; 10.7% with a P-T2D) completed questionnaires of anxiety and depressive symptoms, eating in the absence of hunger, and emotional-eating. Loss-of-control (LOC)-eating was assessed by interview. In two separate sub-samples, energy intake was explored using laboratory test meals simulating eating in the absence of hunger and LOC-eating, respectively. Analyses were adjusted for age, sex, race/ethnicity. In follow-up analyses, fat mass (kg) and height, and IR were included as covariates, respectively. Results Adjusting for all covariates including adiposity and IR, compared to youth without a P-T2D, youth with a P-T2D reported more anxiety and depression symptoms, greater eating in the absence of hunger, and emotional-eating (ps<.05). No significant differences were found for LOC-eating, or in exploratory analyses of energy intake for either test meal (ps>.16). Conclusions Self-reported negative affect and disinhibited-eating may be higher among youth with P-T2D compared to those without P-T2D. Prospective studies should examine whether, among those with a P-T2D, what role such symptoms may play for their subsequent risk for T2D. This article is protected by copyright. All rights reserved.
... It is well established that people with a first degree relative with type 2 diabetes are at higher risk of developing the disorder, with rates two-to sixfold greater than those without a family history [3]. Even in the presence of normal blood glucose levels, people with a positive family history of type 2 diabetes (FH+) often display whole-body insulin resistance [4], with skeletal muscle insulin resistance identified as a major contributor [5,6]. ...
... Here we extend these findings and demonstrate an impaired MBF response in apparently healthy (normoglycaemic) FH+ individuals in response to an MMC. It is well established that FH+ individuals are at higher risk of developing type 2 diabetes than those without a family history of diabetes [3]. In particular, FH+ people often display skeletal muscle insulin resistance as a major contributor of disease progression [5,6]. ...
Article
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Aims/hypothesis Microvascular blood flow (MBF) increases in skeletal muscle postprandially to aid in glucose delivery and uptake in muscle. This vascular action is impaired in individuals who are obese or have type 2 diabetes. Whether MBF is impaired in normoglycaemic people at risk of type 2 diabetes is unknown. We aimed to determine whether apparently healthy people at risk of type 2 diabetes display impaired skeletal muscle microvascular responses to a mixed-nutrient meal. Methods In this cross-sectional study, participants with no family history of type 2 diabetes (FH−) for two generations (n = 18), participants with a positive family history of type 2 diabetes (FH+; i.e. a parent with type 2 diabetes; n = 16) and those with type 2 diabetes (n = 12) underwent a mixed meal challenge (MMC). Metabolic responses (blood glucose, plasma insulin and indirect calorimetry) were measured before and during the MMC. Skeletal muscle large artery haemodynamics (2D and Doppler ultrasound, and Mobil-O-graph) and microvascular responses (contrast-enhanced ultrasound) were measured at baseline and 1 h post MMC. Results Despite normal blood glucose concentrations, FH+ individuals displayed impaired metabolic flexibility (reduced ability to switch from fat to carbohydrate oxidation vs FH−; p < 0.05) during the MMC. The MMC increased forearm muscle microvascular blood volume in both the FH− (1.3-fold, p < 0.01) and FH+ (1.3-fold, p < 0.05) groups but not in participants with type 2 diabetes. However, the MMC increased MBF (1.9-fold, p < 0.01), brachial artery diameter (1.1-fold, p < 0.01) and brachial artery blood flow (1.7-fold, p < 0.001) and reduced vascular resistance (0.7-fold, p < 0.001) only in FH− participants, with these changes being absent in FH+ and type 2 diabetes. Participants with type 2 diabetes displayed significantly higher vascular stiffness (p < 0.001) compared with those in the FH− and FH+ groups; however, vascular stiffness did not change during the MMC in any participant group. Conclusions/interpretation Normoglycaemic FH+ participants display impaired postprandial skeletal muscle macro- and microvascular responses, suggesting that poor vascular responses to a meal may contribute to their increased risk of type 2 diabetes. We conclude that vascular insulin resistance may be an early precursor to type 2 diabetes in humans, which can be revealed using an MMC. Graphical abstract
... Heritability (h 2 ) refers to the degree to which genetic factors play a role in the development of disease. Large populationbased studies have shown that the heritability of T2DM was estimated at 20-80% (6)(7)(8). However, there are great differences in heritability estimates among different regions and populations. ...
... Similarly, a U.S. twin cohort study showed that no sex differences were among sex found when analyzing the heritability of T2DM (24). However, the Framingham study pointed out that although there was no sex difference in the prevalence of T2DM between offspring and parents, the prevalence of T2DM in males was higher than that in females (8). The potential reasons for this difference are as follows: (1) there is no significant sex difference in the prevalence of obesity in rural China. ...
Article
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Objective: The prevalence of type 2 diabetes mellitus (T2DM) varies greatly in different regions and populations. This study aims to assess the heritability and environmental risk factors of T2DM among rural Chinese adults. Methods: Thousand five hundred thirty three participants from 499 extended families, which included 24 nuclear families, were recruited in the family-based study to assess the heritable risk of T2DM. Heritability of T2DM was estimated by the Falconer method. Using conditional logistic regression model, couple case-control study involving 127 couples were applied to assess the environmental risk factors of T2DM. Results: Compared with the Henan Rural Cohort, T2DM was significantly clustered in the nuclear families (OR: 8.389, 95% CI: 5.537–12.711, P < 0.001) and heritability was 0.74. No association between the heredity of T2DM and sex was observed between the extended families and the Henan Rural Cohort. Besides, results from the couple case-control study showed that physical activity (OR: 0.482, 95% CI: 0.261–0.893, P = 0.020) and fat intake (OR: 3.036, 95% CI: 1.070–8.610, P = 0.037) was associated with T2DM, and the proportion of offspring engaged in medium and high physical activity was higher than that of mothers in mother-offspring pairs. Conclusion: People with a family history of T2DM may have a higher risk of developing T2DM, however, there was no difference in genetic risk between males and females. Adherence to active physical activity and low fat intake can reduce the risk of T2DM.
... 22 Family history is a determining factor in seeking an early diagnosis of diabetes, as individuals with a family history of the disease in a first-degree relative have two to three times greater risk of developing it. 23,24 This result agrees with the present study (PRa= 5.00; 95%CI 2.53-9.88), and the risk in those with a maternal and paternal history of DM is even greater. ...
... and the risk in those with a maternal and paternal history of DM is even greater. 23,24 Also, in relation to diabetic individuals, there was an association with the use of UBS (PRa=2.38; 95%CI 1.03--5.54), ...
Article
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Introdução: As doenças crônicas não transmissíveis (DCNT) — incluindo diabetes (DM) e hipertensão arterial sistêmica (HAS) — são responsáveis por grande parte das mortes mundiais atualmente, sendo a identificação de fatores associados uma ferramenta fundamental para sua prevenção e estratégias de promoção da saúde. Objetivo: Determinar a prevalência de HAS e DM na população adulta atendida pelo Projeto Vozes das Ruas (PVR) em Jundiaí (SP) e fatores associados. Métodos: Os participantes do estudo transversal, conduzido de março a novembro de 2019, foram adultos acima de 18 anos, voluntários das ações de promoção de saúde do PVR em 2019, que consistiram na aplicação de um questionário sociodemográfico e de comportamentos em saúde; na avaliação de glicemia capilar, pressão arterial, peso, altura e circunferência abdominal; e posterior aconselhamento em saúde. Realizou-se análise descritiva dos dados para verificar a associação dos desfechos DM e HAS com variáveis independentes. Utilizaram-se teste χ2 e regressão logística multivariada para variáveis com p<0,20, adotando-se a significância de 5%. Resultados: A amostra foi composta de 580 participantes, 50% do sexo feminino e com idade média de 48,56 anos. A prevalência autodeclarada de DM foi 16,2% e de HAS, 30,2%. Os fatores associados em comum foram: faixa etária acima de 39 anos e uso de medicação contínua. Associados à DM foram: antecedente familiar de DM, uso de unidade básica de saúde, histórico de tabagismo. Em relação à HAS as associações foram: menos de oito anos de estudo, sobrepeso e obesidade. Conclusões: Na população estudada houve elevada prevalência de duas das principais DCNT — HAS e DM — que apresentaram fatores associados de extrema relevância para o planejamento de estratégias de promoção da saúde e prevenção de doenças.
... Figure 3 shows that the PRS was highly significantly associated with T2D status across different percentage cutoffs and ancestral groups, with comparable predictive performance in the European and East Asian populations and lower prediction accuracy in the African population. Individuals in the top 2% of the PRS distribution had significantly increased T2D risk, with the OR estimates ranging from 2.55 in the African samples to 4.58 in the East Asian samples, which corresponds to the increased risk of T2D for first-degree relatives [41] and suggests a clinical value of the transancestry PRS in diverse populations. ...
... We have shown that the top 2% of a trans-ancestry PRS distribution can identify individuals of European, African, Hispanic/Latino, and East Asian ancestry with a roughly 2.5-4.5-fold of increase in T2D risk, which corresponds to numerous studies that showed a similar increased risk of T2D for first degree relatives (see e.g., [41]). By integrating GWAS summary statistics from multiple populations using PRS-CSx, the trans-ancestry PRS was significantly associated with T2D status in all populations examined, providing a robust and potentially clinically meaningful index of risk among diverse patients in clinical settings. ...
Article
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Background Type 2 diabetes (T2D) is a worldwide scourge caused by both genetic and environmental risk factors that disproportionately afflicts communities of color. Leveraging existing large-scale genome-wide association studies (GWAS), polygenic risk scores (PRS) have shown promise to complement established clinical risk factors and intervention paradigms, and improve early diagnosis and prevention of T2D. However, to date, T2D PRS have been most widely developed and validated in individuals of European descent. Comprehensive assessment of T2D PRS in non-European populations is critical for equitable deployment of PRS to clinical practice that benefits global populations. Methods We integrated T2D GWAS in European, African, and East Asian populations to construct a trans-ancestry T2D PRS using a newly developed Bayesian polygenic modeling method, and assessed the prediction accuracy of the PRS in the multi-ethnic Electronic Medical Records and Genomics (eMERGE) study (11,945 cases; 57,694 controls), four Black cohorts (5137 cases; 9657 controls), and the Taiwan Biobank (4570 cases; 84,996 controls). We additionally evaluated a post hoc ancestry adjustment method that can express the polygenic risk on the same scale across ancestrally diverse individuals and facilitate the clinical implementation of the PRS in prospective cohorts. Results The trans-ancestry PRS was significantly associated with T2D status across the ancestral groups examined. The top 2% of the PRS distribution can identify individuals with an approximately 2.5–4.5-fold of increase in T2D risk, which corresponds to the increased risk of T2D for first-degree relatives. The post hoc ancestry adjustment method eliminated major distributional differences in the PRS across ancestries without compromising its predictive performance. Conclusions By integrating T2D GWAS from multiple populations, we developed and validated a trans-ancestry PRS, and demonstrated its potential as a meaningful index of risk among diverse patients in clinical settings. Our efforts represent the first step towards the implementation of the T2D PRS into routine healthcare.
... Normoglycemic first-degree relatives of different groups of prediabetes subjects had significantly increased fasting serum glucose compared to controls. The results indicate that although all the subjects were normoglycemic but the first-degree relatives of prediabetes subjects were at increased risk of developing glucose intolerance which mimics the results of first degree relatives of type 2 diabetes in different populations (1,(17)(18)(19). Fasting serum insulin level is not a good indicator of beta-cell function. ...
Article
Defects in insulin secretion and insulin action are common in both diabetes and prediabetes but which one is primary, is still unsettled. The present study focused on the normoglycemic first degree relatives of subjects with prediabetes to resolve this issue. Forty one first degree relatives of 14 isolated impaired fasting glucose (IFG) cases (R_IFG), 116 first degree relatives of 36 isolated impaired glucose tolerance (IGT) cases (R_IGT) and 77 first degree relatives of 20 combined IFG-IGT cases (R_IFG-IGT) and 20 healthy subjects without any family history of known diabetes or prediabetes were also included in this study. Serum insulin level was determined by enzyme linked immunosorbent assay (ELISA) method. Insulin secretory capacity (HOMA %B) and insulin sensitivity (HOMA %S) were calculated from fasting glucose and fasting insulin using HOMA-CIGMA software. Although fasting blood glucose in controls and normoglycemic first degree relatives of subjects with prediabetes were within normal range but the values were significantly higher among the normoglycemic first degree relatives of IFG, IGT and IFG-IGT, (p < 0.05) subjects compared to controls. HOMA %B in normoglycemic first degree relatives of subjects with prediabetes (R_IFG 80 ± 39, R_IGT 81 ± 34, R_IFG-IGT 90 ± 28) were significantly decreased compared to control subjects (107 ± 27). Dyslipidemia was evident in normoglycemic first degree relatives of subjects with prediabetes. Binary logistic regression analysis showed that HOMA %B was negatively associated (beta =-0.026, p = 0.009) with normoglycemic first degree relatives of subjects with prediabetes after adjusting for age, body mass index (BMI), high density lipoprotein (HDL) cholesterol, and low density lipoprotein (LDL) cholesterol. Beta cell secretory dysfunction is evident in normoglycemic first degree relatives of subjects with prediabetes in a Bangladeshi population.
... A number of factors including physical inactivity, poor diet, rapid urbanisation and ageing contribute to the high incidence of diabetes in Ghana [7]. Besides these factors, T2DM has a strong genetic predisposition, taking the combination of inequalities across different populations, familial aggregation, and concordance among monozygotic twins [8,9]. Specifically, in T2DM, these factors are closely related to the metabolic abnormalities that underline the conditions of impaired insulin action, obesity, increased endogenous glucose output, and insulin secretory dysfunction [10]. ...
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Type-2 diabetes mellitus (T2DM) have been strongly associated with single nucleotide polymorphisms (SNPs) in the TCF7L2 gene. This study investigated the association between rs12255372, rs7903146 and T2DM in a Ghanaian population. A case-control study design was used for this study. A total of 106 T2DM patients and 110 control participants were selected. Basic data collected included body mass index, blood pressure and socio-demographics. Fasting blood samples were collected and used for serum lipid analysis, HbA1c, plasma glucose estimation and DNA extraction. Common and allele-specific primers were designed for genotyping using the Modified Tetra-Primer Amplification assay. Associations were evaluated using logistic regression models. The rs7903146 risk variant was significantly associated with 2.16 vs 4.06 increased odds for T2DM in patients
... T2D is often associated with a strong genetic predisposition, with a heritability ranging from 30-70% [99]. People with a first-degree family member with T2D have five to ten times greater lifetime risk for T2D as compared with those having no family history of T2D [100]. ...
Thesis
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\Participants in Healthy Life Centres presumptions for lifestyle change- preventing overweight, obesity and type 2 diabetes in the Norwegian Primary Health Care.
... First-degree relatives of patients with diabetes are at increased risk of developing this disorder or having adverse metabolic outcomes compared with those with no FH of diabetes. [25][26][27][28] This is also the case for second-degree relatives of patients with diabetes. 29,30 First-degree relatives of patients with PCOS have a high risk of diabetes and glucose intolerance. ...
Article
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Objective We aimed to investigate whether patients with polycystic ovary syndrome (PCOS) and a family history (FH) of type 2 diabetes mellitus (T2DM) are at increased risk of endocrinological and metabolic abnormalities, and whether this risk differs between first-degree and second-degree relatives, and between maternal and paternal transmission. Methods A total of 680 patients with PCOS were enrolled in this retrospective, single-center study. Endocrine and glycolipid metabolism parameters were compared. Results The free androgen index (FAI), and levels of fasting blood glucose (FBG), fasting insulin (FINS), homeostatic model assessment-insulin resistance (HOMA-IR), total cholesterol (TC), and low-density lipoprotein cholesterol were significantly higher, whereas sex hormone binding globulin (SHBG) levels were significantly lower in patients with PCOS and a FH of T2DM. In patients with PCOS with a FH of T2DM in first-degree relatives, age and levels of FBG, FINS, and HOMA-IR were significantly higher than those who had a FH of T2DM in second-degree relatives. A maternal history of T2DM was associated with a higher body mass index, FAI, and TG levels, and lower SHBG levels. Conclusions Patients with PCOS and a FH of T2DM have more severe hyperandrogenism and metabolic disorders, especially in those with maternal transmission.
... Despite T2D having an important genetic component [3][4][5], the recent rise in T2D cases can be mostly attributed to the increase in obesity and lack of physical activity; both being insulin resistance-promoting states [1,2]. Moreover, central (or visceral) adiposity is better linked to insulin resistance and plasma levels of glucose, insulin, cholesterol, triglycerides and high-density lipoprotein cholesterol than total adiposity. ...
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A high caloric intake, rich in saturated fats, greatly contributes to the development of obesity, which is the leading risk factor for type 2 diabetes (T2D). A persistent caloric surplus increases plasma levels of fatty acids (FAs), especially saturated ones, which were shown to negatively impact pancreatic β-cell function and survival in a process called lipotoxicity. Lipotoxicity in β- cells activates different stress pathways, culminating in β-cells dysfunction and death. Among all stresses, endoplasmic reticulum (ER) stress and oxidative stress have been shown to be strongly correlated. One main source of oxidative stress in pancreatic β-cells appears to be the reactive oxygen species producer NADPH oxidase (NOX) enzyme, which has a role in the glucose-stimulated insulin secretion and in the β-cell demise during both T1 and T2D. In this review, we focus on the acute and chronic effects of FAs and the lipotoxicity-induced β-cell failure during T2D development, with special emphasis on the oxidative stress induced by NOX, the ER stress, and the crosstalk between NOX and ER stress.
... Familial aggregation (Meigs et al., 2000), ethnic differences (Kodama et al., 2013), and higher concordance rate of T2DM in monozygotic than in dizygotic twins (Poulsen et al., 1999) all indicate genetic contribution to T2DM. In the early 2000s, peroxisome proliferator-activated receptor gamma (PPARG) (Altshuler et al., 2000) and transcription factor 7-like 2 (TCF7L2) (Grant et al., 2006) were confirmed to be associated with T2DM via linkage analyses and candidate approaches. ...
Article
Metabolic diseases including type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), and metabolic syndrome (MetS) are alarming health burdens around the world, while therapies for these diseases are far from satisfying as their etiologies are not completely clear yet. T2DM, NAFLD, and MetS are all complex and multifactorial metabolic disorders based on the interactions between genetics and environment. Omics studies such as genetics, transcriptomics, epigenetics, proteomics, and metabolomics are all promising approaches in accurately characterizing these diseases. And the most effective treatments for individuals can be achieved via omics pathways, which is the theme of precision medicine. In this review, we summarized the multi-omics studies of T2DM, NAFLD, and MetS in recent years, provided a theoretical basis for their pathogenesis and the effective prevention and treatment, and highlighted the biomarkers and future strategies for precision medicine.
... Despite the study's success in discovering variants that have an association with T2DM risk, it was limited in that a study of disease risk based exclusively on specific populations was still required [7]. Heritability of T2DM is reported to be about 20%-80% from progeny or twin studies [8,9], but T2DM genetic risk is not always inherited, and is well-known as "missing heritability". Gene-environment and gene-gene interaction might contribute to missing heritability of T2DM [10,11]. ...
Article
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Background Adenosine monophosphate (AMP)-activated protein kinase (AMPK; EC 2.7.11.31) enzymes play a pivotal role in cell metabolism. They are involved in type 2 diabetes mellitus (T2DM) pathogenesis. Genetic variation of PRKAA2 coding for the AMPK α2 catalytic subunit (AMPKα2) is reported to be associated with susceptibility for T2DM. Objectives To determine the association between PRKAA2 genetic variations (rs2796498, rs9803799, and rs2746342) with clinical characteristics in patients newly diagnosed with T2DM. Methods We performed a cross-sectional study including 166 T2DM patients from 10 primary health care centers in Yogyakarta, Indonesia. We measured fasting plasma glucose, hemoglobin A1c, serum creatinine, glomerular filtration rate, blood pressure, and body mass index as clinical characteristics. PRKAA2 genetic variations were determined by TaqMan SNP genotyping assay. Hardy–Weinberg equilibrium was calculated using χ ² tests. Results There was no difference in clinical characteristics for genotypes rs2796498, rs9803799, or rs2746342 ( P > 0.05). No significant association was found between PRKAA2 genetic variations and any clinical feature observed. Further subgroup analysis adjusting for age, sex, and waist circumference did not detect any significant association of PRKAA2 genetic variations with clinical characteristics ( P > 0.05). Conclusion PRKAA2 genetic variation is not associated with the clinical characteristics of Indonesian patients with newly diagnosed T2DM.
... People with a family history of diabetes have a much higher risk of disease development (142)(143)(144)(145)(146). However, genetic linkage can account for only a small percentage of diabetes cases associated with family history. ...
Article
Pancreatic beta cells play a central role in regulating glucose homeostasis by secreting the hormone insulin. Failure of beta cells due to reduced function and mass and the resulting insulin insufficiency can drive the dysregulation of glycemic control, causing diabetes. Epigenetic regulation by DNA methylation is central to shaping the gene expression patterns that define the fully functional beta cell phenotype and regulate beta cell growth. Establishment of stage-specific DNA methylation guides beta cell differentiation during fetal development, while faithful restoration of these signatures during DNA replication ensures the maintenance of beta cell identity and function in postnatal life. Lineage-specific transcription factor networks interact with methylated DNA at specific genomic regions to enhance the regulatory specificity and ensure the stability of gene expression patterns. Recent genome-wide DNA methylation profiling studies comparing islets from diabetic and non-diabetic human subjects demonstrate the perturbation of beta cell DNA methylation patterns, corresponding to the dysregulation of gene expression associated with mature beta cell state in diabetes. This article will discuss the molecular underpinnings of shaping the islet DNA methylation landscape, its mechanistic role in the specification and maintenance of the functional beta cell phenotype, and its dysregulation in diabetes. We will also review recent advances in utilizing beta cell specific DNA methylation patterns for the development of biomarkers for diabetes, and targeting DNA methylation to develop translational approaches for supplementing the functional beta cell mass deficit in diabetes.
... Studies aimed at exploring the genetic architecture of T2D revealed that it results from a strong hereditary component influenced by environmental exposures experienced throughout the lifespan; in addition, epigenetic factors might play an important role [23]. T2D hereditability ranges from 20% to 80% as estimated from population, family and twin-based studies [24,25]. Different approaches have been employed to identify T2D risk genes throughout the years. ...
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Diabetes mellitus is a heterogeneous disease characterized by hyperglycemia due to impaired insulin secretion and/or action. All diabetes types have a strong genetic component. The most frequent forms, type 1 diabetes (T1D), type 2 diabetes (T2D) and gestational diabetes mellitus (GDM), are multifactorial syndromes associated with several genes' effects together with environmental factors. Conversely, rare forms, neonatal diabetes mellitus (NDM) and maturity onset diabetes of the young (MODY), are caused by mutations in single genes. Large scale genome screenings led to the identification of hundreds of putative causative genes for multigenic diabetes, but all the loci identified so far explain only a small proportion of heritability. Nevertheless, several recent studies allowed not only the identification of some genes as causative, but also as putative targets of new drugs. Although monogenic forms of diabetes are the most suited to perform a precision approach and allow an accurate diagnosis, at least 80% of all monogenic cases remain still undiag-nosed. The knowledge acquired so far addresses the future work towards a study more focused on the identification of diabetes causal variants; this aim will be reached only by combining expertise from different areas. In this perspective, model organism research is crucial. This review traces an overview of the genetics of diabetes and mainly focuses on Drosophila as a model system, describing how flies can contribute to diabetes knowledge advancement.
... It has been reported that subjects withT2DM-affected siblings have a two-to three fold increased risk of developing T2DM compared with the general population [4]. Having one parent with diabetes increases the risk of developing T2DM by 30-40%, and having two parents with diabetes increases the risk to 70% [5]. Furthermore, some research reported that genetic polymorphisms in candidate genes could influence the formation and course of T2DM [6,7]. ...
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Background Diabetes mellitus (DM) is a complex metabolic disease that is caused by a complex interplay between genetic and environmental factors. This research aimed to investigate the association of genetic polymorphisms in PDX1 and MC4R with T2DM risk. Methods The genotypes of 10 selected SNPs in PDX1 and MC4R were identified using the Agena MassARRAY platform. We utilized odds ratio (OR) and 95% confidence intervals (CIs) to assess the correlation between genetic polymorphisms and T2DM risk. Results We found that PDX1-rs9581943 decreased susceptibility to T2DM among in a Chinese Han population (OR = 0.76, p = 0.045). We also found that selected genetic polymorphisms in PDX1 and MC4R could modify the risk of T2DM, which might also be influenced by age, sex, BMI, smoking status, and drinking status (p < 0.05). Conclusions We concluded that PDX1 and MC4R genetic variants were significantly associated with T2DM risk in a Chinese Han population. These single polymorphic markers may be considered to be new targets in the assessment and prevention of T2DM among Chinese Han people.
... A number of factors including physical inactivity, poor diet, rapid urbanisation and ageing contribute to the high incidence of diabetes in Ghana [7]. Besides these factors, T2DM has a strong genetic predisposition, taking the combination of inequalities across different populations, familial aggregation, and concordance among monozygotic twins [8,9]. Specifically, in T2DM, these factors are closely related to the metabolic abnormalities that underline the conditions of impaired insulin action, obesity, increased endogenous glucose output, and insulin secretory dysfunction [10]. ...
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Type 2 diabetes mellitus (T2DM) has been strongly associated with single nucleotide poly-morphisms (SNPs) in the TCF7L2 gene. This study investigated the association between rs12255372, rs7903146 in the TCF7L2 gene and T2DM in a Ghanaian population. A case-control study design was used for this study. A total of 106 T2DM patients and 110 control participants were selected. Basic data collected included body mass index, blood pressure and socio-demographics. Fasting blood samples were collected and processed for: serum lipid analysis, plasma glucose estimation and plasma HbA1c estimation. Parts of the whole blood samples were used for DNA extraction using a modified salting-out method. Common and allele-specific primers were designed for genotyping using the Modified Tetra-Primer Amplification assay. Associations were evaluated using logistic regression models. The rs7903146 risk variant was significantly associated with 2.16 vs. 4.06 increased odds for T2DM in patients <60 years vs. ≥60 years. Both rs7903146 and rs12255372 were significantly associated with increased odds of T2DM in women, overweight/obese, T2DM negative family history (T2DM-NFH) and low-HDL-C. In a multivariate model, rs7903146 but not rs12255372 was significantly associated with 2.18, 5.01 and 2.25 increased odds of T2DM, under the codominant, recessive and additive model, respectively (p < 0.05). The association between rs7903146 and rs12255372 with T2DM is more highly associated in a subgroup-women and those with T2DM-NFH, yet who have cardiometabolic risk.
... 1,5-8 Erasmus et al. found that there was a significant maternal aggregation with 64.7% of patients having a diabetic mother compared with 27% who had a diabetic father (p < 0.01). 1 However, those with a combined maternal and paternal FHD are seen to have a greater risk where the combined risk equals the sum when either parent is affected. 12 Glycaemic control in PLWD and HIV (PLWDH) has been shown to be suboptimal. [13][14][15] This can occur in those who are antiretroviral therapy (ART) naive, those on ART, as well as in those with a lower cluster of differentiation (CD4) level < 200 cell/μl. ...
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Background: Type 2 diabetes mellitus (T2DM) is a familial condition with a strong genetic component. International studies have highlighted associations between a positive family history of diabetes (FHD) and poorer glycaemic control. No current data are available on this association within the context of HIV. Objectives: To determine a relationship between FHD and glycaemic control in patients living with DM (PLWD) in an HIV endemic area. Methods: Standardised clinic sheets were used from the DM clinic at Edendale Hospital, Pietermaritzburg, South Africa, from January 1, 2019 to December 31, 2019. Statistical analysis was done. Results: This study had 957 patients living with diabetes (PLWD); 498 (52.2%) had a positive FHD while 456 (47.8%) had no FHD. There were 146 (15.3%) HIV-infected patients; with 84 (57.5%) on a fixed dose combination (FDC) of anti-retroviral treatment (ART). Patients aged between 18 and 30 with a maternal FHD had significantly higher mean HbA1c levels than those without a maternal FHD (HbA1c: 10.80% vs. 9.72%, p = 0.025). Patients living with type 1 DM (PLWT1DM) in the HIV-uninfected cohort had significantly higher HbA1c levels than patients living with type 2 DM (PLWT2DM) (10.38% vs. 9.46%, p = 0.002). HIV-infected PLWD (PLWDH) on a FDC with a positive FHD had significantly higher HbA1c levels than those without a FHD (9.52% vs. 8.52%, p = 0.04). PLWDH with a positive maternal FHD on an FDC had increased HbA1c levels (9.81% vs. 8.55%, p = 0.009). Conclusion: Genes significantly affect glycaemic control among PLWD. PLWT1DM and PLWDH with a positive FHD (especially a maternal FHD) should be regarded as being in a higher risk category requiring more intensive lifestyle and therapeutic intervention to achieve optimal diabetes control. Our study suggests that a positive FHD affects glycaemia in PLWT1DM as significantly, if not more, than in PLWT2DM and recommends screening for a FHD to be incorporated in the comprehensive management of DM.
... A growth rate this high makes diabetes mellitus one of the most significant health challenges of the 21st century, with type II diabetes mellitus (T2DM) being the fastest growing chronic disorder worldwide (25). Type 2 diabetes is characterized by persistent hyperglycaemia (26) and can be attributed to multifactorial integrating factors such as genetics (27), age, socioeconomic status, education (28), as well as, modifiable risk factors including diet (29), smoking (30), and levels of physical activity (31). ...
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is the most common cause of dementia. Over a third of dementia cases are estimated to be due to potentially modifiable risk factors, thus offering opportunities for both identification of those most likely to be in early disease as well as secondary prevention. Diabetes, hypertension and chronic kidney failure have all been linked to increased risk for AD and dementia and through their high prevalence are particularly apt targets for initiatives to reduce burden of AD. This can take place through targeted interventions of cardiovascular risk factors (shown to improve cognitive outcomes) or novel disease modifying treatments in people with confirmed AD pathology. The success of this approach to secondary prevention depends on the availability of inexpensive and scalable methods for detecting preclinical and prodromal dementia states. Developments in blood-based biomarkers for Alzheimer's disease are rapidly becoming a viable such method for monitoring large at-risk groups. In addition, digital technologies for remote monitoring of cognitive and behavioral changes can add clinically relevant data to further improve personalisation of prevention strategies. This review sets the scene for this approach to secondary care of dementia through a review of the evidence for cardiovascular risk factors (diabetes, hypertension and chronic kidney disease) as major risk factors for AD. We then summarize the developments in blood-based and cognitive biomarkers that allow the detection of pathological states at the earliest possible stage. We propose that at-risk cohorts should be created based on the interaction between cardiovascular and constitutional risk factors. These cohorts can then be monitored effectively using a combination of blood-based biomarkers and digital technologies. We argue that this strategy allows for both risk factor reduction-based prevention programmes as well as for optimisation of any benefits offered by current and future disease modifying treatment through rapid identification of individuals most likely to benefit from them.
... Family history of type 2 diabetes (T2D) increases the risk of developing diabetes up to 10-fold but the molecular causes of this susceptibility are only partially understood. [1][2][3][4] Genomewide association studies (GWAS) have identified hundreds of genetic variants associated with the risk of T2D or related glycemic traits. 5 Cluster analysis of physiologic traits, including fasting glucose, fasting insulin, homeostatic model assessments of beta cells function (HOMA-B) and of insulin resistance (HOMA-IR), and T2D loci have also revealed that the majority of these variants affect beta-cell function, though some clearly impact insulin resistance. ...
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First-degree relatives (FDRs) of type 2 diabetics (T2D) feature dysfunction of subcutaneous adipose tissue (SAT) long before T2D onset. miRNAs have a role in adipocyte precursor cells (APC) differentiation and in adipocyte identity. Thus, impaired miRNA expression may contribute to SAT dysfunction in FDRs. In the present work, we have explored changes in miRNA expression associated with T2D family history which may affect gene expression in SAT APCs from FDRs. Small RNA-seq was performed in APCs from healthy FDRs and matched controls and omics data were validated by qPCR. Integrative analyses of APC miRNome and transcriptome from FDRs revealed down-regulated hsa-miR-23a-5p, -193a-5p and -193b-5p accompanied by up-regulated Insulin-like Growth Factor 2 (IGF2) gene which proved to be their direct target. The expression changes in these marks were associated with SAT adipocyte hypertrophy in FDRs. APCs from FDRs further demonstrated reduced capability to differentiate into adipocytes. Treatment with IGF2 protein decreased APC adipogenesis, while over-expression of hsa-miR-23a-5p, -193a-5p and -193b-5p enhanced adipogenesis by IGF2 targeting. Indeed, IGF2 increased the Wnt Family Member 10B gene expression in APCs. Down-regulation of the three miRNAs and IGF2 up-regulation was also observed in Peripheral Blood Leukocytes (PBLs) from FDRs. In conclusion, APCs from FDRs feature a specific miRNA/gene profile, which associates with SAT adipocyte hypertrophy and appears to contribute to impaired adipogenesis. PBL detection of this profile may help in identifying adipocyte hypertrophy in individuals at high risk of T2D.
... On the other hand, when a parent has T2DM, then the offspring has a 40% chance of getting diabetes. Moreover, the chances become 70%, when both parents have diabetes (Meigs et al., 2000). Many studies of twins show that genetic causes are responsible for diabetes. ...
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Diabetes is a global health concern that has affected almost 415 million people globally. Bromocriptine is a dopamine D2 agonist, which is a Food and Drug Administration (FDA)–approved drug to treat type 2 diabetes mellitus (T2DM) patients. However, it is considered that a novel treatment therapy is required which can be used in the treatment of diabetes with or without other antidiabetic agents. Dopamine agonists are usually used in neurological disorders like Parkinson’s disease (PD), restless leg syndrome, and hyperprolactinemia. However, dopamine agonists including bromocriptine and cabergoline are also effective in reducing the glycemic level in T2DM patients. Bromocriptine was formerly used for the treatment of PD, hyperprolactinemia, and restless leg syndrome, but now it is used for improving glycemic levels as well as reducing free fatty acids and triglycerides. In addition, cabergoline has been found to be effective in glycemic control, but this drug is yet to be approved by the FDA due to its limitations and lack of study. Findings of the clinical trials of bromocriptine have suggested that it reduces almost 0.4–0.8% glycated hemoglobin and cardiovascular risk by 40% in insulin-resistant patients. Moreover, the safe use of bromocriptine in obese T2DM patients makes it a more attractive option as it causes weight loss. Indeed, bromocriptine is a novel therapy for T2DM patients, as its mechanism of action is unique in T2DM patients with minimal adverse effects. This review summarizes the potential of dopamine agonists in the treatment of T2DM.
... Despite the fact that environmental factors such as high-calorie diet and lack of exercise play a role in T2D, genetic factors are a major determinant for the development of the disorder [3]. Heritability estimates for T2D and its key components are high, with some estimates exceeding 50% [4,5]. Only a small subset of type 2 diabetic cases are caused by monogenic mutants observable as Mendelian traits segregating in families. ...
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Dyslipidemia is considered a risk factor for type 2 diabetes (T2D), yet studies with statins and candidate genes suggest that circulating lipids may protect against T2D development. Apoe-null (Apoe-/-) mouse strains develop spontaneous dyslipidemia and exhibit a wide variation in susceptibility to diet-induced T2D. We thus used Apoe-/- mice to elucidate phenotypic and genetic relationships of circulating lipids with T2D. A male F2 cohort was generated from an intercross between LP/J and BALB/cJ Apoe-/- mice and fed 12 weeks of a Western diet. Fasting, non-fasting plasma glucose, and lipid levels were measured and genotyping was performed using miniMUGA arrays. We uncovered a major QTL near 60 Mb on chromosome 15, Nhdlq18, which affected non-HDL cholesterol and triglyceride levels under both fasting and non-fasting states. This QTL was coincident with Bglu20, a QTL that modulates fasting and non-fasting glucose levels. The plasma levels of non-HDL cholesterol and triglycerides were closely correlated with the plasma glucose levels in F2 mice. Bglu20 disappeared after adjustment for non-HDL cholesterol or triglycerides. These results demonstrate a causative role for dyslipidemia in T2D development in mice.
... An RCT involving older adults at high risk for ischemic stroke revealed that 12 weeks of tai chi training significantly reduced FBG levels compared to the usual physical activity (control group) (n = 170) [31], suggesting that tai chi training provides sufficient improvements in glycemic control of elderly people at high risk for ischemic stroke. Genetic predisposition has been considered one of the major risk factors for diabetes [38][39][40][41][42]. In fact, an RCT on non-diabetic offspring whose parents have diabetes found that 8 weeks of yoga significantly reduced FPG levels, oral glucose tolerance test post-2 h glucose levels, fasting insulin levels, and insulin resistance, whereas the control group showed no significant changes (n = 57) [32]. ...
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Recent findings suggest a correlation between COVID-19 and diabetes, although the underlying causes are still little understood. COVID-19 infection tends to induce severe symptoms in patients with underlying diabetes, increasing their mortality rate. Moreover, COVID-19 itself appears to be a diabetogenic factor. In addition, mental health conditions, such as depression due to lockdown and anxiety about infection, were found to affect glycemic control and immunity, highlighting the importance of mental health care during the pandemic. Mind–Body Intervention (MBI), which includes meditation, yoga, and qigong, has emerged as a tool for mental health management due to its effects on stress reduction and the promotion of mental and physical well-being. Here, we review the latest randomized controlled trials to determine the effects of MBI on glycemic control and the immune system and discuss the underlying mechanisms by which MBI facilitates the virtuous cycle of stress management, glycemic control, and immune modulation. Furthermore, we examine the actual utilization of MBI during the COVID-19 pandemic era through recent studies. With proper online education, non-pharmacological MBI may be more widely used as an important tool for self-health care that complements the usual treatment of COVID-19 patients and survivors.
... A family history (FH) of diabetes or a first-degree relative with diabetes (FH1) are risk factors for developing non-diabetic hyperglycemia or diabetes [14][15][16], and the risk is reportedly higher for among individuals with FH1 than among those with a second-degree relative with diabetes (FH2) [17]. The risk is also reportedly higher for among individuals with a mother who has diabetes than for among those with a father who has diabetes [18][19][20]. PG levels after glucose loading are higher, and insulin secretion and sensitivity indices are lower among individuals with more than one FH1 or FH2 [21]. Such findings reports suggest that an FH involving more than one relative is associated with lower insulin secretion and sensitivity and raises the risk of for diabetes. ...
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Aims The present study aimed to clarify the relationships between diabetic family history (FH), and dysglycemic response to the oral glucose tolerance test (OGTT), insulin secretion, and insulin sensitivity in young Japanese persons with normal glucose tolerance (NGT). Methods We measured plasma glucose (PG) and immunoreactive insulin levels in 1,309 young Japanese persons (age <40 years) with NGT before and at 30, 60, and 120 min during a 75-g OGTT. Dysglycemia during OGTT was analyzed by k-means clustering analysis. Body mass index (BMI), blood pressure (BP), and lipids were measured. Insulin secretion and sensitivity indices were calculated. Results PG levels during OGTT were classified by k-means clustering analysis into three groups with stepwise decreases in glucose tolerance even among individuals with NGT. In these clusters, proportion of males, BMI, BP and frequency of FH were higher, and lipid levels were worse, together with decreasing glucose tolerance. Subjects with a diabetic FH showed increases in PG after glucose loading and decreases in insulinogenic index and Matsuda index. Conclusions Dysglycemic response to OGTT by k-means clustering analysis was associated with FH in young Japanese persons with NGT. FH was also associated with post-loading glucose, insulinogenic index, and Matsuda index.
... 18 The chances of diabetes escalate by 40% if one parent has diabetes and by 70% if both parents have diabetes. 19 Genetic studies hold great promise in predicting an individual's disease risk, exploring disease molecular pathways, and selecting treatment therapy as per individual-specific biology. 20 To date, genetic studies have provided plentiful information on the pathogenesis of T2DM. ...
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Objective. Recent GWAS largely conducted in European populations have successfully identified multiple genetic risk variants associated with Type 2 Diabetes Mellitus (T2DM). However, the effects conferred by these variants in the Pakistani population have not yet been fully elucidated. The objective of this study was to examine European GWAS-identified T2DM risk variants in the Pakistani Pashtun population to better understand the shared genetic basis of T2DM in the European and Pakistani cohorts. Methodology. A total of 100 T2DM patients and 100 healthy volunteers of Pashtun ethnicity were enrolled in this study. Both groups were genotyped for 8 selected single nucleotide polymorphisms (SNPs) using the Sequenom MassARRAY ® platform. The association between selected SNPs and T2DM was determined by using appropriate statistical tests. Results. Of the 8 studied SNPs, 5 SNPs, SLC30A8/ rs13266634 (p=0.031, OR=2.13), IGF2BP2/ rs4402960 (p=0.001, OR=3.01), KCNJ11/ rs5219 (p=0.042, OR=1.78), PPARG/ rs1801282 (p=0.042, OR=2.81) and TCF7L2/ rs7903146 (p=0.00006, 3.41) had significant association with T2DM. SNP GLIS3/ rs7041847 (p=0.051, OR=2.01) showed no sufficient evidence of association. SNPs KCNQ1/ rs2237892 (p=0.140, OR=1.61) and HHEX/IDE/ s1111875 (p=0.112, OR=1.31) showed opposite allelic effects and were not validated for T2DM risk in the study population. Among the studied SNPs, TCF7L2/ rs7903146 showed the most significant association. Conclusion. Our study finding indicates that selected genome-wide significant T2DM risk variants previously identified in European descent also increase the risk of developing T2DM in the Pakistani Pashtun population
... Type 2 diabetes (T2D) is a global epidemic that affects more than 463 million people and is a leading cause of morbidity and mortality worldwide. Family-based studies have shown that T2D is highly heritable, with an estimated heritability range of 20%-80% (1,2). Currently, worldwide prevalent unhealthy lifestyles (especially TV watching and breakfast skipping) are also considered to be the key contributors to T2D. ...
Article
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Background Epidemiological investigations have established unhealthy lifestyles, such as excessive leisurely sedentary behavior (especially TV/television watching) and breakfast skipping, increase the risk of type 2 diabetes (T2D), but the causal relationship is unclear. We aimed to understand how single nucleotide variants contribute to the co-occurrence of unhealthy lifestyles and T2D, thereby providing meaningful insights into disease mechanisms. Methods Combining summary statistics from genome-wide association studies (GWAS) on TV watching ( N = 422218), breakfast skipping ( N = 193860) and T2D ( N = 159208) in European pedigrees, we conducted comprehensive pairwise genetic analysis, including high-definition likelihood (HDL-method), cross-phenotype association studies (CPASSOC), GWAS-eQTL colocalization analysis and transcriptome-wide association studies (TWAS), to understand the genetic overlap between them. We also performed bidirectional two-sample Mendelian randomization (MR) analysis for causal inference using genetic instrumental variables, and two-step MR mediation analysis was used to assess any effects explained by body mass index, lipid traits and glycemic traits. Results HDL-method showed that T2D shared a strong genetic correlation with TV watching ( r g = 0.26; P = 1.63×10 ⁻²⁹ ) and skipping breakfast ( r g = 0.15; P =2.02×10 ⁻⁶ ). CPASSOC identifies eight independent SNPs shared between T2D and TV watching, including one novel shared locus. TWAS and CPASSOC showed that shared genes were enriched in lung, esophageal, adipose, and thyroid tissues and highlighted potential shared regulatory pathways for lipoprotein metabolism, pancreatic β-cell function, cellular senescence and multi-mediator factors. MR showed TV watching had a causal effect on T2D (β IVW = 0.629, P IVW = 1.80×10 ⁻¹⁰ ), but no significant results were observed between breakfast skipping and T2D. Mediation analysis provided evidence that body mass index, fasting glucose, hemoglobin A1c and high-density lipoprotein are potential factors that mediate the causal relationship between TV and T2D. Conclusions Our findings provide strong evidence of shared genetics and causation between TV watching and T2D and facilitate our identification of common genetic architectures shared between them.
... While over 700 loci identified by common variant association studies (i.e., GWAS) combine to explain almost 20% of T2D heritability [19•], each individual common variant (i.e., SNP) has a small to modest effect (10-30%) on disease risk as compared to simply knowing family history of T2D, which if present in a parent confers a large increase in risk (~ two-threefold) [23]. Combining multiple variants genotyped in a single person into a genetic risk score (GRS, also commonly referred to as polygenic risk score) is a logical strategy to enhance the clinical utility of genetic information from common variants to identify individuals at high risk [24]. ...
Article
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Purpose of Review Type 2 diabetes (T2D) is a multifactorial, heritable syndrome characterized by dysregulated glucose homeostasis that results from impaired insulin secretion and insulin resistance. Genetic association studies have successfully identified hundreds of T2D risk loci implicating many genes in disease pathogenesis. In this review, we provide an overview of the recent T2D genetic studies from the past 3 years with particular focus on the effects of sample size and ancestral diversity on genetic discovery as well as discuss recent work on the use and limitations of genetic risk scores (GRS) for T2D risk prediction. Recent Findings Recent large-scale, multi-ancestry genetic studies of T2D have identified over 500 novel risk loci. The genetic variants (i.e., single nucleotide polymorphisms (SNPs)) marking these novel loci in general have smaller effect sizes than previously discovered loci. Inclusion of samples from diverse ancestral backgrounds shows a few ancestry specific loci marked by common variants, but overall, the majority of loci discovered are common across ancestries. Inclusion of common variant GRS, even with hundreds of loci, does not substantially increase T2D risk prediction over standard clinical risk factors such as age and family history. Summary Common variant association studies of T2D have now identified over 700 T2D risk loci, half of which have been discovered in the past 3 years. These recent studies demonstrate that inclusion of ancestrally diverse samples can enhance locus discovery and improve accuracy of GRS for T2D risk prediction. GRS based on common variants, however, only minimally enhances risk prediction over standard clinical risk factors.
... 3.5 (2.3-5.2), and 6.1 (2.9-13.0), respectively (2). Progress in genome-wide association study (GWAS) and global collaborations in the field of genome projects have enabled the identification of 243 new candidate loci associated with susceptibility to T2DM from 32 European-descent GWAS, including 74,124 T2DM cases (3). ...
Article
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Hundreds of research and review articles concerning genome-wide association study (GWAS) in diabetes have been published in the last two decades. We aimed to evaluate the hotspots and future trends in GWAS in diabetes research through bibliometric analysis. Accordingly, 567 research and review articles published between 2001 and 2021 were included. A rising trend was noted in the annual number of publications and citations on GWAS in diabetes during this period. Harvard University and Harvard Medical School have played leading roles in genome research. Hotspot analyses indicated that DNA methylation and genetic variation, especially in type 2 diabetes mellitus, are likely to remain the research hotspots. Moreover, the identification of genetic phenotypes associated with adiposity, metabolic memory, pancreatic islet, and inflammation is the leading trend in this research field. Through this review, we provide predictions on the main research trends in the future so as to shed light on new directions and ideas for further investigations on the genetic etiology of diabetes for its prevention and treatment.
... Generally, patients with type 2 diabetes do not need treatment if they lose weight or stop eating ( 6 ) Type 2 diabetes affected more than 70% in Libya which is the highest prevalence in North Africa and among Arabic nations (7). The association between family history of diabetes and risk for the disease has been well documented as an important factor in the onset and manifestation of type 2 diabetes (8)(9)(10)(11). However, there are very few studies on the prevalence the rates of complications of diabetes 2 diabetes in Libya. ...
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Diabetes is a complex condition with several types and no clear cause, genetic factors can make some people more vulnerable to some types of diabetes. This study was aimed to determine complications of diabetes type 2 in the elderly, and the relationship of the disease to heredity. 185 adult patients (110 male; 75 female; age range, 45-89 years), a multi-were centered randomized trial of type 2 diabetes patients. The highest cause of diabetes was found with family history (70.3%), followed by advanced age (63.2%), obesity and inactivity (44.3%), psychological stress (37.3%), smoking (27.6%), Fast food (17.8%) and frequent intake of sugars (13.0%). As for complications arising from diabetes, the most common were retinopathy (56.80%), followed by nephropathy (48.10%), heart disease (43.20%), and decreased sense of the hand and feet (28.10%). The elderly citizens must raise awareness of the seriousness of diabetes complications, and urge them to reduce sugar intake, and everyone who has a family history should reduce their intake of sugars so that they do not develop diabetes.
... The heritability of diabetes is estimated at 20-80% [61,62]. However, only 5-15% of this heritability has been explained [63]. ...
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Background: Type 2 diabetes mellitus (T2DM) is caused by a combination of environmental, genetic, and epigenetic factors including, fasting blood glucose (FBG), genetic variant rs841853, and cg19693031 methylation. We evaluated the interaction between rs841853 and cg19693031 on the FBG levels of non-diabetic Taiwanese adults. Methods: We used Taiwan Biobank (TWB) data collected between 2008 and 2016. The TWB data source contains information on basic demographics, personal lifestyles, medical history, methylation, and genotype. The study participants included 1300 people with DNA methylation data. The association of cg19693031 methylation (stratified into quartiles) with rs841853 and FBG was determined using multiple linear regression analysis. The beta-coefficients (β) and p-values were estimated. Results: The mean ± standard deviation (SD) of FBG in rs841853-CC individuals (92.07 ± 7.78) did not differ significantly from that in the CA + AA individuals (91.62 ± 7.14). However, the cg19693031 methylation levels were significantly different in the two groups (0.7716 ± 0.05 in CC individuals and 0.7631 ± 0.05 in CA + AA individuals (p = 0.002). The cg19693031 methylation levels according to quartiles were β < 0.738592 (< Q1), 0.738592 ≤ 0.769992 (Q1-Q2), 0.769992 ≤ 0.800918 (Q2-Q3), and β ≥ 0.800918 (≥ Q3). FBG increased with decreasing cg19693031 methylation levels in a dose-response manner (ptrend = 0.005). The β-coefficient was - 0.0236 (p = 0.965) for Q2-Q3, 1.0317 (p = 0.058) for Q1-Q2, and 1.3336 (p = 0.019 for < Q1 compared to the reference quartile (≥ Q3). The genetic variant rs841853 was not significantly associated with FBG. However, its interaction with cg19693031 methylation was significant (p-value = 0.036). Based on stratification by rs841853 genotypes, only the CC group retained the inverse and dose-response association between FBG and cg19693031 methylation. The β (p-value) was 0.8082 (0.255) for Q2-Q3, 1.6930 (0.022) for Q1-Q2, and 2.2190 (0.004) for < Q1 compared to the reference quartile (≥ Q3). The ptrend was 0.002. Conclusion: Summarily, methylation at cg19693031 was inversely associated with fasting blood glucose in a dose-dependent manner. The inverse association was more prominent in rs841853-CC individuals, suggesting that rs841853 could modulate the association between cg19693031 methylation and FBG. Our results suggest that genetic variants may be involved in epigenetic mechanisms associated with FBG, a hallmark of diabetes. Therefore, integrating genetic and epigenetic data may provide more insight into the early-onset of diabetes.
... 18 The chances of diabetes escalate by 40% if one parent has diabetes and by 70% if both parents have diabetes. 19 Genetic studies hold great promise in predicting an individual's disease risk, exploring disease molecular pathways, and selecting treatment therapy as per individual-specific biology. 20 To date, genetic studies have provided plentiful information on the pathogenesis of T2DM. ...
Article
Objective. Recent GWAS largely conducted in European populations have successfully identified multiple genetic risk variants associated with Type 2 Diabetes Mellitus (T2DM). However, the effects conferred by these variants in the Pakistani population have not yet been fully elucidated. The objective of this study was to examine European GWASidentified T2DM risk variants in the Pakistani Pashtun population to better understand the shared genetic basis of T2DM in the European and Pakistani cohorts. Methodology. A total of 100 T2DM patients and 100 healthy volunteers of Pashtun ethnicity were enrolled in this study. Both groups were genotyped for 8 selected single nucleotide polymorphisms (SNPs) using the Sequenom MassARRAY® platform. The association between selected SNPs and T2DM was determined by using appropriate statistical tests. Results. Of the 8 studied SNPs, 5 SNPs, SLC30A8/ rs13266634 (p=0.031, OR=2.13), IGF2BP2/ rs4402960 (p=0.001, OR=3.01), KCNJ11/ rs5219 (p=0.042, OR=1.78), PPARG/ rs1801282 (p=0.042, OR=2.81) and TCF7L2/ rs7903146 (p=0.00006, 3.41) had significant association with T2DM. SNP GLIS3/ rs7041847 (p=0.051, OR=2.01) showed no sufficient evidence of association. SNPs KCNQ1/ rs2237892 (p=0.140, OR=1.61) and HHEX/IDE/ s1111875 (p=0.112, OR=1.31) showed opposite allelic effects and were not validated for T2DM risk in the study population. Among the studied SNPs, TCF7L2/ rs7903146 showed the most significant association. Conclusion. Our study finding indicates that selected genome-wide significant T2DM risk variants previously identified in European descent also increase the risk of developing T2DM in the Pakistani Pashtun population
... Birinci derece akrabasında tip-2 DM olan kişilerin tip-2 DM'ye yakalanma olasılığı, ailesinde Tip-2 DM aile öyküsü olmayan bireylere oranla 2-3 kat daha fazladır. Her iki ebeveyninde de tip 2 DM olan kişilerin olmayanlara göre tip-2 DM'a yakalanma olasığı 5-6 kat daha fazladır (Meigs, Cupples & Wilson 2000;Scott & Langenberg, 2013). ...
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ÖZET Giriş: Diyabetin topluma ve toplumda yaşayan bireylere yükünü azaltmak için erken dönemde tanınması ve doğru şekilde tedavi edilmesi gerekir. Bu çalışma, Sağlık Hizmetleri Meslek Yüksekokulu öğrencilerinin diyabet risklerinin değerlendirilmesi amacıyla yapılmıştır. Materyal Metot: Tanımlayıcı olarak planlanan bu çalışma, bir devlet üniversitesinde Sağlık Hizmetleri Meslek Yüksekokulunda öğrenim görmekte olan 169 öğrenci ile gerçekleştirilmiştir. Araştırma verileri Finlandiya Diyabet Risk Anketi (FINDRISK) ile toplandı. Verilerin analizi, SPSS 18.0 paket programında tanımlayıcı istatistikler, ki-kare, Pearson Chi-Square, Fisher’s Exact testi kullanılarak değerlendirilmiştir. Değerlendirmede p<0,05 önemlilik düzeyi kabul edilmiştir. Çalışmada etik kurul ve kurum izni alınmıştır. Bulgular: Çalışmaya katılan öğrencilerin yaş ortalamasının 19,94±0,08, %50.9’unun kız öğrenci olduğu, %85.8’inin yurtta kaldığı belirlendi. Öğrencilerin ağırlık ortalaması 63,53±0,72 kg, boy ortalamaları 169,98±0,53 cm, beden kitle indeksi (BKI) ortalamaları 21,90±0,19 kg/m2 idi. Öğrencilerin BKI, bel çevresi, egzersiz yapma durumu, antihipertansif ilaç kullanma durumu, kan şekeri yüksekliği öyküsü, ailede diyabetli olma durumları ile 10 yıllık tip-2 DM risk skoru istatiksel olarak anlamlı bulunmuştur (p<0.05). Öğrencilerin FINDRISK puan ortalamaları 4,26±0,23 olup, % 83,4 ‘i düşük risk, % 16,6’sı hafif ve orta risk taşımaktadır. Sonuç ve Öneriler: Tip 2 diyabet riskinin belirlenmesinde, girişimsel olmayan FINDRISK tarama ölçeği kullanılabilir. Öğrencilere okul ortamında sağlıklı yiyecek temin etme ve fiziksel aktivite yapabilme olanaklarının sağlanması önerilmektedir. Anahtar Sözcükler: Öğrenci, Diyabet, FINDRISK, Risk faktörleri
... For that reason, heredity is an important element in the detection of individuals in high risk of diabetes and heart disease. [41][42][43] ...
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Melina Gade Sikjær,1,2 Allan Klitgaard,1,2 Ole Hilberg,1,2 Anders Løkke1,2 1Department of Medicine, Lillebaelt Hospital, Vejle, Denmark; 2Department of Regional Health Research, University of Southern Denmark, Odense, DenmarkCorrespondence: Melina Gade Sikjær, Department of Regional Health Research, University of Southern Denmark, J.B.Winsløws vej 19, 3, Odense, 5000, Denmark, Email melina.gade.sikjaer@rsyd.dkBackground: There is sparse literature on parental chronic obstructive pulmonary disease (COPD) as a risk factor for the development of COPD in adult offspring, and the impact on disease severity. We aimed to map the literature reporting on the prevalence of and/or association between parental COPD and COPD in offspring, and to evaluate whether or not the literature reports on the severity of COPD or other health-related outcomes in offspring with parental COPD.Methods: A systematic literature search in Embase and Ovid MEDLINE was performed in June 2021. Search terms revolved around COPD and predisposition.Results: Thirteen studies were identified: 10 case–control studies, two cross-sectional studies and one cohort study. Population size varied from 44 to 2668 offspring cases; the distribution of female cases varied from 5% to 80% and mean age ranged from 27 to 65. Nine studies used an antecedents approach and evaluated the prevalence of parental COPD in patients with COPD, which ranged from 19% to 58%. Four studies used a descendants approach, by identifying patients with COPD and subsequently evaluated prevalence of COPD in their offspring, and found a prevalence of 0% to 17%. Apart from one, all the studies found an increased odds ratio for COPD in individuals with parental COPD. Four studies reported on parental smoking history and nine studies reported on smoking history in offspring. Three studies evaluated the association between parental COPD and COPD-related outcomes in patients with COPD.Conclusion: This review indicates that parental COPD is associated with a higher risk of COPD in offspring. The literature is sparse, and we identified a knowledge gap on whether parental COPD is a risk factor for severe COPD and other health conditions in offspring.Keywords: COPD severity, disease predisposition, familial predisposition, family history
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Background: Diabetes mellitus (DM) is a major comorbidity in people living with HIV (PWH). Hyperglycemia below diabetic range defines pre-diabetes (pre-DM). We compared the progression from pre-DM to DM in PWH and people without HIV (PWOH). Methods: Fasting glucose (FG) was measured semi-annually in the MACS since 1999. Men with pre-DM (FG between 100-125 mg/dL, confirmed within a year by FG in the pre-DM range or HbA1c between 5.7-6.4%) were included. The first visit with pre-DM was the baseline visit. Incident DM was defined as FG ≥ 126 mg/dL, confirmed at a subsequent visit, or self-reported DM, or use of anti-DM medication. We used binomial transition models to compare the progression from pre-DM to DM by HIV serostatus, adjusted for age, number of previous pre-DM to DM transitions, ethnicity, body mass index (BMI), family history of DM, and hepatitis C virus (HCV) infection. Results: Between 1999 and 2019, 1584 men (793 PWH; 791 PWOH) with pre-DM were included. At baseline, PWH were younger (48 vs 51 years, p < 0.01), had lower BMI (26 vs 27), were more frequently non-white (47% vs 30%), and HCV-infected as per last measure (8% vs 4%) than PWOH (all p < 0.01). Over a median 12-year follow-up, 23% of participants developed DM. In adjusted analyses, the risk for incident DM was 40% [95% CI: 0% to 80%] higher among PWH than PWOH (p = 0.04). Conclusion: Among men with pre-DM, PWH had an increased risk of incident DM adjusted for competing risk factors, warranting the evaluation of DM prevention strategies.
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During the last two decades, there have been several reports of an increasing incidence of type 2 diabetes mellitus (T2DM) in children and adolescents, especially among those belonging to minority ethnic groups. This trend, which parallels the increases in prevalence and degree of pediatric obesity, has caused great concern, even though T2DM remains a relatively rare disease in children. Youth T2DM differs not only from type 1 diabetes in children, from which it is sometimes difficult to differentiate, but also from T2DM in adults, since it appears to be an aggressive disease with rapidly progressive β-cell decline, high treatment failure rate, and accelerated development of complications. Despite the recent research, many aspects of youth T2DM still remain unknown, regarding both its pathophysiology and risk factor contribution, and its optimal management and prevention. Current management approaches include lifestyle changes, such as improved diet and increased physical activity, together with pharmacological interventions, including metformin, insulin, and the recently approved glucagon-like peptide-1 analog liraglutide. What is more important for everyone to realize though, from patients, families and physicians to schools, health services and policy-makers alike, is that T2DM is a largely preventable disease that will be addressed effectively only if its major contributor (i.e., pediatric obesity) is confronted and prevented at every possible stage of life, from conception until adulthood. Therefore, relevant comprehensive, coordinated, and innovative strategies are urgently needed.
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Objectives Previous research suggests intergenerational influence of diabetes on bone health. We examined the association between parental diabetes and major osteoporotic fracture (MOF) risk in offspring. Methods This population-based cohort study used de-identified administrative health data from Manitoba, Canada, which capture population-level records of hospitalizations, physician visits and drug dispensations. The cohort included individuals 40+ years with at least one parent identified in the data between 1997 and 2015. The exposure was parental diagnosis of diabetes since 1970; the outcome was offspring incident MOF diagnosis in hip, forearm, spine, or humerus. Both measures were identified from hospital and physician visit records using validated case definitions. Multivariable Cox proportional hazards regression models tested the association of parental diabetes and offspring MOF risk. Results The cohort included 279,085 offspring; 48.5% were females and 86.8% were age 44 years or younger. Both parents were identified for 89.4% ; 36.7% had a parental diabetes diagnosis. During a median follow-up of 12.0 years (IQR 6.0 – 18.0), 8762 offspring had a MOF diagnosis. After adjusting for fracture risk factors, parental diabetes diagnosis was not associated with MOF risk whether diagnosed in fathers (adjusted hazard ratio [aHR] 1.02, 95% confidence interval [CI] 0.97 – 1.08), mothers (aHR 1.02, 95% CI 0.97 – 1.07) or both parents (aHR 1.01, 95% CI 0.93 – 1.11). The results remained consistent in a stratified analysis by offspring sex, secondary analysis based on MOF site, and sensitivity analyses. Conclusions The results indicate parental diabetes is not associated with offspring MOF risk.
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Diabetes mellitus (DM) is a metabolic disorder and characterized by hyperglycemia. Being a concern of both the developed and developing world, diabetes is a global health burden and is a major cause of mortality world-wide. The most common is the type 2 diabetes mellitus (T2DM), which is mainly caused by resistance to insulin. Long-term complications of diabetes cause microvascular related problems (eg. nephropathy, neuropathy and retinopathy) along with macrovascular complications (eg. cardiovascular diseases, ischemic heart disease, peripheral vascular disease). Renin-angiotensin-aldosterone system (RAAS) regulates homeostasis of body fluid that in turn, maintains blood pressure. Thus, RAAS plays pivotal role in the pathogenesis of long-term DM complications like cardiovascular diseases and chronic kidney diseases. T2DM is a polygenic disease, and the roles of RAAS components in insulin signaling pathway and insulin resistance have been well documented. Hyperglycemia has been found to be associated with the increased plasma renin activity, arterial pressure and renal vascular resistance. Several studies have reported involvement of single variants within particular genes in initiation and development of T2D using different approaches. This chapter aims to investigate and discuss potential genetic polymorphisms underlying T2D identified through candidate gene studies, genetic linkage studies, genome wide association studies.
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Adipose tissue microvascular blood flow (MBF) is stimulated postprandially to augment delivery of nutrients and hormones to adipocytes. Adipose tissue MBF is impaired in type 2 diabetes (T2D). Whether healthy individuals at-risk of T2D show similar impairments is unknown. We aimed to determine whether adipose tissue MBF is impaired in apparently healthy individuals with a family history of T2D. Overnight-fasted individuals with no family history of T2D for two generations (FH-, n=13), with at least one parent with T2D (FH+, n=14) and clinically diagnosed T2D (n=11) underwent a mixed meal challenge (MMC). Metabolic responses (blood glucose, plasma insulin, plasma non-esterified fatty acids [NEFA] and fat oxidation) were measured before and during the MMC. MBF in truncal subcutaneous adipose tissue was assessed by contrast ultrasound while fasting and 60 minutes post-MMC. FH+ had normal blood glucoses, increased adiposity, impaired post-MMC adipose tissue MBF (D0.70±0.22 versus 2.45±0.60 AI/sec, p=0.003) and post-MMC adipose tissue insulin resistance (Adipo-IR index; D45.5±13.9 versus 7.8±5.1 mmol/L x pmol/L, p=0.006) compared to FH-. FH+ and T2D had an impaired ability to suppress fat oxidation post-MMC. Fat oxidation incremental area under the curve (35-55 minutes post-MMC, iAUC) was higher in FH+ and T2D, compared to FH- (p=0.002 and 0.004, respectively). Postprandial MBF was negatively associated with postprandial fat oxidation iAUC (p=0.01). We conclude that apparently healthy FH+ individuals display blunted postprandial adipose tissue MBF that occurs in parallel with adipose tissue insulin resistance and impaired suppression of fat oxidation, which may help explain their heightened risk for developing T2D.
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Several factors, including genetics, family history, diet, physical activity, obesity, and insulin resistance in puberty, appear to increase the risk of type 2 diabetes in youth. Youth-onset type 2 diabetes is often thought of as a single entity but rather exists as a spectrum of disease with differences in presentation, metabolic characteristics, clinical progression, and complication rates. We review what is currently known regarding the risks associated with developing type 2 diabetes in youth. Additionally, we focus on the spectrum of phenotypes of pediatric type 2 diabetes, discuss the pathogenic underpinnings and potential therapeutic relevance of this heterogeneity, and compare youth-onset type 2 diabetes with type 1 diabetes and adult-onset type 2 diabetes. Finally, we highlight knowledge gaps in prediction and prevention of youth-onset type 2 diabetes.
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Family health history (FHH) is one of the most important tools in precision medicine and is integral to improving health outcomes through early identification of individuals at risk for both rare and chronic conditions. Additionally, FHH represents both a family's shared genetics and environment adding important nuances to disease risk interpretation beyond those represented by genetics alone. In this chapter, we describe health risk assessments (HRAs), explore how FHH affects HRAs, how FHH improves outcomes, and the role of FHH in both rare and chronic disease, as well as review how to collect FHH and why it is underutilized.
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Aims/introduction: Identifying the diabetes-susceptible genetic variants will help to provide the personalized therapy for management of type 2 diabetes. Previous studies have reported a genetic risk score (GRS), computed by the sum of nuclear DNA (nDNA) risk alleles, may predict the future requirement of insulin therapy. Although mitochondrial dysfunction has close association with insulin resistance (IR), there are few studies investigate whether genetic variants of mitochondrial DNA (mtDNA) will affect the clinical characteristics of type 2 diabetes. Materials and methods: We determined mitochondrial haplogroups using mtDNA whole genome next generation sequencing and 13 single nucleotide polymorphisms (SNPs) in nDNA susceptibility loci of 13 genes in 604 Taiwanese subjects with type 2 diabetes. A GRS of nDNA was computed by summation of the number of risk alleles. The correlation between mtDNA haplogroup and the clinical characteristics of type 2 diabetes was assessed by logistic regression analysis. The results were compared with the GRS subgroups for the risk of insulin requirement. Results: Mitochondrial haplogroups modulate the clinical characteristics of type 2 diabetes, in which patients harboring haplogroup D4, as compared to those harboring non-D4 haplotypes were less prone to require insulin treatment, after adjusting for age, gender and diabetes duration. However, there was no association between insulin requirement and GRS calculated from nuclear genetic variants. Conclusions: Mitochondrial haplogroups, but not nuclear genetic variants, have a better association with the insulin requirement. Our results highlight the role of mitochondria in the management of common metabolic diseases.
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Background: The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). Methods: The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2022 Statistical Update is the product of a full year's worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year's edition includes data on the monitoring and benefits of cardiovascular health in the population and an enhanced focus on social determinants of health, adverse pregnancy outcomes, vascular contributions to brain health, and the global burden of cardiovascular disease and healthy life expectancy. Results: Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. Conclusions: The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.
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Globally, cardiovascular disease remains the leading cause of death. Most concerning is the rise in cardiovascular risk factors including obesity, diabetes and hypertension among youth, which increases the likelihood of the development of earlier and more severe cardiovascular disease. While lifestyle factors are involved in these trends, an increasing body of evidence implicates environmental exposures in early life on health outcomes in adulthood. Maternal obesity and diabetes during pregnancy, which have increased dramatically in recent years, also have profound effects on fetal growth and development. Mounting evidence is emerging that maternal obesity and diabetes during pregnancy have lifelong effects on cardiovascular risk factors and heart disease development. However, the mechanisms responsible for these observations are unknown. In this review, we summarize the findings of recent experimental studies, showing that maternal obesity and diabetes during pregnancy affect energy metabolism and heart disease development in the offspring, with a focus on the mechanisms involved. We also evaluate early proof-of-concept studies for interventions that could mitigate maternal obesity and gestational diabetes-induced cardiovascular disease risk in the offspring.
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This chapter provides an overview of recent epigenetic finding in type 2 diabetes (T2D), focusing on twin and family studies. Following a brief description of the disease and its importance, the chapter outlines evidence for links between T2D and epigenetics in both families and unrelated subjects, focusing on DNA methylation modifications. A discussion of the value of twin studies in the context of T2D and epigenetics is provided. Finally, the chapter reviews specific studies carried out to date exploring DNA methylation differences in twins discordant for T2D. The findings have potential to lead to enhanced prediction and a better understanding of the pathogenesis and progression of T2D.
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Gestational diabetes mellitus (GDM) is a common condition affecting many women worldwide. In addition to the well-known complications during pregnancy and at birth, recent studies have linked GDM to risk for long-term disease in offspring, including impaired glucose tolerance and obesity. Investigations of the mechanisms by which GDM may “program” the exposed offspring to a higher risk of cardiometabolic disease later in life have suggested epigenetic mechanisms affecting gene methylation, hormonal alterations, and hypothalamic changes. Identifying such mechanisms will allow targeted intervention in pregnancy and childhood to prevent the development of long-term adult disease.
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Diabetic retinopathy (DR) is the most frequent microvascular complication of diabetes mellitus (DM) and a leading cause of blindness worldwide. Evidence has shown that DR is an inflammatory disease with hyperglycemia playing a causative role in the development of its main features, including inflammation, cellular apoptosis, neurodegeneration, oxidative stress, and neovascularization. Toll-like receptors (TLRs) are a well-known family of pattern recognition receptors (PRRs) responsible for the initiation of inflammatory and immune responses. TLR4 identifies both endogenous and exogenous ligands and is associated with various physiological and pathological pathways in the body. While the detailed pathophysiology of DR is still unclear, increasing data suggests a crucial role for TLR4 in the development of DR. Due to hyperglycemia, TLR4 expression increases in diabetic retina, which activates various pathways leading to DR. Considering the role of TLR4 in DR, several studies have focused on the association of TLR4 polymorphisms and risk of DR development. Moreover, evidence concerning the effect of microRNAs in the pathogenesis of DR, through their interaction with TLR4, indicates the determinant role of TLR4 in this disease. Of note, several agents have proven as effective in alleviating DR through the inhibition of the TLR4 pathway, suggesting new avenues in DR treatment. In this review, we provided a brief overview of the TLR4 structure and biological function and a more comprehensive discussion about the mechanisms of TLR4 activation in DR. Furthermore, we summarized the relationship between TLR4 polymorphisms and risk of DR and the relationship between microRNAs and TLR4 in DR. Finally, we discussed the current progress in designing TLR4 inhibitors, which could be helpful in DR clinical management.
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An increasing pandemic of obesity and diabetes (diabetes mellitus, DM) has become a serious health concern worldwide because these diseases contribute to the development of many chronic diseases including cardiovascular diseases, stroke, kidney diseases, ocular diseases, hypertension, non-alcoholic fatty liver disease (NAFLD), obstructive sleep apnea, osteoarthritis, and some types of cancer, among others. Obesity is a complex metabolic disease commonly accompanied by insulin resistance, increased oxidative stress, and low-grade inflammation and is characterized by accumulation of an excess fat mass in the body. Diabetes is a metabolic disorder characterized by destruction of pancreatic beta-cells or impaired insulin secretion and insulin action. The rise of obesity has been attributed to different potential factors including genetic predisposition, Western-type fast food diet, lack of physical activity, and social status. According to the report of the International Obesity Task Force, more than 600 million people are obese, and the number of obese-born children in developing countries is increasing at an alarming rate. One of three children born in this century is expected to develop obesity-related diabetes. Currently prescribed synthetic drugs for obesity and diabetes have several side effects on long-term use. A variety of natural products including antioxidant phytochemicals has emerged as promising potent herbal drugs for the treatment of obesity, diabetes, and their associated complications. Recent “omics” technologies (genomics, proteomics, transcriptomics, metabolomics, and microbiomics) have potentially improved our knowledge to identify the mechanism of action of these traditional natural medicines and the process of biosynthesis in nature and their efficient identification. Recent understanding on the diagnosis, clinical pathogenesis, epidemiology, risk factors, clinical treatments, and consequences of obesity and diabetes are summarized in this chapter.
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Epigenetics is characterized by molecular modifications able to shape gene expression profiles in response to inner and external stimuli. Therefore, epigenetic elements are able to provide intriguing and useful information for the comprehension and management of different human conditions, including aging process, and diseases. On this subject, Age-related Macular Degeneration (AMD) represents one of the most frequent age-related disorders, dramatically affecting the quality of life of older adults worldwide. The etiopathogenesis is characterized by an interplay among multiple genetic and non-genetic factors, which have been extensively studied. Nevertheless, a deeper dissection of molecular machinery associated with risk, onset, progression and effectiveness of therapies is still missing. In this regard, epigenetic signals may be further explored to disentangle disease etiopathogenesis, the possible therapeutic avenues and the differential response to AMD treatment. This review will discuss the epigenomic signatures mostly investigated in AMD, which could be applied to improve the knowledge of disease mechanisms and to set-up novel or modified treatment options.
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Variation at the variable number tandem repeat (VNTR) minisatellite 5' of the insulin gene (INS) is associated with several phenotypes, including type 1 diabetes, polycystic ovary syndrome, and birth weight. Case-control studies have suggested that class III VNTR alleles are also associated with type 2 diabetes, but results have been inconsistent and may reflect population stratification. To explore further the role of the INS-VNTR in type 2 diabetes susceptibility, we used family-based association methods in 155 parent-offspring trios from the British Diabetic Association-Warren Trios repository, each ascertained via a Europid proband with type 2 diabetes. Overall, there was no significant association between diabetes and the INS-VNTR genotype, with 65 of 119 heterozygous parents (55%) transmitting class III and 54 class I (P = 0.16, one-sided). However, whereas maternal transmissions followed Mendelian expectation, there was a marked excess of class III transmission from the 49 heterozygous fathers (34 [69%] vs. 15, P = 0.003 vs. 50% expectation, P = 0.003 vs. maternal transmission). These results confirm that variation within the TH-INS-IGF2 locus, most plausibly at the VNTR itself, influences type 2 diabetes susceptibility. By demonstrating that this effect is mediated exclusively by the paternally derived allele, these findings implicate imprinted genes in the pathogenesis of type 2 diabetes.
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To determine whether diabetes risk is influenced by which parent (a parental history of diabetes is a well-documented risk factor for NIDDM) is reported to have diabetes. We compared the prevalence of NIDDM and IGT for 4914 subjects according to their parental history of diabetes (mother only, father only, both parents, neither parent). Subjects were drawn from the San Antonio Heart Study, a population-based survey of diabetes and cardiovascular risk factors conducted in Mexican American and non-Hispanic white individuals between 1979-1988. Men with a parental history of diabetes had a higher prevalence of both NIDDM and impaired glucose tolerance than men reporting no parental history of diabetes. Prevalence was equally high regardless of which parent, or whether both parents, had diabetes. In contrast, in women, only a maternal history of diabetes was associated with a higher prevalence of NIDDM and impaired glucose tolerance. Virtually no difference in NIDDM prevalence was found between women with a paternal-only history of diabetes and women with no parental history of diabetes. Results differed markedly between men and women. The reason for this sex difference is unclear. It may represent a measurement bias, a sex-specific environmental effect, or a genetic effect that is expressed or transmitted differently between the sexes.
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To investigate the mechanisms underlying the association between birth weight and type 2 diabetes in a population-based study of 3,061 Pima Indians aged 5-29 years. Glucose and insulin concentrations were measured during a 75-g oral glucose tolerance test, and insulin resistance was estimated according to the homeostatic model (homeostasis model assessment-insulin resistance [HOMA-IR]). Relationships between birth weight, height, weight, fasting and postload concentrations of glucose and insulin, and HOMA-IR were examined with multiple regression analyses. Birth weight was positively related to current weight and height (P < 0.0001, controlled for age and sex, in each age-group). The 2-h glucose concentrations showed a U-shaped relationship with birth weight in subjects > 10 years of age, and this relation was independent of current body size. In 2,272 nondiabetic subjects, after adjustment for weight and height, fasting and 2-h insulin concentrations and HOMA-IR were negatively correlated with birth weight. Low-birth-weight Pimas are thinner at ages 5-29 years, yet they are more insulin resistant relative to their body size than those of normal birth weight. By contrast, those with high birth weight are more obese but less insulin resistant relative to their body size. The insulin resistance of low-birth-weight Pima Indians may explain their increased risk for type 2 diabetes.
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To assess excess maternal transmission of type 2 diabetes in a multiethnic cohort. Previous studies have reported higher prevalence of diabetes among mothers of probands with type 2 diabetes than among fathers. This analysis is vulnerable to biases, and this pattern has not been observed in all populations or races. We assessed evidence for excess maternal transmission among 42,533 survey respondents with type 2 diabetes (probands) by calculating the prevalence of diabetes in their siblings and offspring. To assess data quality, we evaluated completeness of family history data provided. Accuracy of family information reported by probands was also evaluated by comparing survey responses in a subsample of 206 probands with family histories modified after further interviews with relatives. Siblings (n = 60,532) of probands with affected mothers had a greater prevalence of diabetes (20%) than those with affected fathers (17%) (P < 0.001 for adjusted odds ratios). Prevalence of diabetes was higher among the offspring (n = 72,087) of female (3.4%) versus male (2.2%) probands (P < 0.001 for adjusted odds ratios). These patterns were evident in all races and both sexes; however, the effect size was clinically insignificant in African-Americans and male offspring. In general, probands provided more complete data about diabetes status for the maternal arm of the pedigree than the paternal arm. Completeness of knowledge was not related to proband sex, but was related to education and race, and inversely to age. Accuracy of proband-reported family history was consistently good (kappa statistics generally > 0.70). Excess maternal transmission was observed in all races and both sexes, although the size of the excess was negligible in African-Americans and male offspring. Potential reporting and censoring biases are discussed.
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Recently, a new stage in glucose tolerance, impaired fasting glucose (IFG) (fasting plasma glucose level of 6.1-6.9 mmol/l), was introduced in addition to impaired glucose tolerance (IGT) (2-h glucose level of 7.8-11.0 mmol/l). It is not clear whether IFG and IGT differ with respect to insulin secretion or sensitivity. To address this question, we estimated insulin secretion (by measuring both insulin levels and the ratio of insulin-to-glucose levels in 30-min intervals) and insulin sensitivity (by using the homeostasis model assessment [HOMA] index) from an oral glucose tolerance test (OGTT) in 5,396 individuals from the Botnia Study who had varying degrees of glucose tolerance. There was poor concordance between IFG and IGT: only 36% (303 of 840) of the subjects with IFG had IGT, whereas 62% (493 of 796) of the subjects with IGT did not have IFG. Compared with subjects with normal glucose tolerance (NGT), subjects with IFG were more insulin resistant (HOMA-insulin resistance [IR] values 2.64 +/- 0.08 vs. 1.73 +/- 0.03, P < 0.0005), had greater insulin responses during an OGTT (P = 0.0001), had higher waist-to-hip ratios (P < 0.005), had higher triglyceride and total cholesterol concentrations (P < 0.0005), and had lower HDL cholesterol concentrations (P = 0.0001). Compared with subjects with IFG, subjects with IGT had a lower incremental 30-min insulin-to-glucose area during an OGTT (13.8 +/- 1.7 vs. 21.7 +/- 1.7, P = 0.0008). Compared with subjects with IGT, subjects with mild diabetes (fasting plasma glucose levels <7.8 mmol/l) showed markedly impaired insulin secretion that could no longer compensate for IR and elevated glucose levels. A progressive decline in insulin sensitivity was observed when moving from NGT to IGT and to subjects with diabetes (P < 0.05 for trend), whereas insulin secretion followed an inverted U-shaped form. We conclude that IFG is characterized by basal IR and other features of the metabolic syndrome, whereas subjects with IGT have impaired insulin secretion in relation to glucose concentrations. An absolute decompensation of beta-cell function characterizes the transition from IGT to mild diabetes.
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Lower birth weight is associated with an increased occurrence of type 2 diabetes in later life. Whether this relationship is explained by environmental or genetic factors is unknown. We have examined the potential for genetic influences by determining whether parental diabetes is associated with lower birth weight in 1,608 children of known birth weight and gestational age born between 1941 and 1993 in the Gila River Indian Community in Arizona. The previously described relationships of maternal diabetes to increased birth weight and offspring diabetes were observed. In contrast to this we have determined novel relationships between low birth weight and paternal diabetes. The offspring of diabetic fathers were, on average, 78 g lighter than the offspring of nondiabetic fathers. For fathers, lower birth weight in their offspring was associated with an increased risk of later diabetes, i.e., fathers of offspring in the lowest quintile of birth weight, who were not diabetic at the time of birth of their child, had a 1.8-fold increased risk of developing diabetes later in life (95% CI 1.2-2.7; P = 0.004). For children, lower birth weight predicted diabetes in the offspring if paternal but not maternal diabetes was present, but it was not associated with higher plasma glucose if neither parent had diabetes. We conclude that the risk of diabetes associated with low birth weight is strongly related to the development of paternal diabetes, suggesting a genetic link between lower birth weight and later diabetes.
Article
The Framingham Heart Study (FHS) was started in 1948 as a prospective investigation of cardiovascular disease in a cohort of adult men and women. Continuous surveillance of this sample of 5209 subjects has been maintained through biennial physical examinations. In 1971 examinations were begun on the children of the FHS cohort. This study, called the Framingham Offspring Study (FOS), was undertaken to expand upon knowledge of cardiovascular disease, particularly in the area of familial clustering of the disease and its risk factors. This report reviews the sampling design of the FHS and describes the nature of the FOS sample. The FOS families appear to be of typical size and age structure for families with parents born in the late 19th or early 20th century. In addition, there is little evidence that coronary heart disease (CHD) experience and CHD risk factors differ in parents of those who volunteered for this study and the parents of those who did not volunteer.
Article
Non-insulin-dependent diabetes mellitus (NIDDM) is known to have a strong genetic basis, but the mode of inheritance is still unknown. Recent studies have suggested that maternal inheritance is important; this complicates the transmission pattern of NIDDM. In our study, the familial aggregation of diabetes and the maternal effect were investigated through three generations. The CODIAB Study recruited 536 NIDDM patients between 35 and 74 years of age from 10 diabetes centers in France. Familial aggregation was confirmed: among 218 NIDDM patients, 66% had at least one diabetic relative. Mothers were implicated 2 times more frequently than fathers ( P 0.2). The genetic component was more important when the diagnosis was made earlier, but the maternal effect was homogeneous ( P > 0.3). In conclusion, we found a familial aggregation of diabetes that suggests a strong genetic component with a mode of inheritance that may be influenced by a maternal environment.
Article
Written for clinicians and biostatisticians, describes nonparametric and quasiparametric (regression) methods of analyzing survivorship data in clinical studies, emphasizing the interpretation and reasoning behind the methods. Explains the established methods for summarizing the results of the major
Article
Obesity and family history of non-lnsulin-dependent diabetes mellitus were examined in a cross-sectional study of 32,662 white women in the United States and Canada who were members of the TOPS (Take Off Pounds Sensibly) Club, Inc., with respect to the association between these two factors and the prevalence of diabetes by using questionnaire data originally collected in 1969. A family history index based upon the reported presence of diabetes among siblings, parents, and grandparents was used to grade hereditary factors on a scale of zero to five. The ratio of actual to ideal weight was used to categorize levels of obesity. The prevalence of diabetes increased consistently with increasing levels of either obesity or family history. The two factors appear to present independent risks for diabetes. Among women with no family history of diabetes, the odds ratio for diabetes associated with a weight 75 per cent or more above ideal in comparison with a weight less than 10 per cent above ideal was 7.2. Among women who were less than 10 per cent above ideal weight for their height, a comparison between women with a family history index of 1.5 or greater and women with no family history of the disease showed an odds ratio for diabetes of 6.0. Women with both risk factors (family history index of 1.5 or greater and relative weight of 1.75 or greater) had an overall odds ratio for diabetes of 22.8 when compared with women who had no family history of diabetes and a weight less than 10 per cent above ideal. Further analysis showed the combination of these factors to have a positive synergistic effect The interaction follows a multiplicative pattern.
Article
The Framingham Heart Study (FHS) was started in 1948 as a prospective investigation of cardiovascular disease in a cohort of adult men and women. Continuous surveillance of this sample of 5209 subjects has been maintained through biennial physical examinations. In 1971 examinations were begun on the children of the FHS cohort. This study, called the Framingham Offspring Study (FOS), was undertaken to expand upon knowledge of cardiovascular disease, particularly in the area of familial clustering of the disease and its risk factors. This report reviews the sampling design of the FHS and describes the nature of the FOS sample. The FOS families appear to be of typical size and age structure for families with parents born in the late 19th or early 20th century. In addition, there is little evidence that coronary heart disease (CHD) experience and CHD risk factors differ in parents of those who volunteered for this study and the parents of those who did not volunteer.
Article
This brief review discusses the current level of understanding of the role of genetic defects in the etiology of non-insulin-dependent diabetes mellitus (NIDDM) and the use of molecular-genetic methods for this study. Evidence for genetic susceptibility is strong, and defects in both insulin production and action are suspect. With restriction-fragment-length polymorphisms and genomic sequencing, various candidate loci are being evaluated. Evidence that multiple genes are involved is only circumstantial. If NIDDM is genetically heterogeneous and also influenced by environmental components, population associations and linkage analyses in families may not be as easily interpreted as for diseases involving single major gene defects.
Article
To assess the family history of diabetes in non-insulin dependent diabetes mellitus with particular emphasis on parental phenotype. Family histories were obtained from an existing computerised database and supplemented by postal questionnaires. Diabetic service of a provincial teaching hospital. A total of 1326 patients with non-insulin dependent diabetes who had been referred to diabetic clinics over the past 10 years and from whom data had been collected for inclusion in the database, of whom 347 had affected first degree relatives. Nineteen non-white patients were excluded because of the differential hereditability of the disease, and 230 (70%) patients with an affected first degree relative responded to the postal questionnaire. Mothers were implicated in significantly more cases than fathers in patients with a single affected parent: 125 mothers and 48 fathers from database; 82 mothers and 34 fathers from postal questionnaire; p less than 0.001 in both cases. Maternal influences seem to have an important role in the inheritance of non-insulin dependent diabetes.
Article
Growth factors are thought to function as pivotal autocrine-paracrine regulatory signals during embryonic development. Insulin-like growth factor II (IGF-II), a mitogenic polypeptide for a variety of cell lines, could have such a role, as indicated by the pattern of expression of its gene during rodent development. The IGF-II gene uses at least three promoters and expresses several transcripts in many tissues during the embryonic and neonatal periods, whereas expression in adult animals is confined to the choroid plexus and the leptomeninges. To examine the developmental role of IGF-II, we have begun to study the consequences of introducing mutations at the IGF-II gene locus in the mouse germ line. We have disrupted one of the IGF-II alleles in cultured mouse embryonic stem (ES) cells by gene targeting and constructed chimaeric animals. Germ-line transmission of the inactivated IGF-II gene from male chimaeras yielded heterozygous progeny that were smaller than their ES cell-derived wild-type littermates (about 60% of normal body weight). These growth-deficient animals were otherwise apparently normal and fertile. The effect of the mutation was exerted during the embryonic period. These results provide the first direct evidence for a physiological role of IGF-II in embryonic growth.
Article
The hypothesis that diuretic use may increase the risk of diabetes mellitus was prospectively examined in men and women aged 50 years and over in the Framingham study. Age-adjusted relative risk estimates were calculated comparing the rate of diabetes among those who took diuretics to those who did not take these medications. The relative risks (95% confidence limits) were statistically elevated (P less than 0.05) in both sexes; 2.1 (1.2, 3.6) in men and 2.5 (1.4, 4.5) in women. After covariate adjustment for body mass index, concentrations of total cholesterol, high density lipoprotein cholesterol, very low density cholesterol, systolic blood pressure, and cigarette smoking the relative risks were no longer statistically significant; 1.2 (0.6, 2.4) for men and 1.6 (0.8, 3.2) for women. These results are suggestive of a possible deleterious affect of diuretic use particularly in women and indicate that persons receiving diuretic agents should be carefully monitored for adverse changes in other risk factors.
Article
Non-insulin-dependent diabetes mellitus (NIDDM) during pregnancy in Pima Indian women results in offspring who have a higher prevalence of NIDDM (45%) at age 20-24 yr than in offspring of nondiabetic women (1.4%) or offspring of prediabetic women (8.6%), i.e., women who developed diabetes only after the pregnancy. These differences persist after taking into account paternal diabetes, age at onset of diabetes in the parents, and the offspring's weight relative to height. The findings suggest that the intrauterine environment is an important determinant of the development of diabetes and that its effect is in addition to effects of genetic factors.
Article
Concordance for Type 2 (non-insulin-dependent) diabetes was determined in 250 monozygotic and 264 dizygotic white male twin pairs who participated in the National Heart, Lung, and Blood Institute Twin Study. These twins were born between 1917 and 1927 and were identified from military records without regard to disease status. We examined surviving members of the cohort twice--at mean ages of 47 and 57 years--and obtained 1-h post-load glucose tests and medication histories. Diagnostic criteria for Type 2 diabetes included a glucose value greater than or equal to 13.9 mmol/l or current use of antidiabetic medication; possible Type 1 (insulin-dependent) diabetic twins were excluded. A strong genetic predisposition to Type 2 diabetes was suggested by 3 lines of evidence from the second examination: (1) 58% of monozygotic co-twins of diabetic twins were themselves diabetic compared with an expected prevalence of 10%; (2) only 1 of 15 originally disease-discordant, monozygotic twin pairs remained discordant for diabetes; and (3) 65% of non-diabetic monozygotic co-twins of diabetic twins had elevated glucose values. Because concordance for diabetes was less than 100% for twins aged 52-65 years and because twins varied in age at onset of disease, non-genetic factors may also influence diabetes development. Among the 19 monozygotic twins pairs discordant for diabetes, diabetic twins did not differ from their non-diabetic co-twins in obesity, diet, alcohol consumption, or education. However, compared with unrelated non-diabetic twins of the same ages, non-diabetic co-twins of diabetic twins gained more weight as adults (p less than 0.02) and had higher glucose levels (p less than 0.03).
Article
Harlan, L C. (U. of Michigan School of Public Hearth, Ann Arbor, Ml 48109), W. R. Harlan, J. R. Landis, and N. G. Goldstein. Factors associated with glucose tolerance in adults in the United States. Am J Epidemiol 1987; 126:674–84. Glucose tolerance data from the second National Health and Nutrition Examination Survey were analyzed to determine factors predicting fasting plasma glucose levels and glucose tolerance in a representative US population. Central adiposity (subscapular skinfolds), age, and family history of diabetes were the major predictors of fasting levels and of glucose tolerance. For women, having a diabetic mother was significantly related to fasting glucose and glucose tolerance, but for men the proportion of siblings with diabetes was positively related. Multiple regression analyses, after adjustment for age and subscapular skinfolds, identified white cell count, systolic blood pressure, natural logarithm total iron binding capacity, and family history variables as being significant predictors of glucose tolerance in both sexes. In addition, several other variables were predictive for men or women, but not for both. These data confirm the importance of the major predictors of glucose tolerance and suggest provocative new associations in the general population.
Article
Factors potentially associated with adult-onset diabetes mellitus in the elderly were reviewed, using the Framingham Heart Study data and other population data. Incidence data for diabetes mellitus in the elderly are sparse, but they indicate that the prevalence of diabetes increases greatly with age. Prevalence rates commonly exceeded 10 percent in those over the age of 60. Men and women in the Framingham Study who were overweight by more than 40 percent had twice the prevalence of diabetes mellitus compared with those of normal weight. Hypertension and coexistent vascular disease were particularly common in elderly diabetic patients, with rates markedly greater than those found among younger adult-onset diabetic patients. In those 50 years of age or older, the later development of diabetes mellitus was associated with increased levels of very-low-density lipoprotein cholesterol, decreased levels of high-density lipoprotein cholesterol, obesity, elevated casual glucose levels, use of diuretics, and preexisting vascular disease.
Article
Longitudinal data sets are comprised of repeated observations of an outcome and a set of covariates for each of many subjects. One objective of statistical analysis is to describe the marginal expectation of the outcome variable as a function of the covariates while accounting for the correlation among the repeated observations for a given subject. This paper proposes a unifying approach to such analysis for a variety of discrete and continuous outcomes. A class of generalized estimating equations (GEEs) for the regression parameters is proposed. The equations are extensions of those used in quasi-likelihood (Wedderburn, 1974, Biometrika 61, 439-447) methods. The GEEs have solutions which are consistent and asymptotically Gaussian even when the time dependence is misspecified as we often expect. A consistent variance estimate is presented. We illustrate the use of the GEE approach with longitudinal data from a study of the effect of mothers' stress on children's morbidity.
Article
The prevalence of physician-diagnosed diabetes and of undiagnosed diabetes and impaired glucose tolerance (IGT) that meet National Diabetes Data Group (NDDG) and World Health Organization (WHO) criteria have been estimated for the U.S. population aged 20-74 yr from the 1976-1980 National Health and Nutrition Examination Survey. This survey included a demographic/medical history questionnaire administered in the participant's home and a detailed examination composed of a physician's exam, special clinical procedures, other tests, and collection of blood and urine specimens. Survey participants were selected from 1970 census data through a stratified multistage probability sampling scheme. Of 17,390 eligible residents aged 20-74 yr, 15,357 (88.3%) participated in the interview and are the basis for estimates of diagnosed diabetes; 11,858 (68%) participated in the exam. A half sample of 5901 examinees was selected to receive a 75-g oral glucose tolerance test (OGTT) performed in the morning after an overnight 10- to 16-h fast. Of these examinees, valid OGTT data were obtained for 3772 people without a medical history of diabetes, and these are the basis for estimates of undiagnosed diabetes and IGT. The major reasons for incomplete OGTT data were inability of participants to attend the examination center in the morning and lack of adherence to the fasting instructions. Despite the relatively low response rates, evidence is presented that data on both the interviewed sample and those receiving the OGTT, when adjusted for the 1970-1980 census characteristics by age, race, sex, income, and geographic location, are representative of the U.S. population. Extrapolation of these data to the U.S. population aged 20-74 yr indicates a total diabetes prevalence of 6.6% by NDDG criteria, or more than 8 million people with diabetes. The prevalence of undiagnosed diabetes (3.2%) was almost equal to that of previously diagnosed diabetes (3.4%). Total rates of diabetes increased with age, from 2.0% at age 20-44 yr to 17.7% at age 65-74 yr. Rates were approximately equal by sex but were greater in Blacks than in Whites. The prevalence of undiagnosed diabetes by WHO criteria (3.4%) was similar to that by NDDG criteria, but the rate of impaired glucose tolerance (11.2%) was more than twice the NDDG estimate (4.6%). Both obesity and parental history of diabetes were associated with significantly higher rates of diabetes and IGT. Fasting plasma glucose was relatively insensitive to age, but 1-h and 2-h post-75-g glucose values increased significantly with age.
Article
We have estimated the prevalence of non-insulin-dependent diabetes mellitus (NIDDM) in Mexican Americans and Anglos in three San Antonio neighborhoods. The age-adjusted NIDDM rates (both sexes pooled) for Mexican Americans were 14.5%, 10%, and 5% for residents of a low-income barrio, a middle-income transitional neighborhood, and a high-income suburb, respectively. In Mexican American women, though not in men, obesity also declined from barrio to suburbs. We have previously shown, however, that, although obesity is an important cause of NIDDM in Mexican Americans, there is a two- to fourfold excess in the rate of NIDDM in this ethnic group over and above that which can be attributed to obesity. We therefore speculated that genetic factors might also contribute to excess NIDDM in this ethnic group. The percent native American admixture of Mexican Americans as estimated from skin color measurements was 46% in the barrio, 27% in the transitional neighborhood, and 18% in the suburbs. The NIDDM rates in Mexican Americans thus paralleled the proportion of native American genes. Furthermore, the San Antonio Mexican American rates were intermediate between the NIDDM rates of "full-blooded" Pima Indians (49.9%), who presumably have close to 100% native American genes, and the San Antonio Anglo population (3.0%) and the predominantly Anglo HANES II population (3.1%), both of which presumably have few if any native American genes. The association of genetic admixture with NIDDM rates suggests that much of the epidemic of NIDDM in Mexican Americans is confined to that part of the population with a substantial native American heritage.
Article
Knowler, W. C. (NIAMDD, Phoenix, AZ 85014), D. J. Pettitt, P. J. Savage, and P. H. Bennett. Diabetes incidence in Pima Indians: contributions of obesity and parental diabetes. Am J Epidemiol 1981;113:144–56. The incidence of diabetes mellitus was determined In 3137 Pima indians during periodic examinations that included measurement of weight, height, and glucose tolerance. Incidence was strongly related to preceding obesity, increasing steadily from 0.8 ± 0.8 cases/1000 person-years in subjects with body mass index <20 kg/m² to 72.2 ± 14.5 cases/1000 person-years (rate ± standard error) in those with body mass index ≧40 kg/m², when age-sex adjusted to the 1970 US white population. There was little relationship between diabetes prevalence and concurrent obesity, illustrating the importance of longitudinal studies in estimating the effect of obesity on the occurrence of a disease for which weight loss is a manifestation. The association of diabetes incidence with obesity remained within each group when subjects were classified by the diabetic status of their parents, another important risk factor for diabetes. Adjusted for age and obesity, incidence was 2.3 times as high (p = 0.039) in subjects with one diabetic parent and 3.9 times as high (p = 0.0003) In those with two diabetic parents as in those with two nondiabetic parents. In the Pimas, both obesity and diabetes have become more common during this century, perhaps as a result of rapid cultural and dietary changes in a population genetically susceptible to diabetes. Similar increases in obesity and diabetes appear to be occurring in many other parts of the world.
Article
We examined the records of 2576 patients with non-insulin-dependent diabetes mellitus (NIDDM) and categorised them according to race and family history of diabetes. Family history of diabetes is known to play an important role in the development of NIDDM, and a maternal history is thought to be most influential. We found that a maternal history of diabetes was present in 60% of Caucasian and West Indian patients with a parental history of diabetes, whereas in Asian patients the figure was only 34%. Asian men were also more likely to have a father with diabetes. This anomaly may be due to cultural differences in the reporting of the disease. Our data support the dominant maternal role in the development of NIDDM in their offspring and suggest an under-reporting of NIDDM in Asian females.
Article
Family studies have demonstrated that there is a strong genetic component to the aetiology of non-insulin-dependent diabetes mellitus (NIDDM), although the mode of inheritance is unknown. A number of recent family history studies, including one in Mexican Americans, have suggested that there is an excess of maternal transmission of NIDDM. Family history studies are subject to various types of bias, however, and the potential for bias in many of these studies has not been thoroughly evaluated. We therefore tested the hypothesis that diabetes is more likely to be transmitted from mothers than from fathers using data collected from a large family study of low-income Mexican Americans in San Antonio, Texas. The parents and offspring from 318 different nuclear families attended our medical clinic, where they received a 2-h oral glucose test. Diabetes was diagnosed on the basis of World Health Organization criteria. The sibships were classified into diabetic sibships (at least one sibling in the sibship was diabetic; n = 54) and non-diabetic siblings (no diabetic siblings; n = 264). The prevalence of diabetes among mothers of diabetic siblings was 61.4% (27 of 44) compared to 64.3% (18 of 28) among fathers of diabetic siblings (rate ratio = 0.95; 95% confidence interval; 0.51-1.84). For the non-diabetic sibships, the prevalence of diabetes was 31.7% (78 of 246) and 28.9% (37 of 128) among mothers and fathers, respectively (rate ratio = 1.09; 95% confidence interval: 0.73-1.67). These data provide no evidence for an excess maternal transmission of diabetes in Mexican Americans.
Article
Non-insulin-dependent diabetes mellitus (NIDDM) has a substantial genetic component, but the mode of inheritance and the molecular basis are unknown. We have undertaken segregation analysis of NIDDM after studying 247 subjects in 59 Caucasian nuclear pedigrees ascertained without regard to family history of the disorder. The analyses were performed using POINTER and COMDS, which are computer programs which apply statistical models to the data. POINTER analysis was performed defining the phenotype as a presence or absence of hyperglycaemia. Among single locus hypothesis, the analyses rejected a recessive model and favoured a dominant model, but could not statistically show that this fitted better than a mixed model (a single locus against a polygenic background) or a polygenic model. COMDS analysis assumed a continuum of hyperglycaemia from normality to NIDDM, classified family members into a series of diathesis classes with increasing plasma glucose levels and compared the distribution with that found by screening the normal population. This analysis improved the likelihood of a dominant single locus model and suggested a gene frequency of 7.4%. It raised the possibility of a second locus, but cannot identify or exclude a polygenic model. In conclusion, two types of segregation analyses rejected a recessive model and favoured a dominant model of inheritance, although they could not statistically show that this fitted better than the polygenic model. The results raised the possibility of a common dominant gene with incomplete penetrance, but genetic analysis of NIDDM needs to take into account the likelihood of polygenic inheritance with genetic heterogeneity.
Article
Non-insulin-dependent diabetes mellitus (NIDDM) is known to have a strong genetic basis, but the mode of inheritance is still unknown. Recent studies have suggested that maternal inheritance is important; this complicates the transmission pattern of NIDDM. In our study, the familial aggregation of diabetes and the maternal effect were investigated through three generations. The CODIAB Study recruited 536 NIDDM patients between 35 and 74 years of age from 10 diabetes centers in France. Familial aggregation was confirmed: among 218 NIDDM patients, 66% had at least one diabetic relative. Mothers were implicated 2 times more frequently than fathers (P < 0.001). This maternal effect was confirmed because more diabetic cases were noted among maternal than paternal aunts and uncles (P < 0.02). When we considered the next generation, women had more diabetic offspring than men (P < 0.01). Other factors susceptible to modify the familial aggregation were considered. The maternal effect was not significantly related to the patients' ages (P > 0.2). The genetic component was more important when the diagnosis was made earlier, but the maternal effect was homogeneous (P > 0.3). In conclusion, we found a familial aggregation of diabetes that suggests a strong genetic component with a mode of inheritance that may be influenced by a maternal environment.