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Parental transmission of type 2 diabetes: The Framingham Offspring Study
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.
... These alterations occurred long before the onset of T2D and were shown to be central in the progression toward T2D [11][12][13][14]. FDR individuals also show a risk of developing T2D up to tenfold higher compared to age-matched subjects without a T2D family history, depending on the number of affected relatives [15][16][17]. In FDR individuals, early senescence, insulin resistance, impaired adipogenesis, dysfunctional adipose tissue, and the risk of T2D are closely associated with hypertrophic SAT and are detectable even when glucose tolerance is preserved [9-11, 13, 18-20]. ...
... Here, we have explored the molecular mechanisms determining adipose tissue dysfunction in healthy non-obese subjects who are FDR of T2D. These individuals represent a unique study population, which features a high risk of T2D [15][16][17]. They exhibit SAT hypertrophy and dysfunction similar to those of T2D enabling the analysis of mechanisms responsible for these adipose tissue abnormalities without obesity confounders. ...
Background
First-degree relatives of type 2 diabetics (FDR) exhibit a high risk of developing type 2 diabetes (T2D) and feature subcutaneous adipocyte hypertrophy, independent of obesity. In FDR, adipose cell abnormalities contribute to early insulin-resistance and are determined by adipocyte precursor cells (APCs) early senescence and impaired recruitment into the adipogenic pathway. Epigenetic mechanisms signal adipocyte differentiation, leading us to hypothesize that abnormal epigenetic modifications cause adipocyte dysfunction and enhance T2D risk. To test this hypothesis, we examined the genome-wide histone profile in APCs from the subcutaneous adipose tissue of healthy FDR.
Results
Sequencing-data analysis revealed 2644 regions differentially enriched in lysine 4 tri-methylated H3-histone (H3K4me3) in FDR compared to controls (CTRL) with significant enrichment in mitochondrial-related genes. These included TFAM, which regulates mitochondrial DNA (mtDNA) content and stability. In FDR APCs, a significant reduction in H3K4me3 abundance at the TFAM promoter was accompanied by a reduction in TFAM mRNA and protein levels. FDR APCs also exhibited reduced mtDNA content and mitochondrial-genome transcription. In parallel, FDR APCs exhibited impaired differentiation and TFAM induction during adipogenesis. In CTRL APCs, TFAM -siRNA reduced mtDNA content, mitochondrial transcription and adipocyte differentiation in parallel with upregulation of the CDKN1A and ZMAT3 senescence genes. Furthermore, TFAM -siRNA significantly expanded hydrogen peroxide (H 2 O 2 )-induced senescence, while H 2 O 2 did not affect TFAM expression.
Conclusions
Histone modifications regulate APCs ability to differentiate in mature cells, at least in part by modulating TFAM expression and affecting mitochondrial function. Reduced H3K4me3 enrichment at the TFAM promoter renders human APCs senescent and dysfunctional, increasing T2D risk.
Graphical abstract
... [2] There is a sixfold increased risk of diabetes in persons with prediabetes when compared to persons with normal glucose tolerance as well as a two to threefold increased risk of future cardiovascular events. [3] It is estimated that without any lifestyle intervention 15-30% of these people diagnosed with prediabetes will go on to develop diabetes in the next 5 years. [2] According to the to the World Health Organization (WHO), impaired fasting glucose (IFG) is defined as fasting plasma glucose (FPG) of 6.1-6.9 mmol/L (in the absence of impaired glucose tolerance (IGT), while IGT is defined as post load plasma glucose of 7.8-11.0 ...
... [2] Microvascular and macrovascular damage starts during prediabetes and is associated with an increased risk of cardiovascular disease early in the progression to T2DM. [3] The present study reported a prevalence of 23.9% of prediabetes in first degree relatives of patients with type 2 diabetes. Out of a total of 180 FDRs, 43 of them were identified as prediabetic based on FBG, HbA1C and 2hour plasma glucose tests. ...
... There is a 3.5-fold increased risk of getting diabetes if a single parent is affected and this risk increases up to 6-fold if both parents are affected. [1] The concordance rate of incidence of T2DM in monozygotic and dizygotic twins is 60% and 20%-30%, respectively. [2] Having a parental history of T2DM not only predisposes an individual to an early onset of diabetes but also the cluster of metabolic abnormalities known as metabolic syndrome (MetS). ...
... [5] Belonging to Asian ethnicity is another risk factor for developing diabetes as Asian Indians are more prone to accumulate higher hepatic fat leading to greater IR. [6] Evaluating diabetes in offspring of T2DM patients provides insight into the parental transmission of diabetes and variable contribution by maternal and paternal genetic makeup. [1] Various genome-wide association studies have identified more than 50 genetic variants but these variants only explain <10% of the observed heritability. This variability could be explained by environmental factors and the adoption of the same unhealthy habits as of parents. ...
Background: The risk of developing type 2 diabetes mellitus (T2DM) and associated metabolic abnormalities is higher in adult offspring of patients with T2DM. Various genetic and environmental influences play a facilitatory role. These determinants can lead to the early onset of hyperglycemia, unrecognized end-organ changes, and cardiovascular morbidity. Objective: The objective of this study was to identify the presence of undiagnosed diabetes and prediabetes in the otherwise healthy adult offspring of patients with T2DM and to study early metabolic abnormalities among these individuals. Materials and Methods: The study population consisted of 100 healthy offspring aged 18 years and above, of parents with T2DM, enrolled from the medicine outpatient area. Anthropometric characteristics, routine investigations and diabetes defining parameters, fasting plasma insulin, and homeostatic model assessment-estimated insulin resistance (HOMA-IR) were assessed. Results: The age and body mass index of participants were 32.30 ± 9.33 years and 25.08 ± 4.58 kg/m2, respectively. About 33.3% of males and 76.4% of females had abnormal waist circumference and metabolic syndrome was found in 26% of the offspring. Twenty-eight participants displayed dysglycemia, of which 10 were diagnosed with prediabetes and 18 with diabetes. C-reactive protein, total cholesterol, triglyceride values, apolipoprotein A, B, and their ratio, and HOMA-IR were significantly raised, and high-density lipoprotein was found significantly low in patients with this newly diagnosed T2DM. Conclusion: A significant number of asymptomatic offspring of patients with T2DM have incipient diabetes and prediabetes status, which is unidentified. Further, metabolic parameters are more deranged in those with newly diagnosed diabetes and prediabetes. Therefore, opportunistic screening for these offspring should be done routinely.
... There is a 3.5-fold increased risk of getting diabetes if a single parent is affected and this risk increases up to 6-fold if both parents are affected. [1] The concordance rate of incidence of T2DM in monozygotic and dizygotic twins is 60% and 20%-30%, respectively. [2] Having a parental history of T2DM not only predisposes an individual to an early onset of diabetes but also the cluster of metabolic abnormalities known as metabolic syndrome (MetS). ...
... [5] Belonging to Asian ethnicity is another risk factor for developing diabetes as Asian Indians are more prone to accumulate higher hepatic fat leading to greater IR. [6] Evaluating diabetes in offspring of T2DM patients provides insight into the parental transmission of diabetes and variable contribution by maternal and paternal genetic makeup. [1] Various genome-wide association studies have identified more than 50 genetic variants but these variants only explain <10% of the observed heritability. This variability could be explained by environmental factors and the adoption of the same unhealthy habits as of parents. ...
... There is a 3.5-fold increased risk of getting diabetes if a single parent is affected and this risk increases up to 6-fold if both parents are affected. [1] The concordance rate of incidence of T2DM in monozygotic and dizygotic twins is 60% and 20%-30%, respectively. [2] Having a parental history of T2DM not only predisposes an individual to an early onset of diabetes but also the cluster of metabolic abnormalities known as metabolic syndrome (MetS). ...
... [5] Belonging to Asian ethnicity is another risk factor for developing diabetes as Asian Indians are more prone to accumulate higher hepatic fat leading to greater IR. [6] Evaluating diabetes in offspring of T2DM patients provides insight into the parental transmission of diabetes and variable contribution by maternal and paternal genetic makeup. [1] Various genome-wide association studies have identified more than 50 genetic variants but these variants only explain <10% of the observed heritability. This variability could be explained by environmental factors and the adoption of the same unhealthy habits as of parents. ...
... 1,2 Additionally, it is observed that a subject's chance of having T2Ds rises in proportion to the number of members of his or her family who have the disease. 3,4 Clinical family history of diabetes has been recognized as a T2D risk factor and provides genuine genomic data that identifies the interactions between genetic, behavioral, and environmental factors. 2,3 To the best of our knowledge, there has been minimal research done on the factors that influence DPF. ...
... 3,4 Clinical family history of diabetes has been recognized as a T2D risk factor and provides genuine genomic data that identifies the interactions between genetic, behavioral, and environmental factors. 2,3 To the best of our knowledge, there has been minimal research done on the factors that influence DPF. It is intriguing to investigate how age, body mass index (BMI), subject type (ST), such as diabetic (=2) or non-diabetic (=1), etc., relate to DPF and diabetes biomarkers. ...
Diabetes pedigree function (DPF) predicts diabetes risk based on age and family history, regardless of whether the person is diabetic or not.
... In T2DM, a family history of diabetes markedly increases an individual's lifetime risk for developing diabetes, especially if the mother or both parents are affected. This may be caused by the interaction of environmental as well as genetic factors [3][4][5]. Thereby, genetic research discovered more than 100 genes that increase susceptibility to T2DM. Despite this polygenetic nature of T2DM, genetics explains only about one tenth of familial cases [3,6,7]. ...
... Thereby, both genetic and environmental factors may be responsible for the adverse glucometabolic profiles observed in these women. Traditionally, the risk of T2DM was considered higher in the case of a family history of diabetes on maternal side [4,25,26]. A recent Danish registry study also showed an association between family history of T2DM in the mother and the development of T2DM, although this was stronger when both parents were affected [3]. ...
Aims
A family history of type 2 diabetes mellitus (T2DM) markedly increases an individual's lifetime risk of developing the disease. For gestational diabetes (GDM), this risk factor is less well characterized. This study aimed to investigate the relationship between family history of T2DM in first- and second-degree relatives in women with GDM and the differences in metabolic characteristics at early gestation.
Methods
This prospective cohort study included 1129 pregnant women. A broad risk evaluation was performed before 16 + 0 weeks of gestation, including a detailed family history of the different types of diabetes and a laboratory examination of glucometabolic parameters. Participants were followed up until delivery and GDM assessed according to the latest diagnosis criteria.
Results
We showed that pregnant women with first- (FHD1, 26.6%, OR 1.91, 95%CI 1.16 to 3.16, p = 0.005), second- (FHD2, 26.3%, OR 1.88, 95%CI 1.16 to 3.05, p = 0.005) or both first- and second-degree relatives with T2DM (FHD1 + D2, 33.3%, OR 2.64, 95%CI 1.41 to 4.94, p < 0.001) had a markedly increased risk of GDM compared to those with negative family history (FHN) ( n = 100, 15.9%). The association was strongest if both parents were affected (OR 4.69, 95%CI 1.33 to 16.55, p = 0.009). Women with FHD1 and FHD1 + D2 had adverse glucometabolic profiles already in early pregnancy.
Conclusions
Family history of T2DM is an important risk factor for GDM, also by applying the current diagnostic criteria. Furthermore, we showed that the degree of kinship plays an essential role in quantifying the risk already at early pregnancy.
... The present study also reported the maternal history of T2DM to be stronger compared to paternal history of T2DM. Studies reported relatively higher risk with maternal history of diabetes compared to paternal (Meigs, 2000). When both parents were diabetic, the risk increases synergistically. ...
... Family history of diabetes could be an important public health tool in predicting development of diabetes. 26 The present study showed that smoking is associated with diabetes. Smoking habits were associated with 1.94 times odds for incident T2DM. ...
Background: Diabetes mellitus is emerging as a major health problem due to its serious complications. It is important to assess the various factors contributing to the occurrence of the diseases so that by limiting these factors the progression of the disease in patients can be controlled. Prediabetes is a state characterized by impaired fasting glucose or impaired glucose tolerance. Aims and Objective: The present study was undertaken to determine the risk factors for Type 2 diabetes mellitus (T2DM) among adults, prediabetic subjects were identified from first degree relatives of T2DMpatients. Materials and Methods: The present observational study was carried out at Department of Physiology, S.P. Medical College and Hospital in collaboration with diabetic research center P.B.M. hospital Bikaner (Rajasthan). Prediabetic subjects were identified from first degree relatives of T2DMpatients, enrolled in diabetic research center P.B.M. hospital Bikaner. Prediabetics (impaired fasting glucose) subjects were identified on the basis of fasting blood glucose 100–125 mg/dL and HbA1C (5.7–6.4%) as per American Diabetic Association (ADA) 2011 guidelines. Consecutive sampling was conducted till sample size satisfied during the period of study. Subjects of age group 20–74 years having FPG between 100 and 125 mg/dL, HbA1C between 5.7% and 6.4%, and gave informed written consent were included in study. Pre-structured performa was used to collect general information, sociodemographic information, baseline physical characteristics, personal habits, biochemical analysis, and for blood parameters. Results: Age, occupation, body mass index (BMI), diet, smoking, alcohol, truncal obesity, and family history of DM were significantly associated with prevalence of T2DM/prediabetes whereas gender and literacy were not. Conclusion: In the present study, it was observed that advanced age, occupational changes, BMI, substance abuse such as alcohol and smoking, truncal obesity, and family history of diabetes were highly associated risk factors for T2DM whereas literacy, gender, and central obesity showed no association with risk of T2DM.
... A study on 16,388 adults for the National Health and Nutrition Examination Survey between 1999 and 2004 in US has classified the T2DM risk level into low, median, and high according to affected cases in different kinship relations and found a doseeresponse relationship between risk level and T2DM occurrence [7]. The Framingham study dataset has demonstrated that the mother's T2DM history increased the child's risk of having abnormal blood sugar levels more significantly than does that of the father [8]. Similarly, a population-based ascertainment of diabetes in youth with onset at <20 years of age in the US Colorado and South Carolina has shown that a fetus is likely to have an increased T2DM risk if the mother has obesity or T2DM [9]. ...
... The findings of this study are consistent with previous studies [8,13e15]. The study with Framingham dataset has demonstrated that T2DM or impaired glucose tolerance occurs more frequently among those with affected mother than affected father [8]. Possible explanations lie in the intrauterine environment, gestational diabetes, inheriting impaired mitochondrial capacity, and postnatal environmental [16]. ...
Background
Family disease history plays a vital role in type 2 diabetes mellitus (T2DM) risk. However, the familial aggregation of T2DM among different kinship relatives warrants further investigation.
Material and methods
This nationwide kinship relationship study collected 2000–2016 data of two to five generations of the Taiwanese population from the National Health Insurance Research Database. Approximately 4 million family trees were constructed from the records of 20, 890, 264 Taiwanese residents during the study period. T2DM was diagnosed on the basis of ICD-9-CM codes 250.x0 or 250.x2, with three consecutive related prescriptions. The Cox proportional hazard model was used for statistical analysis.
Results
Compared with their counterparts, individuals who had first-degree relatives with T2DM were more likely to develop T2DM during the follow-up period (hazard ratio [HR], 2.37–27.75), followed by individuals who had second-degree relatives with T2DM (HR, 1.29–1.88). T2DM relative risk was higher in those with an affected mother than in those with affected father. The HR for T2DM was 20.32 (95%CI = 15.64–26.42) among male individuals with an affected twin brother, whereas among female individuals with an affected twin sister, it was 60.07 (95%CI = 40.83–88.36). The HRs presented a dose–response relationship with the number of affected family members.
Conclusions
The study suggests a significant familial aggregation of T2DM occurrence; these findings could aid in identifying the high-risk group for T2DM and designing early intervention strategies and treatment plans.
... 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. ...
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.
... The heritability estimates of T2D range from 30% -70%, based on twin and family studies in different populations [8][9][10][11], providing a compelling evidence about the strong influence of genetic factors. The lifetime risk of developing T2D is 40% for individuals who have one parent with T2D and 70% if both parents are affected [12]. ...
Background
More than 250 loci have been identified by genome-wide scans for type 2 diabetes in different populations. South Asians have a very different manifestation of the diseases and hence role of these loci need to be investigated among Indians with huge burden of cardio-metabolic disorders. Thus the present study aims to validate the recently identified GWAS loci in an endogamous caste population in North India.
Methods
219 T2D cases and 184 controls were recruited from hospitals and genotyped for 15 GWAS loci of T2D. Regression models adjusted for covariates were run to examine the association for T2D and fasting glucose levels.
Results
We validated three variants for T2D namely, rs11634397 at ZFAND6 (OR = 3.05, 95%CI = 1.02–9.19, p = 0.047) and rs8042680 at PRC1 (OR = 3.67, 95%CI = 1.13–11.93, p = 0.031) showing higher risk and rs6813195 at TMEM154 (OR = 0.28, 95%CI = 0.09–0.90, p = 0.033) showing protective effect. The combined risk of 9 directionally consistent variants was also found to be significantly associated with T2D (OR = 1.91, 95%CI = 1.18–3.08, p = 0.008). One variant rs10842994 at KLHDC5 was validated for 9.15mg/dl decreased fasting glucose levels (SE = -17.25–1.05, p = 0.027).
Conclusion
We confirm the role of ZFAND6 , PRC1 and TMEM154 in the pathophysiology of type 2 diabetes among Indians. More efforts are needed with larger sample sizes to validate the diabetes GWAS loci in South Asian populations for wider applicability.
... El riesgo familiar es uno de los factores de riesgo de diabetes con mayor reconocimiento entre los investigadores. Algunas evidencias muestran que, en comparación con personas que no tienen una historia familiar de diabetes, los que sí la tienen son dos a seis veces más propensos a desarrollar DM2 [89,90,91,92]. En consecuencia, la hiperglucemia en el embarazo también es influenciada por este factor. ...
En febrero de 2020, un grupo de investigadores y académicos de la Región Caribe de Colombia propuso revisar las pautas actuales que se aplicaban en ese país, y lo que registra la literatura científica internacional más reciente, relacionada con la atención de la hiperglucemia en el embarazo. La razón de tal iniciativa era decidir el alcance de una nueva actualización de la Guía de Detección y Manejo de la Diabetes Gestacional del Programa Vida Nueva Hiperglucemia en el Embarazo Fase 3.
Este proyecto es una alianza interinstitucional e intersectorial de sociedades científicas, instituciones académicas, entidades gubernamentales y entes no gubernamentales, integradas a partir de la decisión de sus miembros de afrontar en el ámbito local, regional y nacional la pandemia mundial de la diabetes. Fue promovido hace 12 años por un grupo de profesionales de la salud de la Costa Caribe Colombiana, ejecutándose actualmente en los 8 departamentos de esa región. Se concibió con un horizonte de varias décadas, siendo apoyado desde su inicio por el Fondo Mundial de la Diabetes, que tiene sede en Dinamarca.
Al cierre del año 2012 el Proyecto ya había desarrollado la primera guía de diabetes gestacional en Colombia con destino a ser aplicada en una población a gran escala. Esa Guía fue actualizada en 2016, año en el cual también fue expedida la “Guía de práctica clínica para el diagnóstico, tratamiento y seguimiento de la diabetes Gestacional. Sistema General de Seguridad Social en Salud” por parte del Ministerio de Salud y Protección Social de Colombia, con similitudes en los criterios de tamizaje/diagnóstico y en las metas de tratamiento recomendados.
Atendiendo la propuesta de los investigadores, se realizaron varias reuniones con expertos en el tema, obteniéndose un informe inicial de sus hallazgos y recomendaciones, que partían de acoger las directrices de la OMS en su informe de 2013, y sugerían planificar una nueva actualización de las pautas registradas en la guía del Proyecto, ampliando su alcance a la diabetes preexistente y la diabetes manifiesta. De hecho, en la revisión realizada posteriormente, no se registró en Colombia algún conjunto de recomendaciones clínicas para la atención de la hiperglucemia en el embarazo, con la amplitud conceptual que establece la OMS 2013. Este vacío fue la principal razón por la que el proyecto Generación Vida Nueva Hiperglucemia en el Embarazo Fase 3 promoviera el desarrollo de las pautas que se presentan en este documento.
En principio fue convocado un número importante de expertos vinculados a sociedades científicas y centros de investigación de universidades de la Región para debatir el tema, conformándose luego un grupo gestor que planificó el proceso de actualización y se crearon cinco grupos desarrolladores. El funcionamiento de los diferentes grupos enfrentó dificultades, en especial, por la aparición de la pandemia del Covid 19, pero logró tenerse un primer informe al finalizar 2021 y ajustarse en 2022.
El documento resultante se divide en tres secciones:
En la primera parte se especifican las razones para el desarrollo de estas pautas, se definen las partes interesadas, los participantes en el proceso de desarrollo y los aspectos metodológicos, y se resumen las recomendaciones en pautas claves que el clínico podrá utilizar.
En la segunda parte se estableció, por un lado, los objetivos y alcances que permitieran determinar la población diana, las intervenciones que aborda, los resultados que se esperan y las comparaciones entre ellos, como insumo para la posterior búsqueda de evidencias, su análisis y derivación en recomendaciones clínicas. Por el otro lado, se muestra el marco conceptual para facilitar una mayor comprensión del concepto hiperglucemia en el embarazo, en tanto entidad clínica independiente, sus factores de riesgo, patogenia y tratamiento; complementado con el marco normativo para asegurar la viabilidad en la implementación de las pautas que se proponen, en la realidad colombiana.
En la tercera y última parte se registran los hallazgos encontrados en la revisión de evidencias en cuanto a consulta preconcepcional, tamizaje/diagnóstico y tratamiento de la hiperglucemia en el embarazo, y su seguimiento postparto. Con base en el análisis de ellos, se formulan las recomendaciones en los diferentes momentos de desarrollo de la enfermedad.
El conjunto de evidencias seleccionadas, que aquí se registran, fueron analizadas y discutidas por un panel de expertos celebrado en Barranquilla, durante el primer semestre de 2022, estableciéndose un consenso regional en cuanto recomendaciones para la atención de la hiperglucemia en el embarazo, que el usuario podrá encontrar en la sección final del documento, y en el resumen ya aludido.
... T2D has a polygenic and multifactorial mode of inheritance 5,6 . The significant risk factors include genetic components, food intake, and environmental exposures 7,8 . ...
Type 2 diabetes (T2D) is a global public health concern due to its increasing prevalence. Risk assessment and early detection of T2D are vital in improving individuals’ health, reducing the burden on health insurance, and enhancing well-being. This study leverages artificial intelligence (AI), specifically eXtreme Gradient Boosting (XGBoost), to develop predictive models for T2D based on genetic and medical imaging data. The study aims to establish a prediction model and identify high-risk subgroups for T2D within a cohort of 68,911 Taiwan Biobank (TWB) participants. The approach integrates the Polygenic Risk Score (PRS) and Multi-image Risk Score (MRS) with demographic factors and environmental exposures to assess T2D risk. The model’s performance is evaluated using the Area Under the Receiver Operating Curve (AUC). Results demonstrate that genetic information alone is insufficient for accurate T2D prediction (AUC = 0.73), whereas medical imaging data, including abdominal ultrasonography, vertebral artery ultrasonography, bone density scan, and electrocardiography, significantly improves prediction accuracy (AUC = 0.89). The best-performing model integrates genetic, medical imaging, and demographic variables (AUC = 0.94), successfully identifying subgroups at high risk of developing T2D. The study also presents an online risk assessment website for T2D. In summary, this research represents the first integration of genetic and medical imaging data for T2D risk assessment. The genetic-only model outperforms previous genetic prediction studies, and integrating genetic and medical imaging information significantly enhances prediction. By utilizing artificial intelligence to analyze genetic, medical imaging, and demographic factors, this study contributes to early detection and precision health of T2D.
... Say, Z is type 2 diabetes of the mother (diagnosed before or after the childbirth). According to literature [13], the association between the mother's and the child's type 2 diabetes has an odds ratio ...
The classical Cornfield inequalities state that if a third confounding variable is fully responsible for an observed association between the exposure and the outcome variables, then the association between both the exposure and the confounder, and the confounder and the outcome, must be at least as strong as the association between the exposure and the outcome, as measured by the risk ratio. The work of Ding and VanderWeele on assumption-free sensitivity analysis sharpens this bound to a bivariate function of the two risk ratios involving the confounder. Analogous results are non-existent for the odds ratio, even though the conversion from odds ratios to risk ratios can sometimes be problematic.
We present a version of the classical Cornfield inequalities for the odds ratio. The proof is based on the mediant inequality dating back to ancient Alexandria. We also develop several sharp bivariate bounds of the observed association, where the two variables are either risk ratios or odds ratios involving the confounder.
... The influence of maternal history of T2D is more important than paternal influence, at least for early development of T2D [50]. In this study, we observed that the parental history of T2D through the mother (unilateral) may play an important role in differences in the association of risk alleles between the sexes in early-diagnosed T2D. ...
Background
This study investigated the effect of sex and age at type 2 diabetes (T2D) diagnosis on the influence of T2D-related genes, parental history of T2D, and obesity on T2D development.
Methods
In this case–control study, 1012 T2D cases and 1008 healthy subjects were selected from the Diabetes in Mexico Study database. Participants were stratified by sex and age at T2D diagnosis (early, ≤ 45 years; late, ≥ 46 years). Sixty-nine T2D-associated single nucleotide polymorphisms were explored and the percentage contribution ( R ² ) of T2D-related genes, parental history of T2D, and obesity (body mass index [BMI] and waist–hip ratio [WHR]) on T2D development was calculated using univariate and multivariate logistic regression models.
Results
T2D-related genes influenced T2D development most in males who were diagnosed early ( R ² = 23.5%; females, R ² = 13.5%; males and females diagnosed late, R ² = 11.9% and R ² = 7.3%, respectively). With an early diagnosis, insulin production-related genes were more influential in males (76.0% of R ² ) while peripheral insulin resistance-associated genes were more influential in females (52.3% of R ² ). With a late diagnosis, insulin production-related genes from chromosome region 11p15.5 notably influenced males while peripheral insulin resistance and genes associated with inflammation and other processes notably influenced females. Influence of parental history was higher among those diagnosed early (males, 19.9%; females, 17.5%) versus late (males, 6.4%; females, 5,3%). Unilateral maternal T2D history was more influential than paternal T2D history. BMI influenced T2D development for all, while WHR exclusively influenced males.
Conclusions
The influence of T2D-related genes, maternal T2D history, and fat distribution on T2D development was greater in males than females.
... Currently, over 34 million individuals in the U.S. are estimated to have diabetes mellitus (DM), and another one-third of adults are at risk of developing type 2 diabetes mellitus (T2DM) in the next several years (Centers for Disease Control and Prevention, 2020). Several studies find a strong intergenerational association between parental and offspring diabetes risk (Aasbjerg et al., 2020;American Diabetes Association, 2000;Hemminki et al., 2011;Meigs et al., 2000;Nguyen et al., 2009). Heritability estimates of T2DM range from 20 to 80% (Ali, 2013), and the relative risk of T2DM is around 2.7 for persons who have first-degree relatives with T2DM compared to those without this family health history (InterAct Consortium et al., 2013). ...
Substantial intergenerational transmission of diabetes mellitus (DM) risk exists. However, less is known regarding whether parental DM and DM among extended family members relate to adult offspring’s body mass index (BMI), and whether any of these associations vary by sex. Using data from the National Longitudinal Study of Youth 1997 cohort (NLSY97), we assess the sex-specific relationship between DM present in first-degree parents and second-degree relatives and BMI among the parents’ young adult offspring.
Multivariate regressions reveal a positive relationship between parental DM and young adults’ BMI for both daughters and sons, and the magnitude of coefficients is somewhat larger for the same-sex parent. Further, we observe that the link between parental DM and young adults’ BMI is strongest when both parents have diagnosed diabetes. In contrast, the relationship between second-degree relatives with DM and the respondent’s BMI is weaker and appears to be sex-specific, through same-sex parent and respondent. Logistic regressions show the association is especially strong when assessing how parental DM status relates to young adults’ obesity risk. These results generally persist when controlling for parental BMI. The findings of this study point to the need to better distinguish the role of shared family environments (e.g., eating and physical activity patterns) from shared genes in order to understand factors that may influence young adults’ BMI. Young adult offspring of parents with diabetes should be targeted for obesity prevention efforts in order to reduce their risks of obesity and perhaps diabetes.
... In two-child families, having an obese sibling is associated with five times greater risk of obesity than if the sibling were not obese [38]. • Insulin resistance as a precursor to type 2 diabetes also has a strong familial basis with a 40% risk of developing T2DM if present in one parent, increasing to 70% if present in both [39,40]. • Family history of dyslipidemia of any type significantly increases the risk for abnormal lipids in a child, with the magnitude of risk varying with the lipid diagnosis. ...
Purpose of Review
Combined dyslipidemia (CD), the predominant abnormal lipid pattern in children and adolescents, is characterized by moderate/severe triglyceride elevation with reduced high-density lipoprotein cholesterol. CD is prevalent, present in 30–50% of obese adolescents. Epidemiologic and lipid sub-population findings demonstrate CD to be highly atherogenic. In the short term, CD responds well to lifestyle change; long-term results are lacking.
Recent Findings
Major longitudinal studies now confirm that CD in childhood predicts early cardiovascular disease events in adults. Targeted nutritional interventions can be safely and effectively introduced in young children. These findings support introduction of a new approach to CD management.
Summary
New evidence supporting the atherosclerotic risk associated with CD and the effectiveness of lifelong diet interventions is reviewed and a new family-based primordial approach to CD beginning in infancy is proposed. Aligned with existing pediatric care recommendations, this has the potential to significantly decrease the development of CD.
... Maternal GDM could affect the metabolic status of offspring all life-long. In fact, a higher risk of obesity and dysglycemia during infancy and adulthood has been shown in the sons and daughters of women with GDM [196][197][198][199][200]. Several studies agree about the role of fetal GDM exposure on the development of neuro-psychiatric disorders (substance use disorders, schizophrenia, mood and anxiety disorders, eating disorders, intellectual and developmental disorders) in childhood and adulthood [201,202]. ...
Purpose:
Gestational diabetes mellitus (GDM) and thyroid dysfunction during gestation (GTD) are the two most prevalent endocrinopathies during pregnancy. The aim of the present review is to provide an overview of the peculiar aspects of GDM and GTD, to highlight the potential interactions and clinical consequences of these two frequent clinical conditions.
Methods:
A literature review regarding GDM and GTD was carried out with particular interest on meta-analyses and human studies dealing with the (i) shared risk factors between GDM and GTD, (ii) the epidemiological link between GTD and GDM, (iii) physiopathologic link between GTD and GDM, (iv) clinical consequences of GDM and GTD, and (v) post-partum implications of GDM and GTD.
Results:
The association between GDM and GTD is common and may be explained by the insulin-resistance state due to maternal GTD, to alterations in the placentation process or to the many shared risk factors. Discrepant results of epidemiologic studies can be explained, at least in part, by the changes in diagnostic criteria and screening strategies throughout the years for both conditions. GDM and GTD impact pregnancy outcome and have post-partum long-term consequences, but more studies are needed to prove an additional adverse effect.
Conclusions:
Based on the epidemiological and physio-pathological link between GDM and GTD, it could be suggested that a diagnosis of GTD could lead to screen GDM and the other way round.
... If untreated, T2D may escalate to various microvascular and macrovascular complications such as retinopathy, diabetic kidney disease, peripheral neuropathy, atherosclerotic vascular disease, etc. Its underlying pathogenesis is complex and includes an approximately 40-70% contribution of genetic factors [3][4][5]. The majority of the genetic risk loci, however, have been found to decrease insulin secretion rather than its action [6]. ...
Insulin resistance (IR) is considered the precursor and the key pathophysiological mechanism of type 2 diabetes (T2D) and metabolic syndrome (MetS). However, the pathways that IR shares with T2D are not clearly understood. Meta-analysis of multiple DNA microarray datasets could provide a robust set of metagenes identified across multiple studies. These metagenes would likely include a subset of genes (key metagenes) shared by both IR and T2D, and possibly responsible for the transition between them. In this study, we attempted to find these key metagenes using a feature selection method, LASSO, and then used the expression profiles of these genes to train five machine learning models: LASSO, SVM, XGBoost, Random Forest, and ANN. Among them, ANN performed well, with an area under the curve (AUC) > 95%. It also demonstrated fairly good performance in differentiating diabetics from normal glucose tolerant (NGT) persons in the test dataset, with 73% accuracy across 64 human adipose tissue samples. Furthermore, these core metagenes were also enriched in diabetes-associated terms and were found in previous genome-wide association studies of T2D and its associated glycemic traits HOMA-IR and HOMA-B. Therefore, this metagenome deserves further investigation with regard to the cardinal molecular pathological defects/pathways underlying both IR and T2D.
... Selfcare is fundamental in diabetes management and prevention, and existing guidelines state the need for patient education as a prerequisite to prevent ulceration (ADA, 2008). 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 II diabetes (Meigs et al., 2000, Goldfine et al., 2003, Harrison et al., 2003. According to WHO, it is estimated that there were 88,000 diabetics in Libya in the year of 2000; this prevalence is estimated to reach 245,000 diabetics by the year 2030 (Kadiki and Roaed 1999).The records of the Diabetes Hospital in Tripoli -Libya for the years 1961-1983 were examined and the available particulars relating to 24,962 diabetic patients registered during this period were obtained (Rao 1992). ...
... Although GDM usually returns to normal after delivery, increased metabolic demands during pregnancy lead to temporary defects in glucose metabolism. As the incidence of obesity increases, the incidence of GDM also gradually increases, which will affect the health of offspring, because embryos will undergo epigenetic changes due to long-term exposure to a disturbed metabolic environment [126]. Several factors, including placental hormone (PH), released by the placenta, have been implicated in the development of insulin resistance and GDM. ...
Diabetes mellitus (DM) is a first-line priority among the problems facing medical science and public health in almost all countries of the world. The main problem of DM is the high incidence of damage to the cardiovascular system, which in turn leads to diseases such as myocardial infarction, stroke, gangrene of the lower extremities, blindness and chronic renal failure. As a result, the study of the molecular genetic mechanisms of the pathogenesis of DM is of critical importance for the development of new diagnostic and therapeutic strategies. Molecular genetic aspects of the etiology and pathogenesis of diabetes mellitus are intensively studied in well-known laboratories around the world. One of the strategies in this direction is to study the role of exosomes in the pathogenesis of DM. Exosomes are microscopic extracellular vesicles with a diameter of 30-100 nm, released into the intercellular space by cells of various tissues and organs. The content of exosomes depends on the cell type and includes mRNA, non-coding RNAs, DNA, and so on. Non-coding RNAs, a group of RNAs with limited transcriptional activity, have been discovered to play a significant role in regulating gene expression through epigenetic and posttranscriptional modulation, such as silencing of messenger RNA. One of the problems of usage exosomes in DM is the identification of the cellular origin of exosomes and the standardization of protocols for molecular genetic studies in clinical laboratories. In addition, the question of the target orientation of exosomes and their targeted activity requires additional study. Solving these and other problems will make it possible to use exosomes for the diagnosis and delivery of drugs directly to target cells in DM. This study presents an analysis of literature data on the role of exosomes and ncRNAs in the development and progression of DM, as well as the prospects for the use of exosomes in clinical practice in this disease.
... Family clinical history reveals important genomic information, which characterizes the joint interactions between behavioral, environmental, and genetic factors. [1][2][3] Practically, it is found in the society that a type 2 diabetic patient has some of her/his family members such as at least a sibling, or a parent, may have type 2 diabetes (T2D). 3,4 But there is no standard proof that T2D can be recognized as an inherited disease. ...
... Mechanistically, the aetiology of insulin resistance, and ultimately T2D, is multifactorial and complex, with an element of genetic (Elgzyri et al., 2012;Meigs, Cupples, & Wilson, 2000) and epigenetic (Lehnen, Zechner, & Haaf, 2013;Rizzo et al., 2020) susceptibility. In this thesis, it is the role of lifestyle-associated factors that are of principal interest in the aetiology of insulin resistance, specifically within the skeletal muscle. ...
Background: Obesity is often associated with impaired sensitivity to the effects of insulin (insulin resistance) and dietary protein (anabolic resistance) and may exacerbate the age-related decline of skeletal muscle (sarcopenia). Myostatin is a protein that negatively regulates skeletal muscle growth but its inhibition in rodents also improves insulin sensitivity. In humans, myostatin appears to be upregulated by obesity and associated with insulin resistance, but observations are confounded by lifestyle factors and ageing. Aims: To delineate between the effects of obesity and ageing on myostatin expression in human skeletal muscle; to investigate the underlying causes of these effects; and to establish the functional significance and interconnectivity of modulating insulin sensitivity and myostatin expression in human skeletal muscle cells. Methods: In Chapter 3 a cross-sectional analysis of skeletal muscle gene expression was undertaken, in conjunction with correlation analyses between serum myostatin and descriptive characteristics, to isolate the effects of obesity and ageing per se on myostatin expression and abundance. In Chapters 4 and 5, in vitro and ex vivo techniques were employed using human primary myotubes to investigate the potential involvement of lipid-induced insulin and anabolic resistance and secretory cross-talk between subcutaneous adipose tissue and muscle, in the obesity-mediated upregulation of myostatin and the associated impairment of insulin and anabolic sensitivity. In Chapter 6, the novel polyphenol metabolite Urolithin A was applied to human myotubes and a model of adipocytes, to investigate its therapeutic potential to enhance insulin and anabolic sensitivity and to suppress myostatin expression. Results: In Chapter 3 it was revealed that muscle myostatin expression is uniquely upregulated by obesity with ageing, but not by ageing in the absence of obesity, and occurs concurrently with insulin resistance and abnormal regulation of pathways involved in the maintenance of skeletal muscle mass. This association was corroborated by positive correlations between serum myostatin and multiple indices of adiposity, but not age. In Chapters 4 and 5 it was demonstrated that neither acutely elevated fatty acid availability (which induced insulin and anabolic resistance), nor chronic exposure to obese subcutaneous adipose tissue conditioned medium (which did not induce insulin or anabolic resistance but altered the expression of genes involved in myogenesis and muscle protein breakdown) recapitulated the obesity-mediated upregulation of myostatin expression. In Chapter 6 it was demonstrated for the first time that Urolithin A suppresses myostatin expression and enhances glucose transport in human myotubes (and 3T3-L1 adipocytes), the latter of which was associated with an upregulation of GLUT4 expression. Conclusions: Skeletal muscle myostatin expression is uniquely upregulated by obesity per se, but this does not appear to be mediated by lipid-induced insulin resistance, nor by the secretory milieux of obese subcutaneous adipose tissue. Nevertheless, both models perturbed factors involved in myogenesis and muscle protein breakdown, independent of an upregulation of myostatin. Thus, the factors responsible for the obesity-mediated upregulation of myostatin remain to be elucidated and future work to establish such causality is required. Furthermore, translational research to investigate the potential of Urolithin A to enhance glucose handling in peripheral tissues and to repress myostatin’s inhibitory effects on muscle growth is warranted in humans and could be of particular benefit in conditions such as sarcopenic obesity.
... People with the 1 st degree T2DM family history have a higher risk of developing diabetes as compared with those without T2DM in their family as they present a reduced basal energy expenditure and decreased IS long prior to developing clinical signs of diabetes (Meigs et al., 2000;Russell et al., 2013). Recently, a study conducted by Szczerbiński et al (2019) revealed that family history is in converse to genetic risk scores, and has a strong association with a higher prevalence of T2DM. ...
Summary
The present study aimed to determine the level of DNA methylation in IRS1 and IGF1R genes and evaluate the association between these levels and biochemical parameters in patients with type 2 diabetes (T2DM) compared with control.
Eighty one patients with T2DM (35 men and 46 women) in addition to healthy subjects as a control group (9 men and 11 women) have been involved in this study during their attendance to Diabetes and Endocrine Care Center of Marjan Teaching Hospital / Babylon Province. Blood samples were collected from all subjects to determine the levels of glycaemic control parameters [fasting blood glucose (FBG), glycated hemoglobin (HbA1C), insulin, insulin resistance (IR) and insulin sensitivity (IS)]; renal function test (urea and creatinine); and antioxidant and oxidant parameters [total antioxidant capacity (TAC) and reactive oxygen species (ROS)]. In addition to measurement of blood pressure parameters [systolic blood pressure (SBP) and diastolic blood pressure (DBP)]. The levels of DNA methylation in insulin receptor substrate 1(IRS1) and insulin like growth factor1 receptor (IGF1R) genes was determine.
Statistical analysis showed that FBG, HbA1C, insulin, IR, TAC, ROS, SBP and DBP significantly (P≤0.05) increased in T2DM patients, while IS showed a significant (P≤0.05) decrease in T2DM patients.
According to the family history, statistical analysis showed that FBG, IR, IS, ROS and SBP had only a significant (P≤0.05) differences between-groups comparison, while HbA1C and insulin showed a significant differences between-groups and within-patients comparison.
According to physical activity, some parameters (HbA1C, insulin, IR, IS, ROS, SBP and DBP) had significant (P≤0.05) differences only between-groups comparison, while FBG, it showed significant (P≤0.05) differences between-groups and within-patients comparison. Regarding smoking habit, some studied parameters (FBG, HbA1C, insulin, IR, IS, SBP and DBP) increase in smokers’ patients and control,compared with non-smokers but statistical analysis showed only a significant (P≤0.05) differences between-groups comparison, while ROS had a significant (P≤0.05) differences between-groups and within-patients groups.
The highest percentage of T2DM patients was recorded within the (≥ 60 years) category, and the lowest percentage were within the (30-39 years) category. Result showed that FBG, HbA1C, IR, urea, creatinine, ROS, SBP and DBP were significant (P≤0.05) increase with increasing age, while IS and TAC significantly (P≤0.05) decreased by age. The distribution of T2DM patients according to their gender showed that women’s percentage (57%) was higher than men (43%). Levels of FBG, IR and ROS significantly (P≤0.05) increased in women compared with men, while IS value was significantly (P≤0.05) decrease in women. Creatinine and DBP showed a significant (P≤0.05) increase in men as compared with women.
The distribution of T2DM patients according to their body mass index (BMI) showed that the majority of T2DM patients were obese (50.60%), while (33.30%) were overweight and only (16.10%) had a normal weight. The results revealed a significant (P≤0.05) differences in some studied parameters (FBG, HbA1C, insulin, IR, IS creatinine, ROS, SBP and DBP) among BMI categories.
According to duration of disease, patients were divided into four duration groups: (≤5, 6-10, 11-15,>15 years), the high percent of patients was in the 1st and 2nd groups. Only urea, creatinine and DBP showed a significant (P≤0.05) differences among duration groups.
The present study revealed that the majority of T2DM patients were with complications 81.48% whereas 18.52% of patients were without complications. All studied parameters showed a significantly (P≤0.05) increased in patients with complication, except (insulin, urea, ROS and TAC).
The methylation analysis included evaluation of DNA methylation in IRS1 and IGF1R genes in both T2DM patients and control. The DNA methylation levels in the promoters of IRS1and IGF1R genes in T2DM were 24.05% and 20.19%, respectively,these levels significantly (P≤0.05) higher than those in control were 10% and 11.13% ,respectively.
According to the levels of methylation in both genes, patients and control were subdividing into three groups (< 15, 15-30, >30); the impact of different methylation levels of IRS1 and IGF1R on studied parameters were investigated. The results showed that FBG, HbA1C, insulin, IR, IS, ROS and DBP parameters were increased while IS was decrease as the levels of DNA methylation in both genes increased, and showed a significant (P≤0.05)differences within-patients and between-groups comparison. While urea, creatinine and TAC showed significant (P≤0.05) differences within-patients comparison. The SBP showed only a significant (P≤0.05) differences between-groups comparison.
Correlation analysis between methylation levels in IRS1 and IGF1R genes and studied parameters revealed that methylation levels in both genes showed a significant (P≤0.05) positive correlation with FBG, HbA1C, IR, urea, TAC and ROS, while both genes showed a significant (P≤0.05) negative correlation with IS. Creatinine had a significant (P≤0.05) positive correlation with IRS1 methylation. The SBP and DBP showed a significant (P≤0.05) positive correlations with IGF1R methylation. The levels of IRS1 and IGF1R methylation showed a significant (P≤0.05) positive correlation with age and BMI values of both T2DM patients and control.
According to physical activity, IGF1R gene only shows a significant (P≤0.05) differences within-control groups.
The methylation in both genes is increased in smokers patients and control compared with non-smokers, but only IGF1R methylation level showed a significant (P≤0.05) differences within-patients groups only.
It can be concluded that increased methylation levels at IRS1 and IGF1R genes could affect T2DM patients and explain the overall variability of their metabolic changes."
... The odd's of having diabetes for offspring is more in a single affected parent compared with no parental history of diabetes and it doubles if both the parents are affected [21]. The 80% concordance in monozygotic twins compared to 50% lesser in dizygotic twins gives a strong evidence for the genetic factor in development of diabetes mellitus [22]. ...
Objective: Diabetes is a chronic state of hyperglycemia which results in complications involving organs such as eyes, kidneys, nerves, heart, and blood vessels. Identifying the risk factors at an early stage can help in reducing the complications and co-morbidities of the disease. Hence, the study is carried out to assess the socio-demographic profile and associated risk factors of adult patients with diabetes mellitus. Methods: It was a cross-sectional study carried out in the urban field practice area of M.K.C.G Medical College for a period of 2 years. Multistage simple random sampling was used to select 160 known diabetic cases. Data were collected using a pre-tested questionnaire and anthropometric measurements were taken. Data were analyzed in SPSS version 17 and appropriate statistical tests were used. Results: The mean age of study participants was 53.94. About 41.88% and 21.25% were current tobacco and alcohol users, respectively. Inadequate fruit and vegetable consumption, mixed type diet, obesity in the form of increased body mass index, and waist hip ratio and sedentary life style were found to be the predisposing factors of the disease. Conclusion: Early identification of at risk individuals and appropriate intervention to increase physical activity, bring about changes in dietary habits, maintenance of correct body weight could help to prevent or delay the onset of the disease to a great extent.
... The higher BMI, higher percentage of men and lower prevalence of other autoimmune diseases also point towards the presence of type 2 diabetes as a major contributor to non-autoimmune diabetes in this group. It is well reported that a family history of diabetes is more common in type 2 diabetes than in type 1 diabetes [36][37][38]; therefore, the higher prevalence of a family history of diabetes in the autoantibody-negative group (despite a reduced T1DGRS) also supports the inadvertent inclusion of individuals with type 2 diabetes in this group. These individuals with possible type 2 diabetes are likely to represent a very small fraction of the total type 2 diabetes population and are atypical. ...
Aims/hypothesis
The reason for the observed lower rate of islet autoantibody positivity in clinician-diagnosed adult-onset vs childhood-onset type 1 diabetes is not known. We aimed to explore this by assessing the genetic risk of type 1 diabetes in autoantibody-negative and -positive children and adults.
Methods
We analysed GAD autoantibodies, insulinoma-2 antigen autoantibodies and zinc transporter-8 autoantibodies (ZnT8A) and measured type 1 diabetes genetic risk by genotyping 30 type 1 diabetes-associated variants at diagnosis in 1814 individuals with clinician-diagnosed type 1 diabetes (1112 adult-onset, 702 childhood-onset). We compared the overall type 1 diabetes genetic risk score (T1DGRS) and non-HLA and HLA (DR3-DQ2, DR4-DQ8 and DR15-DQ6) components with autoantibody status in those with adult-onset and childhood-onset diabetes. We also measured the T1DGRS in 1924 individuals with type 2 diabetes from the Wellcome Trust Case Control Consortium to represent non-autoimmune diabetes control participants.
Results
The T1DGRS was similar in autoantibody-negative and autoantibody-positive clinician-diagnosed childhood-onset type 1 diabetes (mean [SD] 0.274 [0.034] vs 0.277 [0.026], p =0.4). In contrast, the T1DGRS in autoantibody-negative adult-onset type 1 diabetes was lower than that in autoantibody-positive adult-onset type 1 diabetes (mean [SD] 0.243 [0.036] vs 0.271 [0.026], p <0.0001) but higher than that in type 2 diabetes (mean [SD] 0.229 [0.034], p <0.0001). Autoantibody-negative adults were more likely to have the more protective HLA DR15-DQ6 genotype (15% vs 3%, p <0.0001), were less likely to have the high-risk HLA DR3-DQ2/DR4-DQ8 genotype (6% vs 19%, p <0.0001) and had a lower non-HLA T1DGRS ( p< 0.0001) than autoantibody-positive adults. In contrast to children, autoantibody-negative adults were more likely to be male (75% vs 59%), had a higher BMI (27 vs 24 kg/m ² ) and were less likely to have other autoimmune conditions (2% vs 10%) than autoantibody-positive adults (all p <0.0001). In both adults and children, type 1 diabetes genetic risk was unaffected by the number of autoantibodies ( p> 0.3). These findings, along with the identification of seven misclassified adults with monogenic diabetes among autoantibody-negative adults and the results of a sensitivity analysis with and without measurement of ZnT8A, suggest that the intermediate type 1 diabetes genetic risk in autoantibody-negative adults is more likely to be explained by the inclusion of misclassified non-autoimmune diabetes (estimated to represent 67% of all antibody-negative adults, 95% CI 61%, 73%) than by the presence of unmeasured autoantibodies or by a discrete form of diabetes. When these estimated individuals with non-autoimmune diabetes were adjusted for, the prevalence of autoantibody positivity in adult-onset type 1 diabetes was similar to that in children (93% vs 91%, p =0.4).
Conclusions/interpretation
The inclusion of non-autoimmune diabetes is the most likely explanation for the observed lower rate of autoantibody positivity in clinician-diagnosed adult-onset type 1 diabetes. Our data support the utility of islet autoantibody measurement in clinician-suspected adult-onset type 1 diabetes in routine clinical practice.
Graphical abstract
... The type 2 diabetes mellitus (T2DM) epidemic is continuously growing, threatening patients with premature death and morbidity, characterized by cardiovascular disease, cancer and various other long-term complications. About 50% of the disorder is attributed to genetic influences and family history, and the other half is believed to be responsive to prevention and treatment including lifestyle measures [1][2][3]. T2DM is partially caused and thereby partially treatable by changes in eating behavior, physical activity and other lifestyle factors. Large prevention trials in Caucasian and Asian cohorts have consistently demonstrated that the implementation of a complex lifestyle intervention can result in a risk reduction of diabetes incidence of about 40-60% [4][5][6][7]. ...
Background:
T2DM heterogeneity affects responsiveness to lifestyle treatment. Beta-cell failure and nonalcoholic fatty liver disease (NAFLD) independently predict T2DM, but NAFLD inconsistently predicts metabolic response to lifestyle intervention.
Aim:
We attempt to replicate a prediction model deducted from the Tübinger Lifestyle Intervention Program by assessing similar metabolic factors to predict conversion to normal glucose regulation (NGR) in a comparable lifestyle intervention trial.
Methods:
In the Optimal Fiber Trial (OptiFiT), 131 Caucasian participants with prediabetes completed a one-year lifestyle intervention program and received a fiber or placebo supplement. We compared baseline parameters for responders and non-responders, assessed correlations of major metabolic changes and conducted a logistic regression analysis for predictors of remission to NGR.
Results:
NGR was achieved by 33 participants, respectively. At baseline, for the placebo group only, 1 h and 2 h glucose levels, glucose AUC and Cederholm index predicted conversion to NGR. HOMA-beta, HOMA-IR or liver fat indices did not differ between responders and non-responders of the placebo or the fiber group. Changes in waist circumference or fatty liver index correlated with changes in glycemia and insulin resistance, but not with changes in insulin secretion. Insulin-resistant NAFLD did not predict non-response. Differences in compliance did not explain the results.
Conclusions:
Higher post-challenge glucose levels strongly predicted the metabolic non-response to complex lifestyle intervention in our cohort. Depending on the specific intervention and the investigated cohort, fasting glucose levels and insulin sensitivity might contribute to the risk pattern. Beta-cell function did not improve in accordance with other metabolic improvements, qualifying as a potential risk factor for non-response. We could not replicate previous data suggesting that an insulin-resistant fatty liver is a specific risk factor for treatment failure. Replication studies are required.
... Although one of the criteria for diagnosing T2DM is fasting blood glucose above 126 mg/dl, it is clear that beta-cell function is abnormal with glucose levels >100 mg/dl [38]. ...
Type II Diabetes mellitus (T2DM) is the most common of two types of Diabetes disease. T2DM is a metabolic disease characterized mainly by insulin resistance, reduction of insulin secretion, and hyperglycemia. T2DM is a major public health cause of concern not only by the increase in morbidity and mortality associated with patients with the disease, but also by the significant reduction in quality of life and productivity among the economically active population. Isolated hyperglycemia refers to patients with T2DM with normal fasting plasma glucose and no ketoacidosis. With the rise of T2DM and the presence of hidden symptoms, it is vital to determine a diagnostic sequence, blood-glucose control with sulfonylureas or insulin, and diet and exercise.
... The first-degree relatives of T2D patients that have IR are at the highest risk of developing the disease [6,7]. Since they are considered to carry this genetic imprint of IR and T2D, multiple comprehensive clinical and skeletal muscle biopsy studies have been conducted on them which postulated defective post-insulin receptor (INSR) signaling events and mitochondrial function as underlying defect causing IR and T2D at molecular level. ...
Background
The genetic factors associated with insulin resistance (IR) are not well understood. Clinical studies on first-degree relatives of type 2 diabetic (T2D) patients, which have the highest genetic predisposition to T2D, have given insights into the role of IR in T2D pathogenesis. Induced pluripotent stem cells (iPSCs) are excellent tools for disease modeling as they can retain the genetic imprint of the disease. Therefore, in this study, we aimed to investigate the genetic perturbations associated with insulin resistance (IR) in the offspring of T2D parents using patient-specific iPSCs.
Methods
We generated iPSCs from IR individuals (IR-iPSCs) that were offspring of T2D parents as well as from insulin-sensitive (IS-iPSCs) individuals. We then performed transcriptomics to identify key dysregulated gene networks in the IR-iPSCs in comparison to IS-iPSCs and functionally validated them.
Results
Transcriptomics on IR-iPSCs revealed dysregulated gene networks and biological processes indicating that they carry the genetic defects associated with IR that may lead to T2D. The IR-iPSCs had increased lactate secretion and a higher phosphorylation of AKT upon stimulation with insulin. IR-iPSCs have increased cellular oxidative stress indicated by a high production of reactive oxygen species and higher susceptibility to H 2 O 2 -induced apoptosis.
Conclusions
IR-iPSCs generated from offspring of diabetic patients confirm that oxidative stress and increased lactate secretion, associated with IR, are inherited in this population, and may place them at a high risk of T2D. Overall, our IR-iPSC model can be employed for T2D modeling and drug screening studies that target genetic perturbations associated with IR in individuals with a high risk for T2D.
... 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. ...
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
... 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. ...
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 a 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 1 diabetes is around twice as common in the offspring of men with type 1 diabetes than in the offspring of women with type 1 diabetes, but the reasons for this difference are unclear. This Review summarises the evidence on the rate of transmission of type 1 diabetes to the offspring of affected fathers compared with affected mothers. The findings of nine major studies are presented, describing the magnitude of the effect observed and the relative strengths and weaknesses of these studies. This Review also explores possible underlying mechanisms for this effect, such as genetic mechanisms (eg, the selective loss of fetuses with high-risk genes in mothers with type 1 diabetes, preferential transmission of susceptibility genes from fathers, and parent-of-origin effects influencing gene expression), environmental exposures (eg, exposure to maternal hyperglycaemia, exogenous insulin exposure, and transplacental antibody transfer), and maternal microchimerism. Understanding why type 1 diabetes is more common in the offspring of men versus women with type 1 diabetes will help in the identification of individuals at high risk of the disease and can pave the way in the development of interventions that mimic the protective elements of maternal type 1 diabetes to reduce the risk of disease in individuals at high risk.
A person’s place of residence is a strong risk factor for important diagnosed chronic diseases such as diabetes. It is unclear whether neighborhood-level risk factors also predict the probability of undiagnosed disease. The objective of this study was to identify neighborhood-level variables associated with severe hyperglycemia among emergency department (ED) patients without a history of diabetes. We analyzed patients without previously diagnosed diabetes for whom a random serum glucose value was obtained in the ED. We defined random glucose values ≥ 200 mg/dL as severe hyperglycemia, indicating probable undiagnosed diabetes. Patient addresses were geocoded and matched with neighborhood-level socioeconomic measures from the American Community Survey and claims-based surveillance estimates of diabetes prevalence. Neighborhood-level exposure variables were standardized based on z-scores, and a series of logistic regression models were used to assess the association of selected exposures and hyperglycemia adjusting for biological and social individual-level risk factors for diabetes. Of 77,882 ED patients without a history of diabetes presenting in 2021, 1,715 (2.2%) had severe hyperglycemia. Many geospatial exposures were associated with uncontrolled hyperglycemia, even after controlling for individual-level risk factors. The most strongly associated neighborhood-level variables included lower markers of educational attainment, higher percentage of households where limited English is spoken, lower rates of white-collar employment, and higher rates of Medicaid insurance. Including these geospatial factors in risk assessment models may help identify important subgroups of patients with undiagnosed disease.
Diabetes and cardiovascular disease have become increasingly associated with one another over recent years. Once treated in separate silos, improved the understanding of how these two diseases are related, and novel therapies for both, have accelerated the desire to discover and treat common underlying mechanisms. In this introductory chapter, we will place the coevolution of medical care for diabetes and cardiovascular disease in historical context, as well as describe the epidemiological trends which portend the current and future challenges to society of providing care to these patients. We will also provide an overview of what is known about the subtypes of diabetes and how these are defined, as well as recent developments in diabetes therapy, in order to provide a background from which to proceed to the fascinating and important topics detailed in this book.KeywordsHistory of diabetesDiabetes epidemiologyDiabetes subtypesGenetics of diabetes
This study aimed to examine the association between familial aggregation of chronic kidney disease (CKD) and risk of CKD development and its progression. This nationwide family study comprised 881,453 cases with newly diagnosed CKD between 2004 and 2017 and 881,453 controls without CKD matched by age and sex, using data from the Korean National Health Insurance Service with linkage to the family tree database. The risks of CKD development and disease progression, defined as an incident end-stage renal disease (ESRD), were evaluated. The presence of any affected family member with CKD was associated with a significantly higher risk of CKD with adjusted ORs (95% CI) of 1.42 (1.38–1.45), 1.50 (1.46–1.55), 1.70 (1.64–1.77), and 1.30 (1.27–1.33) for individuals with affected parents, offspring, siblings, and spouses, respectively. In Cox models conducted on patients with predialysis CKD, risk of incident ESRD was significantly higher in those with affected family members with ESRD. The corresponding HRs (95% CI) were 1.10 (1.05–1.15), 1.38 (1.32–1.46), 1.57 (1.49–1.65), and 1.14 (1.08–1.19) for individuals listed above, respectively. Familial aggregation of CKD was strongly associated with a higher risk of CKD development and disease progression to ESRD.
The availability of polygenic scores for type 2 diabetes (T2D) raises the question, whether assessing family history might become redundant. However, family history not only involves shared genetics, but also shared environment. It was the aim of this study to assess the independent and combined effects of one family risk score (FamRS) and a polygenic score (PGS) on prevalent and incident T2D risk in a population-based study from Germany (n = 3071). The study was conducted in 2004/2005 with up to 12 years of follow-up. The FamRS takes into account not only the number of diseased first grade relatives, but also age at onset of the relatives and age of participants. 256 prevalent and additional 163 incident T2D cases were recorded. Prevalence of T2D increased sharply for those within the top quantile of the PGS distribution resulting in an OR of 19.16 (p < 2 × 10–16) for the top 20% compared to the remainder of the population, independent of age, sex, BMI, physical activity and FamRS. On the other hand, having a very strong family risk compared to average was still associated with an OR of 2.78 (p = 0.001), independent of the aforementioned factors and the PGS. The PGS and FamRS were only slightly correlated (r²Spearman = 0.018). The combined contribution of both factors varied with varying age-groups, though, with decreasing influence of the PGS with increasing age. To conclude, both, genetic information and family history are relevant for the prediction of T2D risk and might be used for identification of high risk groups to personalize prevention measures.
Background and aims:
Diabetes is associated with increased risk of certain cardiovascular diseases, yet the causality remains to be determined. Meanwhile, given that first-degree relatives share 50% of genes, the effect of familial diabetes is also worthy of attention. Therefore, we sought to investigate the causal relations of individual or familial diabetes with eight cardiovascular diseases, including myocardial infarction, hypertension, atrial fibrillation, heart failure, cardiac death, pulmonary embolism, transient ischemic attack, and ischemic stroke.
Methods and results:
Applying two-sample Mendelian randomization, we selected instruments for genetic predisposition to individual or familial diabetes based on published genome-wide association studies. The primary analyses were conducted using the random-effects inverse-variance weighted method. We found that genetically predicted individual diabetes was causally associated with higher risks of myocardial infarction (odd ratio [OR] = 1.09; 95% confidence interval [CI]: 1.05-1.13; P < 0.0001), hypertension (OR = 1.08; 95% CI: 1.03-1.13; P = 0.0006), and ischemic stroke (OR = 1.10; 95% CI: 1.05-1.15; P < 0.0001). Genetically predicted paternal diabetes could increase the risk of ischemic stroke (OR = 1.16; 95% CI: 1.04-1.30; P = 0.0061). Genetically predicted maternal diabetes could increase the risk of myocardial infarction (OR = 1.18; 95% CI: 1.09-1.29; P = 0.0001). Genetically predicted siblings' diabetes was causally associated with higher risks of myocardial infarction (OR = 1.17; 95% CI: 1.08-1.27; P = 0.0001) and hypertension (OR = 1.19; 95% CI: 1.06-1.34; P = 0.0036). No significant differences were observed in other outcomes.
Conclusion:
This study supports causal effects of not only individual but also familial diabetes on the development of cardiovascular diseases, which will help realize the potential effect of family history in the prevention of cardiovascular diseases.
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 Epidemiology and Prevention 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 with review of published literature through the year before writing. The 2023 Statistical Update is the product of a full year's worth of effort in 2022 by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. The American Heart Association strives to further understand and help heal health problems inflicted by structural racism, a public health crisis that can significantly damage physical and mental health and perpetuate disparities in access to health care, education, income, housing, and several other factors vital to healthy lives. This year's edition includes additional COVID-19 (coronavirus disease 2019) publications, as well as data on the monitoring and benefits of cardiovascular health in the population, with an enhanced focus on health equity across several key domains.
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.
Type 2 diabetes (T2D) represents a global threat affecting millions of patients worldwide. However, its causes remain incompletely dissected and we lack the tools to predict which individuals will develop T2D. Although there is a clear proven clinical association of T2D with metabolic disorders such as obesity and nonalcoholic fatty liver disease (NAFLD), the existence of a significant number of nondiabetic obese subjects suggests yet-uncovered features of such relationships. Here, we propose that a significant proportion of individuals may harbor an immune profile that renders them susceptible to developing T2D. We note the heterogeneity of circulating monocytes and tissue macrophages in organs that are key to metabolic disorders such as liver, white adipose tissue (WAT), and endocrine pancreas, as well as their contribution to T2D genesis.
Background
This study aimed to examine the association between familial aggregation of chronic kidney disease (CKD) and risk of CKD development and its progression.
Methods
This nationwide family study comprised 881,453 cases with newly diagnosed CKD between 2004 and 2017 and 881,453 controls without CKD matched by age and sex, using data from the Korean National Health Insurance Service with linkage to the family tree database. The risks of CKD development and disease progression, defined as an incident end-stage renal disease (ESRD), were evaluated.
Results
The presence of any affected family member with CKD was associated with a significantly higher risk of CKD with adjusted ORs (95% CI) of 1.42 (1.38–1.45), 1.50 (1.46–1.55), 1.70 (1.64–1.77), and 1.30 (1.27–1.33) for individuals with affected parents, offspring, siblings, and spouses, respectively. In Cox models conducted on patients with predialysis CKD, risk of incident ESRD was significantly higher in those with affected family members with ESRD. The corresponding HRs (95% CI) were 1.10 (1.05–1.15), 1.38 (1.32–1.46), 1.57 (1.49–1.65), and 1.14 (1.08–1.19) for individuals listed above, respectively.
Conclusions
Familial aggregation of CKD was strongly associated with a higher risk of CKD development and disease progression to ESRD.
Amaç: Çalışmanın amacı, hemşirelik öğrencilerinin diyabet risklerini belirlemektir. Yöntem: Tanımlayıcı ve kesitsel tipte planlanan araştırmanın örneklemini 271 hemşirelik öğrencisi oluşturdu. Veriler, “Öğrenci Tanıtım Formu” ve “FINDRISK Anketi“ ile toplandı. Verilerin istatistiksel analizinde sayı yüzde dağılımı, Mann Whitney U, Kruskall Wallis ve Spearman korelasyon analizi kullanıldı. Bulgular: Çalışmaya katılan öğrencilerin yaş ortalamasının 19,53±1,15, %76,8’inin kadın, %52,8’inin birinci sınıf öğrencisi olduğu belirlendi. Öğrencilerin ağırlık ortalaması 62,15±11,91 kg, boy ortalamaları 167,35±7,72 cm, bel ölçüsü ortalamaları 74, 13±10,90 idi. Öğrencilerin %17,2’si sigara kullandığını, %19,2’si alkol kullandığını, %38,4’ü boş zamanlarından günde en az 30 dakika yürüyüş yaptığını, %45’i her gün düzenli olarak sebze ve meyve tükettiğini, %31,8’inin birinci ve ikinci derece akrabalarında diyabet hastası olduğunu belirtti. Öğrencilerin 10 yıllık tip-2 diyabet riskinin puan ortalamaları 4,43±3,25 olup, %82, 1’inde düşük %12,6’sında hafif ve %5,3’ünde orta ve yüksek düzeyde olduğu saptandı. Sonuç: Öğrencilerin büyük çoğunluğunun 10 yıllık tip-2 diyabet riskinin düşük olmasına rağmen, yaklaşık yarısının düzenli beslenmediği, yaklaşık %40’ının düzenli egzersiz yapmadığı belirlendi. Bu bağlamda, öğrencilerin akrabalarındaki diyabet oranı da dikkate alındığında düzenli egzersiz ve beslenme konusunda desteklenmesi ve bu araştırmanın retrospektif olarak öğrencilerin tüm öğrenim yaşamı boyunca takip edilecek şekilde planlanması önerilmektedir.
By 2030, diabetes will be the 7th leading cause of premature mortality worldwide, according to the World Health Organisation. The application of nanotechnology in medicine holds many possible advantages and over the past few decades, there has been huge progress in its utilisation. Nanotechnology is widely applied for cancer treatment and other diseases but, the use of it for diabetes treatment is now starting to flourish. This book presents the latest developments of nanomedicine for the treatment of different facets of diabetes and related disorders. With a multidisciplinary approach, chapters focus on previously overlooked topics in glucose sensing, insulin delivery and secretion, bioimaging and transplantation of islets. This book is suitable for researchers of nanomedicine, nanotechnology and diabetes looking into the emergence of new approaches for the treatment of this life-threatening disease.
Due to their advantages of low cost, flexibility, ease of manufacture and biocompatibility, organic thin film transistor (OTFT) hold great commercial potential. Specifically, there are two types of OTFT, OFET and OECT, which are widely used in the field of flexible biological sensors and have great ability for glucose and DNA detection of diabetes. In this paper, we describe the working principles of OFET and OECT, and compare the differences between them. Some examples are given and clarified, including the materials, fabrication and chemical reactions. There is still a lot of space to be explored in OTFT for other biomarker sensing applications. With the emergence of new materials and fabrication techniques, OTFT-based biosensor would be more widely used in diagnostic equipment to improve patient outcomes.
Objective
Type 2 diabetes mellitus (T2DM) is a chronic disorder characterized by pancreatic beta-cell dysfunction and insulin resistance because of unsettled hyperglycemia. The present study was designed to understand the association of genetic variations in SLC30A8 and GLIS3 genes with T2DM.
Method
A total of 600 samples were taken with 400 T2DM cases (240 males and 160 females; mean age 42.4 ± 9.3) and 200 control cases (130 males and 70 females; mean age 40.7 ± 8.2) in the study from regions across North India. A genetic study was conducted by PCR-RFLP methods. P parametric and non-parametric tests were used to analyze the data based on the qualitative and quantitative data.
Results
Significant difference was found in biochemical parameters and sedentary lifestyle compared between T2DM patients and healthy controls such as triglycerides, HbA1c, T-cholesterol, LDL-C, BMI, systolic and diastolic BP, PPG, FPG, weight loss, fatigue, slow wound healing, blur vision, urination, appetite, urination, consumption of alcohol, non-veg, fast food and sugary drink, excessive consumption of calorie, normal and brisk (20 min) walk, prolonged sitting 3 h work, leisure sitting (3 h) and standing work (3 h) while no significant differences were observed in parameters such as HDLC, WHR, family history, household chores and exercise among T2DM patients and controls. In SLC30A8 rs13266634 variant, it was observed that TC and CC genotypes frequencies were significantly higher in T2DM cases as compared to healthy controls (OR- 2.88; 95%CI- 1.93–4.31; p < 0.0001 and OR- 5.6; 95%CI- 2.33–13.55; p = 0.0001). C allele frequency was higher as compared to healthy controls. For the GLIS3 rs7034200 variant, no significant difference was found in allelic frequency in cases and controls (p-0.434). We did not find any significant association of T2DM with GLIS3 gene variant under dominant as well as recessive models.
Conclusion
Present study concludes that the association of genetic variations between T2DM cases and control was found to have a significant difference and play a vital role in T2DM risk based on odds ratio. However, the difference in frequency of alleles in the GLIS3 variant was non-significant among T2DM patients and healthy controls.
Background:
Bipolar disorder (BD) presents with high obesity and type 2 diabetes (T2D) and pathophysiological and phenomenological abnormalities shared with cardiometabolic disorders. Genomic studies may help define if they share genetic liability. This selective review of BD with obesity and T2D will focus on genomic studies, stress their current limitations and guide future steps in developing the field.
Methods:
We searched electronic databases (PubMed, Scopus) until December 2021 to identify genome-wide association studies, polygenic risk score analyses, and functional genomics of BD accounting for body mass index (BMI), obesity, or T2D.
Results:
The first genome-wide association studies (GWAS) of BD accounting for obesity found a promising genome-wide association in an intronic gene variant of TCF7L2 that was further replicated. Polygenic risk scores of obesity and T2D have also been associated with BD, yet, no genetic correlations have been demonstrated. Finally, human-induced stem cell studies of the intronic variant in TCF7L2 show a potential biological impact of the products of this genetic variant in BD risk.
Limitations:
The narrative nature of this review.
Conclusions:
Findings from BD GWAS accounting for obesity and their functional testing, have prompted potential biological insights. Yet, BD, obesity, and T2D display high phenotypic, genetic, and population-related heterogeneity, limiting our ability to detect genetic associations. Further studies should refine cardiometabolic phenotypes, test gene-environmental interactions and add population diversity.
Background: The primary causes of Type 2 Diabetes Mellitus (T2DM) are largely unknown but insulin insensitivity has been reported to be a risk factor for the T2DM through the alteration of insulin sensitivity pattern. There is paucity of studies on the effect of exercise on occurrence of T2DM in offspring of diabetic parents in our population. Objectives: This study was designed to assess the effect of exercise on insulin sensitivity (IS) on offspring of T2DM parents compared with offspring of non-diabetic parents. Design: This study involved 60 offspring of T2DM parents attending University College Hospital, Ibadan and 60 offspring of non-diabetic parents who are undergraduate students of the University of Ibadan, Nigeria. Participants were randomly assigned into two groups. Each participant followed a protocol of graded exercise using ‘‘tummy trimmer’’ everyday spending 45 minutes daily for 24 weeks. Blood samples were obtained after an overnight fasting for determination of insulin sensitivity using standard methods at baseline and at 24 weeks. Data were analyzed using descriptive statistic and student t test with significance at p<0.05). Results: The most populated aged group was 26 to 35 years of which 47.3% (n=26) were OODP and 52.7% (n=29) were OONDP. However, all subjects were overweight with mean BMI of OODP and OONDP (29.30kg/m2±0.71 versus 26.37kg/m2±0.88) p=.0.035. Significantly, total insulin sensitivity between the two groups increased after 6 months of exercise p=0.045(3.36µ /l±0.24 versus 3.48µ /l±0.24). Conclusions: Male subjects tend to have higher insulin sensitivity than females.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
To estimate prevalence rates of diabetes and impaired glucose tolerance (IGT) in three American Indian populations, using standardized diagnostic criteria, and to assess the association of diabetes with the following selected possible risk factors: age, obesity, family history of diabetes, and amount of Indian ancestry.
This cross-sectional study involved enrolled members, men and women aged 45-74 years, of 13 American Indian tribes or communities in Arizona, Oklahoma, and South and North Dakota. Eligible participants were invited to the clinic for a personal interview and a physical examination. Diabetes and IGT status were defined by the World Health Organization criteria and were based on fasting plasma glucose and oral glucose tolerance test results. Data on age, family history of diabetes, and amount of Indian ancestry were obtained from the personal interview, and measures of obesity included body mass index, percentage body fat, and waist-to-hip ratio.
A total of 4,549 eligible participants were examined, and diabetes status was determined for 4,304 (1,446 in Arizona, 1,449 in Oklahoma, and 1,409 in the Dakotas). In all three centers, diabetes was more prevalent in women than in men. Arizona had the highest age-adjusted rates of diabetes: 65% in men and 72% in women. Diabetes rates in Oklahoma (38% in men and 42% in women) and South and North Dakota (33% in men and 40% in women), although considerably lower than in Arizona, were several times higher than those reported for the U.S. population. Rates of IGT among the three populations (14-17%) were similar to those in the U.S. population. Diabetes rates were positively associated with age, level of obesity, amount of Indian ancestry, and parental diabetes status.
Diabetes is found in epidemic proportions in Native American populations. Prevention programs and periodic screening should be implemented among American Indians. Standards of care and intervention have been developed by the Indian Health Service for individuals in whom diabetes is diagnosed. These programs should be expanded to include those with IGT to improve glycemic control or to reduce the risk of development of diabetes as well as to reduce the risk of diabetic complications.
