Risk Of Diabetes In Offspring Research Articles

Preventive Epigenetic Mechanisms of Functional Foods for Type 2 Diabetes

Type 2 diabetes (T2D) is a growing global health problem that requires new and effective prevention and management strategies. Recent research has highlighted the role of epigenetic changes in the development and progression of T2D, and the potential of functional foods as a complementary therapy for the disease. This review aims to provide an overview of the current state of knowledge on the preventive epigenetic mechanisms of functional foods in T2D. We provide background information on T2D and its current treatment approaches, an explanation of the concept of epigenetics, and an overview of the different functional foods with demonstrated preventive epigenetic effects in T2D. We also discuss the epigenetic mechanisms by which these functional foods prevent or manage T2D, and the studies that have investigated their preventive epigenetic effects. In addition, we revisit works on the beneficial influence of functional foods against the programming and complications of parentally-triggered offspring diabetes. We also suggest, albeit based on scarce data, that epigenetic inheritance mechanistically mediates the impacts of functional nutrition against the metabolic risk of diabetes in offspring. Finally, our review highlights the importance of considering the preventive epigenetic mechanisms of functional foods as a potential avenue for the development of new prevention and management strategies for T2D.

1731-P: Determining the Mechanistic Relationship between Maternal Diet and Postnatal Beta-Cell Function

Previous studies have shown that intrauterine nutrient levels impact the risk of diabetes in offspring postnatally, but the molecular mechanisms underpinning this phenomenon remain poorly characterized. We hypothesize that maternal malnutrition during gestation may disrupt the fetus’ epigenetic program during development, leading to insufficient functional beta-cell mass postnatally. To this end, we show that: 1) endocrine progenitor cells with different DNA methylation signatures give rise to beta-cell subsets with different functional and proliferative capacity; 2) de novo DNA methyltransferases Dnmt3a and Dnmt3b are downregulated in embryonic endocrine progenitors exposed to a low-protein or high-fat diet in utero, while DNA demethyltransferases Tet1 and Tet2 are upregulated; 3) beta cells in offspring of dams fed a low-protein or high-fat diet during gestation demonstrate reduced expression of genes associated with beta cell maturation and function both during development and postnatally (e.g. Pdx1, MafA); 4) islets from adult mice exposed to maternal high-fat diet in utero have compromised insulin secretion when treated with sustained high glucose or free fatty acids in vitro. These findings are consistent with a model in which abnormal DNA methylation in islet progenitors is a key mechanism by which maternal nutrients mediate postnatal functional beta-cell mass and diabetes risk. Disclosure S.Nevills: None. G.Gu: None. Funding National Institutes of Health (5R01DK125696-03, 5T32HD007502-25)

Development of pups born to rats established as a model of underweight Japanese women and the onset of impaired glucose tolerance

An increasing number of Japanese women of childbearing age are underweight (BMI <18.5), but the association between this and the increased number of low-birth-weight babies born remains unclear. Here, a rat model was established to mimic the undernutrition (85% of the energy required for those with normal activity levels) experienced by such women and to evaluate the associated impaired glucose tolerance. The undernourished Wistar rat group showed increased serum corticosterone level reflecting stress, and greater adrenal weight and size. It also showed greater insulin resistance, higher expression of FOXO-1, a transcription factor related to muscle atrophy, and lower expression of p-Akt, an insulin-dependent signaling factor. Overall, this work shows the key role of undernutrition during pregnancy as a cause of impaired glucose tolerance and increased diabetes risk in offspring. The findings of this study may inform preemptive measures to prevent the development of metabolic syndrome in offspring of undernourished mothers.

Plasma Exosome-Enriched Extracellular Vesicles From Lactating Mothers With Type 1 Diabetes Contain Aberrant Levels of miRNAs During the Postpartum Period.

Type 1 diabetes is an immune-driven disease, where the insulin-producing beta cells from the pancreatic islets of Langerhans becomes target of immune-mediated destruction. Several studies have highlighted the implication of circulating and exosomal microRNAs (miRNAs) in type 1 diabetes, underlining its biomarker value and novel therapeutic potential. Recently, we discovered that exosome-enriched extracellular vesicles carry altered levels of both known and novel miRNAs in breast milk from lactating mothers with type 1 diabetes. In this study, we aimed to characterize exosomal miRNAs in the circulation of lactating mothers with and without type 1 diabetes, hypothesizing that differences in type 1 diabetes risk in offspring from these groups are reflected in the circulating miRNA profile. We performed small RNA sequencing on exosome-enriched extracellular vesicles extracted from plasma of 52 lactating mothers around 5 weeks postpartum (26 with type 1 diabetes and 26 age-matched controls), and found a total of 2,289 miRNAs in vesicles from type 1 diabetes and control libraries. Of these, 176 were differentially expressed in plasma from mothers with type 1 diabetes (167 upregulated; 9 downregulated, using a cut-off of abs(log2FC) >1 and FDR adjusted p-value <0.05). Extracellular vesicles were verified by nanoparticle tracking analysis, transmission electron microscopy and immunoblotting. Five candidate miRNAs were selected based on their involvement in diabetes and immune modulation/beta-cell functions: hsa-miR-127-3p, hsa-miR-146a-5p, hsa-miR-26a-5p, hsa-miR-24-3p and hsa-miR-30d-5p. Real-time qPCR validation confirmed that hsa-miR-146a-5p, hsa-miR-26a-5p, hsa-miR-24-3p, and hsa-miR-30d-5p were significantly upregulated in lactating mothers with type 1 diabetes as compared to lactating healthy mothers. To determine possible target genes and affected pathways of the 5 miRNA candidates, computational network-based analyses were carried out with TargetScan, mirTarBase, QIAGEN Ingenuity Pathway Analysis and PantherDB database. The candidates showed significant association with inflammatory response and cytokine and chemokine mediated signaling pathways. With this study, we detect aberrant levels of miRNAs within plasma extracellular vesicles from lactating mothers with type 1 diabetes during the postpartum period, including miRNAs with associations to disease pathogenesis and inflammatory responses.

Maternal sitagliptin treatment attenuates offspring glucose metabolism and intestinal proinflammatory cytokines IL-6 and TNF-α expression in male rats.

Increasing evidence shows that maternal overnutrition may increase the risk of diabetes in offspring. We hypothesized that maternal sitagliptin intervention may improve glucose intolerance through gut targeting. Female Sprague-Dawley (SD) rats were fed a normal diet (ND) or a high-fat diet (HFD) for 4 weeks before mating. ND pregnant rats were divided into two subgroups: ND group (ND alone) and the ND-sitagliptin group (ND combined with 10 mg/kg/day sitagliptin treatment). HFD pregnant rats were randomized to one of two groups: HFD group (HFD alone) and the HFD-sitagliptin group (HFD combined with 10 mg/kg/day sitagliptin treatment) during pregnancy and lactation. Glucose metabolism was assessed in offspring at weaning. Intestinal gene expression levels were investigated. Maternal sitagliptin intervention moderated glucose intolerance and insulin resistance in male pups. Moreover, maternal sitagliptin treatment inhibited offspring disordered intestinal expression of proinflammatory markers, including interleukin-6 (Il6), ll1b, and tumor necrosis factor (Tnf), at weaning and reduced intestinal IL-6, TNF-α expression by immunohistochemical staining and serum IL-6, TNF-α levels. However, maternal sitagliptin intervention did not affect offspring serum anti-inflammatory cytokine IL-10 level. Our results are the first to show that maternal sitagliptin intervention moderated glucose metabolism in male offspring. It may be involved with moderating intestinal IL-6 and TNF-α expression in male rat offspring.

Paternal bisphenol A exposure in mice impairs glucose tolerance in female offspring

Humans are ubiquitously exposed bisphenol A (BPA), and epidemiological studies show a positive association between BPA exposure and diabetes risk, but the impact of parental exposure on offspring diabetes risk in humans is unknown. Our previous studies in mice show disruption of metabolic health upon maternal BPA exposure. The current study was undertaken to determine whether exposure in fathers causes adverse metabolic consequences in offspring. Male C57BL/6 J mice were exposed to BPA in the diet beginning at 5 weeks of age resulting in the following dietary exposure groups: Control (0 μg/kg/day), Lower BPA (10 μg/kg/day) and Upper BPA (10 mg/kg/day). After 12 weeks of dietary exposure, males were mated to control females. Mothers and offspring were maintained on the control diet. Post-pubertal paternal BPA exposure did not affect offspring body weight, body composition or glucose tolerance. However, when fathers were exposed to BPA during gestation and lactation, their female offspring displayed impaired glucose tolerance in the absence of compromised in vivo insulin sensitivity or reduced ex vivo glucose-stimulated insulin secretion. Male offspring exhibited normal glucose tolerance. Taken together, these studies show there is an early window of susceptibility in which paternal BPA exposure can cause sex-specific impairments in glucose homeostasis.

A Retrospective Study of 6-Month Reduction in Risk of Developing Cardiovascular Diseases and Type 2 Diabetes Mellitus in Severely Obese Patients Over 60 Years of Age Following Bariatric Surgery.

BackgroundControversy exists with regard to the effectiveness and reasons for bariatric procedures in patients older than 60 years. The goal of our study was to determine the reduction in risk of developing cardiovascular disease and type 2 diabetes mellitus after undergoing bariatric surgery in obese patients over age 60 at our institution.Material/MethodsPatients with severe obesity (BMI >40 kg/m2) were retrospectively included in the study. Risk of cardiovascular disease and type 2 diabetes at baseline and their reduction during the follow-up period were evaluated with the following selected, currently preferred risk algorithms: (1) the Systemic Coronary Risk Evaluation (SCORE) scale; (2) the Framingham Risk Score (of myocardial infarction or coronary death) for patients with no prior history of diabetes, coronary heart disease, or intermittent claudication; and (3) the Framingham Offspring Diabetes Risk Score, which estimates the 8-year risk of developing type 2 diabetes.ResultsAll 33 elderly patients (32 women and 1 man, mean age 62.3±2.7 (BMI 44.3±6.2 kg/m2) significantly reduced their risk levels. We observed a decrease in the 10-year risk of a first fatal cardiovascular event (3.5±0.5 vs. 2.4±0.5, absolute risk reduction [ARR] 1.0); reduced 10-year risk of myocardial infarction or death (5.0±1.6 vs. 3.25±1.6, ARR 1.7); and reduced predicted 8-year risk of developing type 2 diabetes (7.4±7.2 vs. 3.1±0.3, ARR 4.3). No intra- or postoperative complications were observed.ConclusionsOur study showed a significant reduction in risk of developing cardiovascular diseases and type 2 diabetes, as measured by available risk scores, in elderly patients undergoing bariatric procedures.

Diabetes and Sperm DNA Damage: Efficacy of Antioxidants

Diabetes mellitus (DM) represents one of the major threats to human health all over the world, affecting almost every system of the body. Its prevalence is escalating globally and is associated with reproductive impairment in both males and females. Reports on male infertility due to DM is lacking since most affected individuals are unaware of their infertility condition due to the late onset of DM. Glucose metabolism is an imperative occasion in spermatogenesis, causing adverse effects on male fertility, principally on sperm DNA quality, motility, and ingredients of seminal plasma. DM is coupled with an increased oxidative stress (OS), causing sperm nuclear and mitochondrial DNA damage. Reactive oxygen species (ROS) hassles the fluidity of sperm plasma membrane, decreases sperm motility and ability to fuse with oocyte as well as altering the sperm DNA integrity. Lamentably, spermatozoa cannot repair the damage initiated by excessive ROS as they do not have the cytoplasmic enzymes required to achieve the repair. Diabetes may impact the epigenetic change during spermatogenesis which may be inherited through male gamete to more than one generation increasing the risk of diabetes in offspring. Administration of antioxidants in male infertility has started to pull in significant intrigue. Many studies have shown that antioxidants amazingly reduce the oxidative stress markers and boost the antioxidant enzymes. Currently treatment strategies are aimed at lowering ROS levels to maintain normal cell function. This review highlights the potential impact of DM on sperm DNA integrity, epigenetic dysregulation and efficacy of antioxidant therapy.

High Maternal Intake Of Gluten During Pregnancy Increases Risk Of Type-1 Diabetes In Offspring

High Maternal Intake Of Gluten During Pregnancy Increases Risk Of Type-1 Diabetes In Offspring

‘Could my son have diabetes too?’

A 32-year-old man with type 1 diabetes brought his 23-month-old son in for evaluation. The father said that he had noticed his son had had increased numbers of wet diapers and increased thirst in the past week. He said that he could have tested the finger blood stick on his son using his own glucometer but he did not want to ‘make the diagnosis’. The system review of the toddler and his physical examination were both unremarkable. The family history was significant for the diagnosis of type 1 diabetes (T1DM) in the father at the age of six years. In the clinic, the non-fasting glucose level of the toddler was 29.082mmol/L (524mg/dL) and his HbA1c level was 53mmol/mol, confirming the diagnosis of diabetes. The father cried in the clinic feeling guilty that he had caused diabetes in his son. We provided positive reinforcement to the father, reassuring him that his good vigilance led to the early diagnosis. Further laboratory evaluation showed positive islet cell antibodies and positive anti-glutamic acid decarboxylase. A diabetes education session was held in the clinic; the father was able to check the glucose and give insulin to his son successfully. The incidence of T1DM varies according to age, ethnic background and geographical area. It is estimated that 24.5 per 100 000 children up to the age of 14 years in the UK are diagnosed with the condition every year.1 The children of patients with T1DM are at increased risk of developing the disease.2 The increased risk is around 6% if the father is affected while it is around 3% if the mother is affected.3, 4 Table 1 shows the increased risk if a parent or sibling has the disease. It is estimated that at diagnosis of T1DM 4–7% of children have a father with T1DM whereas only 1.5–3% have an affected mother.5 A study from Finland showed that the greatest increase of T1DM occurred in the youngest offspring, aged 0–4 years, when the father had T1DM.4 Since there is no typical Mendelian inheritance of T1DM, it is very important that physicians discuss with their T1DM patients this increased risk once it is known they are planning to have children. Understanding the risk of diabetes in offspring of affected parents is important not only in T1DM but also in type 2 diabetes due to the increased rate of childhood obesity related type 2 diabetes,6 as well as in rare forms of maturity-onset diabetes of the young.7 Parents with diabetes may be more vigilant in detecting early symptoms of diabetes, compared to those without diabetes. Early detection of T1DM can prevent life-threatening diabetic ketoacidosis (DKA), especially in very young children.8 Thus, identifying children at risk for diabetes even before the clinical onset can help both physicians and parents in preventing the dramatic course of DKA. The early detection and management of T1DM in children with parents who have diabetes may provide an easier course, faster education process, and better overall management of diabetes at home; nevertheless, parents may have a tremendous feeling of guilt about transmitting diabetes to their children. This emotional factor should be recognised and addressed appropriately by the health care team, stressing the positive benefits about parents’ diabetes knowledge.

In utero exposure to gestational diabetes and adiposity: does breastfeeding make a difference?

Short-term breastfeeding from mothers with gestational diabetes (GDM) may programme metabolism and increase offspring diabetes risk. We examined the association of in utero GDM exposure with adiposity from infancy to adolescence, and whether any association was modified by breastfeeding during early infancy. In the prospective Chinese birth cohort "Children of 1997" (n = 7342, 88% follow-up rate), generalised estimate equations with multiple imputation were used to assess associations of in utero GDM exposure with age- and sex-specific body mass index (BMI) z-score during infancy (3 and 9 months), childhood (2- < 8 years) and adolescence (8-16 years), adjusted for sex, parity, maternal age, birth place, preeclampisa, smoking, and family socio-economic position. We also tested whether the associations differed by mode of infant feeding (always formula-fed, mixed, always breastfed) during the first three months of life. In utero GDM exposure (7.5%) was associated with a lower BMI z-score during infancy (-0.13, 95% confidence interval (CI) -0.22, -0.05) but higher BMI z-scores during childhood (0.14, 95% CI 0.03, 0.25) and adolescence (0.25 95% CI 0.11, 0.38). Breastfeeding for the first three months did not modify the association of in utero GDM status with subsequent BMI (all p values for interaction >0.4). In utero GDM exposure was associated with greater adiposity during childhood and adolescence. Breastfeeding in early infancy from mothers with GDM was not associated with greater adiposity in children and thus should still be encouraged.

Regulation of malonyl-CoA-acyl carrier protein transacylase network in umbilical cord blood affected by intrauterine hyperglycemia.

BackgroundGestational diabetes mellitus (GDM) has been shown to be associated with high risk of diabetes in offspring. However, the mechanisms involved in the insulin resistance in offspring are still unclear. Mitochondrial dysfunction is related with insulin resistance. In mitochondria, malonyl-CoA-acyl carrier protein transacylase (MCAT) is the key enzyme of mitochondrial fatty acid synthesis and is estimated to contribute to insulin resistance. In this study, we aimed to examine the role of MCAT and its network in the umbilical cord blood in GDM-induced offspring insulin resistance.MethodsWe isolated lymphocytes from umbilical cord vein blood in 6 GDM patients and 6 controls and examined the differences of RNA by RNA sequencing. qRT-PCR and western blot were used to measure mRNA and protein changes. Bisulfite genomic sequencing PCR was applied to detect DNA methylation.ResultsWe found more than 400 genes were differentially regulated in the lymphocytes of umbilical cord blood from GDM patients and these genes were mainly enriched in immune system and endocrine system, which relate to mitochondrial dysfunction and insulin resistance. MCAT closely related with PTPN1 (Protein Tyrosine Phosphatase, Non-Receptor Type1) and STAT5A (Signal Transducer And Activator of Transcription 5A), which were all increased in umbilical cord blood from GDM patients. Increase in MCAT may be due to decreased MCAT DNA methylation.ConclusionMCAT and its network with PTPN1, STAT5A are regulated in umbilical cord blood affected by maternal intrauterine hyperglycemia.

Regulation of hepatic pyruvate dehydrogenase phosphorylation in offspring glucose intolerance induced by intrauterine hyperglycemia.

AimGestational diabetes mellitus (GDM) has been shown to be associated with a high risk of diabetes in offspring. In mitochondria, the inhibition of pyruvate dehydrogenase (PDH) activity by PDH phosphorylation is involved in the development of diabetes. We aimed to determine the role of PDH phosphorylation in the liver in GDM-induced offspring glucose intolerance.ResultsPDH phosphorylation was increased in lymphocytes from the umbilical cord blood of the GDM patients and in high glucose-treated hepatic cells. Both the male and female offspring from GDM mice had elevated liver weights and glucose intolerance. Further, PDH phosphorylation was increased in the livers of both the male and female offspring from GDM mice, and elevated acetylation may have contributed to this increased phosphorylation.Materials and methodsWe obtained lymphocytes from umbilical cord blood collected from both normal and GDM pregnant women. In addition, we obtained the offspring of streptozotocin-induced GDM female pregnant mice. The glucose tolerance test was performed to assess glucose tolerance in the offspring. Further, Western blotting was conducted to detect changes in protein levels.ConclusionsIntrauterine hyperglycemia induced offspring glucose intolerance by inhibiting PDH activity, along with increased PDH phosphorylation in the liver, and this effect might be mediated by enhanced mitochondrial protein acetylation.

Elevated Diabetes Risk in Offspring of Mothers with Gestational Diabetes: A Preliminary Analysis

Elevated Diabetes Risk in Offspring of Mothers with Gestational Diabetes: A Preliminary Analysis

Metabolic factors and genetic risk mediate familial type 2 diabetes risk in the Framingham Heart Study.

Type 2 diabetes mellitus in parents is a strong determinant of diabetes risk in their offspring. We hypothesise that offspring diabetes risk associated with parental diabetes is mediated by metabolic risk factors. We studied initially non-diabetic participants of the Framingham Offspring Study. Metabolic risk was estimated using beta cell corrected insulin response (CIR), HOMA-IR or a count of metabolic syndrome components (metabolic syndrome score [MSS]). Dietary risk and physical activity were estimated using questionnaire responses. Genetic risk score (GRS) was estimated as the count of 62 type 2 diabetes risk alleles. The outcome of incident diabetes in offspring was examined across levels of parental diabetes exposure, accounting for sibling correlation and adjusting for age, sex and putative mediators. The proportion mediated was estimated by comparing regression coefficients for parental diabetes with (β adj) and without (β unadj) adjustments for CIR, HOMA-IR, MSS and GRS (percentage mediated = 1 - β adj / β unadj). Metabolic factors mediated 11% of offspring diabetes risk associated with parental diabetes, corresponding to a reduction in OR per diabetic parent from 2.13 to 1.96. GRS mediated 9% of risk, corresponding to a reduction in OR per diabetic parent from 2.13 to 1.99. Metabolic risk factors partially mediated offspring type 2 diabetes risk conferred by parental diabetes to a similar magnitude as genetic risk. However, a substantial proportion of offspring diabetes risk associated with parental diabetes remains unexplained by metabolic factors, genetic risk, diet and physical activity, suggesting that important familial influences on diabetes risk remain undiscovered.

The effects of diabetes on male fertility and epigenetic regulation during spermatogenesis.

The effects of diabetes mellitus include long-term damages, dysfunctions, and failures of various organs. An important complication of diabetes is the disturbance in the male reproductive system. Glucose metabolism is an important event in spermatogenesis. Moreover, glucose metabolism is also important for maintaining basic cell activity, as well as specific functions, such as motility and fertilization ability in mature sperm. Diabetic disease and experimentally induced diabetes both demonstrated that either type 1 diabetes or type 2 diabetes could have detrimental effects on male fertility, especially on sperm quality, such as sperm motility, sperm DNA integrity, and ingredients of seminal plasma. Epigenetic modifications are essential during spermatogenesis. The epigenetic regulation represents chromatin modifications including DNA methylation, histone modifications, remodeling of nucleosomes and the higher-order chromatin reorganization and noncoding RNAs. If spermatogenesis is affected during the critical developmental window, embryonic gonadal development, and germline differentiation, environmentally-induced epigenetic modifications may become permanent in the germ line epigenome and have a potential impact on subsequent generations through epigenetic transgenerational inheritance. Diabetes may influence the epigenetic modification during sperm spermatogenesis and that these epigenetic dysregulation may be inherited through the male germ line and passed onto more than one generation, which in turn may increase the risk of diabetes in offspring.

Understanding perceived risk of type 2 diabetes in healthy middle-aged adults: A cross-sectional study of associations with modelled risk, clinical risk factors, and psychological factors

AimsTo determine the perceived risk of type 2 diabetes in a sample of healthy middle-aged adults and examine the association between perceived risk and modelled risk, clinical risk factors, and psychological factors theorised to be antecedents of behaviour change. MethodsAn exploratory, cross-sectional analysis of perceived risk of type 2 diabetes (framed according to time and in comparison with peers) was conducted using baseline data collected from 569 participants of the Diabetes Risk Communication Trial (Cambridgeshire, UK). Type 2 diabetes risk factors were measured during a health assessment and the Framingham Offspring Diabetes Risk Score was used to model risk. Questionnaires assessed psychological factors including anxiety, diabetes-related worry, behavioural intentions, and other theory-based antecedents of behaviour change. Multivariable regression analyses were used to examine associations between perceived risk and potential correlates. ResultsParticipants with a high perceived risk were at higher risk according to the Framingham Offspring Diabetes Risk Score (p<0.001). Higher perceived risk was observed in those with a higher body fat percentage, lower self-rated health, higher diabetes-related worry, and lower self-efficacy for adhering to governmental recommendations for physical activity (all p<0.001). The framing of perceived risk according to time and in comparison with peers did not influence these results. ConclusionsHigh perceived risk of type 2 diabetes is associated with higher risk of developing the disease, and a decreased likelihood of engagement in risk-reducing health behaviours. Risk communication interventions should target high-risk individuals with messages about the effectiveness of prevention strategies.

Effect of hyperglycaemia in pregnancy on adiposity in their infants in India: a protocol of a multicentre cohort study

IntroductionThe carbohydrate ‘fuel’ metabolism in a pregnant woman may have a long-term impact on the development of her offspring (‘fuel-mediated teratogenesis’ hypothesis) including in utero exposure to maternal hyperglycaemia leading...

Abstract P289: Understanding Perceived Risk of Type 2 Diabetes in Healthy Middle-aged Adults

Introduction: For type 2 diabetes (T2D) prevention programs to successfully reach their intended targets, high-risk individuals must first be aware that they are at high risk. Greater understanding of factors associated with perceived risk might inform the development of more effective risk communication and prevention efforts. We aimed to determine the perceived risk of T2D in a population-based sample of healthy middle-aged adults and examine its relation to modelled risk, clinical risk factors, and psychological factors theorised to be antecedents of behaviour change. Methods: An exploratory, cross-sectional analysis of perceived lifetime risk of T2D was conducted using baseline data collected from 569 participants in the Diabetes Risk Communication Trial (Cambridgeshire, UK). T2D risk factors were measured during a health assessment and the Framingham Offspring Diabetes Risk Score was used to model risk. Questionnaires assessed various psychological factors. Multivariable regression analyses were used to determine associations with perceived risk. Results: Table 1 shows that participants (mean (SD) age = 48.8 (7.3) years; n (%) male = 265 (47.5); mean (SD) BMI = 26.1 (4.23) kg/m2) with a higher lifetime perceived risk (mean (SD) = 34.8% (24.05%)) were at higher risk according to the Framingham Offspring Diabetes Risk Score (mean (SD) = 11.7% (19.0%)) (p &lt; 0.001). Higher perceived risk was associated with higher body fat percentage, lower self-rated health, higher diabetes-related worry, and lower self-efficacy for adhering to governmental recommendations for physical activity (all p &lt; 0.001). Conclusions: Overestimation of T2D risk is common. Higher perceived risk is associated with higher risk of developing the disease, and decreased likelihood of engagement in risk-reducing health behaviours. Risk communication interventions should target high-risk individuals with messages about the effectiveness of prevention strategies and address ability to engage in risk-reducing health behaviours.

Developmental Programming by Maternal Insulin Resistance: Hyperinsulinemia, Glucose Intolerance, and Dysregulated Lipid Metabolism in Male Offspring of Insulin-Resistant Mice

Maternal obesity and gestational diabetes mellitus (GDM) are associated with obesity and diabetes risk in offspring. We tested whether maternal insulin resistance, which frequently coexists with GDM and obesity, could independently contribute to dysregulation of offspring metabolism. Female mice haploinsufficient for insulin receptor substrate-1 (IRS1-het) are hyperinsulinemic and insulin resistant during pregnancy, despite normal plasma glucose and body weight, and thus serve as a model of isolated maternal insulin resistance. Wild-type (WT) offspring of IRS1-het dams insulin resistance-exposed [IR-exposed] were compared with WT offspring of WT dams. Despite no differences in adiposity, male IR-exposed pups were glucose intolerant (P = 0.04) and hyperinsulinemic (1.3-fold increase, P = 0.02) by 1 month of age and developed progressive fasting hyperglycemia. Moreover, male IR-exposed pups challenged with high-fat diet exhibited insulin resistance. Liver lipidomic analysis of 3-week-old IR-exposed males revealed increases in the 16:1n7 fraction of several lipid classes, suggesting increased Scd1 activity. By 6 months of age, IR-exposed males had increased lipid accumulation in liver as well as increased plasma refed fatty acids, consistent with disrupted lipid metabolism. Our results indicate that isolated maternal insulin resistance, even in the absence of hyperglycemia or obesity, can promote metabolic perturbations in male offspring.