Insulin Resistance In Offspring Research Articles

Maternal vitamin D deficiency during pregnancy results in insulin resistance in rat offspring, which is associated with inflammation and Iκbα methylation.

We aimed to investigate the impact of maternal vitamin D deficiency during pregnancy on insulin resistance in male offspring and examine its mechanism. Pregnant Sprague-Dawley rats were maintained on a vitamin-D-free diet with ultraviolet-free light during pregnancy (early-VDD group). Insulin resistance in the male offspring was assessed by HOMA-IR, OGTT and euglycaemic clamp. NEFA, oxidative stress and inflammation levels were estimated as risk factors for insulin resistance. DNA methylation was examined by bisulfate sequencing PCR analysis. Luciferase reporter assay was performed to validate the effect of DNA methylation. The offspring in the early-VDD group had significantly higher fasting insulin and HOMA-IR levels, markedly reduced glucose tolerance and significantly lower tissue sensitivity to exogenous insulin at 16 weeks (all p < 0.05) compared with control offspring. Significantly higher serum and liver IL-1β, IL-6, IL-8 and TNF-α concentrations were observed in the offspring of the early-VDD group at 0, 3, 8 and 16 weeks. Expression of hepatic Iκbα (also known as Nfkbia) mRNA and nuclear factor κB inhibitor α (IκBα) protein was persistently lower in the early-VDD offspring at all time points, and their hepatic Iκbα methylation levels at the cytosine phosphate guanine site +331 were significantly higher at 0 and 16 weeks (all p < 0.01). Methylation at Iκbα first exon +331 markedly decreased the luciferase activity (p < 0.05). Maternal vitamin D deficiency during pregnancy results in insulin resistance in the offspring, which is associated with persistently increased inflammation. Persistently decreased Iκbα expression, potentially caused by changes in Iκbα methylation, plays an important role in persistent inflammation.

Maternal high-fat diet induces insulin resistance and deterioration of pancreatic β-cell function in adult offspring with sex differences in mice

Intrauterine environment may influence the health of postnatal offspring. There have been many studies on the effects of maternal high-fat diet (HFD) on diabetes and glucose metabolism in offspring. Here, we investigated the effects in male and female offspring. C57/BL6J mice were bred and fed either control diet (CD) or HFD from conception to weaning, and offspring were fed CD or HFD from 6 to 20 wk. At 20 wk, maternal HFD induced glucose intolerance and insulin resistance in offspring. Additionally, liver triacylglycerol content, adipose tissue mass, and inflammation increased in maternal HFD. In contrast, extending previous observations, insulin secretion at glucose tolerance test, islet area, insulin content, and PDX-1 mRNA levels in isolated islets were lower in maternal HFD in males, whereas they were higher in females. Oxidative stress in islets increased in maternal HFD in males, whereas there were no differences in females. Plasma estradiol levels were lower in males than in females and decreased in offspring fed HFD and also decreased by maternal HFD, suggesting that females may be protected from insulin deficiency by inhibiting oxidative stress. In conclusion, maternal HFD induced insulin resistance and deterioration of pancreatic β-cell function, with marked sex differences in adult offspring accompanied by adipose tissue inflammation and liver steatosis. Additionally, our results demonstrate that potential mechanisms underlying sex differences in pancreatic β-cell function may be related partially to increases in oxidative stress in male islets and decreased plasma estradiol levels in males.

Hypothalamic endoplasmic reticulum stress and insulin resistance in offspring of mice dams fed high-fat diet during pregnancy and lactation

ObjectiveThe goal of this study was to determine the presence early of markers of endoplasmic reticulum stress (ERS) and insulin resistance in the offspring from dams fed HFD (HFD-O) or standard chow diet (SC-O) during pregnancy and lactation. Materials/MethodsTo address this question, we evaluated the hypothalamic and hepatic tissues in recently weaned mice (d28) and the hypothalamus of newborn mice (d0) from dams fed HFD or SC during pregnancy and lactation. ResultsBody weight, adipose tissue mass, and food intake were more accentuated in HFD-O mice than in SC-O mice. In addition, intolerance to glucose and insulin was higher in HFD-O mice than in SC-O mice. Compared with SC-O mice, levels of hypothalamic IL1-β mRNA, NFκB protein, and p-JNK were increased in HFD-O mice. Furthermore, compared with SC-O mice, hypothalamic AKT phosphorylation after insulin challenge was reduced, while markers of ERS (p-PERK, p-eIF2α, XBP1s, GRP78, and GRP94) and p-AMPK were increased in the hypothalamic tissue of HFD-O at d28 but not at d0. These damages to hypothalamic signaling were accompanied by increased triglyceride deposits, activation of NFκB, p-JNK, p-PERK and p-eIF2α. ConclusionThese point out lactation period as maternal trigger for metabolic changes in the offspring. These changes may occur early and quietly contribute to obesity and associated pathologies in adulthood. Although in rodents the establishment of ARC neuronal projections occurs during the lactation period, in humans it occurs during the third trimester. Gestational diabetes and obesity in this period may contribute to impairment of energy homeostasis.

Association between maternal folate concentrations during pregnancy and insulin resistance in Indian children

Aims/hypothesisIn an Indian birth cohort, higher maternal homocysteine concentration in pregnancy was associated with lower birthweight of the offspring. Lower maternal vitamin B12 and higher folate concentrations were associated with higher offspring insulin resistance. Disordered one-carbon metabolism during early development may increase later metabolic risk. We explored these associations in another birth cohort in India at three age points.MethodsWe measured plasma vitamin B12, folate and homocysteine concentrations at 30 ± 2 weeks’ gestation in 654 women who delivered at one hospital. Neonatal anthropometry was recorded, and the children’s glucose and insulin concentrations were measured at 5, 9.5 and 13.5 years of age. Insulin resistance was estimated using HOMA of insulin resistance (HOMA-IR).ResultsMaternal homocysteine concentrations were inversely associated with all neonatal anthropometric measurements (p < 0.05), and positively associated with glucose concentrations in the children at 5 (30 min; p = 0.007) and 9.5 years of age (120 min; p = 0.02). Higher maternal folate concentrations were associated with higher HOMA-IR in the children at 9.5 (p = 0.03) and 13.5 years of age (p = 0.03). Maternal vitamin B12 concentrations were unrelated to offspring outcomes.Conclusions/interpretationMaternal vitamin B12 status did not predict insulin resistance in our cohort. However, associations of maternal homocysteine and folate concentrations with birth size, and with childhood insulin resistance and glycaemia in the offspring, suggest a role for nutritionally driven disturbances in one-carbon metabolism in fetal programming of diabetes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-013-3086-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Prenatal Low-Protein and Postnatal High-Fat Diets Induce Rapid Adipose Tissue Growth by Inducing Igf2 Expression in Sprague Dawley Rat Offspring1–3

Maternal low-protein diets result in lower birth weight followed by accelerated catch-up growth that is accompanied by the development of obesity and glucose intolerance in later life. Whether postnatal high-fat (HF) diets further contribute to the development of obesity and insulin resistance in offspring by affecting adipose tissue metabolism and DNA methylation is currently unknown. Obese-prone Sprague-Dawley rats were fed 8% low protein (LP) or 20% normal protein diets for 3 wk prior to conception and throughout pregnancy and lactation to investigate whether prenatal LP and postnatal HF diets affect the rate of adipose tissue growth, insulin-like growth factor 2 (Igf2) expression, and DNA methylation in male offspring. At weaning, the offspring were fed 10% normal fat or 45% HF diets for 12 wk. The adipose tissue growth rate was increased (up to 26-fold) by the LP prenatal and HF postnatal diets. Adipose tissue Igf2 mRNAs and DNA methylation were increased by the LP prenatal and HF postnatal diets. The LP prenatal and HF postnatal diet increased the number of small adipocytes in adipose tissue and decreased insulin sensitivity. These findings suggest that prenatal LP and postnatal HF intake result in adipose tissue catch-up growth through alterations in the expression of the Igf2 gene and DNA methylation within adipocytes. These alterations in adiposity are accompanied by an increased risk of development of type 2 diabetes.

Experiences and prospects for cohorts and biobanks

There has been a complete turnaround in scientific thinking about malnutrition as a protective factor to that of a major determinant of diabetes. Development of Type 2 diabetes is attributed to a combination of genetic susceptibility and precipitation factors in adult or early adult life. Current trials and preventive interventions are based on this gene-obesity model causing glucose intolerance necessitating food restriction for management. However when we compare the burden of low birth weight and intrauterine growth restriction with that of type 2 diabetes it can be hypothesised that good nutrition during intrauterine development and early childhood is more important. Foetal programming due to under nutrition can result in intergenerational transfer of long latency disorders. This hypothesis led to the establishment of the Pune maternal nutrition study and Pune children study involving cohorts. The Pune children study involving 400 children has completed 21 years of follow up and has shown an inverse relationship between birth weight and risk of diabetes mellitus measured by high glucose and high insulin levels. The maternal nutrition study which started with 2675 pregnant women in six villages has now completed 17 years. Both the mothers and children are being followed with very good follow up rates. The study involved consensus building among village leaders, consultation of experts, focus group discussions and training of local girls as Auxiliary Nurse Midwives (ANMs). The study involves assessment of weight and haemoglobin of young women, nutritional intake during pregnancy, foetal growth monitoring, biochemical assessments, storage of maternal and cord blood samples, detailed anthropometry at birth and continuing monitoring for cardiovascular disease risk markers. A steering committee of all stakeholders was constituted to oversee the study. The observations have shown that the intra abdominal fat content of Indian babies is higher. Low vitamin B12 levels, folate levels and high homocysteine levels are shown to be associated with low birth weight and insulin resistance in offspring. This demonstrates that maternal micro nutrient status influences risk of diabetes in the offspring and birth weight is a marker of intrauterine environment. Policy implications include ensuring the health of the young girl and addition of vitamin B12 along with folate for pregnant women. The biochemical estimation was made possible by storage of samples in biobanks which is a most useful resource for subsequent measurements, but there are ethical concerns and issues of subject approval.

Metabolic profile Assessment in offspring of wistar rats treated during pregnancy and lactation with sodium selenite

The essential micronutrient selenium has been linked to property exhibiting insulin‐mimetic effects in metabolism. On the other hand, some studies shows that selenium supplementation at high doses can increase the incidence risk of diabetes. Thereby, due to an inverse correlation between the serum selenium concentration and the progressing gestational period, the objective here was evaluating offspring metabolism of female Wistar rats treated during pregnancy and lactation with sodium selenite. For this purpose, two groups (n=6 each and ~ 250g) of female Wistar rats were underwent to the following treatments: isotonic saline or sodium selenite (1mg/kg, p.o). Our results indicate that treated group, after weaning, had higher expression of type 2 deiodinase in brown adipose tissue than control. Moreover, the programmed offspring had higher milk intake and had an increased lipid oxidation. Therefore, we conclude that selenium supplementation during pregnancy and lactation alters offspring metabolic profile. In this context, we conjecture that possible selenium induced insulin resistance in offspring can be caused by thyroid hormones genomic and non genomic actions.Support: FAPERJ &amp; CNPq.

Restrictive diet during pregnancy‐induced vascular dysfunction and hypertension in mice is associated with insulin resistance

In mice, restrictive diet pregnancy (RDP), a model mimicking preeclampsia in humans, induces vascular dysfunction in the offspring that is related to decreased vascular nitric oxide (NO) bioavailability. There is abundant evidence that NO plays an important role in the regulation of insulin sensitivity in animals and humans. We speculated that offspring of RDP mice are insulin‐resistant.We, therefore, assessed insulin sensitivity (euglycemic‐hyperinsulinemic clamp studies) in offspring of RDP and control mice fed with high‐fat diet (HFD) for 8 wks. The main new finding was that HFD induced much more severe insulin resistance in offspring of RDP than in control mice, as evidenced by a markedly smaller glucose infusion rate to maintain euglycemia (77.4±10.7 vs. 96.7±12.2, P&lt;.001) in offspring of RDP than in control mice. Insulin resistance was not related to an intrinsic defect of skeletal muscle because muscle glucose uptake was comparable in the 2 groups. In analogy to other NO‐deficient states, this problem is probably related to vascular dysfunction resulting in impaired insulin stimulation of blood flow and substrate delivery to skeletal muscle tissue. Preeclampsia‐induced vascular dysfunction has also been found in humans. We speculate that preeclampsia represents a novel risk factor facilitating diet‐induced insulin resistance in humans.Grant support: Swiss National Science Foundation and Swiss Society of Hypertension

Maternal/Fetal Determinants of Insulin Resistance in Women During Pregnancy and in Offspring Over Life

Insulin resistance is a component of the pathophysiology of both type 2 diabetes and gestational diabetes mellitus (GDM), but is also characteristic of normal glycemic physiology during pregnancy. In recent years, many studies have tried to understand determinants of insulin resistance in normal pregnancy and GDM, revealing that the placenta is capable of secreting many cytokines and hormones, classically considered as adipokines. More specifically, it appears that leptin and TNFα could be implicated in gestational insulin resistance and GDM pathophysiology. In addition, the maternal metabolic milieu was also identified as a key determinant of later insulin resistance in offspring, a phenomenon often described as 'fetal programming'. This article reviews the established risk factors and the more novel suspected biomarkers involved in maternal insulin resistance during pregnancy as well as the maternal and early life determinants of insulin resistance in offspring later in their life. We are also highlighting recent reports of the potential mechanisms involved in 'programming' of insulin resistance such as epigenetic modulation.

Treatment with constitutive androstane receptor ligand during pregnancy prevents insulin resistance in offspring from high-fat diet-induced obese pregnant mice

The constitutive androstane receptor (CAR) has been reported to decrease insulin resistance even during pregnancy, while exposure to a high-fat diet (HFD) in utero in mice can induce a type 2 diabetes phenotype that can be transmitted to the progeny. Therefore, we examined whether treatment with a CAR ligand during pregnancy could prevent hypertension, insulin resistance, and hyperlipidemia in the offspring from HFD-induced obese pregnant mice (OH mice). We employed four groups of offspring from HFD-fed and control diet-fed pregnant mice with or without treatment with a CAR ligand. Treatment with a CAR ligand during pregnancy improved glucose tolerance and the levels of triglyceride and adipocytokine and restored the changes induced by HFD with amelioration of hypertension in the adult OH mice. This treatment also increased adiponectin mRNA expression, suppressed leptin expression in adipose tissues of OH mice, and abolished the effect of HFD on the epigenetic modifications of the genes encoding adiponectin and leptin in the offspring during immaturity and adulthood. Our data suggest that CAR might be a potential therapeutic target to prevent metabolic syndrome in adulthood of offspring exposed to an HFD in utero.

Voluntary post weaning exercise restores metabolic homeostasis in offspring of obese rats

AimPhysical exercise reduces obesity, insulin resistance and dyslipidemia. We previously found that maternal obesity alters central appetite circuits and contributes to increased adiposity, glucose intolerance and metabolic disease in offspring. Here we hypothesized that voluntary exercise would ameliorate the adverse metabolic effects of maternal obesity on offspring. Methods and ResultsSprague–Dawley females fed chow (C) or high-fat diet HFD (H) were mated. Female offspring from C dams were weaned onto chow (CC); those from H dams recieved chow (HC) or HFD (HH). Half of each group was provided with running wheels (CCEX, HCEX, HHEX; n=10–12).Maternal obesity increased body weight (12%), adiposity, plasma lipids and induced glucose intolerance (HC vs CC; P<0.05). These were exaggerated by postweaning HFD (HH vs HC; P<0.01), showed doubled energy intake, a 37% increase in body weight, insulin resistance and glucose intolerance (HH vs HC; P<0.01). Exercise reduced fat mass, plasma lipids, HOMA and fasting glucose in HCEX (vs HC; P<0.05) and HHEX (vs HH; P<0.01). Values in HCEX were indistinguishable from CC, however in HHEX these metabolic parameters remained higher than the sedentary HC and CC rats (P<0.01). mRNA expression of hypothalamic pro-opiomelanocortin, and adipose tumour necrosis factor α and 11β-hydroxysteroid dehydrogenase type 1 were reduced by exercise in HHEX (vs HH; P<0.05). ConclusionWhile voluntary exercise almost completely reversed the metabolic effects of maternal obesity in chow fed offspring, it did not fully attenuate the increased adiposity, glucose intolerance and insulin resistance in offspring weaned onto HFD.

73: In utero exposure to maternal obesity programs offspring insulin resistance

73: In utero exposure to maternal obesity programs offspring insulin resistance

Low Maternal Vitamin B-12 Status Is Associated with Offspring Insulin Resistance Regardless of Antenatal Micronutrient Supplementation in Rural Nepal ,

Questions have been raised about potentially negative effects of antenatal folic acid use in populations with a high prevalence of vitamin B-12 deficiency. Our objective was to examine the association between maternal folate and vitamin B-12 status in pregnancy on offspring insulin resistance and examine whether the effects of maternal micronutrient supplementation varied by baseline maternal folate and/or vitamin B-12 status. Pregnant women were cluster randomized to receive daily supplements containing vitamin A alone or with folic acid, folic acid+iron, folic acid+iron+zinc, or a multiple micronutrient. In a subsample (n = 1132), micronutrient status biomarkers were analyzed at baseline and late pregnancy. Children born to the women who participated in the trial were visited at 6–8 y of age. Fasting plasma glucose and insulin were used to estimate insulin resistance using the homeostasis model assessment (HOMA-IR). Children whose mothers were deficient in vitamin B-12 (<148 pmol/L, 27%) during early pregnancy had a 26.7% increase in HOMA-IR (P = 0.02), but there was no association with maternal folate status. Among children born to women who were vitamin B-12 deficient at baseline, the percent difference in HOMA-IR compared to the control group was 15.1% (95% CI: −35.9, 106.4), 4.9% (−41.6, 88.5), 3.3% (−38.4, 73.5), and 18.1% (−29.0, 96.7) in the folic acid, folic acid-iron, folic acid-iron-zinc, and multiple micronutrient supplementation groups, respectively, none of which were significant. Maternal vitamin B-12 deficiency is associated with an elevated risk of insulin resistance, but supplementation with folic acid or other micronutrients led to no significant change in insulin resistance in school-aged offspring.

Nine Days of Intensive Exercise Training Improves Mitochondrial Function But Not Insulin Action in Adult Offspring of Mothers with Type 2 Diabetes

A close association between insulin resistance and reduced skeletal muscle oxidative capacity has been reported in adult offspring of people with type 2 diabetes (T2D), prompting a hypothesis that insulin resistance may result from mitochondrial dysfunction or vice versa. We determined whether 9 d of intensive exercise training ameliorates the mitochondrial dysfunction and insulin resistance in offspring of T2D. We compared the response to 9 d of intensive exercise training in eight (seven females, one male) healthy adult offspring of mothers with T2D with eight (six females, two males) nondiabetic controls. Skeletal muscle mitochondrial ATP production was assessed using a luciferase-based assay, and insulin sensitivity was measured using hyperinsulinemic-euglycemic clamps. Short-term intensive training increased skeletal muscle mitochondrial ATP production and citrate synthase activity similarly in both groups (P < 0.01). In contrast, whereas short-term intensive training reduced the fasting glucose (~5%, P = 0.035) and insulin levels (~40%, P = 0.011) as well as increased the glucose infusion rate during the hyperinsulinemic-euglycemic clamp (~50%, P = 0.028) among controls, no changes in these parameters were observed among offspring except for an increase in fasting glucose (~7%, P = 0.004). A short-term intensive exercise training program was equally effective at increasing skeletal muscle oxidative capacity in nondiabetic people and in the offspring of mothers with diabetes. In contrast, the exercise improved insulin sensitivity only in nondiabetic people but not in the offspring of T2D mothers, revealing dissociation between improvements in skeletal muscle mitochondrial function and insulin sensitivity. The exercise effect on mitochondrial function and insulin sensitivity seems to be mediated by different regulatory pathways.

Low maternal B12 status is associated with offspring insulin resistance but B12 or folate supplementation does not alter that risk

There is concern that high maternal folate and low B12 status are associated with offspring insulin resistance (HOMA). We previously reported that maternal micronutrient supplementation had no effect on HOMA. Here, we report the association between maternal folate and B12 status and HOMA. In a substudy (n=1132) of a RCT of vitamin A alone (control) or with folic acid, folic acid-iron, folic acid-iron-zinc, or multiple micronutrient supplements, micronutrient status was assessed in early and late pregnancy (~10 and 36 wks gestation). In the offspring at 6–8 y, insulin resistance was estimated with the HOMA model using fasting insulin and glucose. Child HOMA was not associated with maternal plasma folate or B12 at early (folate β=0.05, p=0.48; B12 β=−0.05, p=0.42) or late (folate β=−0.02, p=0.77; B12 β=−0.09, p=0.21) pregnancy in continuous models. However, children whose mothers were B12 deficient (<148 pmol/L) at enrollment had a 26.7% increase in HOMA (p=0.02); this was not observed for low or high folate levels. Among B12 deficient women, micronutrient supplements containing folate with or without B12 among other nutrients did not affect HOMA (p>0.05 for all). Low B12 but not folate status during pregnancy is associated with insulin resistance in childhood, but maternal micronutrient supplementation that includes B12 does not alter that risk. Funded by the Gates Foundation and USAID.

Gestational Exposure to Maternal Obesity Decreases Mitochondrial SIRT3 and Components of Oxidative Phosphorylation in Offspring Liver

Exposure to maternal overweight (OW) during development influences the risk of obesity in adult‐life. We reported that by postnatal day (PND) 120 male offspring from OW rat dams have greater body weight and fat mass (p&lt;0.005), and develop insulin resistance when fed high‐fat diets (HFD, 45% fat). OW dam offspring develop hepatic steatosis and lipogenic gene expression signature at PND21, prior to obesity. Here we examined systemic and hepatic metabolic adaptations in offspring from lean and OW dams at PND21. Offspring from OW dams had decreased energy expenditure (p&lt;0.05) and higher respiratory exchange ratio (RER) values (p&lt;0.05) on AIN‐93G diet. HFD consumption further exacerbated the decrease in EE and RER as compared to offspring of lean dams, indicating an impaired capacity to utilize fatty acids (FA). Mitochondrial function in the liver is an important regulator of FA utilization. Liver protein content of electron transport chain complexes (II, III, and ATPase) was decreased (p&lt;0.03) in offspring from OW dams. Hepatic mRNA and protein expression of SIRT3, an important epigenetic regulator of mitochondrial oxidative capacity was decreased (p&lt;0.002) in offspring from OW dams. In conclusion, mitochondrial dysfunction may precede the development of energy utilization perturbations, hepatic steatosis, adiposity, and insulin resistance in offspring from OW rat dams at weaning. Support NIHR01‐DK084225

Prevalence and Predictors of Overweight and Insulin Resistance in Offspring of Mothers With Gestational Diabetes Mellitus

OBJECTIVEGestational diabetes mellitus (GDM) is associated with high birth weight in the offspring. This may lead to overweight and insulin resistance during childhood. The aim of the study was to assess the impact of GDM on overweight risk and insulin resistance in offspring.RESEARCH DESIGN AND METHODSBMI measurements were collected at age 2, 8, and 11 years from 232 offspring of mothers with GDM (OGDM) and compared with those from 757 offspring of mothers with type 1 diabetes (OT1D) and 431 offspring of nondiabetic mothers (ONDM) born between 1989 and 2000. Insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR]) was determined at age 8 and 11 years in 751 children (74 OGDM). Overweight was defined as BMI percentile ≥90; insulin resistance was defined by HOMA-IR.RESULTSOverweight prevalence was increased in OGDM compared with OT1D and to ONDM throughout childhood (age 11 years 31.1, 15.8, and 15.5%; P = 0.005). Maternal obesity was an important predictor of overweight risk in children (age 11 years odds ratio 7.0 [95% CI 1.8–27.7]; P = 0.006); birth size and maternal smoking during pregnancy were inconsistently associated with and treatment of GDM during pregnancy did not affect overweight risk. HOMA-IR was increased in OGDM compared with offspring of ONDM mothers (P = 0.01, adjusted for sex and age) and was associated with the child's BMI (P = 0.004).CONCLUSIONSOverweight and insulin resistance in children is increased in OGDM compared with OT1D or ONDM. The finding that overweight risk is associated mainly with maternal obesity suggests that familial predisposition contributes to childhood growth in these offspring.

Variant near ADAMTS9 Known to Associate with Type 2 Diabetes Is Related to Insulin Resistance in Offspring of Type 2 Diabetes Patients—EUGENE2 Study

BackroundA meta-analysis combining results from three genome-wide association studies and followed by large-scale replication identified six novel type 2 diabetes loci. Subsequent studies of the effect of these variants on estimates of the beta-cell function and insulin sensitivity have been inconclusive. We examined these variants located in or near the JAZF1 (rs864745), THADA (rs7578597), TSPAN8 (rs7961581), ADAMTS9 (rs4607103), NOTCH2 (rs10923931) and the CDC123/CAMK1D (rs12779790) genes for associations with measures of pancreatic beta-cell function and insulin sensitivity.Methodology/ResultsOral and intravenous glucose stimulated insulin release (n = 849) and insulin sensitivity (n = 596) estimated from a hyperinsulinemic euglycemic clamp were measured in non-diabetic offspring of type 2 diabetic patients from five European populations. Assuming an additive genetic model the diabetes-associated major C-allele of rs4607103 near ADAMTS9 associated with reduced insulin-stimulated glucose uptake (p = 0.002) during a hyperinsulinemic euglycemic clamp. However, following intravenous and oral administration of glucose serum insulin release was increased in individuals with the C-allele (p = 0.003 and p = 0.01, respectively). A meta-analyse combining clamp and IVGTT data from a total of 905 non-diabetic individuals showed that the C-risk allele associated with decreased insulin sensitivity (p = 0.003) and increased insulin release (p = 0.002). The major T-allele of the intronic JAZF1 rs864745 conferring increased diabetes risk was associated with increased 2nd phase serum insulin release during an IVGTT (p = 0.03), and an increased fasting serum insulin level (p = 0.001). The remaining variants did not show any associations with insulin response, insulin sensitivity or any other measured quantitative traits.ConclusionThe present studies suggest that the diabetogenic impact of the C-allele of rs4607103 near ADAMTS9 may in part be mediated through decreased insulin sensitivity of peripheral tissues.

Altered skeletal muscle insulin signaling and mitochondrial complex II-III linked activity in adult offspring of obese mice

We recently reported insulin resistance in adult offspring of obese C57BL/6J mice. We have now evaluated whether parameters of skeletal muscle structure and function may play a role in insulin resistance in this model of developmental programming. Obesity was induced in female mice by feeding a highly palatable sugar and fat-rich diet for 6 wk prior to pregnancy, and during pregnancy and lactation. Offspring of obese dams were weaned onto standard laboratory chow. At 3 mo of age, skeletal muscle insulin signaling protein expression, mitochondrial electron transport chain activity (ETC), muscle fiber type, fiber density, and fiber cross-sectional area were compared with that of offspring of control dams weaned onto the chow diet. Female offspring of obese dams demonstrated decreased skeletal muscle expression of p110beta, the catalytic subunit of PI3K (P < 0.01), as well as reduced Akt phosphorylation at Serine residue 473 compared with control offspring. Male offspring of obese dams demonstrated increased skeletal muscle Akt2 and PKCzeta expression (P < 0.01; P < 0.001, respectively). A decrease in mitochondrial-linked complex II-III was observed in male offspring of obese dams (P < 0.01), which was unrelated to CoQ deficiency. This was not observed in females. There were no differences in muscle fiber density between offspring of obese dams and control offspring in either sex. Sex-related alterations in key insulin-signaling proteins and in mitochondrial ETC may contribute to a state of insulin resistance in offspring of obese mice.

Maternal obesity is necessary for programming effect of high-fat diet on offspring

We tested the hypothesis that maternal consumption of dietary fat, independent from obesity, increases serum leptin in neonatal pups and predisposes them to adult obesity. Female rats either were fed a high-fat (HF) diet or a low-fat (LF) diet or were fed the HF diet but pair fed (PF) to the caloric intake of the LF group for 4 wk before breeding and throughout gestation and lactation. Dams consuming the HF diet had increased adiposity and were hyperphagic. At weaning, pups born to obese dams had significantly higher body fat and serum leptin levels and reduced insulin tolerance compared with offspring of LF-fed dams. Pups were weaned onto a chow diet until 8 wk of age, when they were then fed either HF or LF diet. At 18 wk of age, offspring from obese HF dams weighed more than offspring from nonobese LF or PF dams, and offspring eating HF diet weighed significantly more than those eating LF diet. Consequently, HF-fed offspring of obese HF dams weighed the most and LF-fed offspring from obese HF dams were similar in weight to HF-fed offspring from nonobese LF dams. These data suggest that maternal obesity exerts an independent effect on offspring body weight that is of similar magnitude as the effect of the offspring's adult diet. Furthermore, there was no difference in body weight between the nonobese LF and PF offspring on either diet. Together, these data suggest that maternal adiposity, and not dietary fat per se, induces hyperleptinemia and insulin resistance in offspring, as well as an increased body weight that persists into adulthood.