SH2B1 regulation of energy balance,body weight,and glucose metabolism

The Src homology 2B(SH2B)family members(SH2B1,SH2B2 and SH2B3)are adaptor signaling proteins containing characteristic SH2 and PH domains.SH2B1(also called SH2-B and PSM)and SH2B2(also called APS)are able to form homo-or hetero-dimers via their N-terminal dimerization domains.Their C-terminal SH2 domains bind to tyrosyl phosphorylated proteins,including Janus kinase 2(JAK2),TrkA,insulin receptors,insulin-like growth factor-1 receptors,insulin receptor substrate-1(IRS1),and IRS2.SH2B1 enhances leptin signaling by both stimulating JAK2 activity and assembling a JAK2/IRS1/2 signaling complex.SH2B1 promotes insulin signaling by both enhancing insulin receptor catalytic activity and protecting against dephosphorylation of IRS proteins.Accordingly,genetic deletion of SH2B1 results in severe leptin resistance,insulin resistance,hyperphagia,obesity,and type 2 diabetes in mice.Neuronspecific overexpression of SH2B1βtransgenes protects against diet-induced obesity and insulin resistance.SH2B1 in pancreaticβcells promotesβcell expansion and insulin secretion to counteract insulin resistance in obesity.Moreover,numerous SH2B1 mutations are genetically linked to leptin resistance,insulin resistance,obesity,and type 2 diabetes in humans.Unlike SH2B1,SH2B2 and SH2B3 are not required for the maintenance of normal energy and glucose homeostasis.The metabolic function of the SH2B family is conserved from insects to humans.     

Impaired glucose transport and insulin receptor tyrosine phosphorylation in skeletal muscle from obese women with gestational diabetes.

Women who develop gestational diabetes mellitus (GDM) have severe insulin resistance and markedly increased risk to develop subsequent type 2 diabetes. We investigated the effects of pregnancy and GDM on glucose transport activity and the expression and phosphorylation of the insulin receptor and insulin receptor substrate (IRS)-1 in human skeletal muscle fiber strips in vitro. Rectus abdominis muscle biopsies were obtained at the time of cesarean section from 11 pregnant women with normal glucose tolerance (pregnant control), 7 pregnant women with GDM, and 11 nonpregnant women undergoing elective surgery (nonpregnant control). Subjects were matched for age and similar degree of obesity. The rate of maximal insulin (10(-7) mol/l)-stimulated 2-deoxyglucose transport was reduced by 32% (P < 0.05) in muscle strips from the pregnant control group and even further in GDM subjects by 54% (P < 0.05 vs. pregnant control). The maximal effect of insulin on tyrosine phosphorylation of the insulin receptor was 37% lower (P < 0.05) in GDM subjects than in pregnant control subjects and was not related to changes in the abundance of the insulin receptor. Compared with nonpregnant control subjects, maximal insulin-stimulated IRS-1 tyrosine phosphorylation was significantly lower by 59 +/- 24% (mean +/- SD) (P < 0.05) and 62 +/- 28% (P < 0.05) in pregnant control and GDM subjects, respectively. This was reflected by a 23% (P < 0.05) and 44% (P < 0.002) reduction in IRS-1 protein levels in muscle from pregnant control and GDM subjects. Both pregnant control and GDM subjects exhibited a 1.5- to 2-fold increase in the levels of IRS-2 (P < 0.01) and p85alpha regulatory subunit of phosphatidylinositol (PI) 3-kinase (P < 0.05), despite reduced glucose transport activity. These data indicate that insulin resistance to glucose transport during pregnancy is uniquely associated with a decrease in IRS-1 tyrosine phosphorylation, primarily due to decreased expression of IRS-1 protein. However, in GDM subjects, a decrease in tyrosine phosphorylation of the insulin receptor beta-subunit is associated with further decreases in glucose transport activity. Thus, impaired insulin receptor autophosphorylation is an important early distinction underlying muscle insulin resistance in young women with GDM, and it may underlie future risk for the development of type 2 diabetes.     

Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1

Increased plasminogen activator inhibitor 1 (PAI-1) has been linked to not only thrombosis and fibrosis but also to obesity and insulin resistance. Increased PAI-1 levels have been presumed to be consequent to obesity. We investigated the interrelationships of PAI-1, obesity, and insulin resistance in a high-fat/high-carbohydrate (HF) diet-induced obesity model in wild-type (WT) and PAI-1-deficient mice (PAI-1(-/-)). Obesity and insulin resistance developing in WT mice on an HF diet were completely prevented in mice lacking PAI-1. PAI-1(-/-) mice on an HF diet had increased resting metabolic rates and total energy expenditure compared with WT mice, along with a marked increase in uncoupling protein 3 mRNA expression in skeletal muscle, likely mechanisms contributing to the prevention of obesity. In addition, insulin sensitivity was enhanced significantly in PAI-1(-/-) mice on an HF diet, as shown by euglycemic-hyperinsulinemic clamp studies. Peroxisome proliferator-activated receptor (PPAR)-gamma and adiponectin mRNA, key control molecules in lipid metabolism and insulin sensitivity, were maintained in response to an HF diet in white adipose tissue in PAI-1(-/-) mice, contrasting with downregulation in WT mice. This maintenance of PPAR-gamma and adiponectin may also contribute to the observed maintenance of body weight and insulin sensitivity in PAI-1(-/-) mice. Treatment in WT mice on an HF diet with the angiotensin type 1 receptor antagonist to downregulate PAI-1 indeed inhibited PAI-1 increases and ameliorated diet-induced obesity, hyperglycemia, and hyperinsulinemia. PAI-1 deficiency also enhanced basal and insulin-stimulated glucose uptake in adipose cells in vitro. Our data suggest that PAI-1 may not merely increase in response to obesity and insulin resistance, but may have a direct causal role in obesity and insulin resistance. Inhibition of PAI-1 might provide a novel anti-obesity and anti-insulin resistance treatment.     

Inheritance of diabetes mellitus as consequence of gestational hyperglycemia in rats

Our study investigated whether a deterioration of glucose homeostasis and insulin secretion in adult female rats from hyperglycemic dams could be transmitted to the next generation independent of genetic interferences. Dams (F0) were rendered hyperglycemic by continuous glucose infusion during the last week of pregnancy. Females born of these rats (F1) exhibited glucose intolerance and impaired insulin secretion in vivo at adulthood. When they were 3 mo old, they were matched with males born of control dams. During pregnancy, their glucose tolerance remained impaired compared with that of controls. Consequently, F2 newborns of F1 hyperglycemic dams showed the main features of newborns from diabetic mothers: they were hyperglycemic, hyperinsulinemic, and macrosomic. As adults, they displayed basal hyperglycemia and defective glucose tolerance and insulin secretion. This indicates that the long-range deteriorating effects on glucose homeostasis of gestational hyperglycemia in the F1 generation are transmitted to the F2 generation and suggests that a perturbed fetal metabolic environment contributes to the inheritance of diabetes mellitus.     

Deletion of the androgen receptor in adipose tissue in male mice elevates retinol binding protein 4 and reveals independent effects on visceral fat mass and on glucose homeostasis

Testosterone deficiency is epidemic in obese ageing males with type 2 diabetes, but the direction of causality remains unclear. Testosterone-deficient males and global androgen receptor (AR) knockout mice are insulin resistant with increased fat, but it is unclear whether AR signaling in adipose tissue mediates body fat redistribution and alters glucose homoeostasis. To investigate this, mice with selective knockdown of AR in adipocytes (fARKO) were generated. Male fARKO mice on normal diet had reduced perigonadal fat but were hyperinsulinemic and by age 12 months, were insulin deficient in the absence of obesity. On high-fat diet, fARKO mice had impaired compensatory insulin secretion and hyperglycemia, with increased susceptibility to visceral obesity. Adipokine screening in fARKO mice revealed a selective increase in plasma and intra-adipose retinol binding protein 4 (RBP4) that preceded obesity. AR activation in murine 3T3 adipocytes downregulated RBP4 mRNA. We conclude that AR signaling in adipocytes not only protects against high-fat diet-induced visceral obesity but also regulates insulin action and glucose homeostasis, independently of adiposity. Androgen deficiency in adipocytes in mice resembles human type 2 diabetes, with early insulin resistance and evolving insulin deficiency.     

Sleep Fragmentation During Late Gestation Induces Metabolic Perturbations and Epigenetic Changes in Adiponectin Gene Expression in Male Adult Offspring Mice

Sleep fragmentation (SF) is a common condition among pregnant women, particularly during late gestation. Gestational perturbations promote the emergence of adiposity and metabolic disease risk in offspring, most likely through epigenetic modifications. Adiponectin (AdipoQ) expression inversely correlates with obesity and insulin resistance. The effects of SF during late gestation on metabolic function and AdipoQ expression in visceral white adipose tissue (VWAT) of offspring mice are unknown. Male offspring mice were assessed at 24 weeks after dams were exposed to SF or control sleep during late gestation. Increased food intake, body weight, VWAT mass, and insulin resistance, with reductions in AdipoQ expression in VWAT, emerged in SF offspring. Increased DNMT3a and -b and global DNA methylation and reduced histone acetyltransferase activity and TET1, -2, and -3 expression were detected in VWAT of SF offspring. Reductions in 5-hydroxymethylcytosine and H3K4m3 and an increase in DNA 5-methylcytosine and H3K9m2 in the promoter and enhancer regions of AdipoQ emerged in adipocytes from VWAT and correlated with AdipoQ expression. SF during late gestation induces epigenetic modifications in AdipoQ in male offspring mouse VWAT adipocytes along with a metabolic syndrome–like phenotype. Thus, altered gestational environments elicited by SF impose the emergence of adverse, long-lasting metabolic consequences in the next generation.     

Early Life Exposure to Maternal Insulin Resistance Has Persistent Effects on Hepatic NAFLD in Juvenile Nonhuman Primates

The origins of nonalcoholic fatty liver disease (NAFLD) may lie in early intrauterine exposures. Here we examined the maternal response to chronic maternal high-fat (HF) diet and the impact of postweaning healthy diet on mechanisms for NAFLD development in juvenile nonhuman primate (NHP) offspring at 1 year of age. Pregnant females on HF diet were segregated as insulin resistant (IR; HF+IR) or insulin sensitive (IS; HF+IS) compared with control (CON)-fed mothers. HF+IR mothers have increased body mass, higher triglycerides, and increased placental cytokines. At weaning, offspring were placed on a CON or HF diet. Only offspring from HF+IR mothers had increased liver triglycerides and upregulated pathways for hepatic de novo lipid synthesis and inflammation that was irreversible upon switching to a healthy diet. These juvenile livers also showed a combination of classical and alternatively activated hepatic macrophages and natural killer T cells, in the absence of obesity or insulin resistance. Our findings suggest that maternal insulin resistance, including elevated triglycerides, insulin, and weight gain, initiates dysregulation of the juvenile hepatic immune system and development of de novo lipogenic pathways that persist in vitro and may be an irreversible “first hit” in the pathogenesis of NAFLD in NHP.     

Effect of gestational diabetes mellitus on testis and pancreatic tissues of male offspring

The purpose of this study was to determine the effect of gestational diabetes mellitus (GDM) on some reproductive characteristics, testicular and pancreatic oxidative status and pancreatic endocrine receptor densities of male offspring at post‐pubertal stage. A total of 36 1‐day‐old Wistar Albino male offspring including 12 pups of nontreated mothers (control group), 14 pups of 40 mg/kg STZ‐injected mothers (STZ‐40 group) and 10 pups of 60 mg/kg STZ‐injected mothers (STZ‐60 group) were used. The offspring were euthanised on post‐natal day 60, their blood, reproductive organs and pancreatic tissues were obtained and examined. When compared with the control group, there was a significant decrease in body and absolute reproductive organ weights, serum testosterone level, testicular and pancreatic catalase activities, pancreatic glutathione level, epididymal sperm concentration of both STZ‐40 and STZ‐60 groups as well as in testicular glutathione level of only STZ‐60 group. Significant increases were determined in testicular and pancreatic malondialdehyde level and glutathione peroxidase activity in both groups and in fasting serum glucose of only STZ‐60 group in comparison with the control group. Although some histopathological damages were observed in testes of both STZ‐40 and STZ‐60 groups, there were no detectable differences between the groups in density of insulin, glucagon and somatostatin receptors in pancreas. In conclusion, GDM has negative effects on reproductive efficiency and testicular–pancreatic tissue oxidant/antioxidant balance of male offspring at post‐pubertal stage.     

Gestational diabetes: A clinical update

Gestational diabetes mellitus (GDM) is increasing in prevalence in tandem with the dramatic increase in the prevalence of overweight and obesity in women of childbearing age. Much controversy surrounds the diagnosis and management of gestational diabetes, emphasizing the importance and relevance of clarity and consensus. If newly proposed criteria are adopted universally a significantly growing number of women will be diagnosed as having GDM, implying new therapeutic challenges to avoid foetal and maternal complications related to the hyperglycemia of gestational diabetes. This review provides an overview of clinical issues related to GDM, including the challenges of screening and diagnosis, the pathophysiology behind GDM, the treatment and prevention of GDM and the long and short term consequences of gestational diabetes for both mother and offspring.     

Effects of overexpression of human GLUT4 gene on maternal diabetes and fetal growth in spontaneous gestational diabetic C57BLKS/J Lepr(db/+) mice.

During gestation, heterozygous C57BLKS/J-Lepr(db/+) mice develop spontaneous gestational diabetes mellitus (GDM), and the newborn fetuses are macrosomic compared with offspring from wild-type (+/+) mothers. To investigate the effects of the leptin receptor mutation on maternal metabolism and fetal growth during pregnancy, we studied +/+, db/+, and db/+ transgenic mice that overexpress the human GLUT4 gene two- to three-fold (db/+TG6). During pregnancy, fasting plasma glucose and hepatic glucose production were twofold greater in db/+ than +/+ mice, despite similar insulin levels. In skeletal muscle, insulin-stimulated tyrosine phosphorylation was decreased in pregnant +/+ mice, and even more so in db/+ mice: insulin receptor beta (IR-beta), +/+ 34%, db/+ 57% decrease, P<0.05; insulin receptor substrate 1 (IRS-1), +/+ 44%, db/+ 61% decrease, P<0.05; and phosphoinositol (PI) 3-kinase (p85alpha), +/+ 33%, db/+ 65% decrease, P<0.05. Overexpression of GLUT4 in db/+TG6 mice markedly improved glucose-stimulated insulin secretion, by 250%, and increased IRbeta, IRS-1, and p85alpha phosphorylation twofold, despite no change in concentration of these proteins. Plasma leptin concentration increased 40-fold during pregnancy, from 2.2+/-0.5 to 92+/-11 ng/ml and 3.6+/-0.1 to 178+/-34 ng/ml in +/+ and db/+ mice, respectively (P<0.01), but was increased to only 23+/-3 ng/ml in pregnant db/+TG6 mice (P<0.001). Maternal fat mass and energy intake were greater in db/+ mice, and fat mass was reduced by GLUT4 overexpression, independent of food intake. Fetal body weight was increased by 8.1 and 7.9% in db/+ and db/+TG6 mothers, respectively (P<0.05), regardless of fetal genotype, whereas fetuses from db/+TG8 mothers (four- to fivefold overexpression) weighed significantly less compared with pups from +/+ or db/+ mothers (P<0.05). These results suggest that the single mutant db allele effects susceptibility to GDM through abnormalities in insulin receptor signaling, defective insulin secretion, and greater nutrient availability. GLUT4 overexpression markedly improves insulin-signaling in GDM, resulting in increased insulin secretion and improved glycemic control. However, maternal hyperglycemia appears not to be the sole cause of fetal macrosomia. These data suggest that GDM is associated with defects in insulin receptor signaling in maternal skeletal muscle, and this may be an important factor provoking maternal and fetal perinatal complications.     

Higher offspring birth weight predicts the metabolic syndrome in mothers but not fathers 8 years after delivery: the Pune Children's Study

In Europid populations, low birth weight of offspring predicts insulin resistance in the mother and cardiovascular disease in both parents. We investigated the association between birth weight of offspring and obesity and cardiovascular risk in the parents of 477 8-year-old children born at the King Edward Memorial Hospital, Pune, India. Eight years after the birth of the child, mothers (33 years of age, n = 459) of heavier babies were taller and more obese (BMI, fat mass, and waist circumference, all P < 0.001) than mothers of lighter babies. Increasing offspring birth weight predicted higher homeostasis model assessment for insulin resistance (P < 0.01) and metabolic syndrome in mothers (P < 0.001) (adjusted for offspring sex and birth order, maternal age, and socioeconomic status) but not hyperglycemia. Fathers (39 years of age, n = 398) of heavier babies were taller and heavier, independent of maternal size (P < 0.01, both), but were not more insulin resistant. Unlike other reports, lower offspring birth weight did not predict insulin resistance in fathers. Thus, urban Indian parents have a higher risk of being obese 8 years after delivery of a heavier child. Mothers but not fathers of heavier babies also have a higher risk of being insulin resistant and developing the metabolic syndrome. Our findings highlight the need for a better understanding of the relation between fetal growth and future health before contemplating public health interventions to improve fetal growth.     

Exercise Before and During Pregnancy Prevents the Deleterious Effects of Maternal High-Fat Feeding on Metabolic Health of Male Offspring

The intrauterine environment during pregnancy is a critical factor in the development of diabetes and obesity in offspring. To determine the effects of maternal exercise during pregnancy on the metabolic health of offspring, 6-week-old C57BL/6 virgin female mice were fed a chow (21%) or high-fat (60%) diet and divided into four subgroups: trained (housed with running wheels for 2 weeks preconception and during gestation), prepregnancy trained (housed with running wheels for 2 weeks preconception), gestation trained (housed with running wheels during gestation), or sedentary (static cages). Male offspring were chow fed, sedentary, and studied at 8, 12, 24, 36, and 52 weeks of age. Offspring from chow-fed dams that trained both before and during gestation had improved glucose tolerance beginning at 8 weeks of age and continuing throughout the 1st year of life, and at 52 weeks of age had significantly lower serum insulin concentrations and percent body fat compared with all other groups. High-fat feeding of sedentary dams resulted in impaired glucose tolerance, increased serum insulin concentrations, and increased percent body fat in offspring. Remarkably, maternal exercise before and during gestation ameliorated the detrimental effect of a maternal high-fat diet on the metabolic profile of offspring. Exercise before and during pregnancy may be a critical component for combating the increasing rates of diabetes and obesity.     

Role of lipid oxidation in pathogenesis of insulin resistance of obesity and type II diabetes

Increased lipid oxidation is generally observed in subjects with obesity and diabetes and has been suggested to be responsible for the insulin resistance associated with these conditions. We measured, by continuous indirect calorimetry, lipid and glucose oxidation and nonoxidative glucose disposal in 82 obese subjects during a 100-g oral glucose tolerance test (OGTT) and in 26 during a euglycemic insulin (40 mU.min-1.m-2) clamp. The obese subjects were subdivided into those with normal glucose tolerance (group A), those with impaired glucose tolerance (group B), and those with overt diabetes (group C). Forty-five healthy nonobese subjects were subdivided into a young and an older control group, which were age-matched to the nondiabetic obese (groups A and B) and diabetic obese (group C) subjects, respectively. In the postabsorptive state, as well as in response to insulin stimulation (both OGTT and insulin clamp), lipid oxidation was significantly increased in all three obese groups in comparison with either young or older controls. Basal glucose oxidation was significantly decreased in obese nondiabetic and obese glucose--intolerant subjects (groups A and B) compared with age-matched controls. During the OGTT and during the insulin clamp, insulin-stimulated glucose oxidation was decreased in all three obese groups. In contrast, nonoxidative glucose disposal was markedly inhibited in nondiabetic and diabetic obese patients during the euglycemic insulin clamp but not during the OGTT. After glucose ingestion, nonoxidative glucose uptake was normal in nondiabetic obese and glucose-intolerant obese subjects and decreased in diabetic obese subjects. Statistical analysis revealed that lipid and glucose oxidation were strongly and inversely related in the basal state, during euglycemic insulin clamp, and during OGTT. The negative correlation between lipid oxidation and nonoxidative glucose uptake, although significant, was much weaker. Fasting and post-OGTT hyperglycemia were the strongest (negative) correlates of nonoxidative glucose disposal in both single and multiple regression models. We conclude that 1) reduced glucose oxidation and reduced nonoxidative glucose disposal partake of the insulin resistance of nondiabetic obese and diabetic obese individuals; 2) hyperglycemia provides a compensatory mechanism for the defect in nonoxidative glucose disposal in nondiabetic obese subjects; however, this compensation is characteristically lost when overt diabetes ensues; and 3) increased lipid oxidation may contribute, in part, to the defects in glucose oxidation and nonoxidative glucose uptake in obesity.     

Effects of maternal hypercholesterolemia on pregnancy and development of offspring

The effect of maternal hypercholesterolemia on the course of pregnancy and the development of offspring was investigated. Rats were fed either an enriched-cholesterol diet (HC) or a standard diet (control) from 1 week before mating until weaning of offspring. Compared with the control group, HC dams showed a fourfold increase in abortions, a twofold increase in neonatal mortality, smaller litter size, and lower birth weight of pups. At weaning, Na(+),K(+)-ATPase activity in the outer renal medulla was reduced in HC pups compared with control pups, suggesting retarded or impaired development of medullary nephron segments. At this point, to better examine the adverse effects of maternal hypercholesterolemia, the HC pups were divided into two groups: one fed a cholesterol-enriched diet (HC/hc) and the other a standard diet (HC/nc), while control pups were maintained on the standard diet. In adulthood, the HC/hc group showed growth impairment and reduced renal function, demonstrated by low creatinine clearance (0.24+/-0.04 ml/min per 100 g body weight) and high fractional excretion of sodium, potassium, and water ( P<0.05 vs. control). These effects were partially reversed in the HC/nc group. In this study, neither dams nor offspring developed hypertension. Thus, maternal hypercholesterolemia adversely affected pregnancy outcomes and the development of offspring by inducing abnormalities and thereby reducing renal function.     

Maternal Ileal Interposition Surgery Confers Metabolic Improvements to Offspring Independent of Effects on Maternal Body Weight in UCD-T2DM Rats

Background

Increasing numbers of people are undergoing bariatric surgery, of which approximately half are women in their childbearing years. However, information on the long-term effects of maternal bariatric surgery in their children is lacking. Furthermore, since bariatric surgery is performed to reduce body weight, clinical studies have not been able to differentiate between benefits to the child due to maternal body weight loss versus other maternal postoperative metabolic changes. Therefore, we used the University of California, Davis, type 2 diabetes mellitus (UCD-T2DM) rat model to test the hypothesis that maternal ileal interposition (IT) surgery would confer beneficial metabolic effects in offspring, independent of effects on maternal body weight.

Methods

IT surgery was performed on 2-month-old prediabetic female UCD-T2DM rats. Females were bred 3 weeks after surgery, and male pups were studied longitudinally.

Results

Maternal IT surgery resulted in decreased body weight in offspring compared with sham offspring (P?<?0.05). IT offspring exhibited improvements of glucose-stimulated insulin secretion and nutrient-stimulated glucagon-like peptide-2 (GLP-2) secretion (P?<?0.05). Fasting plasma unconjugated bile acid concentrations were 4-fold lower in IT offspring compared with sham offspring at two months of age (P?<?0.001).

Conclusions

Overall, maternal IT surgery confers modest improvements of body weight and improves insulin secretion and nutrient-stimulated GLP-2 secretion in offspring in the UCD-T2DM rat model of type 2 diabetes, indicating that this is a useful model for investigating the weight-independent metabolic effects of maternal bariatric surgery.     

Lactational exposure of polychlorinated biphenyls downregulates critical genes in Leydig cells of F1 male progeny (PND21)

Polychlorinated biphenyls (PCBs) are environmental contaminants. The present study was aimed to test the effect of lactational exposure of PCBs on Leydig cellular mRNA and protein expressions of 5α‐reductase, aromatase and androgen receptor (AR) in F1 male offspring. Lactating dams were orally gavaged with different doses of PCBs (Aroclor 1254) 0, 1, 2 and 5 mg kg b.wt^?1 day^?1, respectively, from PND1 to PND21. Male offsprings were sacrificed at PND21. Testes were used to isolate Leydig cells. Blood was collected. Serum testosterone (T) and oestradiol (E₂) were measured. Anogenital distance was measured. Dams’ milk lipid and serum lipids of male pups were estimated. PCB (Aroclor 1254) concentration of dams’ milk and serum of male pups were analysed by GC‐ECD. Leydig cellular mRNA and protein expressions of 5α‐reductase, aromatase and AR were significantly decreased. Our data suggest that lactational exposure of PCBs downregulates selected genes in Leydig cells of F1 generation on post‐natal day 21.     

Cellular Stress,Excessive Apoptosis,and the Effect of Metformin in a Mouse Model of Type 2 Diabetic Embryopathy

Increasing prevalence of type 2 diabetes in women of childbearing age has led to a higher incidence of diabetes-associated birth defects. We established a model of type 2 diabetic embryopathy by feeding 4-week-old female mice a high-fat diet (HFD) (60% fat). After 15 weeks on HFD, the mice showed characteristics of type 2 diabetes mellitus (DM) and were mated with lean male mice. During pregnancy, control dams fed a normal diet (10% fat) were maintained on either normal diet or HFD, serving as a control group with elevated circulating free fatty acids. DM dams produced offspring at a rate of 11.3% for neural tube defect (NTD) formation, whereas no embryos in the control groups developed NTDs. Elevated markers of oxidative stress, endoplasmic reticulum stress, caspase activation, and neuroepithelial cell apoptosis (causal events in type 1 diabetic embryopathy) were observed in embryos of DM dams. DM dams treated with 200 mg/kg metformin in drinking water ameliorated fasting hyperglycemia, glucose intolerance, and insulin resistance with consequent reduction of cellular stress, apoptosis, and NTDs in their embryos. We conclude that cellular stress and apoptosis occur and that metformin effectively reduces type 2 diabetic embryopathy in a useful rodent model.     

Exploration of the shared pathophysiological mechanisms of gestational diabetes and large for gestational age offspring

Gestational diabetes mellitus(GDM) and large for gestational age(LGA)offspring are two common pregnancy complications. Connections also exist between the two conditions, including mutual maternal risk factors for the conditions and an increased prevalence of LGA offspring amongst pregnancies affected by GDM. Thus, it is important to elucidate potential shared underlying mechanisms of both LGA and GDM. One potential mechanistic link relates to macronutrient metabolism. Indeed, derangement of carbohydrate and lipid metabolism is present in GDM, and maternal biomarkers of glucose and lipid control are associated with LGA neonates in such pregnancies. The aim of this paper is therefore to reflect on the existing nutritional guidelines for GDM in light of our understanding of the pathophysiological mechanisms of GDM and LGA offspring. Lifestyle modification is first line treatment for GDM, and while there is some promise that nutritional interventions may favourably impact outcomes, there is a lack of definitive evidence that changing the macronutrient composition of the diet reduces the incidence of either GDM or LGA offspring.The quality of the available evidence is a major issue, and rigorous trials are needed to inform evidence-based treatment guidelines.     

Insulin effect during embryogenesis determines fetal growth: a possible molecular link between birth weight and susceptibility to type 2 diabetes

Low birth weight has been reported to be associated with impaired insulin secretion and insulin resistance. It has been proposed that this association results from fetal programming in response to the intrauterine environment (the thrifty phenotype hypothesis). To elucidate the relationship between birth weight and genetically determined defects in insulin secretion, we measured the birth weights of neonates derived from crosses of male pancreatic beta-cell type glucokinase knockout (Gck+/-) mice and female wild-type (WT) or Gck+/- mice. In 135 offspring, birth weights were lower in the presence of a fetal heterozygous mutation and higher in the presence of a maternal heterozygous mutation. Moreover, Gck-/- neonates had significantly smaller birth weights than WT or Gck+/- neonates (means +/- SE 1.49+/-0.03 [n = 30] vs. 1.63+/-0.03 [n = 30] or 1.63+/-0.02 [n = 50] g, respectively; P<0.01). Thus, Gck mutations in beta-cells may impair insulin response to glucose and alter intrauterine growth as well as glucose metabolism after birth. This study has confirmed the results of a previous report that human subjects carrying mutations in Gck had reduced birth weights and has provided direct evidence for a link between insulin and fetal growth. Moreover, birth weights were reduced in insulin receptor substrate-1 knockout mice despite normal insulin levels. Taken together, these results suggest that a genetically programmed insulin effect during embryogenesis determines fetal growth and provides a possible molecular link between birth weight and susceptibility to type 2 diabetes.     

Identification of HKDC1 and BACE2 as Genes Influencing Glycemic Traits During Pregnancy Through Genome-Wide Association Studies

Maternal metabolism during pregnancy impacts the developing fetus, affecting offspring birth weight and adiposity. This has important implications for metabolic health later in life (e.g., offspring of mothers with pre-existing or gestational diabetes mellitus have an increased risk of metabolic disorders in childhood). To identify genetic loci associated with measures of maternal metabolism obtained during an oral glucose tolerance test at ∼28 weeks’ gestation, we performed a genome-wide association study of 4,437 pregnant mothers of European (n = 1,367), Thai (n = 1,178), Afro-Caribbean (n = 1,075), and Hispanic (n = 817) ancestry, along with replication of top signals in three additional European ancestry cohorts. In addition to identifying associations with genes previously implicated with measures of glucose metabolism in nonpregnant populations, we identified two novel genome-wide significant associations: 2-h plasma glucose and HKDC1, and fasting C-peptide and BACE2. These results suggest that the genetic architecture underlying glucose metabolism may differ, in part, in pregnancy.The intrauterine milieu of the developing fetus, as determined largely by maternal metabolism, impacts both fetal and later health outcomes. Offspring of mothers with pre-existing or gestational diabetes mellitus (GDM) have an increased risk of metabolic disorders in childhood, including obesity, impaired glucose tolerance, and higher lipid levels (1–3). Maternal glucose levels less than those diagnostic of GDM are also associated with greater offspring birth weight and adiposity and may impose similar risks later in childhood and adulthood (4–6). The mechanisms underlying these risks are not known, but maternal metabolism is important given the impact of the mother’s metabolic profile on the intrauterine milieu of the developing fetus.Maternal glucose metabolism during pregnancy differs from the nongravid state because the mother must meet both her own and the growing fetus’s energy needs (7). Fasting glucose decreases progressively throughout gestation, but insulin resistance increases from the end of the first through the third trimester. As insulin resistance increases, basal and stimulated insulin secretion, postprandial glucose levels, and hepatic glucose production increase compared with the nongravid state.Maternal metabolism is determined by genetic and environmental factors. Given the unique aspects of glucose metabolism in pregnancy, we examined whether genetic variation associated with glycemic traits during pregnancy differs from that known to be important in the nongravid state. This was accomplished using DNA and phenotype data collected by the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study, a multicenter, international study that collected high-quality phenotypic data related to fetal growth and maternal glucose metabolism from ∼25,000 pregnant women of varied geographic, ethnic, and sociodemographic backgrounds. Standardized protocols that were uniform across centers were used to test for associations of maternal glycemia less severe than overt diabetes with risks of adverse pregnancy outcomes (6,8). Genetic loci important for maternal metabolism during pregnancy were identified by genome-wide mapping and replication of single nucleotide polymorphisms (SNPs) demonstrating association.