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Summary: Background: Compared to the exhaustive study of transgenerational programming of obesity and diabetes through exposures in the prenatal period, postnatal programming mechanisms are understudied, including the potential role of breast milk composition linking maternal metabolic status (body mass index and diabetes) and offspring growth, metabolic health and future disease risk. Methods: This narrative review will principally focus on four emergent bioactive compounds [microRNA's (miRNA), lipokines/signalling lipids, small molecules/metabolites and fructose] that, until recently were not known to exist in breast milk. The objective of this narrative review is to integrate evidence across multiple fields of study that demonstrate the importance of these compositional elements of breast milk during lactation and the subsequent effect of breast milk components on the health of the infant. Results: Current knowledge on the presence of miRNA's, lipokines/signalling lipids, small molecules/metabolites and fructose in breast milk and their associations with infant outcomes is compelling, but far from resolved. Two themes emerge: (1) maternal metabolic phenotypes are associated with these bioactives and (2) though existing in milk at low concentrations, they are also associated with offspring growth and body composition. Conclusion: Breast milk research is gaining momentum though we must remain focused on understanding how non‐nutritive bioactive components are affected by the maternal phenotype, how they subsequently impact infant outcomes. Though early, there is evidence to suggest fructose is associated with fat mass in the 1st months of life whereas 12,13 diHOME (brown fat activator) and betaine are negatively associated with early adiposity and growth. [ABSTRACT FROM AUTHOR]

Metformin is a widely prescribed medication that has been used to treat children with type 2 diabetes in the United States for the past 15 years. Metformin now has a variety of clinical applications in pediatrics, and its potential clinical uses continue to expand. In addition to reviewing the current understanding of its mechanisms of action including the newly discovered effects on the gastrointestinal tract, we will also discuss current clinical uses in pediatrics, including in type 1 diabetes. Finally, we examine the existing state of monitoring for metformin efficacy and side effects and discuss prospective future clinical uses. [ABSTRACT FROM AUTHOR]

Objective To describe C-peptide levels in a large cohort of children with type 2 diabetes T2D and examine associations with demographic and clinical factors. Methods The Pediatric Diabetes Consortium ( PDC) T2D Registry has collected clinical and biologic data from youth with T2D cared for at eight US Pediatric Diabetes Centers. In this study, we assessed C-peptide levels in 331 youth with T2D (mean age, 16.1 ± 2.5 yr; median T2D duration, 2.4 yr). Results Median (interquartile range) for 90 fasted C-peptide measurements was 3.5 ng/ mL (2.3-4.8 ng/ mL) [1.2 nmol/L (0.8-1.6 nmol/L)] and for 241 random non-fasted C-peptide measurements were 4.2 ng/ mL (2.6-7.0 ng/ mL) [1.4 nmol/L (0.9-2.3 nmol/L)]. C-peptide levels were lower with insulin therapy (p < 0.001), lower body mass index (p < 0.001), hemoglobin A1c ( HbA1c) ≥9% (p < 0.001), and T2D duration ≥ 6 yr (p = 0.04). Among those with duration ≥6 yr being treated with insulin and with a HbA1c level ≥9.0% (75 mmol/L), 75% of the fasted and 80% of the non-fasted C-peptide values were above 0.2 nmol/L. Conclusions In youth with T2D, a decline in C-peptide is associated with deterioration of metabolic control and the need for insulin treatment. C-peptide levels decrease over time. However, even insulin-treated patients with 6 or more years of T2D and elevated HbA1c levels retain substantial endogenous insulin secretion. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2D) is a complex disease characterized by β-cell failure in the setting of insulin resistance. The current evidence suggests that genetic predisposition, and environmental factors can impair the capacity of the β-cells to respond to insulin resistance and ultimately lead to their failure. However, genetic studies have demonstrated that known variants account for less than 10% of the overall estimated T2D risk, suggesting that additional unidentified factors contribute to susceptibility of this disease. In this review, we will discuss the different stages that contribute to the development of β-cell failure in T2D. We divide the natural history of this process in three major stages: susceptibility, β-cell adaptation and β-cell failure, and provide an overview of the molecular mechanisms involved. Further research into mechanisms will reveal key modulators of β-cell failure and thus identify possible novel therapeutic targets and potential interventions to protect against β-cell failure. [ABSTRACT FROM AUTHOR]

A maternal diet that is low in protein increases the susceptibility of offspring to type 2 diabetes by inducing long-term alterations in β cell mass and function. Nutrients and growth factor signaling converge through mTOR, suggesting that this pathway participates in β cell programming during fetal development. Here, we revealed that newborns of dams exposed to low-protein diet (LP0.5) throughout pregnancy exhibited decreased insulin levels, a lower β cell fraction, and reduced mTOR signaling. Adult offspring of LP0.5-exposed mothers exhibited glucose intolerance as a result of an insulin secretory defect and not β cell mass reduction. The β cell insulin secretory defect was distal to glucose-dependent Ca2+ influx and resulted from reduced proinsulin biosynthesis and insulin content. Islets from offspring of LP0.5-fed dams exhibited reduced mTOR and increased expression of a subset of microRNAs, and blockade of microRNA-199a-3p and -342 in these islets restored mTOR and insulin secretion to normal. Finally, transient β cell activation of mTORC1 signaling in offspring during the last week of pregnancy of mothers fed a LP0.5 rescued the defect in the neonatal β cell fraction and metabolic abnormalities in the adult. Together, these findings indicate that a maternal low-protein diet alters microRNA and mTOR expression in the offspring, influencing insulin secretion and glucose homeostasis. [ABSTRACT FROM AUTHOR]

Background/Aims: P450c17 deficiency is an uncommon steroidogenic disorder that typically presents as a sexually infantile adolescent phenotypic female with hypertension and hypokalemia. Although cortisol synthesis is impaired, elevated corticosterone and deoxycorticosterone ordinarily prevent adrenal insufficiency. Thus, diagnosis prior to puberty is rare. We report novel clinical features of an infant with complete P450c17 deficiency due to two novel mutations in CYP17A1. Methods: A 10-week-old, 46,XY phenotypic female presented with hypotension, developed hypokalemic hypertension post-resuscitation, then hyperkalemic hyponatremia upon weaning salt supplements. All CYP17A1 exons of the proband and parents were PCR-amplified and sequenced. Cosyntropin, GnRH agonist, and hCG tests were performed. Results: Sequencing demonstrated compound heterozygosity for two novel CYP17A1 mutations, C327dupT and C362G>A (W121X), both generating premature stop codons in exon 2 and predicting non-functional enzymes. Plasma corticosterone was very elevated, deoxycorticosterone normal, cortisol detectable, and aldosterone low-normal at baseline. Responses to cosyntropin of corticosterone and progesterone were elevated, deoxycorticosterone and aldosterone normal, cortisol subnormal, and 17α-hydroxycorticosteroid intermediates undetectable. GnRH agonist/hCG testing showed no androgenic response. Conclusion: This is the first report of P450c17 deficiency presenting in a 46,XY female infant with hypotensive shock, a state exacerbated by the atypical absence of deoxycorticosterone elevation. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

"Implicit bias," also called "unconscious bias," refers to associations outside of conscious awareness that adversely affect one's perception of a person or group. Awareness of implicit bias has been increasing in the realm of diabetes care. Here, the authors highlight several types of unconscious bias on the part of clinicians and patients, including biases based on race, ethnicity, and obesity. They discuss how these biases can negatively affect patient-centered clinical interactions and diabetes care delivery, and they recommend implementation of evidence-based interventions and other health system policy approaches to reduce the potential impact of such biases in health care settings. [ABSTRACT FROM AUTHOR]

Lipids play a critical role in neonate development and breastmilk is the newborn's major source of lipids. Milk lipids directly influence the neonate plasma lipid profile. The milk lipidome is dynamic, influenced by maternal factors and related to the maternal plasma lipidome. The close inter-relationship between the maternal plasma, milk and neonate plasma lipidomes is critical to understanding maternal-child health and nutrition. In this exploratory study, lipidomes of blood and breast milk from Suffolk sheep and matched lamb blood (n = 13), were profiled on day 34 post birth by untargeted mass spectrometry. Comparative multivariate analysis of the three matrices identified distinct differences in lipids and class of lipids amongst them. Paired analysis identified 346 differential lipids (DL) and 31 correlated lipids (CL) in maternal plasma and milk, 340 DL and 32 CL in lamb plasma and milk and 295 DL and 16 CL in maternal plasma and lamb plasma. Conversion of phosphatidic acid to phosphatidyl inositol was the most active pathway in lamb plasma compared to maternal plasma. This exploratory study illustrates the partitioning of lipids across maternal plasma, milk and lamb plasma and the dynamic relationship between them, reiterating the need to study these three matrices as one biological system. [ABSTRACT FROM AUTHOR]

Insulin receptor (IR) expression on the T cell surface can indicate an activated state; however, the IR is also chemotactic, enabling T cells with high IR expression to physically move toward insulin. In humans with type 1 diabetes (T1D) and the NOD mouse model, a T cell-mediated autoimmune destruction of insulin-producing pancreatic b cells occurs. In previous work, when purified IR+ and IR2 T cells were sorted from diabetic NOD mice and transferred into irradiated nondiabetic NOD mice, only those that received IR+ T cells developed insulitis and diabetes. In this study, peripheral blood samples from individuals with T1D (new onset to 14 y of duration), relatives at high-risk for T1D, defined by positivity for islet autoantibodies, and healthy controls were examined for frequency of IR+ T cells. High-risk individuals had significantly higher numbers of IR+ T cells as compared with those with T1D (p < 0.01) and controls (p < 0.001); however, the percentage of IR+ T cells in circulation did not differ significantly between T1D and control subjects. With the hypothesis that IR+ T cells traffic to the pancreas in T1D, we developed a (to our knowledge) novel mouse model exhibiting a FLAG-tagged mouse IR on T cells on the C57BL/6 background, which is not susceptible to developing T1D. Interestingly, these C57BL/6-CD3FLAGmIR/mfm mice showed evidence of increased IR+ T cell trafficking into the islets compared with C57BL/6 controls (p < 0.001). This transgenic animal model provides a (to our knowledge) novel platform for investigating the influence of IR expression on T cell trafficking and the development of insulitis. [ABSTRACT FROM AUTHOR]

The timing of food intake is a novel dietary component that impacts health. Time-restricted feeding (TRF), a form of intermittent fasting, manipulates food timing. The timing of eating may be an important factor to consider during critical periods, such as pregnancy. Nutrition during pregnancy, too, can have a lasting impact on offspring health. The timing of food intake has not been thoroughly investigated in models of pregnancy, despite evidence that interest in the practice exists. Therefore, using a mouse model, we tested body composition and glycemic health of gestational early TRF (eTRF) in male and female offspring from weaning to adulthood on a chow diet and after a high-fat, high-sucrose (HFHS) diet challenge. Body composition was similar between groups in both sexes from weaning to adulthood, with minor increases in food intake in eTRF females and slightly improved glucose tolerance in males while on a chow diet. However, after 10 weeks of HFHS, male eTRF offspring developed glucose intolerance. Further studies should assess the susceptibility of males, and apparent resilience of females, to gestational eTRF and assess mechanisms underlying these changes in adult males. [ABSTRACT FROM AUTHOR]

Insulin secretion from β-cells is tightly regulated by local signaling from preproglucagon (Gcg) products from neighboring α-cells. Physiological paracrine signaling within the microenvironment of the β-cell is altered after metabolic stress, such as high-fat diet or the β-cell toxin, streptozotocin (STZ). Here, we examined the role and source of Gcg peptides in β-cell function and in response to STZ-induced hyperglycemia. We used whole body Gcg null (GcgNull) mice and mice with Gcg expression either specifically within the pancreas (GcgΔPanc) or the intestine (GcgΔIntest). With lower doses of STZ exposure, insulin levels were greater and glucose levels were lower in GcgNull mice compared with wild-type mice. When Gcg was functional only in the intestine, plasma glucagon-like peptide-1 (GLP-1) levels were fully restored but these mice did not have any additional protection from STZ-induced diabetes. Pancreatic Gcg reactivation normalized the hyperglycemic response to STZ. In animals not treated with STZ, GcgNull mice had increased pancreas mass via both α- and β-cell hyperplasia and reactivation of Gcg in the intestine normalized β- but not α-cell mass, whereas pancreatic reactivation normalized both β- and α-cell mass. GcgNull and GcgDIntest mice maintained higher β-cell mass after treatment with STZ compared with control and GcgΔPanc mice. Although in vivo insulin response to glucose was normal, global lack of Gcg impaired glucose-stimulated insulin secretion in isolated islets. Congenital replacement of Gcg either in the pancreas or intestine normalized glucose-stimulated insulin secretion. Interestingly, mice that had intestinal Gcg reactivated in adulthood had impaired insulin response to KCl. We surmise that the expansion of β-cell mass in the GcgNull mice compensated for decreased individual β-cell insulin secretion, which is sufficient to normalize glucose under physiological conditions and conferred some protection after STZ-induced diabetes. NEW & NOTEWORTHY We examined the role of Gcg on β-cell function under normal and high glucose conditions. GcgNull mice had decreased glucose-stimulated insulin secretion, increased β-cell mass, and partial protection against STZ-induced hyperglycemia. Expression of Gcg within the pancreas normalized these endpoints. Intestinal expression of Gcg only normalized β-cell mass and glucose-stimulated insulin secretion. Increased β-cell mass in GcgNull mice likely compensated for decreased insulin secretion normalizing physiological glucose levels and conferring some protection after STZ-induced diabetes [ABSTRACT FROM AUTHOR]

Developmental exposure to endocrine disruptors like bisphenol A (BPA) are implicated in later-life metabolic dysfunction. Leveraging a unique sheep model of developmental programming, we conducted an exploratory analysis of the programming effects of BPA on the endocrine pancreas. Pregnant ewes were administered environmentally relevant doses of BPA during gestational days (GD) 30–90, and pancreata from female fetuses and adult offspring were analyzed. Prenatal BPA exposure induced a trend toward decreased islet insulin staining and β-cell count, increased glucagon staining and α-cell count, and increased α-cell/β-cell ratio. Findings were most consistent in fetal pancreata assessed at GD90 and in adult offspring exposed to the lowest BPA dose. While not assessed in fetuses, adult islet fibrosis was increased. Collectively, these data provide further evidence that early-life BPA exposure is a likely threat to human metabolic health. Future studies should corroborate these findings and decipher the molecular mechanisms of BPA's developmental endocrine toxicity. • Prenatal BPA programmed alterations in the endocrine pancreas of female sheep. • BPA reduced β-cell count, islet insulin in gestational day (GD) 90 fetal pancreata. • BPA increased α-cell count, size, α-to-β-cell ratio, islet glucagon in GD90 fetuses. • Low dose BPA increased islet glucagon, α-to-β-cell ratio, collagen in adult females. • Trends in elevated α-cell count, islet insulin and collagen seen in high BPA adults. [ABSTRACT FROM AUTHOR]

Maternal health and diet can have important consequences for offspring nutrition and metabolic health. During lactation, signals are communicated from the mother to the infant through milk via macronutrients, hormones, and bioactive molecules. In this study we designed experiments to probe the mother-milk-infant triad in the condition of normal maternal health and upon exposure to high fat diet (HFD) with or without concurrent metformin exposure. We examined maternal characteristics, milk composition and offspring metabolic parameters on postnatal day 16, prior to offspring weaning. We found that lactational HFD increased maternal adipose tissue weight, mammary gland adipocyte size, and altered milk lipid composition causing a higher amount of omega-6 (n6) long chain fatty acids and lower omega-3 (n3). Offspring of HFD dams were heavier with more body fat during suckling. Metformin (Met) exposure decreased maternal blood glucose and several milk amino acids. Offspring of met dams were smaller during suckling. Gene expression in the lactating mammary glands was impacted to a greater extent by metformin than HFD, but both metformin and HFD altered genes related to muscle contraction, indicating that these genes may be more susceptible to lactational stressors. Our study demonstrates the impact of common maternal exposures during lactation on milk composition, mammary gland function and offspring growth with metformin having little capacity to rescue the offspring from the effects of a maternal HFD during lactation. [ABSTRACT FROM AUTHOR]

Background: Whether current dietary guidelines are appropriate for pregnancy and lactation has not been well studied. Many women of reproductive age are not meeting recommendations for dietary components such as fat, added sugar, and fiber.Objectives: To assess associations between maternal dietary components during pregnancy and lactation and infant growth and adiposity at 6 mo of age.Methods: Mother-infant dyads (n = 349) from the prospective, observational Mothers and Infants Linked for Healthy Growth study were included (100% fully breastfed for 1 mo; 75% to 6 mo). Daily intake of fat, fiber, and added sugar was obtained using the National Cancer Institute Diet History Questionnaire II during the third trimester of pregnancy and at 1 and 3 mo postpartum. Furthermore, intakes were categorized as meeting/exceeding 2015-2020 Dietary Guidelines for Americans. Multiple linear regression models adjusted for numerous potential confounders tested relations between dietary components and infant adiposity (via DXA) and growth parameters. Regression coefficients (β) for continuous variables were expressed per SD to allow for comparison of effect sizes.Results: Maternal intake of total fat and saturated fat was positively associated with infant percent body fat (%BF) (β: 0.84 per SD, P = 0.04; β: 0.96 per SD, P = 0.01, respectively). Added sugar intake was positively associated with infant weight-for-length z score (β: 0.16 per SD, P = 0.02), and excessive added sugar intake was positively associated with %BF at 6 mo (β: 0.75 per SD, P = 0.05).Conclusions: In a predominantly fully breastfeeding cohort of women, maternal intake of fat and added sugar during pregnancy and lactation were associated with small increases in infant adiposity and relative weight at 6 mo. Additional research is needed to determine if these relations persist later in infancy and if such elevations in adiposity are important for long-term obesity risk. [ABSTRACT FROM AUTHOR]

Maternal low-protein diet (LP) throughout gestation affects pancreatic b-cell fraction of the offspring at birth, thus increasing their susceptibility to metabolic dysfunction and type 2 diabetes in adulthood. The present study sought to strictly examine the effects of LP during the last week of gestation (LP12.5) alone as a developmental window for b-cell programming and metabolic dysfunction in adulthood. Islet morphology analysis revealed normal b-cell fraction in LP12.5 newborns. Normal glucose tolerance was observed in 6- to 8-wk-old male and female LP12.5 offspring. However, male LP12.5 offspring displayed glucose intolerance and reduced insulin sensitivity associated with β-cell dysfunction with aging. High-fat diet exposure of metabolically normal 12-wk-old male LP12.5 induced glucose intolerance due to increased body weight, insulin resistance, and insufficient b-cell mass adaptation despite higher insulin secretion. Assessment of epigenetic mechanisms through microRNAs (miRs) by a real-time PCR-based microarray in islets revealed elevation in miRs that regulate insulin secretion (miRs 342, 143), insulin resistance (miR143), and obesity (miR219). In the islets, overexpression of miR143 reduced insulin secretion in response to glucose. In contrast to the model of LP exposure throughout pregnancy, islet protein levels of mTOR and pancreatic and duodenal homeobox 1 were normal in LP12.5 islets. Collectively, these data suggest that LP diet during the last week of pregnancy is critical and sufficient to induce specific and distinct developmental programming effects of tissues that control glucose homeostasis, thus causing permanent changes in specific set of microRNAs that may contribute to the overall vulnerability of the offspring to obesity, insulin resistance, and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Maternal low-protein diet (LP) throughout gestation affects pancreatic β-cell fraction of the offspring at birth, thus increasing their susceptibility to metabolic dysfunction and type 2 diabetes in adulthood. The present study sought to strictly examine the effects of LP during the last week of gestation (LP12.5) alone as a developmental window for β-cell programming and metabolic dysfunction in adulthood. Islet morphology analysis revealed normal β-cell fraction in LP12.5 newborns. Normal glucose tolerance was observed in 6- to 8-wk-old male and female LP12.5 offspring. However, male LP12.5 offspring displayed glucose intolerance and reduced insulin sensitivity associated with β-cell dysfunction with aging. High-fat diet exposure of metabolically normal 12-wk-old male LP12.5 induced glucose intolerance due to increased body weight, insulin resistance, and insufficient β-cell mass adaptation despite higher insulin secretion. Assessment of epigenetic mechanisms through microRNAs (miRs) by a real-time PCR-based microarray in islets revealed elevation in miRs that regulate insulin secretion (miRs 342, 143), insulin resistance (miR143), and obesity (miR219). In the islets, overexpression of miR143 reduced insulin secretion in response to glucose. In contrast to the model of LP exposure throughout pregnancy, islet protein levels of mTOR and pancreatic and duodenal homeobox 1 were normal in LP12.5 islets. Collectively, these data suggest that LP diet during the last week of pregnancy is critical and sufficient to induce specific and distinct developmental programming effects of tissues that control glucose homeostasis, thus causing permanent changes in specific set of microRNAs that may contribute to the overall vulnerability of the offspring to obesity, insulin resistance, and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Overweight and obesity (OW/OB) impact half of the pregnancies in the United States and can have negative consequences for offspring health. Studies are limited on human milk alterations in the context of maternal obesity. Alterations in milk are hypothesized to impact offspring development during the critical period of lactation. We aimed to evaluate the relationships between mothers with OW/OB (body mass index [BMI] ≥25 kg/m2), infant growth, and selected milk nutrients. We recruited mother–infant dyads with pre‐pregnancy OW/OB and normal weight status. The primary study included 52 dyads with infant growth measures through 6 months. Thirty‐two dyads provided milk at 2 weeks, which was analysed for macronutrients, long‐chain fatty acids, and insulin. We used multivariable linear regression to examine the association of maternal weight status with infant growth, maternal weight status with milk components, and milk components with infant growth. Mothers with OW/OB had infants with higher weight‐for‐length (WFL) and BMI Z‐scores at birth. Mothers with OW/OB had higher milk insulin and dihomo‐gamma‐linolenic, adrenic, and palmitic acids and reduced conjugated linoleic and oleic acids. N6 long‐chain polyunsaturated fatty acid (LC‐PUFA)‐driven factor 1 was associated with higher WFL, lower length‐for‐age (LFA), and lower head circumference‐for‐age Z‐scores change from 2 weeks to 2 months in human milk‐fed infants, whereas N6 LC‐PUFA‐driven factor 5 was associated with lower LFA Z‐score change. Human milk composition is associated with maternal pre‐pregnancy weight status and composition may be a contributing factor to early infant growth trajectory. [ABSTRACT FROM AUTHOR]

We previously demonstrated that exposing mouse dams to metformin during gestation results in increased beta-cell mass at birth and increased beta-cell insulin secretion in adult male offspring. Given these favorable changes after a gestational maternal metformin exposure, we wanted to understand the long-term metabolic impact on offspring after exposing dams to metformin during the postnatal window. The newborn period provides a feasible clinical window for intervention and is important for beta-cell proliferation and metabolic tissue development. Using a C57BL/6 model, we administered metformin to dams from the day of birth to postnatal day 21. We monitored maternal health and offspring growth during the lactation window, as well as adult glucose homeostasis through in vivo testing. At necropsy we assessed pancreas and adipocyte morphology using histological and immunofluorescent staining techniques. We found that metformin exposure programmed male and female offspring to be leaner with a higher proportion of small adipocytes in the gonadal white adipose tissue (GWAT). Male, but not female, offspring had an improvement in glucose tolerance as young adults concordant with a mild increase in insulin secretion in response to glucose in vivo. These data demonstrate long-term metabolic programming of offspring associated with maternal exposure to metformin during lactation. [ABSTRACT FROM AUTHOR]

Objective To describe vitamin D levels and prevalence of vitamin D sufficiency, insufficiency and deficiency in a large, ethnically/racially diverse population of youth with type 1 diabetes ( T1D) and type 2 diabetes ( T2D) in comparison to national data and examine the associations between clinical/demographic factors and vitamin D levels. Methods 25-hydroxy vitamin D ( 25OHD) levels were measured in 215 youth with T1D and 326 youth with T2D enrolled in the Pediatric Diabetes Consortium ( PDC). These levels were compared with those of youth of the same age without diabetes from the 2005-2006 NHANES Survey. Results Vitamin D deficiency (<21 ng/ mL) was present in 36% of PDC participants, and insufficiency (21-29 ng/ mL) was present in an additional 34%. About 36% of age-matched youth in the NHANES Survey were vitamin D deficient and an additional 41% were insufficient. Deficiency or insufficiency varied by race/ethnicity, being highest in African-Americans (86%), intermediate in Hispanics (77%), and lowest in non-Hispanic whites (47%). Lower 25OHD levels were observed in African-American and Hispanic youth, during fall and winter, and at sites in the northern United States (all p-values < 0.001). Youth with T2D had significantly lower 25OHD levels than youth with T1D (p < 0.001), but this difference was largely eliminated after adjusting for race/ethnicity and socio-economic status. Conclusions Vitamin D deficiency/insufficiency is present in a substantial proportion of youth with diabetes, particularly minorities, but the prevalence appears similar to that in youth without diabetes. Further studies are needed to examine whether youth with diabetes would benefit from vitamin D supplementation. [ABSTRACT FROM AUTHOR]

Time-Restricted Feeding (TRF) is an increasingly common diet that may improve insulin sensitivity. This practice merits study in the setting of pregnancy, as the diet is common, pregnancy represents a critical period for the health of both mother and offspring, and the effects of TRF during pregnancy on maternal gestational health and long-term offspring consequences remain unexamined. To test these effects, female mice were randomized to 6 hours of food availability in the dark cycle (early-time restricted feeding, eTRF), or given 24-hour ad libitum (AL) food access. After one week of acclimatization, females were mated. Food intake and body composition were measured weekly throughout gestation; insulin sensitivity was assessed at day 16 of pregnancy. Offspring birth rate, survival, birthweight, and gestational age were assessed. Body composition and food intake were assessed weekly. After 70 days on a normal diet, all offspring were switched to a 45% high-fat diet (HFD) with continued weekly monitoring. Glucose tolerance and insulin tolerance tests were conducted before and after 10 weeks of HFD feeding. Our data suggests that maternal eTRF does not affect birth weight or gestational age, but does reduce litter size (7.7 pups vs. 6.0 pups) and 3-day pup survival (95% vs. 58%) compared to AL. eTRF offspring had similar insulin and glucose tolerance compared to AL counterparts until adulthood (70 days of age). After 12 weeks of high-fat diet feeding, eTRF males develop concomitant glucose intolerance (auc, p<0.0001) and insulin sensitivity (auc, p=0.006), which was absent in females. These metabolic changes were present despite eTRF males having similar fat mass, body weight, and food intake when compared to AL males. Taken together, these data suggest that eTRF during pregnancy followed by offspring HFD feeding results in male-specific impaired glucose metabolism. Further work planned will evaluate the role of pancreatic islet insulin secretion in vivo and in vitro in future cohorts. Disclosure: M. E. Carter: None. N. El habbal: None. D. S. Snyder: None. J. R. Redd: None. B. Gregg: None. D. Bridges: None. Funding: National Institute of Diabetes and Digestive and Kidney Diseases (R01DK107535); University of Michigan [ABSTRACT FROM AUTHOR]

The newly established CD3FLAG-mIR transgenic mouse model on a C57Bl/6 background has a FLAG tag on the mouse Insulin Receptor (mIR), specifically on T cells, as the FLAG-tagged mIR gene was engineered behind CD3 promoter and enhancer. The IR is a chemotactic molecule for insulin and the Flag-tagged mIR T cells in the BL/6-CD3FLAGmIR transgenic mice can migrate into the pancreas, as shown by immunofluorescent staining. While the transgenic mice do not become diabetic, there are phenotypic and metabolic changes in the islets. The transgenic islets become enlarged and disorganized by 15 weeks and those phenotypes continue out to 35 weeks of age. We examined the islets by RT-PCR for cell markers, ER stress markers, beta cell proliferation markers, and cytokines, as well as measuring serum insulin and insulin content in the pancreas at 15, 25, and 35 weeks of age. In transgenic mice, insulin in serum was increased at 15 weeks of age and glucose intolerance developed by 25 weeks of age. Passage of transgenic spleen cells into C57Bl/6 RAG−/− mice resulted in enlarged and disorganized islets with T infiltration by 4 to 5 weeks post-transfer, replicating the transgenic mouse studies. Therefore, migration of non-antigen-specific T cells into islets has ramifications for islet organization and function. [ABSTRACT FROM AUTHOR]

Prenatal testosterone (T)- treated female sheep manifest juvenile insulin resistance, post-pubertal increase in insulin sensitivity and return to insulin resistance during adulthood. Since compensatory hyperinsulinemia is associated with insulin resistance, altered pancreatic islet ontogeny may contribute towards metabolic defects. To test this, pregnant sheep were treated with or without T propionate from days 30–90 of gestation and pancreas collected from female fetuses at gestational day 90 and female offspring at 21 months-of-age. Uterine (maternal) and umbilical (fetal) arterial blood insulin/glucose ratios were determined at gestational day 90. The morphological and functional changes in pancreatic islet were assessed through detection of 1) islet hormones (insulin, glucagon) and apoptotic beta cells at fetal day 90 and 2) islet hormones (insulin, glucagon and somatostatin), and pancreatic lipid and collagen accumulation in adults. At gestational day 90, T-treatment led to maternal but not fetal hyperinsulinemia, decrease in pancreatic/fetal weight ratio and alpha cells, and a trend for increase in beta cell apoptosis in fetal pancreas. Adult prenatal T-treated female sheep manifested 1) significant increase in beta cell size and a tendency for increase in insulin and somatostatin stained area and proportion of beta cells in the islet; and 2) significant increase in pancreatic islet collagen and a tendency towards increased lipid accumulation. Gestational T-treatment induced changes in pancreatic islet endocrine cells during both fetal and adult ages track the trajectory of hyperinsulinemic status with the increase in adult pancreatic collagen accumulation indicative of impending beta cell failure with chronic insulin resistance. Image 1 • Gestational T excess induces maternal but not fetal hyperinsulinemia. • Gestational T excess reduced pancreatic/fetal weight ratio and fetal islet α cells. • Prenatal T-excess increased β cell size and collagen content. • Prenatal T excess tended to increase β cell number islet insulin and lipid content. • Prenatal T excess-induced islet disruptions contribute to hyperinsulinemia. [ABSTRACT FROM AUTHOR]