Decreased Insulin Sensitivity Research Articles

Decreased Insulin Sensitivity in Telomerase-Immortalized Mesenchymal Stem Cells Affects Efficacy and Outcome of Adipogenic Differentiation in vitro.

Modern biomedical science still experiences a significant need for easy and reliable sources of human cells. They are used to investigate pathological processes underlying disease, conduct pharmacological studies, and eventually applied as a therapeutic product in regenerative medicine. For decades, the pool of adult mesenchymal stem/stromal cells (MSCs) remains a promising source of stem and progenitor cells. Their isolation is more feasible than most other stem cells from human donors, yet they have a fair share of drawbacks. They include significant variability between donors, loss of potency, and transformation during long-term culture, which may impact the efficacy and reproducibility of research. One possible solution is a derivation of immortalized MSCs lines which receive a broader use in many medical and biological studies. In the present work, we demonstrated that in the most widely spread commercially available hTERT-immortalized MSCs cell line ASC52telo, sensitivity to hormonal stimuli was reduced, affecting their differentiation efficacy. Furthermore, we found that immortalized MSCs have impaired insulin-dependent and cAMP-dependent signaling, which impairs their adipogenic, but not osteogenic or chondrogenic, potential under experimental conditions. Our findings indicate that hTERT-immortalized MSCs may present a suboptimal choice for studies involving modeling or investigation of hormonal sensitivity.

MECHANISMS IN ENDOCRINOLOGY: Transient juvenile hypoglycemia in growth hormone receptor deficiency - mechanistic insights from Laron syndrome and tailored animal models.

The aim of the study is to find possible explanations for vanishing juvenile hypoglycemia in growth hormone receptor deficiency (GHRD) in human patients and animal models. We reviewed parameters of glucose metabolism in distinct age groups into two human cohorts (Israeli and Ecuadorian) of Laron syndrome (LS) patients, a mouse model (Ghr-KO mouse) and provided additional data for a porcine model (GHR-KO pig). Juvenile hypoglycemia is a common symptom of GHRD and vanishes in adulthood. In the Israeli cohort, developing metabolic syndrome is associated with decreasing insulin sensitivity, insulinopenia and glucose intolerance, and increasing glucose levels with age. In the Ecuadorian patients and both animal models, insulin sensitivity is preserved or even enhanced. Alterations in food intake and energy consumption do not explain the differences in glucose levels; neither is the accumulation of body fat associated with negative effects in the Ecuadorian cohort nor in the animal models. A reduced beta-cell mass and resulting insulin secretory capacity is common and leads to glucose intolerance in Ghr-KO mice, while glucose tolerance is preserved in Ecuadorian patients and the GHR-KO pig. In human patients and the GHR-KO pig, a simultaneous occurrence of normoglycemia with the onset of puberty is reported. Reduced gluconeogenesis in GHRD is discussed to cause juvenile hypoglycemia and a counter-regulatory stimulation of gluconeogenesis can be hypothesized. A coherent study assessing endogenous glucose production and beta-cell capacity in the hypoglycemic and normoglycemic age group is needed. This can be performed in GHR-KO pigs, including castrated animals.

Age-related susceptibility to insulin resistance arises from a combination of CPT1B decline and lipid overload

BackgroundThe skeletal muscle plays a central role in glucose homeostasis through the uptake of glucose from the extracellular medium in response to insulin. A number of factors are known to disrupt the normal response to insulin leading to the emergence of insulin resistance (IR). Advanced age and a high-fat diet are factors that increase the susceptibility to IR, with lipid accumulation in the skeletal muscle being a key driver of this phenomenon. It is debated, however, whether lipid accumulation arises due to dietary lipid overload or from a decline of mitochondrial function. To gain insights into the interplay of diet and age in the flexibility of muscle lipid and glucose handling, we combined lipidomics, proteomics, mitochondrial function analysis and computational modelling to investigate young and aged mice on a low- or high-fat diet (HFD).ResultsAs expected, aged mice were more susceptible to IR when given a HFD than young mice. The HFD induced intramuscular lipid accumulation specifically in aged mice, including C18:0-containing ceramides and diacylglycerols. This was reflected by the mitochondrial β-oxidation capacity, which was upregulated by the HFD in young, but not in old mice. Conspicuously, most β-oxidation proteins were upregulated by the HFD in both groups, but carnitine palmitoyltransferase 1B (CPT1B) declined in aged animals. Computational modelling traced the flux control mostly to CPT1B, suggesting a CPT1B-driven loss of flexibility to the HFD with age. Finally, in old animals, glycolytic protein levels were reduced and less flexible to the diet.ConclusionWe conclude that intramuscular lipid accumulation and decreased insulin sensitivity are not due to age-related mitochondrial dysfunction or nutritional overload alone, but rather to their combined effects. Moreover, we identify CPT1B as a potential target to counteract age-dependent intramuscular lipid accumulation and thereby IR.

Ginsenoside Rg5 Improves Insulin Resistance and Mitochondrial Biogenesis of Liver via Regulation of the Sirt1/PGC-1α Signaling Pathway in db/db Mice.

Type 2 diabetes mellitus (T2DM) is a common metabolic syndrome that decreases insulin sensitivity and mitochondrial biogenesis in the liver. Our previous study demonstrated that ginsenoside Rg5 (Rg5) could attenuate renal injury in diabetic mice but its underlying mechanism in mitochondrial biogenesis and insulin sensitivity remains poorly understood. In this study, we found that Rg5 intervention significantly inhibited blood glucose increases in db/db mice, improved liver function damage and hepatocyte apoptosis, and activated the IRS-1/phosphatidylinositol 3-kinase/AKT insulin metabolism signaling pathway. Rg5 treatment also increased the level of glycogen synthesis and activated sirtuin1 (Sirt1) to increase glucose uptake and insulin sensitivity in insulin-resistant HepG2 (IR-HepG2) cells. Rg5 intervention also effectively improved liver oxidative stress and inflammation in db/db mice and increased mitochondrial biogenesis caused by T2DM. Additionally, the Rg5 treatment increased the mitochondrial mass in IR-HepG2 cells and activated Sirt1 to regulate the Sirt1/PGC-1α/mitofusin-2 mitochondrial biosynthesis pathway. Our findings demonstrated that Rg5 enhanced liver mitochondrial biogenesis and insulin sensitivity in db/db mice by activating the Sirt1/PGC-1α signaling pathway, suggesting the potential of Rg5 as a natural product for T2DM interventions.

Potentiation of Acetylcholine-Induced Relaxation of Aorta in Male UC Davis Type 2 Diabetes Mellitus (UCD-T2DM) Rats: Sex-Specific Responses.

Previous reports suggest that diabetes may differentially affect the vascular beds of females and males. The objectives of this study were to examine whether there were (1) sex differences in aortic function and (2) alterations in the relative contribution of endothelium-derived relaxing factors in modulating aortic reactivity in UC Davis Type 2 Diabetes Mellitus (UCD-T2DM) rats. Endothelium-dependent vasorelaxation (EDV) in response to acetylcholine (ACh) was measured in aortic rings before and after exposure to pharmacological inhibitors. Relaxation responses to sodium nitroprusside were assessed in endothelium-denuded rings. Moreover, contractile responses to phenylephrine (PE) were measured before and after incubation of aortic rings with a nitric oxide synthase (NOS) inhibitor in the presence of indomethacin. Metabolic parameters and expression of molecules associated with vascular and insulin signaling as well as reactive oxygen species generation were determined. Diabetes slightly but significantly impaired EDV in response to ACh in aortas from females but potentiated the relaxation response in males. The potentiation of EDV in diabetic male aortas was accompanied by a traces of nitric oxide (NO)- and prostanoid-independent relaxation and elevated aortic expression of small- and intermediate conductance Ca2+-activated K+ channels in this group. The smooth muscle sensitivity to NO was not altered, whereas the responsiveness to PE was significantly enhanced in aortas of diabetic groups in both sexes. Endothelium-derived NO during smooth muscle contraction, as assessed by the potentiation of the response to PE after NOS inhibition, was reduced in aortas of diabetic rats regardless of sex. Accordingly, decreases in pAkt and peNOS were observed in aortas from diabetic rats in both sexes compared with controls. Our data suggest that a decrease in insulin sensitivity via pAkt-peNOS-dependent signaling and an increase in oxidative stress may contribute to the elevated contractile responses observed in diabetic aortas in both sexes. This study demonstrates that aortic function in UCD-T2DM rats is altered in both sexes. Here, we provide the first evidence of sexual dimorphism in aortic relaxation in UCD-T2DM rats.

Changes in abdominal subcutaneous adipose tissue phenotype following menopause is associated with increased visceral fat mass

Menopause is associated with a redistribution of adipose tissue towards central adiposity, known to cause insulin resistance. In this cross-sectional study of 33 women between 45 and 60 years, we assessed adipose tissue inflammation and morphology in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) across menopause and related this to menopausal differences in adipose tissue distribution and insulin resistance. We collected paired SAT and VAT biopsies from all women and combined this with anthropometric measurements and estimated whole-body insulin sensitivity. We found that menopause was associated with changes in adipose tissue phenotype related to metabolic dysfunction. In SAT, postmenopausal women showed adipocyte hypertrophy, increased inflammation, hypoxia and fibrosis. The postmenopausal changes in SAT was associated with increased visceral fat accumulation. In VAT, menopause was associated with adipocyte hypertrophy, immune cell infiltration and fibrosis. The postmenopausal changes in VAT phenotype was associated with decreased insulin sensitivity. Based on these findings we suggest, that menopause is associated with changes in adipose tissue phenotype related to metabolic dysfunction in both SAT and VAT. Whereas increased SAT inflammation in the context of menopause is associated with VAT accumulation, VAT morphology is related to insulin resistance.

Consuming Sucrose- or HFCS-sweetened Beverages Increases Hepatic Lipid and Decreases Insulin Sensitivity in Adults.

ContextStudies in rodents and humans suggest that high-fructose corn syrup (HFCS)–sweetened diets promote greater metabolic dysfunction than sucrose-sweetened diets.ObjectiveTo compare the effects of consuming sucrose-sweetened beverage (SB), HFCS-SB, or a control beverage sweetened with aspartame on metabolic outcomes in humans.MethodsA parallel, double-blinded, NIH-funded study. Experimental procedures were conducted during 3.5 days of inpatient residence with controlled feeding at a research clinic before (baseline) and after a 12-day outpatient intervention period. Seventy-five adults (18-40 years) were assigned to beverage groups matched for sex, body mass index (18-35 kg/m2), and fasting triglyceride, lipoprotein and insulin concentrations. The intervention was 3 servings/day of sucrose- or HFCS-SB providing 25% of energy requirement or aspartame-SB, consumed for 16 days. Main outcome measures were %hepatic lipid, Matsuda insulin sensitivity index (ISI), and Predicted M ISI.ResultsSucrose-SB increased %hepatic lipid (absolute change: 0.6 ± 0.2%) compared with aspartame-SB (-0.2 ± 0.2%, P < 0.05) and compared with baseline (P < 0.001). HFCS-SB increased %hepatic lipid compared with baseline (0.4 ± 0.2%, P < 0.05). Compared with aspartame-SB, Matsuda ISI decreased after consumption of HFCS- (P < 0.01) and sucrose-SB (P < 0.01), and Predicted M ISI decreased after consumption of HFCS-SB (P < 0.05). Sucrose- and HFCS-SB increased plasma concentrations of lipids, lipoproteins, and uric acid compared with aspartame-SB. No outcomes were differentially affected by sucrose- compared with HFCS-SB. Beverage group effects remained significant when analyses were adjusted for changes in body weight.ConclusionConsumption of both sucrose- and HFCS-SB induced detrimental changes in hepatic lipid, insulin sensitivity, and circulating lipids, lipoproteins and uric acid in 2 weeks.

MITOCHONDRIAL FUNCTION AND INSULIN SIGNALLING ARE LOWERED BY SUSTAINED ACYLATED GHRELIN TREATMENT IN RAT ADIPOSE TISSUE

Acylated ghrelin (AG), a gastric orexigenic hormone which plays a relevant role in the regulation of intermediate metabolism, has shown tissue specific effects. In skeletal muscle, both in vitro and in healthy and diseased rodent models experiments show that AG enhances mitochondrial function and insulin signalling, with variable effect in reducing tissue inflammation and redox balance. In the liver, AG improves redox state and gluconeogenesis, limits fat accumulation and reduces insulin signalling with no changes in mitochondrial function. AG effects on adipose tissue metabolism are currently largely undefined. We investigated the impact of four days AG s.c. administration in 12-week-old male healthy Wistar rats (AGT; n=8; twice-a-day 200 ng s.c. non orexigenic dose) compared to vehicle (Con; n=8) on retroperitoneal adipose tissue (AT) mitochondrial enzyme activities (citrate synthase and cytochrome c oxidase), oxidized/total glutathione, cytokine levels (xMAP) and insulin sensitivity in terms of AKT and GSK activating phosphorilation (western blot). No differences were observed among between groups in cumulative food intake or body weight. AGT had lower (p<0.05) mitochondrial enzyme activities compared to Con, with similar (p=NS) inflammatory cytokine profile and redox state. Insulin signalling activation was lower in AGT at AKT level (P<0.05), with similar trend for GSK (p=0.08). In rat adipose tissue, sustained acylated ghrelin adiministration lowers mitochondrial function and insulin sensitivity. These findings are consistent with reports suggesting a potential adaptative role for AG during starvation, as decreased insulin sensitivity and mitochondrial function both lower energy storage by decreasing lipogenesis in adipose tissue.

Defining the Relative Role of Insulin Clearance in Early Dysglycemia in Relation to Insulin Sensitivity and Insulin Secretion: The Microbiome and Insulin Longitudinal Evaluation Study (MILES).

Insulin resistance and insufficient insulin secretion are well-recognized contributors to type 2 diabetes. A potential role of reduced insulin clearance has been suggested, but few studies have investigated the contribution of insulin clearance while simultaneously examining decreased insulin sensitivity and secretion. The goal of this study was to conduct such an investigation in a cohort of 353 non-Hispanic White and African American individuals recruited in the Microbiome and Insulin Longitudinal Evaluation Study (MILES). Participants underwent oral glucose tolerance tests from which insulin sensitivity, insulin secretion, insulin clearance, and disposition index were calculated. Regression models examined the individual and joint contributions of these traits to early dysglycemia (prediabetes or newly diagnosed diabetes). In separate models, reduced insulin sensitivity, reduced disposition index, and reduced insulin clearance were associated with dysglycemia. In a joint model, only insulin resistance and reduced insulin secretion were associated with dysglycemia. Models with insulin sensitivity, disposition index, or three insulin traits had the highest discriminative value for dysglycemia (area under the receiver operating characteristics curve of 0.82 to 0.89). These results suggest that in the race groups studied, insulin resistance and compromised insulin secretion are the main independent underlying defects leading to early dysglycemia.

Exercise and the Prevention of Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is associated with pregnancy complications and fetal complications, as well as long-term health consequences for women and their offspring. Pregnancy is a pseudodiabetogenic state of increasing insulin resistance and decreasing insulin sensitivity, which places a woman at increased risk for GDM. Exercise facilitates the uptake of blood glucose into cells to be used for energy, making exercise a potential strategy in preventing GDM. Extensive evidence has found an association between consistent moderate to vigorous exercise in pregnancy and the prevention of GDM. With close attention to risk factors, maternity care nurses and other health care providers can play an important role in educating pregnant women on exercise recommendations to help them achieve optimal health and wellness.

Associations of plasma sphingolipid profiles with insulin response during oral glucose testing in Icelandic horses.

BackgroundSphingolipids modulate insulin sensitivity in mammals. Increased synthesis of ceramides is linked to decreased insulin sensitivity of tissues. Conversely, activation of the insulin signaling pathway can downregulate ceramide synthesis. Elucidating the association between sphingolipid metabolism and insulin response during oral glucose testing may help explain the pathophysiology of insulin dysregulation in horses.HypothesesHorses with insulin dysregulation will have a plasma sphingolipid profile characterized by increased ceramide concentrations. The plasma sphingolipid profile will have decreased ceramide concentrations after acute activation of the insulin signaling pathway by oral glucose testing.AnimalsTwelve Icelandic horses.MethodsHorses were subjected to an oral glucose test (0.5 g/kg body weight glucose), with plasma insulin concentrations measured at 0, 30, 60, 120, 180, and 240 minutes postglucose administration. Plasma samples were collected at 0 and 120 minutes for sphingolipid profiling using a liquid chromatography‐mass spectrometry‐based metabolomics analysis. Eighty‐three species of sphingolipids were detected, including 3‐ketosphinganines, dihydroceramides, ceramides, dihydrosphingomyelins, sphingomyelins, galatosylceramides, glucosylceramides, lactosylceramides, and ceramide‐1‐phosphates.ResultsGlucose administration did not significantly alter plasma sphingolipid profiles. C22:0‐ceramide, C24:1‐ceramide, C23:0‐ceramide, C16:1‐sphingomyelin, C22:0‐dihydroceramide, and C24:0‐ceramide were positively correlated with the insulin response (area under the curve).Conclusion and Clinical ImportancePositive correlation between the insulin response and sphingolipid concentrations implies upregulated sphingolipid metabolism in insulin dysregulated horses. A high plasma ceramide concentration can indicate insulin dysregulation in horses.

Effects of physical activity and obesity on hypertension: A narrative mini-review of the main effective mechanisms

Physical activity (PA) and obesity are effective interventions for hypertension. The current study is a review to explain possible mechanisms related to the effects of PA and obesity on hypertension. To this end, several scientific databases were searched using the keyword and also some English articles related to obesity and PA were investigated. Then, the mechanisms of obesity and PA associated with hypertension were extracted from the collected articles. Overall, obesity causes an increase in renin-angiotensin-aldosterone (RAA) systems, harmful changes in lipid and lipoprotein profile, a decrease in insulin sensitivity, as well as harmful changes in adipokines, oxidative stress, and inflammatory factors. PA improves the above-mentioned changes caused by obesity. Overall, PA mainly via an effect on oxidative stress, inflammation, endothelial cells, the elasticity of arteries, body weight, the activity of the RAA system, activity of parasympathetic and renal function as well as improve the insulin sensitivity has positive effects on hypertension. It should be noted that the effects of PA against hypertension is highly variable and they are related to PA modes, environmental and genetic factors.

Effects of sprint interval training on substrate oxidation in adults living with and without obesity: The i-FLEX study.

Metabolic flexibility is the ability to adapt substrate oxidation according to metabolic demand. Exercise increases fat oxidation responses in individuals living with obesity; however, limited research exists on the relationship between substrate oxidation and insulin sensitivity after sprint interval training (SIT). The primary objective was to investigate changes in substrate oxidation at rest and during submaximal exercise, and in insulin sensitivity after 4 weeks of SIT in individuals living with or without obesity. The secondary objective was to investigate correlations between changes in substrate oxidation and insulin sensitivity following SIT. Adults living with obesity (n = 16, body mass index (BMI) = 34.1 kg/m2 ± 3.8) and without obesity (n = 18, BMI = 22.9 kg/m2 ± 1.6) took part in a 4‐week SIT intervention. Participants completed three sessions of SIT per week, consisting of repeated sets of a 30‐s Wingate separated by 4 m of active recovery. Substrate oxidation at rest and during submaximal exercise was measured using VCO2/VO2. Insulin sensitivity was calculated using the Matsuda index. No difference in substrate oxidation at rest was observed for either group (p > 0.05), while a significant increase in fat oxidation was observed in individuals living with obesity [F(1,31) = 14.55, p = 0.001] during the submaximal exercise test. A significant decrease in insulin sensitivity was observed among individuals without obesity [F(1,31) = 5.010, p = 0.033]. No correlations were observed between changes in substrate oxidation and insulin sensitivity (p > 0.05). Following SIT, individuals living with obesity increased submaximal fat oxidation compared to individuals without obesity. No correlations were observed between substrate oxidation and insulin sensitivity. Thus, SIT impacts fat oxidation during exercise in individuals living with obesity while having no such influence on insulin sensitivity.

Maternal High-Fat Diet Increases Fetal Muscle Fat Metabolism and Fatty Acid Transporter Expression in an Ovine Model

ObjectivesExcessive maternal dietary fat consumption during pregnancy may be linked to adverse effects on offspring health, including greater risk of developing metabolic syndrome later in life. Metabolic syndrome is generally considered to be a preventable condition, but the extent to which it is “programmed” during fetal development remains unclear. The aim of this study was to determine the effect of a maternal high-fat diet (MHFD) during pregnancy on fetal muscle oxidative metabolism and related protein and mRNA expressions in an ovine model. MethodsWhite-faced ewes were fed either a control diet (Show-rite NewCo Lamb Feed-17% protein, 5% Fat) or a high-fat diet (Show-rite NewCo Lamb Feed + 6% Rumen-protected Fat) from 2–3 weeks before pregnancy until mid-gestation (75 days), when a C-section was performed to collect the placenta and fetal tissues for analysis. ResultsMHFD tended to increase fetal body and organ weights, but only significantly increased fetal body length and liver mass (P < 0.05). MHFD increased mRNA expression of placental (cotyledon) fatty acid transport protein-1 (FATP-1) and peroxisome proliferator activated receptor gamma, suggesting an upregulation of placental fatty acid metabolism and transport. Fetal muscle fatty acid oxidation capacity was greater in animals from MHFD pregnancies, with no effect on pyruvate oxidation. This was associated with greater fetal muscle mRNA and protein expression of FATP4, while mRNA expression glucose transporters (GLUT1 and GLUT3) decreased. Muscle expression of insulin signaling enzymes reflected a mild decreases in insulin sensitivity, but these did not reach statistical significance. ConclusionsThese studies indicate that MHFD induces an increase in placental and fetal muscle fatty acid transport and oxidation capacity, and favors lower blood glucose uptake compared to controls. Whether these shifts in fetal metabolism predispose offspring from MHFD pregnancies to elevated blood sugar and Type 2 diabetes later in life merits further investigation. Funding SourcesColorado Agricultural Experiment Station.

164-LB: Association of Maternal Insulin Sensitivity during Gestation and Neonatal Size

Background: Decrease in insulin sensitivity in late gestation is thought to promote fetal growth in humans. Methods: Cohorts with serial glucose and insulin measurements during pregnancy were included in this study. These include two Indian (n=248), a Mexican (n=115), two European (n=326) and an American (n=32) cohort. HOMA-S was correlated with neonatal weight. Results: Indian mothers were short & thin (153.7 cm, 48.8 kg and 20.2 kg/m2) and gained 5.9 kg between first and third trimesters, babies were 2720g. Mexican mothers were short (156cm, 63 kg and BMI 25.1kg/m2) and gained 7.5 kg, babies were 2955g. European mothers were tall and obese (168.0 cm, 95.5 kg and 33.7 kg/m2), gained 7.4 kg and babies were 3640g. In Indian mothers, FPG progressively decreased with increasing gestation with a small (15%) increase in insulin concentrations, HOMA-S remained stable. In Mexican and European mothers FPG remained stable, insulin increased (>50%) and HOMA-S decreased (>30%). American mothers showed the classic increase in HOMA-S in early pregnancy and a fall in late gestation (Figure 1). In Indian and Mexican mothers HOMA-S was not associated with offspring birth weight while in European cohorts, it was inversely associated. Conclusion: Chronic maternal undernutrition (stunting) and failure to reduce insulin sensitivity in late gestation may contribute to poor fetal growth in India and Mexico. Mechanistic studies are warranted. Disclosure S. Deshpande-joshi: None. O. Perichart-perera: Other Relationship; Self; IFA CELTICS, Nestle. M. Van poppel: None. C. A. Vinter: None. D. M. Jensen: None. G. Desoye: None. P. Catalano: None. C. S. Yajnik: None. H. Damle: None. M. K. Deshmukh: None. D. Bhat: None. N. S. Memane: None. A. A. Bhalerao: None. R. Ladkat: None. P. Tiwari: None. S. R. Otiv: None.

894-P: Monophasic Glucose Response Curve Is Associated with Increased C-Reactive Protein in Obese Adolescents

Three distinct glucose response curves, biphasic, monophasic and incessant increase, have been demonstrated in adults and adolescents during OGTT. Individuals with incessant increase and monophasic curves have increased risk of type 2 diabetes and decreased insulin sensitivity and secretion and thus are likely at increased risk for other cardiometabolic diseases. We, therefore, examined differences in traditional, and nontraditional cardiometabolic risk factors between obese adolescents with biphasic (n=9; age=12.6±0.9 yr, BMI=31.8±5.9 kg/m2; mean±SD) and monophasic (n=6; age=13.1±0.9; BMI=35.3±6.9) glucose response curves. Traditional risk factors were blood pressure and lipids while non-traditional risk factors included reactive hyperemia (RH), inflammatory markers [c-reactive protein (CRP), interleukin-6 (IL-6)], adiponectin, soluble intracellular adhesion molecule 1 (SICAM1), and insulin sensitivity and secretion (OGTT, Matsuda and insulinogenic indices). Systolic and diastolic blood pressure, triglycerides, HDL and LDL did not differ between groups. RH, Il-6 and Matsuda index also did not differ. Subjects with monophasic curves tended to have increased SICAM1 (260±33 vs. 184±21; mean±SE; p=0.087) and had significantly increased CRP levels (4.40±1.03 vs. 1.66±0.28 ng/ml; p=0.009) compared to subjects with biphasic curves. Adiponection (3570±450 vs. 2350±440 ng/ml; p=0.089) and insulin secretion (4.31±0.52 vs. 2.89±0.53 µU dl/mg ml; p=0.089) tended to be lower in subjects with monophasic curves. The difference in CRP remained significant when BMI was included as a covariate (p=0.02). Obese adolescents with monophasic glucose response curves to OGTT have increased inflammation compared to subjects with biphasic curves. Longitudinal studies are needed to determine whether this early phase of glucose intolerance causes increased inflammation or whether early inflammation reduces insulin secretion and causes early glucose intolerance. Disclosure R. P. Hoffman: Consultant; Self; Provention Bio, Inc., Other Relationship; Self; Medscape, Research Support; Self; Provention Bio, Inc. R. Cazeau: None. L. Rauch: None. J. A. Bauer: None. Funding National Center for Research Resources (UL1RR05755)

Diet-Induced Non-anemic Iron Deficiency Attenuates Adaptive Thermogenesis via Defective Iron Metabolism of Adipose Tissue in C57BL/6 Mice

ObjectivesIron deficiency is one of the most common nutrient deficiencies worldwide. Adaptive thermogenesis plays a critical role for maintaining energy homeostasis. Currently, the role of dietary iron deficiency on adaptive thermogenesis is unknown. We hypothesized that dietary iron deficiency attenuates adaptive thermogenesis via dysfunctional iron metabolism in adipose tissue. MethodsC57BL/6 male mice were fed a diet containing either adequate-iron (Cont: 35ppm) or deficient-iron (ID: 3ppm) throughout for 14 weeks and the last 10 weeks were fed a high-fat diet to induce obesity. Systemic iron status was evaluated by measuring serum ferritin, hemoglobin (Hb), and hematocrit (HCt). The iron content of adipose tissue was determined by ICP-MS spectrometer. The protein and gene expressions related to iron-handling and thermogenesis were measured in adipose tissue by Western blot analysis and qPCR. To assess adaptive thermogenic function, mice were exposed to cold temperature acutely (3 hour) or administrated with β3-adrenoceptor agonist (CL) for 5 days. The core body temperature and thermogenesis were determined by a rectal thermometer and infrared camera, respectively. ResultsThe ID mice displayed a non-anemic iron deficiency with reduced serum ferritin (p < 0.01), increased weight gain (p < 0.05) and decreased insulin sensitivity (p < 0.05) compared to Cont. The iron content was significantly reduced in the inguinal (iWAT, p < 0.05) of the ID mice, which was linked with reduced thermogenic heat release upon acute cold treatment. In addition, ID mice markedly reduced the adipose tissue browning and thermogenic heat release upon CL stimulation compared with Cont. In terms of iron metabolism, CL-induced coordinated iron uptake for mitochondrial biogenesis in the iWAT was impaired in the ID mice, which was comparable to inflammation-mediated defective adipose tissue browning and thermogenesis. ConclusionsIron deficiency induced visceral obesity and compromised thermogenic function due to defective iron metabolism in C57BL6 mice. Funding SourcesNational Institutes of Health Grant 1R21HD094273.

Initial Basal and Bolus Rates and Basal Rate Variability During Pump Treatment in Children and Adolescents

Objective:Pump-treated children with type 1 diabetes (T1DM) have widely differing basal insulin (BI) infusion profiles for specific periods of the day. The pattern of BI requirements depends on the timing and magnitude of cortisol and growth hormone secretion within each age group. In adolescents and young adults, a decreased insulin sensitivity is seen, particularly in the early morning (dawn phenomenon) and to a lesser extent, in the late afternoon (dusk phenomenon). Different approaches exist for the inititation of basal rates. However, there is a lack of evidence-based recommendation, especially in young children. Usually the basal rates are set equally throughout day and night or the day is divided into tertiles. The aim of this study was to analyze the change of the initial, equally distributed, BI rates over the first year of standard insulin pump therapy.Methods:A total of 154 patients with T1DM, aged between 0 and <21 years at diagnosis, from a single center were documented. Patients were divided into five age groups according to age at pump initiation: group 1, <5 years (n=36); group 2, 5-8 years (n=20); group 3, 8-15 years (n=74); group 4, 15-18 years, (n=19); and group 5, >18 years, (n=5). Distribution of hourly basal rates at the initiation of the pump and at the end of first year were evaluated.Results:Median (range) age and diabetes duration was 14.46 (1.91-26.15) and 7.89 (1.16-17.15) years, respectively. Forty-four percent were male, 56% were female. Mean total insulin dose/kg in the whole cohort at the initiation and after one year of pump therapy was 0.86±0.23 U/kg and 0.78±0.19 U/kg, respectively and differed significantly between each age group (p<0.001; p<0.001). Mean daily basal rate/kg showed significant differences between the five groups (p<0.001). Circadian distribution of BI differed markedly among the five age groups.Conclusion:At the initiation of insulin pump therapy, circadian profiles by age group should be taken into account in pediatric patients to optimize basal rate faster and more easily.

274-OR: Gestational Diabetes, Epigenetic Age Acceleration, and Insulin Sensitivity and Secretion in the Exploring Perinatal Outcomes among Children Study

Objectives: Epigenetic age acceleration (EAA) occurs when DNA methylation-predicted age is older than chronological age. EAA is associated with glucose intolerance in adults. In-utero exposure to gestational diabetes (GDM) is associated with glucose intolerance in offspring. It is not known if GDM predicts EAA in offspring or if offspring EAA is associated with insulin sensitivity and secretion. Methods: We examined the association between exposure to GDM in-utero and EAA, computed at average age 10.5 years, and EAA and measures of insulin sensitivity (HOMA-2S) and secretion (HOMA-2β) at average age 10.5 and 16.7 years in 209 girls and 209 boys in the Colorado EPOCH (Exploring Perinatal Outcomes Among Children) cohort. We calculated EAA using the Horvath, Hannum, and Levine calculators. Separate general linear mixed models adjusted associations for chronologic age and sex. Results: Exposure to GDM was associated with EAA using the Hannum (beta-coefficient 1.39, p=0.009) and Levine (1.92, p=0.024) but not the Horvath calculator (-0.01, p=0.69). EAA by the Hannum calculator predicted lower insulin sensitivity and higher insulin secretion (Table). Conclusions: We conclude that GDM predicts offspring EAA, and EAA is associated with decreased insulin sensitivity and increased insulin secretion. Associations are dependent upon the EAA calculator used. Disclosure C. Kim: None. K. K. Harrall: None. D. H. Glueck: None. B. Needham: None. D. Dabelea: None. Funding National Institutes of Health (R01DK076648, R01GM121081, R01DK068001307, M01RR00069, 5UG3OD023248)

012 Overnight light exposure acutely increases heart rate during sleep and decreases insulin sensitivity the following day

Abstract Introduction Prior reports indicate that exposure to light at night negatively impacts sleep quality, autonomic and metabolic function, but the interaction between these physiologically interconnected systems is not fully elucidated. We examined the acute effects of nighttime light exposure on sleep macro and microarchitecture, heart rate (HR) and response to oral glucose tolerance test (OGTT), and the relationship between these measures. Methods Twenty healthy adults (18 - 40 years) were randomized into Light or Dark groups and run in parallel for a three-day and two-night laboratory stay. The Light group (n=10) slept in the dark (&amp;lt; 3 lux) on Night 1 and slept with overhead room lights on (100 lux) on Night 2, while the Dark group (n=10) slept in the dark (&amp;lt; 3 lux) on both Nights 1 and 2. Overnight polysomnography (PSG) was used to assess sleep macro and microstructure (slow wave activity: SWA: 0.5–4 Hz, and slow oscillatory (SO) activity: 0.5–1 Hz), and beat-to-beat measurement of HR. A two-hour OGTT was completed each morning. The between groups change in PSG-derived measures and metabolic parameters from Night/Day 2 to Night/Day 1, was calculated. Results While a greater percentage of time was spent in stage 2 (p= 0.003) and a smaller percentage of time was spent in stage 3 (p= 0.04), there were no between group differences in SWA and SO activity. Time series analysis of HR changes across the night from Night 1 to Night 2 showed higher HR in the Light vs the Dark group (p&amp;lt; 0.001). The change from Day 1 to Day 2 of the initial insulin response (60-min. area under the curve, AUC) showed a higher insulin response in the Light vs the Dark group (p= 0.029). The change in HR was positively correlated with the change in the 60-min. AUC of insulin (R= 0.46, p= 0.049). Conclusion A single overnight light exposure acutely increases heart rate during sleep and decreases insulin sensitivity the following day and these responses appear to be associated, suggesting that elevated autonomic activity in response to light at night impacts next day metabolic responses. Support (if any) Center for Circadian and Sleep Medicine, UL1TR001422