Physiological Insulin Resistance Research Articles

FEASIBILITY AND ACCEPTABILITY OF A VIRTUAL EXERCISE PROGRAM IN OLDER ADULTS WITH PREDIABETES

Abstract Through metabolic and physiological changes, aging and insulin resistance precipitate impaired physical function and its progression to type 2 diabetes (T2DM). Further, individuals with T2DM have increased risk for functional disability and mobility limitation. Therefore, the purpose of this study was to evaluate the feasibility and acceptability of Vivo, a commercially available virtual exercise program, for older adults at risk of developing T2DM. A priori criteria for feasibility and acceptability were defined as ≥80% of participants would be retained, ≥80% would attend all 24 classes and ≥90% of the program would be delivered as designed. In this 12-week single arm feasibility study, 28 older adults (69±6 years; 58% female; and 73% non-Hispanic white) with prediabetes were recruited. Out of the 28 individuals enrolled, 22 (79%) successfully completed the 12-week intervention. The results revealed a 27% increase in upper body strength (30-sec arm curl), a 13.5% increase in lower body strength (30-sec chair stand), and a 33% improvement in endurance (2-minute knee raise). Furthermore, the mean change in the 30-second chair stands was 2.0±2.2, with 14 participants increasing by ≥2 stands. Of the 22 participants who completed the intervention, 85% attended all 24 classes. Finally, intervention fidelity was assessed using a 9-item checklist with four focus areas; intervention delivery, workout intensity, safety, and participation and engagement. The intervention was delivered with 96% fidelity across three Vivo trainers. Study findings illustrate that online, live virtual exercise programs that provide tailored programming are highly feasible and acceptable and result in meaningful functional improvements.

Myoinositol and Metformin in the Prevention of Gestational Diabetes in High-Risk Patients: A Narrative Review.

Our hypothesis is that myoinositol and metformin in pregnant women with high-risk factors for glucose intolerance would reduce insulin resistance and consequently lower the incidence of gestational diabetes mellitus (GDM), a metabolic disorder of pregnancy characterized by maternal hyperglycemia due to deficient response to physiological insulin resistance, which may have a negative impact on perinatal outcome and long-term sequelae. In recent years, this pathology has become increasingly important given the global obesity epidemic and the delay in becoming pregnant, especially in industrialized countries. For this reason, the attempt to prevent, rather than cure, gestational diabetes is particularly important. In addition to lifestyle changes (especially diet and doing more exercise), myoinositol and metformin are the most promising factors at the moment, although not all RCTs published so far agree on their real effectiveness. A review of the articles published so far allows us to assume, albeit with some distinctions, that they can play a positive role.

The influence of lactation on insulin and glucose metabolism, lipid profile, and cytokines in pregnant mares

Glucose metabolism adapts to gestation, resulting in progressive physiological insulin resistance and increased insulin secretion to maintain maternal euglycemia and glucose availability for the developing fetus. These changes can impact mare fertility and maternal and neonatal health. This is the first comparison of body condition, regional adiposity, insulin and glucose dynamics, lipid metabolism, and cytokine production between lactating and non-lactating mares before, during pregnancy, and early postpartum. Twelve pregnancies from 9 broodmares, five nonlactating (NL) and seven lactating (L), were used. Evaluations were performed on the day of ovulation, at 55, 110, 165, 220, 275, and 330 days of gestation (D55, D110, D165, D220, D275, D330) and 21 days postpartum (21pp). Mares in the L group had lower basal insulin and glucose at the beginning of pregnancy, smaller area under the curve of insulin and glucose, and greater insulin sensitivity and glucose tolerance. Resistin was higher in D110 and D165 than in D0, D275, 330 and 21pp, while leptin was higher in D55, and in D110, at D110 it was equal to D0, D220, and D275, but higher than at D330 and D21pp. As for the groups, L presented lower body condition score (BCS), crest neck score (CNS), rump fat thickness (RUM), basal insulin, glucose area under the curve (AUCg), MIRG and higher RISQI, adiponectin and tumor necrosis factor (TNFα). There was no effect over time in non-esterified fatty acids (NEFA) concentrations between the L mares; in the NL, D275 presented higher concentrations than those of D0, D55, and D110, which in turn were equal to the other time points; there were higher concentrations in NL mares than L in samples D165 and D275. In conclusion, a different metabolic profile during pregnancy was detected, and NL mares were closer to the metabolic threshold for the occurrence of metabolic syndrome during pregnancy. Understanding the impacts of these differences on mare's health and their offspring's future is fundamental as most of our recipient mares for embryo transfer are non-lactating. Therefore, we suggest that further studies be performed to evaluate lactation's influence on mares' metabolic parameters.

Maternal Lipid Profile Changes in Gestational Diabetes Mellitus

Introduction: Pregnancy is commonly recognized as a state of physiological and temporary insulin resistance. This condition is driven by high concentrations of steroid hormones such as progesterone, estrogens, prolactin, cortisol and placenta-derived human placental lactogen. All of these are diabetogenic and combined cause for decreased sensitivity of insulin receptors within target tissues. Women with prior GDM are at greater risk for developing hypertension, hyperlipidaemia and electrocardiogram abnormalities. Materials and Methods: seventy five patients with Gestational diabetes mellitus and 75 healthy Normal pregnant women were enrolled for the study after the institutional ethical committee’s clearance was obtained. The fasting blood samples of the study subjects were evaluated for the glucose, lipid profile, Glycated Haemoglobin (HbA1c), Malondialdehyde (MDA) and calculated BMI. Results: Lipid peroxidation is enhanced in GDM group as MDA values have elevated significantly (p < 0.0001) compared to normal pregnancy. Total cholesterol (p< 0.001) and LDL (p = 0.001) are found to be significantly higher in GDM, but there are no significant differences in triglycerides and HDL between normal and diabetic pregnant women. Obesity is observed in GDM group as their BMI (p < 0.001) is significantly higher than that of the control group. Conclusions: It was found that GDM is associated with hyperlipidaemia as evidenced by the significantly elevated total cholesterol and LDL concentrations. Obesity and lipid peroxidation are significantly high in GDM. Keywords: Gestational diabetes mellitus, HbA1c, lipid profile, lipid peroxidation, BMI.

The Placental Role in Gestational Diabetes Mellitus: A Molecular Perspective.

During pregnancy, women undergo several metabolic changes to guarantee an adequate supply of glucose to the foetus. These metabolic modifications develop what is known as physiological insulin resistance. When this process is altered, however, gestational diabetes mellitus (GDM) occurs. GDM is a multifactorial disease, and genetic and environmental factors play a crucial role in its aetiopathogenesis. GDM has been linked to both macroscopic and molecular alterations in placental tissues that affect placental physiology. This review summarizes the role of the placenta in the development of GDM from a molecular perspective, including hormonal and pro-inflammatory changes. Inflammation and hormonal imbalance, the characteristics dominating the GDM microenvironment, are responsible for placental changes in size and vascularity, leading to dysregulation in maternal and foetal circulations and to complications in the newborn. In conclusion, since the hormonal mechanisms operating in GDM have not been fully elucidated, more research should be done to improve the quality of life of patients with GDM and their future children.

NGF effects promote the maturation of rat pancreatic beta cells by regulating GLUT2 levels and distribution, and glucokinase activity.

The nerve growth factor (NGF) participates in cell survival and glucose-stimulated insulin secretion (GSIS) processes in rat adult beta cells. GSIS is a complex process in which metabolic events and ionic channel activity are finely coupled. GLUT2 and glucokinase (GK) play central roles in GSIS by regulating the rate of the glycolytic pathway. The biphasic release of insulin upon glucose stimulation characterizes mature adult beta cells. On the other hand, beta cells obtained from neonatal, suckling, and weaning rats are considered immature because they secrete low levels of insulin and do not increase insulin secretion in response to high glucose. The weaning of rats (at postnatal day 20 in laboratory conditions) involves a dietary transition from maternal milk to standard chow. It is characterized by increased basal plasma glucose levels and insulin levels, which we consider physiological insulin resistance. On the other hand, we have observed that incubating rat beta cells with NGF increases GSIS by increasing calcium currents in neonatal cells. In this work, we studied the effects of NGF on the regulation of cellular distribution and activity of GLUT2 and GK to explore its potential role in the maturation of GSIS in beta cells from P20 rats. Pancreatic islet cells from both adult and P20 rats were isolated and incubated with 5.6 mM or 15.6 mM glucose with and without NGF for 4 hours. Specific immunofluorescence assays were conducted following the incubation period to detect insulin and GLUT2. Additionally, we measured glucose uptake, glucokinase activity, and insulin secretion assays at 5.6 mM or 15.6 mM glucose concentrations. We observed an age-dependent variation in the distribution of GLUT2 in pancreatic beta cells and found that glucose plays a regulatory role in GLUT2 distribution independently of age. Moreover, NGF increases GLUT2 abundance, glucose uptake, and GSIS in P20 beta cells and GK activity in adult beta cells. Our results suggest that besides increasing calcium currents, NGF regulates metabolic components of the GSIS, thereby contributing to the maturation process of pancreatic beta cells.

Современный взгляд на метаболические особенности детского ожирения и его осложнения

INTRODUCTION: Over the past several decades, the problem of pediatric exogenous constitutional obesity has acquired the status of a non-infectious pandemic of the 21st century. Statistics shows that both the prevalence of overweight and obese children and the incidence of morbid obesity, its complications and metabolic syndrome are increasing, which most is alarming for healthcare workers. This tendency requires specialists to understand the metabolic bases of formation of obesity, to search for new ways to treat and prevent the disease, as well as to prevent the development of complications. CONCLUSION: The given review considers the main features of metabolic alterations in the formation of childhood obesity, which can be an additional risk factor for both the development of the disease itself, and of its complications, the main ones being physiological insulin resistance of adolescents and a significant secretion of insulin-like growth factor-1 in children in the period of active growth. Understanding of metabolic features of the development of obesity at the pathophysiological and biochemical levels can become the basis for development of the ways to influence these processes. Of attention is the fact of a high prevalence of obesity complications and metabolic syndrome in childhood, with a continuing tendency to growth proportional to increase in the prevalence of obesity itself. A key point is the current absence of ways to predict obesity complications in children. Taking into account very limited possibilities of treatment of childhood obesity and its complications, the existence of prognostic markers may contribute to prevention or earlier, timely diagnosis of the main obesity complications, with a further decline of disability and mortality at a young age, as well as a considerable improvement of the quality of life of obese patients. The presented data require an in-depth analysis of mechanisms of development of childhood obesity — one of the most common problems in the world, and permit to reconceive the problems of treatment and prevention, to open up new prospects for creation of new approaches to diagnosis and control of this disease and its complications.

THU130 Long Term Tracking Of HbA1c Levels Across The Life Span In Type 1 Diabetes: From Infants To Young Adults

Abstract Disclosure: S. Kim: None. K. Song: None. M. Lee: None. J. Seo: None. H. Chae: None. H. Kim: None. A. Kwon: None. Objectives HbA1c is the most important monitoring value and generally used in diabetes. However, HbA1c may change across the life span according to growth and puberty. This study explores the long-term tracking of HbA1c from infants to young adults diagnosed with Type 1 Diabetes mellitus (T1DM) and analyzes the effects of HbA1c according to life span on complications. Method This retrospective study, included 289 patients (M, 43.0%; mean first visit age, 7.39±3.94 years old; mean followed up periods, 4.32±3.15 years) diagnosed with T1DM. The total of 6368 HbA1c values were analyzed. The distribution of HbA1c values according to age and life period was evaluated. In addition, the differences in mean HbA1c values according to sex and the use of continuous glucose monitoring (CGM) were analyzed. Furthermore, it was analyzed which HbA1c of life period has the most influence on occurrence of complications. Result The level of HbA1c was relatively high at the age of 1- to 2-years, and then decreased between 4 to 5-years. After 5 years of age, HbA1C gradually escalated and peaked at the age of 12- to 15-years, during puberty. Especially for girls, HbA1c increased dramatically during puberty between the age of 10- to 13-years, which was consistent with the physiologic insulin resistance. During in childhood to young adulthood, the mean HbA1c of CGM users was lower than that of non-users. The higher mean HbA1c during all ages affected the occurrence of complications. Intriguingly, the HbA1c level during adolescence was important for the occurrence of diabetic retinopathy. Conclusion HbA1c level change across life span, and peaked at pubertal stage, which consistent with physiologic insulin resistance during puberty. In addition, good glycemic control in adolescence may reduce the occurrence of diabetic retinopathy. Therefore, using CGM in adolescence may be helpful for glycemic control and prevention of diabetic complications. Presentation: Thursday, June 15, 2023

177-LB: Association of Pregnancy and Childhood C-Peptide Levels—Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study (HAPO-FUS)

Physiological insulin resistance partitions glucose for the growing fetus during the 2nd and 3rd trimester of pregnancy. The HAPO study has demonstrated that pregnancy hyperglycemia is associated with offspring adiposity, hyperglycemia, and glucose intolerance. Maternal insulin is a key regulator of the glucose physiology but does not cross the placenta. The goal of this study was to identify the association of pregnancy and offspring c-peptide levels, measured during oral glucose tolerance test (OGTT). Method: Using HAPO-FUS data from the NIH-NIDDK repository, multiple linear regression assessed the association of scaled pregnancy fasting and 1-hour c-peptide with cord c-peptide (at birth), and child c-peptide from OGTT at the follow-up visit (ages 10-14 years). Maternal covariates include pregnancy gestational age, BMI, glucose level and field center. Child covariates include age, sex, tanner stage, BMI z-score and glucose level. Multiple imputation was performed using missing at random assumption. Results: A total of 4,802 mother-child pairs were included. Pregnancy c-peptide was associated with cord c-peptide (fasting 0.02 [0.01-0.03], p <.001, 1-hour 0.01 [0.002-0.02], p =.006). Pregnancy fasting c-peptide was also associated with child OGTT c-peptide (fasting 0.03 [0.02-0.04], p <.001; 1-hour 0.11 [0.08-0.15], p <.001; 2-hour 0.01 [0.007-0.02], p <.001) and pregnancy 1-hour c-peptide (fasting 0.01 [0.007-0.02], p <.001; 1-hour 0.15 [0.12-0.17], p <.001; 2-hour 0.11 [0.09-0.14], p <.001). Similar associations were observed with child insulin levels. Pregnancy c-peptide levels were positively associated with HOMA-IR and negatively with child insulin sensitivity and Matsuda index while adjusting for child BMI z-score and pubertal stage. Conclusion: Pregnancy insulin levels are strongly associated with the child insulin response during OGTT. This suggests a role in the offspring pancreas developmental programming. Disclosure H. Zheng: None. A. Rajamoorthi: None. A. Skowronski: None. R. Salem: Other Relationship; Travere Inc. C. A. Leduc: None. V. V. Thaker: None. Funding National Institutes of Health (K23DK110539)

Role of preeclampsia on insulin-induced vasorelaxation

The objective of this project was to evaluate whether PE alters the vascular response to insulin. The physiological insulin resistance characteristic of pregnancy is increased in preeclamptic (PE) conditions. With the hypothesis that PE diminishes insulin vascular effects we used a conventional isolated aorta rings preparation to study insulin-induced relaxation on phenylephrin (Phe) pre-contracted vessels and Phe induced contraction in the presence or absence of insulin. Vessels were obtained from non-pregnant rats (NP) with subrenal aortic coarctation (SRAC), pregnant (P) and pregnant rats with SRAC (PE). Experiments were performed in thoracic or abdominal aorta rings with or without endothelium. The results show that PE increases the contractile response to Phe in the thoracic and abdominal aorta compared to P (PE vs P p<0.01). Incubation with insulin did not modify the thoracic or abdominal aorta Phe induced contraction of any of the three groups with and without endothelium.On the other hand, insulin induced relaxation was more evident in vessels with endothelium and was decreased both in the thoracic and the abdominal aorta of PE group (PE vs P p<0.01; PE vs NP-CARS p<0.01).In conclusion, PE decreases endothelium-dependent insulin-induced relaxation suggesting PE deteriorates insulin-PI3K-NO pathway. Funding: Consejo Nacional de Ciencia y Tecnología(CONACyT) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Impact of Visfatin Level Against Blood Pressure Among Pregnant Women

Visfatin, a protein with a molecular weight of 52 kDa, has been demonstrated to increase in the bloodstream. Visfatin has been shown in several studies to be a potential marker of preeclampsia. The objective of this study was to describe visfatin levels in pregnant women in Gianyar, Bali. An observational design was employed in this study to describe visfatin levels in 41 pregnant women in Ubud, Gianyar regency, Bali. Visfatin levels were determined by examining EDTA blood samples using the Elisa method and reading them at 450 nm on a microplate reader. The average value of visfatin levels was 6.49 ng/ml, according to the results. The average visfatin level based on hypertension blood pressure respondents was 3.74 ng/ml. This result was lower than that of normal blood pressure respondents. This study's decrease in visfatin levels may have a smaller effect on physiological insulin resistance. The average visfatin level in second trimester respondents was 7.9 ng/ml higher than 5.7 ng/ml in third trimester respondents. The increase in visfatin levels suggests that visfatin may play a role in the pathogenesis of preeclampsia. Visfatin has the potential to be used as a biomarker to detect preeclampsia earlier, allowing pregnant women with preeclampsia to receive appropriate treatment.

Lipoprotein lipase concentration in umbilical cord blood reflects neonatal birth weight.

Insulin resistance (IR) is exacerbated during pregnancy via increases in insulin counterregulatory hormones. Maternal lipids are strong determinants of neonatal growth, although triglyceride-rich lipoproteins (TGRLs) cannot be transferred directly to the fetus through the placenta. The catabolism of TGRLs under physiological IR and the reduced synthesis of lipoprotein lipase (LPL) are poorly understood. We examined the association of maternal and umbilical cord blood (UCB)-LPL concentrations with maternal metabolic parameters and fetal development. Changes in anthropometric measures and lipid-, glucose-, and insulin-related parameters, including maternal and UCB-LPL concentrations, were examined in 69 women during pregnancy. The relationship between those parameters and neonatal birth weight was assessed. Parameters reflecting glucose metabolism did not change during pregnancy, whereas those associated with lipid metabolism and IR changed markedly, particularly in the second and third trimesters. In the third trimester, the maternal LPL concentration gradually decreased, by 54%, whereas the UCB-LPL concentration was∼2-fold higher than the maternal LPL concentration. Univariate and multivariate analyses showed that the UCB-LPL concentration was a significant determinant of neonatal birth weight, together with placental birth weight. The LPL concentration in UCB reflects neonatal development under a decreased LPL concentration in maternal serum.

The Impact of Exercise Training Intensity on Physiological Adaptations and Insulin Resistance in Women with Abdominal Obesity.

Abdominal obesity has emerged globally as a major public health issue due to its high prevalence and morbidity. The benefits of physical exercise among the obese population are well documented. However, the optimal exercise intensity for reducing body fat and preventing insulin resistance and metabolic disorders is still under debate. This study aimed to examine the effects of three different intensities of combined endurance and strength training programs on anthropometric variables, physiological and muscular adaptations, and insulin sensitivity. Forty-three obese young women (age 26.4 ± 4.7 years, BMI 33.1 ± 2.5 kg/m2) were randomly assigned to one of four groups: a control group (G0), a moderate-intensity training group (G50, exercising brisk walking at 50% heart rate reserve HRR), a high-intensity training group (G75, exercise jogging at 75% HRR), and an alternated-intensity training group (G50/75, exercise brisk-walking/jogging at 50−75% HRR) with additional strength training once a week for each group. Body composition, waist circumference (WC), fasting blood glucose, insulin sensitivity and resistance (Homa-IR), resting heart rate (RHR), 6-min walk distance (6MWD), 1-repetition maximum (1-RM), and time to exhaustion (TTE) at 45% and 75% maximal voluntary contraction (MVC) for both the flexor and extensor muscle groups of the knees, were recorded before and after three months of exercise training. All training groups showed significant decreases in body mass, BMI, total body fat, body fat percentage, WC, abdominal and visceral mass (p < 0.001), with a greater reduction of body mass and BMI in G75 (p < 0.05). Lean mass increased significantly only in G50/75 (p < 0.05). The insulin sensitivity and Homa-IR decreased in the three training groups (p < 0.01), with greater enhanced resistance in G50 compared to G75 and G50/75 (p < 0.05). In contrast, there were no pre-post changes in all groups for fasting blood glucose (p > 0.05). 1-RM and TTE of the knee flexor and extensor muscles were improved in the three groups (p < 0.01), with greater improvement in G50/75 for 1RM and G75 in most of the TTE parameters (p < 0.05). RHR decreased and 6MWD increased significantly in the three training groups (p < 0.01), with greater 6MWD improvement in G75 (p < 0.05). In conclusion, the three training intensities seem to generate benefits in terms of body composition, physiological and muscular adaptations, and insulin resistance. High training intensity resulted in greater improvements in body mass, BMI, and endurance and strength, whereas moderate training intensity resulted in greater improvements of insulin resistance and homo-IR. Following alternate-intensity training, greater improvements were observed in lean mass and maximal strength performance.

Sexual dimorphism in the molecular mechanisms of insulin resistance during a critical developmental window in Wistar rats

BackgroundInsulin resistance (IR) is a condition in which the response of organs to insulin is impaired. IR is an early marker of metabolic dysfunction. However, IR also appears in physiological contexts during critical developmental windows. The molecular mechanisms of physiological IR are largely unknown in both sexes. Sexual dimorphism in insulin sensitivity is observed since early stages of development. We propose that during periods of accelerated growth, such as around weaning, at postnatal day 20 (p20) in rats, the kinase S6K1 is overactivated and induces impairment of insulin signaling in its target organs. This work aimed to characterize IR at p20, determine its underlying mechanisms, and identify whether sexual dimorphism in physiological IR occurs during this stage.MethodsWe determined systemic insulin sensitivity through insulin tolerance tests, glucose tolerance tests, and blood glucose and insulin levels under fasting and fed conditions at p20 and adult male and female Wistar rats. Furthermore, we quantified levels of S6K1 phosphorylated at threonine 389 (T389) (active form) and its target IRS1 phosphorylated at serine 1101 (S1101) (inhibited form). In addition, we assessed insulin signal transduction by measuring levels of Akt phosphorylated at serine 473 (S473) (active form) in white adipose tissue and skeletal muscle through western blot. Finally, we determined the presence and function of GLUT4 in the plasma membrane by measuring the glucose uptake of adipocytes. Results were compared using two-way ANOVA (With age and sex as factors) and one-way ANOVA with post hoc Tukey’s tests or t-student test in each corresponding case. Statistical significance was considered for P values < 0.05.ResultsWe found that both male and female p20 rats have elevated levels of glucose and insulin, low systemic insulin sensitivity, and glucose intolerance. We identified sex- and tissue-related differences in the activation of insulin signaling proteins in p20 rats compared to adult rats.ConclusionsMale and female p20 rats present physiological insulin resistance with differences in the protein activation of insulin signaling. This suggests that S6K1 overactivation and the resulting IRS1 inhibition by phosphorylation at S1101 may modulate to insulin sensitivity in a sex- and tissue-specific manner.1x839z9cy-UAMHakhorVgrVideo

Calorie Restriction Enhanced Glycogen Metabolism to Compensate for Lipid Insufficiency.

This study aims to investigate the metabolic phenotype and mechanism of 40% calorie restriction (CR) in mice. CR mice exhibit super-stable blood glucose, as evidenced by increased fasting blood glucose (FBG), decreased postprandial blood glucose, and reduced glucose fluctuations. Additionally, both fasting plasma insulin and the homeostasis model assessment of insulin resistance increase significantly in CR mice. Compared with control, the phosphorylation of insulin receptor substrates-1 and serine/threonine kinase decreases in liver and fat but increases in muscle of CR mice after insulin administration, indicating hepatic and adipose insulin resistance, and muscle insulin sensitization. CR reduces visceral fat much more than subcutaneous fat. The elevated FBG is negatively correlated with low-level fasting β-hydroxybutyrate, which may result from insufficient free fatty acids and diminishes ketogenic ability in CR mice. Furthermore, liver glycogen increases dramatically in CR mice. Analysis of glycogen metabolism related proteins indicates active glycogen synthesis and decomposition. Additionally, CR elevates plasma corticosterone and hypothalamic orexigenic gene expression. CR induces lipid insufficiency and stress, resulting in global physiological insulin resistance except muscle and enhances glycogen metabolism, culminating in the stability of blood glucose manifests in increased FBG, which compensates for insufficient blood ketones.

Development of a physiological insulin resistance model in human stem cell-derived adipocytes.

Adipocytes are key regulators of human metabolism, and their dysfunction in insulin signaling is central to metabolic diseases including type II diabetes mellitus (T2D). However, the progression of insulin resistance into T2D is still poorly understood. This limited understanding is due, in part, to the dearth of suitable models of insulin signaling in human adipocytes. Traditionally, adipocyte models fail to recapitulate in vivo insulin signaling, possibly due to exposure to supraphysiological nutrient and hormone conditions. We developed a protocol for human pluripotent stem cell–derived adipocytes that uses physiological nutrient conditions to produce a potent insulin response comparable to in vivo adipocytes. After systematic optimization, this protocol allows robust insulin-stimulated glucose uptake and transcriptional insulin response. Furthermore, exposure of sensitized adipocytes to physiological hyperinsulinemia dampens insulin-stimulated glucose uptake and dysregulates insulin-responsive transcription. Overall, our methodology provides a novel platform for the mechanistic study of insulin signaling and resistance using human pluripotent stem cell–derived adipocytes.

1360-P: Calorie Restriction Enhanced Glycogen Metabolism to Compensate for Lipid Insufficiency

Backgrounds: It's well known that calorie restriction (CR) brings striking benefits in metabolic improvement with complex and unclear mechanism. In this study, we aimed to investigate the specific manifestation and possible mechanisms of metabolism in CR mice. Methods: B6 mice were randomly assigned to three groups: (1) chow diet (control) , (2) chow diet with 40% calorie restriction (CR) , (3) high-fat diet (HFD) . The metabolism status and related examination were performed after 12 weeks of feeding. Results: In this study, we found that CR increased fasting blood glucose and plasma insulin, as well as reduced insulin sensitivity reflected by insulin tolerance test. Comparing to the control mice, the decrease of phosphorylation levels of IRS-1 including serine307 and tyrosine632 residues, and AKT (threonine308) after insulin rejection further confirmed that CR induced insulin resistance. Different from insulin resistance induced by HFD, CR improved glucose tolerance and reduced gluconeogenesis. Meanwhile, CR led to absolute lipid reduction, manifested in decreased plasma lipid, liver lipid deposition and fat mass. In contrast, liver glycogen increased dramatically. Fasting glycogen was twice as much as that of HFD group and 20 times as that of control group. Furthermore, the CR increased p-PYGL, p-GSK3β and decreased p-GS notably indicating active glycogen synthesis and decomposition. Subsequently, we found that CR increased plasma corticosterone and decreased plasma c-reactive protein (CRP) compared with control and HFD groups, while plasma corticosterone and CRP in HFD were higher than those in control group. Additionally, CR lowered levels of orexigenic neuropeptides and elevated levels of anorexigenic neuropeptides. Conclusions: Our study suggested that CR induced lipid insufficiency and stress from starvation, resulting in physiological insulin resistance and enhanced glycogen metabolism, including increased glycogen synthesis, glycogenolysis and glycogen content. Disclosure L.Hu: None. X.Xia: None. Y.Gu: None. J.Yin: None. Funding National Natural Science Foundation of China (No. 82070885) ,Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (No. 20172025)

Hormone metabolic pattern in the preclinical stage of preeclampsia

BACKGROUND: The imbalance of vascular endothelial cell metabolism determines the clinical manifestations of preeclampsia; however, the molecular mechanisms underlying the vessel destabilization are not fully understood. In recent years, researchers have focused on clarifying the role of dysmetabolic disorders in patients with obstetric pathology, including preeclampsia. This is due to the fact that pregnancy is accompanied by metabolic restructuring aimed at switching the energy supply of the pregnant womans body from the carbohydrate to the fat component in order to maintain an effective energoplastic supply of the developing fetus. Impairment of this evolutionary adaptation mechanism realized during pregnancy requires additional in-depth study.&#x0D; AIM: This study was aimed to identify and compare pathogenetic patterns that characterize early and late preeclampsia at the preclinical stage, based on dynamic clinical and laboratory examination of high-risk pregnant women.&#x0D; MATERIALS AND METHODS: A prospective clinical and laboratory examination of 180 pregnant women with independent factors of high risk of developing preeclampsia was carried out. Comparison groups were identified retrospectively, depending on the period of preeclampsia manifestation: Group I consisted of 31 pregnant women with early preeclampsia; Group II comprised 58 pregnant women with late preeclampsia; and Group III (control) included 30 healthy pregnant women with uncomplicated gestation. Pregnant women were examined twice at the preclinical stage of preeclampsia (11-14 and 18-21 weeks of gestation) and once at clinical manifestation of the disease (28-36 weeks of gestation). The markers of metabolic, hormonal, hemocirculatory, hemostasiological and placental disorders were evaluated.&#x0D; RESULTS: We found similar pathophysiological changes in pregnant women with both early and late PE, from early gestation periods. Those were characterized by pathological insulin resistance and hyperinsulinemia, as well as associated atherogenic changes in the lipid profile, hyperleptinemia, hyperuricemia, hypersympathicotonia, visceral fat deposition, and contra-insular hormonal deviations. The observed alterations reflected a single hormonal and metabolic pattern of the preclinical stage of preeclampsia. During pregnancy, there was shown an increase in clustering diabetogenic and atherogenic abnormalities and hormonal changes, which were supplemented by associated endothelial and hemostasiological dysfunction and, in early preeclampsia, placental dysfunction, thus accelerating the time of clinical implementation of preeclampsia.&#x0D; CONCLUSIONS: From the pathogenetic point of view, preeclampsia of various periods of manifestation is an indivisible category with a common basic developmental mechanism characterized by a hormone metabolic pattern from the early stages of pregnancy. These stable changes are the result of the pathologically transformed phylogenetic mechanism of energoplastic supply of the fetus. This transformation is realized via physiological insulin resistance and compensatory hyperinsulinemia development due to the contra-insular activity of placental hormones. The added structural and functional disorders of the embryo (feto) placental system potentiate basic mechanisms (pathological insulin resistance and hyperinsulinemia) and determine the period of preeclampsia clinical manifestation in each particular woman.

Associations of adverse childhood experiences with stress physiology and insulin resistance in adolescents at risk for adult obesity

Adverse childhood experiences (ACEs) heighten the risk for adult obesity and cardiometabolic disease, but physiological factors underlying this connection are not well understood. We determined if ACEs were associated with physiological stress response and insulin resistance in adolescents at risk for adult obesity. Participants were 90 adolescents 12.0-17.5 years (50% female, 30% Hispanic/Latinx), at risk for adult obesity by virtue of above-average body mass index (BMI; kg/m2 ≥ 70th percentile) or parental obesity (BMI ≥ 30 kg/m2 ). ACEs were determined as presence (vs. absence) based upon the Schedule for Affective Disorders and Schizophrenia for School-Aged Children. Physiological stress response was measured as heart rate/blood pressure response to the Trier Social Stress Test. Homeostatic model assessment of insulin resistance was determined from fasting glucose/insulin. Sixty-one percent of adolescents reported positive ACE history. The presence of ACEs predicted greater heart rate (p < .001) and diastolic blood pressure (p = .02) response to stress, controlling for age, sex, race/ethnicity, puberty, and BMI standard score. Systolic blood pressure and insulin resistance did not differ by ACE history (p-values > .08). Findings suggest heightened sympathetic stress response in adolescence could be explanatory in how ACEs increase the risk for later cardiometabolic disease. Future studies should characterize ACEs in relationship to day-to-day variations in adolescents' stress physiology and glucose homeostasis.

12.4 PEDIATRIC MEDICINE UPDATE: MEDICAL COMPLICATIONS OF OBESITY

Pediatric obesity is a growing health problem, with a current prevalence of 18.5% in the United States. Obesity is associated with a variety of physiologic abnormalities, including hyperlipidemia, hypertension, and insulin resistance, which together contribute to the metabolic syndrome. Metabolic derangements are known to be primary contributors to the early mortality experienced by patients with severe mental illness. Various commonly used mental health medications are associated with weight gain and metabolic abnormalities. Evaluating the risk vs benefit of these medications and intervening to minimize these risks remains a challenge for many child and adolescent psychiatrists.