Insulin-resistant States Research Articles

Obesity and Its Multiple Clinical Implications between Inflammatory States and Gut Microbiotic Alterations.

Obesity is a chronic multifactorial disease that has become a serious health problem and is currently widespread over the world. It is, in fact, strongly associated with many other conditions, including insulin resistance, type 2 diabetes, cardiovascular and neurodegenerative diseases, the onset of different types of malignant tumors and alterations in reproductive function. According to the literature, obesity is characterized by a state of low-grade chronic inflammation, with a substantial increase in immune cells, specifically macrophage infiltrates in the adipose tissue which, in turn, secrete a succession of pro-inflammatory mediators. Furthermore, recent studies on microbiota have postulated new possible mechanisms of interaction between obesity and unbalanced nutrition with inflammation. This intestinal "superorganism" complex seems to influence not only the metabolic balance of the host but also the immune response, favoring a state of systemic inflammation and insulin resistance. This review summarizes the major evidence on the interactions between the gut microbiota, energetic metabolism and host immune system, all leading to a convergence of the fields of immunology, nutrients physiology and microbiota in the context of obesity and its possible clinical complications. Finally, possible therapeutic approaches aiming to rebalance the intestinal microbial ecosystem are evaluated to improve the alteration of inflammatory and metabolic states in obesity and related diseases.

HUBUNGAN KADAR HIGH DENSITY LIPOPROTEIN (HDL) TERHADAP GLUKOSA DARAH SEWAKTU PADA PENDERITA DIABETES MELLITUS DI RS BENYAMIN GULUH KOLAKA

Diabetes Mellitus (DM) is a very common health problem. Diabetes mellitus is a chronic disease that generally affects throughout the life of the patient and requires long-term treatment, in addition to the state of insulin resistance or metabolic syndrome and Diabetes Mellitus (DM) cause’s lipid metabolic abnormalities characterized by an increase or decrease in lipid fraction. Increased cholesterol High Density Lipoprotein (HDL) can reduce the risk of atorosclerosis. Besides that, the HDL function is as the main means of transporting excess cholesterol from extra hepatic tissue and cleaning cells then to be released through the bile. This study aims to determine the relationship between of the High Density Lipoprotein (HDL) levels to blood glucose to the patients' of diabetes mellitus at Benyamin Guluh Hospital in Kolaka. The type of this study is analytic observational with the sampling technique of Accidental Sampling and 30 people of total samples. The results of this study showed that there was no relationship between HDL levels and blood glucose. This could be seen in the p-value of 0.107 and the r value of 0.300. Keywords : High Density Lipoprotein (HDL), Diabetes Mellitus (DM)

Alpha-Lipoic Acid and Glucose Metabolism: A Comprehensive Update on Biochemical and Therapeutic Features.

Alpha-lipoic acid (ALA) is a natural compound with antioxidant and pro-oxidant properties which has effects on the regulation of insulin sensitivity and insulin secretion. ALA is widely prescribed in patients with diabetic polyneuropathy due to its positive effects on nerve conduction and alleviation of symptoms. It is, moreover, also prescribed in other insulin resistance conditions such as metabolic syndrome (SM), polycystic ovary syndrome (PCOS) and obesity. However, several cases of Insulin Autoimmune Syndrome (IAS) have been reported in subjects taking ALA. The aim of the present review is to describe the main chemical and biological functions of ALA in glucose metabolism, focusing on its antioxidant activity, its role in modulating insulin sensitivity and secretion and in symptomatic peripheral diabetic polyneuropathy. We also provide a potential explanation for increased risk for the development of IAS.

Visnagin Attenuates Gestational Diabetes Mellitus in Streptozotocin-induced Diabetic Pregnant Rats via Regulating Dyslipidemia, Oxidative Stress, and Inflammatory Response

Background: Gestational diabetes mellitus (GDM) is a condition of glucose intolerance and insulin resistance only diagnosed during pregnancy. GDM has exhibited several adverse effects on both mother and offspring. The current research focuses on discovering visnagin’s beneficial properties against the streptozotocin (STZ)-induced GDM in rats via alleviating the inflammation and oxidative stress. Materials and Methods: GDM was caused in the pregnant rats by the administration of 25 mg/kg of STZ by the intraperitoneal route and then treated with 20 mg/kg of visnagin for 20 consecutive days. The rats’ body weight was measured, and fasting blood glucose (FBG) status was determined using a standard glucometer. The contents of total cholesterol (TCh), triglycerides (TG), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) were assessed using kits. The MDA level, total antioxidant capacity (TAC) status, and activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione S-transferase (GST) were determined using assay kits. Kits also assessed the contents of TNF-α and IL-1β. The contents of TNF-α and IL-1β effectively improved the body weight and decreased the FBG status in the GDM rats. The visnagin also decreased the TCh, TG, and LDL, and elevated the HDL content. The content of MDA was decreased and the visnagin treatment increased SOD, CAT, GST, and GPx, and the visnagin treatment increased SOD, CAT, GST, and GPx activities SOD, CAT, GST, and GPx activities. The visnagin effectively decreased the STZ-induced histopathological alterations in the pancreas. Conclusion: Altogether, our investigation results suggest a beneficial role visnagin against STZ-induced GDM in rats via inhibiting the inflammatory responses. Hence, it can be a talented therapeutic candidate for the successful management of GDM.

Hepatocyte Smoothened Activity Controls Susceptibility to Insulin Resistance and Nonalcoholic Fatty Liver Disease

Nonalcoholic steatohepatitis (NASH), a leading cause of cirrhosis, strongly associates with the metabolic syndrome, an insulin-resistant proinflammatory state that disrupts energy balance and promotes progressive liver degeneration. We aimed to define the role of Smoothened (Smo), an obligatory component of the Hedgehog signaling pathway, in controlling hepatocyte metabolic homeostasis and, thereby, susceptibility to NASH. We conditionally deleted Smo in hepatocytes of healthy chow-fed mice and performed metabolic phenotyping, coupled with single-cell RNA sequencing (RNA-seq), to characterize the role of hepatocyte Smo in regulating basal hepatic and systemic metabolic homeostasis. Liver RNA-seq datasets from 2 large human cohorts were also analyzed to define the relationship between Smo and NASH susceptibility in people. Hepatocyte Smo deletion inhibited the Hedgehog pathway and promoted fatty liver, hyperinsulinemia, and insulin resistance. We identified a plausible mechanism whereby inactivation of Smo stimulated the mTORC1-SREBP1c signaling axis, which promoted lipogenesis while inhibiting the hepatic insulin cascade. Transcriptomics of bulk and single Smo-deficient hepatocytes supported suppression of insulin signaling and also revealed molecular abnormalities associated with oxidative stress and mitochondrial dysfunction. Analysis of human bulk RNA-seq data revealed that Smo expression was (1) highest in healthy livers, (2) lower in livers with NASH than in those with simple steatosis, (3) negatively correlated with markers of insulin resistance and liver injury, and (4) declined progressively as fibrosis severity worsened. The Hedgehog pathway controls insulin sensitivity and energy homeostasis in adult livers. Loss of hepatocyte Hedgehog activity induces hepatic and systemic metabolic stress and enhances susceptibility to NASH by promoting hepatic lipoxicity and insulin resistance.

Acacetin inhibits myocardial mitochondrial dysfunction by activating PI3K/AKT in SHR rats fed with fructose.

To explore the effect of acacetin on myocardial mitochondrial dysfunction in spontaneously hypertensive rats (SHR) with insulin resistance (IR), and the possible mechanism. Rapid IR was first induced in fructose-fed SHR, and they were then treated with acacetin (25, 50mg/kg). After 7weeks, the rats were tested for hypertension, IR, cardiac function, and mitochondrial damage status. Potential mechanisms of action were explored in terms of oxidative stress, mitochondrial fission and division, apoptosis, and the insulin signaling pathway. Subsequently, the PI3K gene was silenced, after intervention with acacetin (5μM) for 24h, and H2O2 was used to stimulate H9c2 for 4h, it was evaluated whether silencing PI3K would affect the therapeutic effect of acacetin. In SHR fed with fructose, acacetin can improve hypertension, IR, cardiac function (LVEF, LVFS), and mitochondrial damage (mitochondria number, ATP); inhibit oxidative stress (ROS, SOD, Nrf2, Keap1), mitochondrial fission (MFF, Drp1), and myocardial cell apoptosis (apoptosis rate, Bax, Bcl-2, cytochrome c); promote mitochondrial fusion (Mfn2) and activate insulin signaling pathways (PI3K/AKT). However, silencing PI3K inhibited the abovementioned effects of acacetin. In conclusion, acacetin improved myocardial mitochondrial dysfunction through regulating oxidative stress, mitochondrial fission and fusion, and mitochondrial pathway apoptosis mediated by PI3K/AKT signaling pathway in hypertensive rats with IR.

Insulin resistance in ischemic stroke: Mechanisms and therapeutic approaches.

The pathological condition of insulin resistance prevents the neuroprotective effects of insulin. Numerous studies have demonstrated that insulin resistance, as an independent risk factor for ischemic stroke, accelerates the formation of thrombosis and promotes the development of atherosclerosis, both of which are major mechanisms of ischemic stroke. Additionally, insulin resistance negatively affects the prognosis of patients with ischemic stroke regardless of whether the patient has diabetes, but the mechanisms are not well studied. We explored the association between insulin resistance and the primary mechanisms of brain injury in ischemic stroke (inflammation, oxidative stress, and neuronal damage), looking for potential causes of poor prognosis in patients with ischemic stroke due to insulin resistance. Furthermore, we summarize insulin resistance therapeutic approaches to propose new therapeutic directions for clinically improving prognosis in patients with ischemic stroke.

Risk Factors for Nonalcoholic Fatty Liver Disease with Different Insulin Resistance in a Nonobese Chinese Population.

The aim of this study is to identify the risk factors of nonobese nonalcoholic fatty liver disease (NAFLD) individuals under different insulin resistance status. This cross-sectional study was conducted at the Medical Center of Beijing Chaoyang Hospital affiliated with Capital Medical University. NAFLD was diagnosed based upon ultrasonographic findings consistent with fatty liver disease. A total of 1257 nonobese adults (625 non-NAFLD and 632 nonobese NAFLD) with body mass index (BMI) 18.5-24.9 kg/m2 were enrolled in the study. And all patients were divided into homeostasis model assessment of insulin resistance (HOMA - IR) > 1 group and HOMA - IR ≤ 1 group. When all the variables were adjusted in both the HOMA - IR > 1 group and HOMA - IR ≤ 1 group, older age (>50 years), higher BMI (23.0-24.9 kg/m2), higher AST (>18 U/L), higher TG (>0.9 mmol/L), higher GLU (>5.25 mmol/L), and higher HbA1C (>5.5%) were associated with higher risks of nonobese NAFLD. In patients with HOMA - IR > 1, lower homeostatic model assessment of β-cell function (HOMA-β) (<47.1%) (OR, 7.460, 95% CI, 3.051-18.238, P < 0.001) was associated with higher risks of nonobese NAFLD. s. Metabolic profiles (i.e., higher BMI, hyperglycemia, hypertriglyceridemia, and higher glycosylated hemoglobin) are risk factors of nonobese NAFLD, regardless of insulin resistance status. Decreased function of pancreatic β-cells may be the risk factor of nonobese NAFLD with insulin resistance, who should pay attention to further development of pancreatic β-cell dysfunction.

Novel Metformin Indications and Skin Disorders

Metformin is the first-line medication to increase insulin sensitivity in insulin-resistant conditions such as type 2 diabetes, polycystic ovary syndrome, and obesity. However, metformin is a drug with a wide range of pharmacological properties, showing the ability to treat various skin conditions. Some inflammatory skin dermatoses, skin neoplasms, endocrinology-related dermatosis, pigmentary disorders, skin aging, and wound healing have all shown improvement when metformin is used. This review discusses the most recent research supporting the use of metformin as a treatment for common skin conditions.

IL-6 as a Surrogate Biomarker: The IL-6 Clinical Value for the Diagnosis of Insulin Resistance and Type 2 Diabetes

Insulin Resistance is the leading cause of Type 2 diabetes mellitus (T2D). It occurs as a result of lipid disorders and increased levels of circulating free fatty acids (FFAs). FFAs accumulate within the insulin sensitive tissues such as muscle, liver and adipose tissues exacerbating different molecular mechanisms. Increased levels fatty acid has been documented to be strongly associated with insulin resistant states and obesity causing inflammation that eventually causes type 2-diabetes. Among the biomarkers that are accompanying low grade inflammation include IL-1β, IL-6 and TNF-α. The current review point out the importance of measuring the inflammatory biomarkers especially focusing on the conductance and measurement for IL-6 as a screening laboratory test and its diagnostic value in clinical practice.

Ліпідні маркери прогнозування неалкогольної жирової хвороби печінки в юнаків із гіпоандрогенією

Metabolic syndrome (MS) and the conditions associated with it are pressing problems for humanity. The gastroenterological component of MS is considered to be non-alcoholic fatty liver disease (NAFLD). There are no scientific studies on the influence of hypoandrogenism (HA) on metabolic control and the formation of NAFLD in adolescent boys. Purpose - to determine the prognostic value of changes in the lipid profile for the formation of NAFLD in adolescent boys with HA. Materials and methods. In 2019-2021 was carried out a comprehensive examination of 107 adolescent boys aged 13-18 with HA: the clinical examination, blood tests to determine the level of γ-glutamyltransferase, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, lipidogram, testosterone, immunoreactive insulin. The morpho-functional state of the hepatobiliary system was studied by ultrasound, according to the results of which adolescent boys with HA were divided into observation groups (the Group 1 - with normal liver parameters, the Group 2 - with signs of steatosis). Prognostic assessment of the formation of liver steatosis in HA was carried out using ROC analysis with AUC calculation. Results. According to the ultrasound signs of NAFLD was detected in a third of adolescent boys with HA. The state of insulin resistance was established in 22% of adolescent boys, significantly more often in patients with NAFLD. Analysis of blood lipid spectrum indicators in young men with HA showed the presence of proatherogenic changes more pronounced in the group with NAFLD. ROC analysis for quantitative biochemical indicators demonstrated that while using the distribution point for β-lipoproteins &gt;5.8 g/l for the detection of liver enlargement as a sign of NAFLD in adolescent boys with HA the sensitivity was 72.0%, the specificity - 55.3%. The value of the area under the ROC curve was 0.624 [0.514; 0.725] with the level of statistical significance p=0.045. Conclusions. A third part of adolescent boys with HA according to ultrasound examination had signs of NAFLD at the stage of steatosis. Atherogenic dyslipidemia was found in all adolescents with HA, which was more pronounced in patients with NAFLD. The predictive value of determining the level of β-lipoproteins for the detection of NAFLD in adolescent boys with HA was revealed. The determination of β-lipoproteins may be economically feasible in relation to the diagnostic examination of adolescent boys with HA. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of all participating institutions. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

GLUT4 translocation and dispersal operate in multiple cell types and are negatively correlated with cell size in adipocytes

The regulated translocation of the glucose transporter, GLUT4, to the surface of adipocytes and muscle is a key action of insulin. This is underpinned by the delivery and fusion of GLUT4-containing vesicles with the plasma membrane. Recent studies have revealed that a further action of insulin is to mediate the dispersal of GLUT4 molecules away from the site of GLUT4 vesicle fusion with the plasma membrane. Although shown in adipocytes, whether insulin-stimulated dispersal occurs in other cells and/or is exhibited by other proteins remains a matter of debate. Here we show that insulin stimulates GLUT4 dispersal in the plasma membrane of adipocytes, induced pluripotent stem cell-derived cardiomyocytes and HeLa cells, suggesting that this phenomenon is specific to GLUT4 expressed in all cell types. By contrast, insulin-stimulated dispersal of TfR was not observed in HeLa cells, suggesting that the mechanism may be unique to GLUT4. Consistent with dispersal being an important physiological mechanism, we observed that insulin-stimulated GLUT4 dispersal is reduced under conditions of insulin resistance. Adipocytes of different sizes have been shown to exhibit distinct metabolic properties: larger adipocytes exhibit reduced insulin-stimulated glucose transport compared to smaller cells. Here we show that both GLUT4 delivery to the plasma membrane and GLUT4 dispersal are reduced in larger adipocytes, supporting the hypothesis that larger adipocytes are refractory to insulin challenge compared to their smaller counterparts, even within a supposedly homogeneous population of cells.

Is there any difference in insulin resistance status between cases of benign and malignant ovarian neoplasms? A study on surrogate markers of insulin resistance in Indonesian non-diabetic women.

The association between insulin resistance (IR) and ovarian neoplasm is little known. The present study attempted to investigate the difference in clinicopathological characteristics, metabolic parameters, and IR prevalence between benign and malignant ovarian neoplasms. The cross-sectional study involved 52 non-diabetic women with benign (n=27) and malignant (n=25) diagnoses in a tertiary hospital in Indonesia. Fasting insulin level (FIL), homeostatic model assessment of IR and β-cell dysfunction (HOMA-IR and HOMA-β), fasting IR index (FIRI), and quantitative insulin sensitivity check index (QUICKI) were used as surrogate markers to evaluate IR. Parametric and nonparametric statistical tests were employed to analyze the different parameters between the two groups. Pearson or Spearman's rank test assessed the correlation between markers and clinical variables. Results revealed that patients with benign neoplasms were younger than those with malignant neoplasms (38.63 vs. 47.40 years; P=0.003) and had a higher median body mass index (BMI) than their counterparts (22.98 vs. 18.61 kg/m2; P=0.014). Different characteristics between benign and malignant neoplasm cases were found in menopausal status, ovary side affected, systolic blood pressure, and BMI classes. Endometrial cysts and mucinous carcinoma were the most often diagnosed benign and malignant neoplasms. Malignant neoplasms had a lower median HOMA-β score than benign neoplasms (49.33 vs. 75.79; P=0.011), indicating more severe β-cell dysfunction. No significant difference was observed in the prevalence of IR between benign and malignant ovarian neoplasms for the following values of each marker: FIL (25.9% vs. 12.0%), HOMA-IR (37.0% vs. 28.0%), FIRI (51.9% vs. 48.0%) and QUICKI (81.5% vs. 92.0%). The indicators of FIL, HOMA-IR, HOMA-β, FIRI, and QUICKI correlated with each other and confirmed the reliability of these surrogate markers for measuring IR status in ovarian neoplasms. In brief, benign ovarian neoplasms tended to have more IR when compared with malignant ovarian neoplasms. However, this difference was not statistically significant.

Potential role of microRNAs in selective hepatic insulin resistance: From paradox to the paradigm.

The paradoxical action of insulin on hepatic glucose metabolism and lipid metabolism in the insulin-resistant state has been of much research interest in recent years. Generally, insulin resistance would promote hepatic gluconeogenesis and demote hepatic de novo lipogenesis. The underlying major drivers of these mechanisms were insulin-dependent, via FOXO-1-mediated gluconeogenesis and SREBP1c-mediated lipogenesis. However, insulin-resistant mouse models have shown high glucose levels as well as excess lipid accumulation. As suggested, the inert insulin resistance causes the activation of the FOXO-1 pathway promoting gluconeogenesis. However, it does not affect the SREBP1c pathway; therefore, cells continue de novo lipogenesis. Many hypotheses were suggested for this paradoxical action occurring in insulin-resistant rodent models. A "downstream branch point" in the insulin-mediated pathway was suggested to act differentially on the FOXO-1 and SREBP1c pathways. MicroRNAs have been widely studied for their action of pathway mediation via suppressing the intermediate protein expressions. Many in vitro studies have postulated the roles of hepato-specific expressions of miRNAs on insulin cascade. Thus, miRNA would play a pivotal role in selective hepatic insulin resistance. As observed, there were confirmations and contradictions between the outcomes of gene knockout studies conducted on selective hepatic insulin resistance and hepato-specific miRNA expression studies. Furthermore, these studies had evaluated only the effect of miRNAs on glucose metabolism and few on hepatic de novo lipogenesis, limiting the ability to conclude their role in selective hepatic insulin resistance. Future studies conducted on the role of miRNAs on selective hepatic insulin resistance warrant the understanding of this paradoxical action of insulin.

Standardization of dry extracts from large cranberry leaves

Aim. To determine the parameters of standardization of a dry extract from large cranberry (Oxycoccus macrocarpus (Ait.)) leaves and a dry extract modified with arginine and develop projects of Drug Quality Control Methods (DQCM) for these substances.Materials and methods. The study object was dry extracts from large cranberry leaves. Leaves were harvested in October 2021 in the Zhytomyr region (Kostivtsi village, 50.326862437345945, 29.54310845594284). The extracts were obtained with a 50 % solution of ethyl alcohol in the ratio of 1:30 by double maceration. Half of the combined extract was dried to a dry extract (Extract 1), and the other half was modified with arginine in the threefold equimolar amount relative to the total amount of phenolic compounds and evaporated to a dry extract (Extract 2). Standard pharmacopoeial methods were used to determine standardization parameters. The quantitative determination was carried out using the spectrophotometric method by the content of flavonoids calculated with reference to hyperoside and hydroxycinnamic acids calculated with reference to chlorogenic acid on an Evolution 60S spectrophotometer (Thermo Scientific Spectronic, USA).Results and discussion. The parameters of standardization of dry extracts from large cranberry leaves were determined. The project of DQCM was proposed according to the following indicators: description, solubility, identification using the thin-layer chromatography method (by the content of flavonoids, hydroxycinnic acids and arginine), loss on drying, the residual amount of organic solvents (ethanol), microbiological purity, and the content of heavy metals. The assay was carried out using spectrophotometry by the content of flavonoids and derivatives of hydroxycinnic acids. Three batches of the extracts obtained, which fully corresponded to the projects of DQCM developed, were analyzed.Conclusions. The parameters of standardization of dry extracts from large cranberry leaves have been determined, and projects of DQCM for the substances obtained have been developed. It is the basis for creating new medicines for the correction of insulin-resistant conditions in Type 2 diabetes mellitus.

PHLPP isoforms differentially regulate Akt isoforms and AS160 affecting neuronal insulin signaling and insulin resistance via Scribble

BackgroundThe aim of the present study was to determine the role of individual PHLPP isoforms in insulin signaling and insulin resistance in neuronal cells.MethodsPHLPP isoforms were either silenced or overexpressed individually, and the effects were observed on individual Akt isoforms, AS160 and on neuronal glucose uptake, under insulin sensitive and resistant conditions. To determine PHLPP regulation itself, we tested effect of scaffold protein, Scribble, on PHLPP isoforms and neuronal glucose uptake.ResultsWe observed elevated expression of both PHLPP1 and PHLPP2 in insulin resistant neuronal cells (Neuro-2A, mouse neuroblastoma; SHSY-5Y, human neuroblastoma) as well as in the whole brain lysates of high-fat-diet mediated diabetic mice. In insulin sensitive condition, PHLPP isoforms differentially affected activation of all Akt isoforms, wherein PHLPP1 regulated serine phosphorylation of Akt2 and Akt3, while PHLPP2 regulated Akt1 and Akt3. This PHLPP mediated Akt isoform specific regulation activated AS160 affecting glucose uptake. Under insulin resistant condition, a similar trend of results were observed in Akt isoforms, AS160 and glucose uptake. Over-expressed PHLPP isoforms combined with elevated endogenous expression under insulin resistant condition drastically affected downstream signaling, reducing neuronal glucose uptake. No compensation was observed amongst PHLPP isoforms under all conditions tested, indicating independent roles and pointing towards possible scaffolding interactions behind isoform specificity. Silencing of Scribble, a scaffolding protein known to interact with PHLPP, affected cellular localization of both PHLPP1 and PHLPP2, and caused increase in glucose uptake.ConclusionsPHLPP isoforms play independent roles via Scribble in regulating Akt isoforms differentially, affecting AS160 and neuronal glucose uptake.BQN7nd48EhvKr6o-7gBbL3Video abstract

Youth versus adult-onset type 2 diabetic kidney disease: Insights into currently known structural differences and the potential underlying mechanisms.

Type 2 diabetes (T2D) is a global health pandemic with significant humanitarian, economic, and societal implications, particularly for youth and young adults who are experiencing an exponential rise in incident disease. Youth-onset T2D has a more aggressive phenotype than adult-onset T2D, and this translates to important differences in rates of progression of diabetic kidney disease (DKD). We hypothesize that youth-onset DKD due to T2D may exhibit morphometric, metabolic, and molecular characteristics that are distinct from adult-onset T2D and develop secondary to inherent differences in renal energy expenditure and substrate metabolism, resulting in a central metabolic imbalance. Kidney structural changes that are evident at the onset of puberty also serve to exacerbate the organ's baseline high rates of energy expenditure. Additionally, the physiologic state of insulin resistance seen during puberty increases the risk for kidney disease and is exacerbated by both concurrent diabetes and obesity. A metabolic mismatch in renal energetics may represent a novel target for pharmacologic intervention, both for prevention and treatment of DKD. Further investigation into the underlying molecular mechanisms resulting in DKD in youth-onset T2D using metabolomics and RNA sequencing of kidney tissue obtained at biopsy is necessary to expand our understanding of early DKD and potential targets for therapeutic intervention. Furthermore, large-scale clinical trials evaluating the duration of kidney protective effects of pharmacologic interventions that target a metabolic mismatch in kidney energy expenditure are needed to help mitigate the risk of DKD in youth-onset T2D.

OR22-1 Temporal And Spatial Cellular Heterogeneity Of Hepatocyte Metabolism

Abstract Gene expression plays a pivotal role in the long-term regulation of gluconeogenesis and lipogenesis in the liver. Although most of the previous studies were analyzed as a whole liver, it is known that hepatocytes across the liver display specific aspects of liver function in a zonation dependent manner. Using a combination of single-cell RNA sequencing (scRNA-seq) and single molecule Fluorescence In Situ Hybridization (smFISH) technologies, we examined several novel molecular and cellular aspects of the normal regulation of hepatocyte metabolic gene expression during the transitions from the fed to fasted, and subsequent starvation states in male C57BL/6J mice. Targeted scRNA-seq was used to quantitively analyze the temporal and spatial differences of gluconeogenic and lipogenic genes following a post-prandial time course. Initially, in the fed state lipogenic genes (such as Fasn) were highly expressed in both the periportal (PP) and pericentral (PC) hepatocytes that were rapidly turned off as the mouse entered the fasted state. In contrast, gluconeogenic genes (such as Pck1) were expressed in a subset of PP hepatocytes in the fully fed state. As the mouse entered the fasted state gluconeogenic genes became activated primarily in the PP hepatocytes. However, as the mouse enters a starvation state the PC hepatocytes also increase their expression of gluconeogenic genes. Analyses by smFISH not only confirmed the scRNA-seq data but is also applicable to determine the spatial context in the native liver tissue as well as analyzing the transcriptional regulation of gluconeogenic and lipogenic genes at the single molecule resolution. In the fed state, few PP hepatocytes expressed gluconeogenic transcription sites (TS), and during a fasted time-course, over time the TS expanded outwards to the PC hepatocytes. On the other hand, lipogenic TS were expressed in both PC and PP hepatocytes in the fed state, but during a fasted time-course, TS were not detected. In summary, these data suggest that hepatocyte zonation of gluconeogenic genes is dynamic and can vary substantially depending upon the fasted and fed states. Understanding the regulation of the liver hepatocyte normal physiology will provide the molecular basis for which we can more precisely determine the dysregulation that occurs in states of insulin resistance. Presentation: Monday, June 13, 2022 11:00 a.m. - 11:15 a.m.

ODP395 Relationship of serum total insulin-like growth factor-binding protein-3 with triglyceride to high-density lipoprotein cholesterol ratio and glucose tolerance in Korean children and adolescents

Abstract Objectives We investigated the relationships between serum IGF-I/ IGFBP-3 levels and degrees of triglyceride to high-density lipoprotein cholesterol (TG/HDL) ratio in Korean children and adolescents who underwentoral glucose tolerance test. Methods children and adolescents without known diabetes were checked an oral glucose tolerance test and collected the clinical and laboratory data. Serum IGF-I and total IGFBP-3 levels, TG/HDL ratio, total cholesterol, low-density lipoprotein cholesterol (LDL),AST, ALT, C-peptide levels, homeostasis model assessment of insulin resistance (HOMA-IR) index, and glycated hemoglobin (HbA1c) levels were measured. Results Serum TG/HDL ratio and IGF-I/ total IGFBP-3 levels were significantly higher in individuals with type 2 diabetes (DM) than in those with normal glucose tolerance (NGT) (P&amp;lt;0. 05). TG/HDL ratio was not related with age and IGF-I levels and it was correlated with serum IGFBP-3 levels, HbA1c, C-peptide, HOMA-IR, and body mass index. However, these relationships were altered in patients with insulin resistance state, especially in those with DM. In the DM group, TG/HDL ratio and total IGFBP-3 levels were positively correlated stronger than no-DM groups. In addition,TG/HDL ratio and total IGFBP-3 levels were positively correlated with total cholesterol and LDL levels but not with age. Conclusions TG/HDL ratio, the marker of small dense LDL particles, is related with IGFBP-3, especially in patients with type 2 diabetes. The IGF-I-IGFBP-3 axis, especially IGFBP-3, may play roles in the pathogenesis and metabolic control of lipid metabolism. Presentation: No date and time listed

PSUN261 Diabetic Ketoacidosis Complicating Gestational Diabetes Mellitus: A Case Report

Abstract Diabetic ketoacidosis (DKA) in pregnancy is a rare but serious medical emergency. Its incidence ranges between 0.2%-9% and carries a fetal mortality rate up to 90%. DKA remains to be an extremely rare complication of gestational diabetes (GDM). Early diagnosis and management may be delayed due to its atypical presentation. We present a case of DKA in GDM with no pre-existing diagnosis of type 1 diabetes (T1DM) or type 2 diabetes (T2DM). A 33-year-old African American woman G2P0010 with GDM on insulin diagnosed in current pregnancy, presented at 30-weeks of gestation with a 3-day history of general malaise, altered mentation, and emesis. Severe DKA (blood glucose 920 mg/dL, pH 7.02, anion gap 38, bicarbonate 5.0 mEq/L, and positive serum ketones), systemic inflammatory response syndrome (tachycardia, WBC of 24,000/mcL), and intrauterine fetal demise via ultrasound were determined upon presentation. MICU admission for prompt and vigorous medical management with intravenous fluid resuscitation, insulin and bicarbonate infusions, and broad-spectrum antibiotic therapy was required. Clinical course was complicated by worsening hypokalemia. Spontaneous vaginal delivery of a non-viable fetus occurred at the MICU. After delivery, resolution of DKA was achieved. Once the patient's mentation was back to her baseline, she admitted complete cessation of insulin 1-week prior to admission. Workup revealed negative glutamic acid decarboxylase, islet cell, and zinc transporter-8 autoantibodies in addition to normal C-peptide levels. A new HbA1C of 9% compared to HbA1C of 5.5% at 6 weeks of gestation, made pre-existing T2DM unlikely. Eventually, the patient was downgraded to the medicine wards for continuity of care. DKA in pregnancy is a rare complication typically associated with T1DM. It may occur at near-normal blood glucose levels, known as euglycemic DKA, causing a delay in diagnosis. Physiologic changes during the last trimester of gestation explain the higher incidence of DKA at this stage. These include the relative state of insulin resistance, which in addition to insulin-antagonistic hormones such as human placental lactogen, prolactin, cortisol, and progesterone contribute to this state. Furthermore, a relative accelerated state of starvation with an increase in maternal ketone body formation, and a reduction in the buffering capacity when exposed to ketonemia places gravida women with impaired glucose tolerance at higher risk to develop DKA. Fetal loss may result from reduced uteroplacental perfusion and fetal hypokalemia leading to fatal arrhythmia. The most common precipitating factors of DKA in pregnancy are infection, including COVID-19, insulin therapy non-adherence, steroid use, dehydration, and unrecognized new-onset diabetes which accounts for up to 30% of cases. It has been described that a genetic polymorphism in SLC26A6 gene may increase the susceptibility to develop DKA in GDM. Prevention, early diagnosis, and vigorous medical management of DKA in pregnancy may possibly reduce maternal and fetal mortality. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.