Evidence Of Insulin Resistance Research Articles

Abstract PO2-08-10: Effect of 6 months of bazedoxifene + conjugated estrogens on body composition and insulin resistance

Abstract Menopause transition is often marked by an acceleration of visceral fat accumulation. Excess visceral fat is associated with insulin resistance and increased risk for breast cancer as well as heart disease and diabetes. We measured change in body composition (via iDXA), fasting insulin and glucose as part of an ongoing, Phase IIB trial (NCT04821141) of 6 months of bazedoxifene (BZA) + conjugated estrogen (CE) vs control with primary endpoints of change in mammographic density and breast tissue Ki-67. Participants are women ages 45-60 with vasomotor symptoms at increased risk for development of breast cancer. Methods: Visceral and total fat, lean, and total mass, were measured with iDXA (GE CoreScan™). Fasting plasma was assayed same day as drawn for total insulin using a chemiluminescence assay and glucose using a hexokinase method. Values generated were used to calculate HOMA IR (as a measure of insulin resistance) using the formula insulin µl/ml x glucose mg/dl/405. HOMA %S was calculated as 1/HOMA IR X100 as a measure of insulin sensitivity. Optimal HOMA IR is considered as ≤1; HOMA IR >1.5 is considered abnormal with >2.0 as evidence of insulin resistance. Optimal HOMA %S is 100%. Results: 24 women (12 BZA+CE, 12 Control) have completed baseline and 6-month body composition and insulin resistance assessments. Women randomized to BZA+CE were more likely to experience reduction in insulin resistance and improved insulin sensitivity despite a small weight gain over the initial 6 months. 7/12 randomized to BZA+CE had ≥15% reduction in HOMA IR vs only 2/12 controls. Three participants had HOMA IR >2 at baseline. Of these, one was randomized to BZA+CE and had a normal HOMA IR value at 6 months. The remaining two women were in the control group and saw no improvement in HOMA IR at 6 months. In addition, one woman randomized to control with normal HOMA-IR at baseline had HOMA IR > 2 at 6 months. Next Steps: The improvements in insulin resistance parameters with BZA+CE are similar to those observed in our rodent studies, supporting this combination as promising for use in breast cancer risk reduction in women with vasomotor symptoms at high-risk for metabolic disease. Citation Format: Carol Fabian, Adrian Zelenchuk, Kandy Powers, Amy Kreutzjans, Krystal Pittman, Bill Hendry, Christy Altman, Erin Giles, Katherine L. Cook, Stephen Hursting, Bruce Kimler. Effect of 6 months of bazedoxifene + conjugated estrogens on body composition and insulin resistance [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-08-10.

Hepatic lipid accumulation is associated with multiple metabolic pathway alterations but not dyslipidemia and insulin resistance in central bearded dragons (Pogona vitticeps).

To investigate associations between hepatic fat accumulation, fibrosis, and plasma values of primary metabolites, biochemical measurands, insulin, and lipoproteins in bearded dragons. 48 adult central bearded dragons (Pogona vitticeps). Dragons were sedated with alfaxalone, and a blood sample was collected. Plasma was submitted for untargeted primary metabolomics using gas chromatography time-of-flight mass spectrometry, a biochemistry panel, and a lipoprotein panel determined by PAGE. Hepatic lipid content was quantified by liver attenuation measurements from CT images and digital image analysis of standardized histologic sections of the liver. Fibrosis was quantified by digital image analysis on Masson's trichrome-stained histologic sections. Severity was determined from pathologic review of liver sections according to a standardized grading system. Statistical associations were investigated using serial linear models adjusted for false discovery rate and multivariate statistics. Both hepatic fat and fibrosis had a significant effect on CT liver attenuation values. Several oligosaccharides (maltotriose, maltose, ribose, trehalose) and alkaline phosphatase were significantly and linearly increased with hepatic lipid content (all q < .05). On partial least square-discriminant analysis, β-hydroxybutyric acid was the most important discriminatory variable between fatty liver severity grades on histology. No significant associations were found with insulin, lipoproteins, and succinic acid. Bearded dragons with hepatic lipid accumulation experienced multiple metabolic pathway disruptions, some being compatible with mitochondrial dysfunction. No evidence of insulin resistance or dyslipidemia was found. Hepatic biopsy and histopathology remain recommended for reliably diagnosing and staging fatty liver disease in bearded dragons.

Effects of prenatal dexamethasone exposure on adult C57BL/6J mouse metabolism and oxidative stress.

Prenatal glucocorticoid exposure has been shown to alter hypothalamic-pituitary-adrenal axis function resulting in altered fetal development that can persist through adulthood. Fetal exposure to excess dexamethasone, a synthetic glucocorticoid, has been shown to alter adult behaviour and metabolism. This study investigated the effects prenatal dexamethasone exposure had on adult offspring cardiac and liver metabolism and oxidative stress. Pregnant C57BL/6 mice received a dose of 0.4 mg/kg dexamethasone on gestational days 15-17. Once pups were approximately 7 months old, glucose uptake was determined using positron emission tomography and insulin resistance (IR) was determined by homeostatic model assessment (HOMA) IR calculation. Oxidative stress was assessed by measuring 4-hydroxynonenal protein adduct formation and total reactive oxygen species. Female dexamethasone group had significantly increased glucose uptake when insulin stimulated compared to vehicle-treated mice. HOMA IR revealed no evidence of IR in either male or female offspring. There was also no change in oxidative stress markers in either cardiac or liver tissues of male or female offspring. These data suggest that prenatal dexamethasone exposure in male mice does not alter oxidative stress or metabolism. However, prenatal dexamethasone exposure increased glucocorticoids, cardiac glucose uptake, and pAkt signaling in female heart tissues in adult mice, suggesting there are sex differences in prenatal dexamethasone exposure.

Metformin mitigates renal dysfunction in obese insulin-resistant rats via activation of the AMPK/PPARα pathway.

Insulin signaling and lipid metabolism are disrupted by long-term consumption of a high-fat diet (HFD). This disruption can lead to insulin resistance, dyslipidemia and subsequently renal dysfunction as a consequence of the inactivation of the AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-α (PPARα) or AMPK/PPARα pathways. We investigated the impact of metformin on the prevention of renal dysfunction through the modulation of AMPK-regulated PPARα-dependent pathways in insulin-resistant rats induced by a HFD. Male Wistar rats were fed a HFD for 16 weeks to induce insulin resistance. After insulin resistance had been confirmed, metformin (30mg/kg) or gemfibrozil (50mg/kg) was given orally for 8 weeks. Evidence of insulin resistance, dyslipidemia, lipid accumulation and kidney injury were observed in HF rats. Impairment of lipid oxidation, energy metabolism and renal organic anion transporter 3 (Oat3) expression and function were demonstrated in HF rats. Metformin can stimulate the AMPK/PPARα pathways and suppress sterol regulatory element-binding transcription factor 1 (SREBP1) and fatty acid synthase (FAS) signaling (SREBP1/FAS) to enable the regulation of lipid metabolism. Renal inflammatory markers and renal fibrosis expression induced by a HFD were more effectively reduced after metformin treatment than after gemfibrozil treatment. Interestingly, renal Oat3 function and expression and kidney injury were improved following metformin and gemfibrozil treatment. Renal cluster of differentiation 36 (CD36) or sodium glucose cotransporter type 2 (SGLT2) expression did not differ after treatment with metformin or gemfibrozil. Metformin and gemfibrozil could reduce the impairment of renal injury in obese conditions induced by a HFD through the AMPK/PPARα-dependent pathway. Interestingly, metformin demonstrated greater efficacy than gemfibrozil in attenuating renal lipotoxicity through the AMPK-regulated SREBP1/FAS signaling pathway.

A Study of Correlation of Alopecia Areata and Metabolic Syndrome in Northwest Indian Population: A Case-Control Study.

Alopecia areata (AA) is the most common cause of inflammatory, nonscarring hair loss, involving hair-bearing areas of the body. The etiology of AA still remains uncertain; however, genetic, environmental, and autoimmunity play a role. Newer theories such as oxidative theory, HPA axis activation, and finally, the role of increased inflammatory cytokines such as interleukin 1 (IL1), tumor necrosis factor-alpha, interferon-gamma, IL-2 IL-4, and MIF are suggested to contribute to both AA and metabolic syndrome (MS). Assessment of the degree of association of MS (NCEP ATP III criteria) in clinically diagnosed cases of AA and compare to that of controls. Similar age/sex-matched AA patients and controls (106 in each group) were taken. Anthropometric measurements, blood-sugar estimation, lipid-profile estimation in venous blood sample, and blood-pressure measurement were done. Prevalence of MS was almost similar among cases of AA 9/106 (8.47%) as well as healthy controls 8/106 (7.54%), and the difference was not statistically significant (P = 1). Among all components of MS, waist circumference (WC) (central obesity) was the most common parameter (100% cases). In controls, high systolic blood pressure (SBP) was the most common parameter (77.78% controls). AA is associated with a higher level of SBP, diastolic blood pressure (DBP), WC although nonsignificant, and low level of high-density lipoprotein cholesterol which was the only significant association. Insignificant correlation between occurrence of MS and evidence of insulin resistance (IR) in AA was observed in this study population. However, some of the observations in the present study may raise awareness in susceptible individuals that lifestyle changes and regular screening in AA can reduce the risk of cardiovascular diseases and other co-existing autoimmune inflammatory condition-IR, dyslipidemia, and hypertension.

PSUN141 Suspected Lipodystrophy in a Thin Young Man With Type 1 Diabetes

Abstract Introduction Lipodystrophies are a group of exceptionally rare adipose disorders typified by complete or partial lack of adipose tissue. They come in two forms, congenital and acquired. Global prevalence is approximately 3 cases per million people. Despite their rarity, lipodystrophies often have common derangements, including, insulin resistance, decreased leptin, lipid abnormalities, and non-alcoholic fatty liver disease. Identifying and diagnosing these disorders is challenging as so few cases exist and may easily be confused for a variety of other illnesses. Case Our patient was a 21 year old African American Male with BMI of 14.0 kg/m2 (46.72 kg, 28.35 cm), with antibody proven type 1 diabetes mellitus diagnosed and extreme weight loss at age 12. His diabetes has been poorly controlled since diagnosis, with episodes of DKA, and a persistently elevated A1c. He has evidence of insulin resistance, requiring about 2.57 units per kilogram of insulin daily. In spite of this fasting blood glucose routinely exceeds 300 mg/dL. Physical exam significant for a generalized lack of adipose tissue. Most recent laboratory results showed: HbA1c &amp;gt;14% (&amp;lt;5.7%), fasting plasma glucose 419 mg/dL (70-99 mg/dL), c-peptide &amp;lt;0.10 ng/mL (0.80-3.85 ng/dL), and GAD65 Ab 18 IU/mL (&amp;lt;5 IU/mL). Interestingly patient also had a decreased leptin of 0.5 ng/mL (1.8-19.9 ng/mL), a known feature of lipodystrophy. However, triglycerides are only 158 mg/dL (&amp;lt;150 mg/dL), which may point more toward isolated leptin deficiency without lipodystrophy. Modified insulin challenge was administered in office to differentiate between true insulin resistance and poor compliance. Insulin lispro 0.3 units per kilogram subcutaneous (14 units total) was administered at time zero, with pre-test SMBG 575 mg/dL. Over the three-hour test, blood sugars reached a nadir of 297 mg/dL. Patient was observed throughout and did not eat or drink anything but water during the test. He showed no signs or symptoms of hypoglycemia at any time during the challenge. Results indicated significant insulin resistance for his body weight. Conclusion Physical exam features, labs, including leptin of 0.5 ng/mL, and relatively severe insulin resistance suggest possible lipodystrophy or isolated leptin deficiency. However, triglycerides were not extremely elevated as expected in lipodystrophy. We have ordered metreleptin for further elucidation of patient's condition. Disclaimer: This research was supported (in whole or in part) by HCA Healthcare and/or an HCA Healthcare affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Clinicoepidemiological study of acanthosis nigricans in pre and primary school children and its association with body mass index, waist circumference and insulin resistance

Acanthosis nigricans is characterised by hyperpigmentation and velvet like thickening of skin. It is seen symmetrically involving the neck, axilla, groins, antecubital and popliteal fossae, umbilical, perianal areas and in advanced conditions, even dorsum of hands and fingers.To evaluate the clinical features and epidemiological factors of acanthosis nigricans in pre and primary school children and to evaluate the association of acanthosis nigricans with body mass index, waist circumference and insulin resistance. A total of 100 children with acanthosis nigricans meeting defined inclusion and exclusion criteria were enrolled in this cross-sectional study after taking an informed consent and approval of institutional ethical committee. All parents of children with acanthosis nigricans were subjected to a detailed history based on a questionnaire. A thorough clinical examination was done to study acanthosis nigricans. Blood samples were collected and fasting serum insulin and fasting blood sugar were determined. Most of the children were boys (M:F=1.3:1) and mean age was 6.66±1.99 years. Twenty four percent were normal weight, 28% were overweight and 48% were obese children. On examination, neck was the commonest site of acanthosis nigricans. Grade 4 neck severity (p=0.0014) and grade 3 neck texture (P=0.0198) of acanthosis nigricans were significantly associated with Insulin resistance (HOMA2-IR). Twenty eight percent of normal weight, 42.8% of overweight and 75% of obese children had insulin resistance. Acanthosis nigricans was associated with insulin resistance in normal, overweight and obese children. Hence, we would like to propose that all the children with acanthosis nigricans must be screened for Insulin resistance irrespective of body mass index. With this evidence of Insulin resistance, guidelines can be given to the parents about life style modification which will help in preventing the onset of diabetes mellitus later and thereby, improving the quality of life of the child.

Effect of Homocysteine and Vitamin D in Polycystic Ovary Syndrome with Iraqi Women

This research has been carried out on the effect of some biochemical parameters on women with polycystic ovaries. The presented work aims to determine the levels of a few biochemical parameters in females with polycystic ovaries syndrome (PCOS) attending the Department of Biotechnology, College of Science, University of Baghdad’s. The study comprised 35 women between 18 and 35 who had PCOS based upon complete Rotterdam criteria. The control group comprised 35 healthy females of one age who had a regular menstrual cycle. The results indicated that females with PCOS have been obese or overweight when their body mass index (BMI) was more than 30. Insulin, fasting blood sugar (FBS), glycated hemoglobin (HbA1c%), and homeostatic model assessment for insulin resistance (HOMA-IR) have all been higher (≤ 0.05) in females with PCOS in comparison with a control group, showing that insulin resistance (IR) has been present. Total cholesterol (TC) and low-density lipoprotein (LDL) levels have been higher (≤ 0.05). Still, very-low-density lipoprotein (VLDL) and triglycerides (TG) levels were within the normal reference range without considerable differences compared to the control group. High-density lipoprotein (HDL) has been lower than the control group. According to this work, the majority of females with PCOS had a high BMI. Those patients showed signs of IR. It was discovered that the patient had dyslipidemia. Those results vary from previous studies that found no evidence of IR. The primary goal of this work is to assess the effects of homocysteine and vitamin D in females who have PCOS, and the findings revealed a significant increase in the homocysteine levels and a considerable drop or deficiency in vitamin D in Iraqi females who have PCOS.

8-OR: Plasminogen Deficiency Protects against Nonalcoholic Fatty Liver Disease and Insulin Resistance, but Not Diet-Induced Obesity

Obesity affects over 40% of the US population and predisposes individuals to metabolic syndrome, which is associated with a 50% increase in the risk of cardiovascular events. A documented clinical manifestation of obesity is a procoagulant and anti-fibrinolytic state. Elevated levels of circulating plasminogen activator inhibitor (PAI) -1 are correlated with metabolic syndrome, and PAI-1-deficient mice are protected from diet-induced obesity (DIO) . However, an unresolved question is whether plasminogen itself influences the development of obesity and associated disease sequelae? Here, we analyzed the impact of genetically-imposed plasminogen deficiency on the development of DIO and associated pathologies. Over the course of 20 weeks, plasminogen-deficient (Plg-) mice gained as much weight as the control mice (Plg+) on HFD, although HFD-fed Plg- mice had larger epididymal white adipose tissues than those of HFD-fed Plg+ mice. In contrast, while HFD-fed Plg+ animals displayed a fatty liver disease phenotype characterized by histological evidence of steatosis, elevated triglyceride content, and hepatocellular injury, HFD-fed Plg- mice were protected from developing each of these pathologies. HFD-fed Plg+ mice also developed hypercholesterolemia, whereas circulating cholesterol levels in Plg- mice were comparable to LFD-fed mice. Intriguingly, while the brown adipose tissue mass was comparable between diet and genotype, there was an upregulation of uncoupling protein-1 (Ucp1) expression in BAT of HFD-fed Plg- mice. Notably, whereas HFD-fed Plg+ mice showed evidence of insulin resistance as revealed by compromised glucose clearance, HFD-fed Plg- mice were partially protected. Collectively, our data suggest that plasmin (ogen) contributes to HFD-induced fatty liver disease and insulin resistance, and that plasminogen deficiency imposes a state of metabolically healthy obesity. Disclosure W.S.Hur: None. Y.Nguyen: None. Y.Patel: None. K.C.King: None. M.J.Flick: None. Funding National Institutes of Health (RDK112778)

Insulin resistance – the basics every medical specialist should know

Introduction and purpose: Insulin resistance (IR) is a health problem as it can accompany obesity and lead to serious metabolic complications. In recent years, it has been "overdiagnosed" in clinical practice due to the lack of specific diagnostic criteria. The article summarizes the current knowledge in the field of pathophysiology, clinical picture and diagnostics.&#x0D; State of knowledge: Obesity remains the leading cause of IR, especially in the 21st century. In a positive energy balance, the adipocyte overloaded with fat protects itself against further influx of glucose and fats and becomes insulin insensitive. A component of IR development is subclinical inflammation of macrophage-rich adipose tissue which is exacerbated by an adipocytokine imbalance, which in turn generates IR. The markers of cellular resistance to insulin are free fatty acids in the bloodstream which are responsible for the lipotoxicity in hepatocytes and myocytes. Compensatory fasting hyperinsulinemia, which is currently considered the most sensitive diagnostic criterion, provides evidence of IR. An effective method of sensitizing cells to insulin is lifestyle modification, including a low-energy diet with regular physical activity in the form of aerobic-resistance exercise. Literature recommends no pharmacological treatment of IR alone, without obesity or other concomitant diseases.&#x0D; Conclusions: IR is not a separate disease, but only a pathological expression of cells' adaptation to excess of consumed energy. However, in its systemic form, when the protective mechanisms become ineffective, it induces metabolic disturbances. Only the causal treatment of IR guarantees therapeutic success.

Canonical insulin signaling is not significantly impaired in early stages of depression.

Patients with major depression (MD) are at high-risk for insulin resistance (IR), type-2 diabetes, metabolic syndrome, cardiovascular morbidity and mortality. However, our recent study published in this journal [Eur Arch Psychiatry Clin Neurosci. 2019 Jun;269(4):373-377], found no evidence of IR in acutely-ill drug-naive first-episode MD (FEMD) using the homeostatic model assessment of insulin resistance (HOMA-IR). We concluded, that MD may be related to impaired glucose/insulin homeostasis in the long-term but not in early disease stages. Now, we performed a complementary analysis of the canonical insulin signalling pathway containing the set of control and FEMD samples from the study mentioned above. The first node (pS312-IRS-1, pY-IRS-1) and downstream pathway which affects glucose and lipid homeostasis (phosphorylated proteins: pS473-AKT, pS9-GSK3β, pS2448-mTOR, pT389-p70S6K; total proteins AKT, GSK3β, mTOR, p70S6K) were analyzed by electrochemiluminescence (ECL) in neuronalextracellular vesicles (nEVs) enriched for L1 neural cell adhesion molecule (L1CAM) expression. No significant diagnosis-related differences were observed for the pS312-IRS-1 / pYIRS-1 ratio (P = 0.093), but the mean ratio was reduced by ~ 70% in FEMD versus controls. Moreover, omnibus analysis of downstream phosphorylated / total signaling protein ratios and respective post-hoc analyses revealed no significant changes in FEMD patients versus controls (P = 0.734). HAMD-21 scores were not correlated with pS312-IRS-1 / pY-IRS-1 or downstream phosphorylated/total signaling protein ratios. In summary, we did not find evidence for altered neuronal insulin signaling in early disease stages of MD. This is in contrast to schizophrenia, where we and otherresearchers have seen evidence of IR in first-episode patients.

Insulin Receptor Autoantibody–mediated Hypoglycemia in a Woman With Mixed Connective Tissue Disease

Autoantibodies to the insulin receptor are rare and typically cause severe insulin resistance and hyperglycemia, a condition termed type B insulin resistance. Uncommonly, antibodies to the insulin receptor can cause hypoglycemia. We present the case of a woman who developed recurrent severe hypoglycemia and myopathy, was found to have insulin receptor autoantibodies and mixed connective tissue disease, and had resolution of hypoglycemia with immunosuppression. A 55-year-old woman with a history of obesity, hypertension, and prior hemorrhagic stroke presented with recurrent severe hypoglycemia. A diagnostic fast resulted in hypoinsulinemic hypoketotic hypoglycemia. Adrenal function was intact. Progressive myopathy had developed simultaneously with her hypoglycemia, and rheumatologic evaluation revealed mixed connective tissue disease. The plasma acylcarnitine profile was normal, extensive oncologic evaluation including insulin-like growth factor 2 measurement was unrevealing, and anti-insulin antibody testing was negative. Ultimately, anti-insulin receptor antibodies were found to be present. The patient was treated with glucocorticoids and rituximab. Eight weeks after initiation of immunosuppression, the insulin receptor antibody titer had decreased and hypoglycemia had resolved. Eight months after diagnosis, the patient remained free of severe hypoglycemia despite tapering of glucocorticoids to a near-physiologic dose. Though antibodies to the insulin receptor typically cause severe insulin resistance, this patient had no evidence of insulin resistance and instead presented with recurrent severe hypoglycemia, which responded to glucocorticoids and rituximab. The diagnosis of insulin receptor antibody–mediated hypoglycemia is rare but should be considered in patients with systemic autoimmune disease, including mixed connective tissue disease, in the appropriate clinical context.

Metformin for pediatric obesity and insulin resistance: a retrospective study within an integrated health care system.

Few treatments exist for pediatric obesity. Metformin holds potential for pediatric weight loss. This large retrospective study examined the effect of metformin on weight, BMI, BMI z score, and cardiometabolic outcomes. The study included 7,068 patients aged 10 to 17 years with BMI at or above the 95th percentile and evidence of insulin resistance. The final cohort of 955 patients with BMI data at 0 to 24 months was categorized into three groups: metformin plus intensive lifestyle changes, intensive counseling alone, and routine counseling. In order to adjust for pubertal BMI changes, a subgroup analysis was conducted for adolescents aged 15 to 17 years. At 6 and 12 months, metformin treatment produced significant reductions in weight (-3.5 kg and -5.3 kg, p<0.0001), BMI (-1.06 kg/m² and -1.23 kg/m², p<0.0001), and BMI z score (-0.05 and -0.07, p ≤ 0.002), which continued to decrease at 24 months (-0.05 and -0.08, p=0.11 and 0.01), compared with control groups. Adolescents aged 15 to 17 years showed similar improvements. Systolic blood pressure and high-density lipoprotein cholesterol also improved in the metformin group. Metformin with lifestyle interventions significantly reduced weight, BMI, and BMI z score in pediatric patients with obesity and insulin resistance up to 24 months, compared with intensive and routine counseling alone.

A Rare Cause of Diabetes: COVID-19

A Rare Cause of Diabetes: COVID-19 Introduction: Environmental factors like viruses have been described in the mechanism of pancreatic beta cell destruction. Various viruses can trigger autoimmunity in individuals genetically predisposed to diabetes. Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) has been shown to bind to angiotensin-converting enzyme 2 (ACE 2) which is expressed throughout the body, including pancreatic cells, leading to direct injury of the endocrine pancreas. We report a case of coronavirus infection disease 2019 (COVID-19) causing a new onset of diabetes mellitus presentation with hyperglycemia, polyuria, polydipsia and weight loss. Case Presentation: A 53 year-old, previously healthy, male presented with five days of fever, fatigue, dry cough, dyspnea and diarrhea. On admission he was hypoxic, with a body mass index of 25 kg/m2 and no evidence of insulin resistance on physical exam. He was diagnosed with SARS CoV-2 and admitted for high requirements of oxygen without the need of the intensive care unit. He was treated with tocilizumab, atazanavir, hydroxychloroquine, full dose anticoagulation and azithromycin. Dexamethasone 4 mg every 8 hours was given for three days. During this admission, his fasting glucose was 75–108 mg/dL. Once started on steroids his fasting and prandial glucose was 85–96 mg/dL and 140 mg/dL on one occasion. He was eventually discharged with 2 liters of nasal cannula which he required for one week. One and a half months after, he presented to the emergency department due to a 6 kg weight loss, polyuria, polydipsia, malaise and fatigue. On arrival his glucose was 549 mg/dL, without anion gap or ketones. He had no evidence of new infection and SARS CoV-2 test was negative. He was started on insulin glargine at night and insulin Humalog before each meal with corrections. Hemoglobin A1c was 13.4% with a C-peptide 0.36 ng/mL and glucose of 195 mg/dL at the time of C-peptide test. His antibodies, anti-islet cell antibody, zinc transporter 8 and glutamic acid decarboxylase-65, were negative. He was discharged with basal/bolus regimen and followed up outpatient with Endocrinology. During follow-up, his c-peptide normalized and he was tapered off insulin. Discussion: In 2003, atypical pneumonia caused by SARS CoV-2 was reported to be associated with hyperglycemia in patients without prior history of diabetes. At 3 year follow-up, the patients no longer had diabetes. Moreover, patients with mild SARS CoV-2 during the first day of hospitalization had a higher fasting plasma glucose than patients admitted for other causes of pneumonia. It is known that SARS CoV-2 binds to ACE 2 which downregulates the receptor, leading to impairment of insulin secretion and hyperglycemia. SARS CoV-2 also produces a direct injury in beta pancreatic cells. It is imperative to monitor patients post COVID-19 to evaluate for new onset diabetes and likely resolution.

Pre-diabetes and Type 2 Diabetes Status in Overweight and Obese Children in a Tertiary Care Hospital of Bangladesh

Introduction: Obesity in childhood is associated with many co-morbid conditions; one of them is alteration of glucose metabolism.&#x0D; Materials and Methods:This cross-sectional study was conducted among 100 overweight and obese children aged 5-16 years to determine the status of pre-diabetes (IFG and IGT) and type 2 diabetes mellitus (T2DM), attending the OPD, BSMMU, Dhaka. All overweight/obese children were included according to BMI for age and sex using CDC growth chart. Children taking steroid for any cause or having any endocrine disorder or syndrome was excluded from the study. Anthropometry and blood pressure measurement were done and skin manifestations of insulin resistance were looked for. Fasting lipid profile and oral glucose tolerance test (OGTT) was done for each child.&#x0D; Result: Among the studied children 62% were male and 38% female, 77% were obese and 23% were over weight. Evidence of insulin resistance were found among most of the children and most common evidence was dyslipidemia (80%) followed by acanthosis nigricans(76%). Skin manifestation of polycystic ovary syndrome (PCOS) was found in 3% of children. Impaired fasting glucose (IFG) was found in 4% and Impaired Glucose Tolerance (IGT) was found in 7% of children among them 4% had both IGT and IFT. No child was found diabetic in this study.&#x0D; Conclusion:Altered glucose metabolism was present in overweight and obese children of our children, so screening is recommended.&#x0D; Bangladesh J Child Health 2020; VOL 44 (3) :143-147

Abstract 13575: Lack of Both Mitochondrial Proteins Sirt3 and Ucp2 in Mice Recapitulates Many Critical Features of Human Pulmonary Arterial Hypertension (PAH), Including Inflammatory Plexogenic Lesions, Supporting the Metabolic Theory of PAH

Loss-of function SNPs for Sirt3 (a mitochondrial deacetylase) and Ucp2 (an atypical uncoupling protein enabling mitochondrial calcium entry) have been associated with insulin resistance and obesity in humans; and patients with PAH have insulin resistance without being obese. In a cohort of PAH patients (n=60) we found these SNPs often both in the same patient in a homozygous or heterozygous manner and their presence correlated positively with the degree of PAH upon referral, the presence of type II diabetes and outcomes (death, transplantation). We generated and studied double KO mice for Sirt3 and Ucp2 using closed-chest right heart catheterization and echocardiography and found increasing severity of pulmonary hypertension (PHT) in Sirt3 +/- -Ucp2 +/ - , Sirt3 -/- -Ucp2 +/ - , Sirt3 +/- -Ucp2 -/- and Sirt3 -/- -Ucp2 -/- , associated with decreasing cardiac output and increasing right ventricular hypertrophy, dilatation and dysfunction (TAPSE), compared to wild-type (WT) mice. The LVEDP in all mice was normal. There was increasing severity of vascular remodeling with increasing levels of CD4 + cell infiltration, while Sirt3 -/- -Ucp2 +/- , Sirt3 +/- -Ucp2 -/- and Sirt3 -/- -Ucp2 -/- mice also developed frequent plexogenic lesions. In vivo and in vitro pulmonary artery smooth muscle cells (PASMC) expressed higher levels of Ki67, compared to WT mice. In vitro, the Sirt3 -/- -Ucp2 +/- , Sirt3 +/- -Ucp2 -/- and Sirt3 -/- -Ucp2 -/- PASMC exhibited more apoptosis-resistance, expressed higher nuclear levels of proliferative transcription factors (HIF1, NFATc2), exhibited decreased respiration and higher levels of glycolysis, similarly to previous reports of animal and human PAH PASMC. The Sirt3 -/- -Ucp2 -/- , but not the WT mice, also developed in vivo evidence of insulin resistance. Our work supports the metabolic theory of PAH and shows that these mice exhibit spontaneous severe PHT (without environmental or chemical triggers) in a gene dose-response dependent manner that mimics human PAH. No other mouse model of PHT has shown frequent and predictable plexogenic lesions. Our study is relevant to the PAH patients that carry loss-of-function SNPs of mitochondrial proteins and offers a new mouse model of PAH, with more features of human PAH than previous mice models.

Interesterified palm oil impairs glucose homeostasis and induces deleterious effects in liver of Swiss mice

BackgroundInteresterified fats have largely replaced the partially hydrogenated oils which are the main dietary source of trans fat in industrialized food. This process promotes a random rearrangement of the native fatty acids and the results are different triacylglycerol (TAG) molecules without generating trans isomers. The role of interesterified fats in metabolism remains unclear. We evaluated metabolic parameters, glucose homeostasis and inflammatory markers in mice fed with normocaloric and normolipidic diets or hypercaloric and high-fat diet enriched with interesterified palm oil. MethodsMale Swiss mice were randomly divided into four experimental groups and submitted to either normolipidic palm oil diet (PO), normolipidic interesterified palm oil diet (IPO), palm oil high-fat diet (POHF) or interesterified palm oil high-fat diet (IPOHF) during an 8 weeks period. ResultsWhen compared to the PO group, IPO group presented higher body mass, hyperglycemia, impaired glucose tolerance, evidence of insulin resistance and greater production of glucose in basal state during pyruvate in situ assay. We also observed higher protein content of hepatic PEPCK and increased cytokine mRNA expression in the IPO group when compared to PO. Interestingly, IPO group showed similar parameters to POHF and IPOHF groups. ConclusionThe results indicate that substitution of palm oil for interesterified palm oil even on normocaloric and normolipidic diet could negatively modulate metabolic parameters and glucose homeostasis as well as cytokine gene expression in the liver and white adipose tissue. This data support concerns about the effects of interesterified fats on health and could promote further discussions about the safety of the utilization of this unnatural fat by food industry.

Intra-abdominal fat estimation by bio-electrical impedance analysis in patients with fibrocalculous pancreatic diabetes compared with BMI matched type 2 diabetic subjects and healthy controls

Background and aimsIntra-abdominal adipose tissue (IAAT) is a major contributor to insulin resistance (IR) in type 2 diabetes mellitus (T2D). Prior studies have demonstrated evidence of IR in fibrocalculous pancreatic diabetes (FCPD). However, no data exists on IAAT estimation in FCPD. Hence, we compared IAAT area among FCPD patients and an equal number of body mass index (BMI) matched T2D patients and healthy controls. MethodsWe recruited 60 patients with FCPD between January 2019 and February 2020. Body composition analysis was performed via bio-electrical impedance analysis. ResultsThe mean ages were 37.82 ± 10.07, 51.02 ± 9.9, and 30.7 ± 11.51 years for patients in the FCPD, T2D, and control groups, respectively. The mean BMI of patients in the three groups was 20.65 ± 2.01, 20.83 ± 1.49, and 20.91 ± 1.59 kg/m2, respectively (P = 0.684). The mean IAAT area of patients in the FCPD, T2D, and control groups was 67.93 ± 43.38, 117.78 ± 48.03, and 100.52 ± 42.31 cm2, respectively. IAAT was significantly lower in patients with FCPD compared with those in the other two groups (P < 0.0001). In the entire cohort, IAAT showed significant positive correlation with age (r = 0.20), abdominal circumference (r = 0.80), waist hip ratio (r = 0.75), and LDL level (r = 0.25) (P < 0.05). ConclusionsPatients with FCPD have significantly lower IAAT compared to BMI matched T2D subjects and healthy controls. IAAT does not appear to be a major contributor to insulin resistance observed in patients with FCPD.

The clinical and histological characteristics of patients with biopsy-proven non-alcoholic fatty liver disease in the absence of insulin resistance.

Background and AimNon-alcoholic fatty liver disease (NAFLD) is closely associated with insulin resistance (IR). While a minority of patients with NAFLD does not have evidence of IR, no detailed characterization of this specific phenotype is currently available. This study was undertaken to investigate the clinical and histological characteristics of this patient group.Materials and MethodsWe retrospectively reviewed the clinical records of 263 patients with biopsy-proven NAFLD. IR was defined by a Homeostatic Model Assessment of IR (HOMA-IR) score >2.73. The histological diagnosis of non-alcoholic steatohepatitis (NASH) was performed using 1) the steatosis, activity and fibrosis score and 2) the NASH Clinical Research Network (NASH CRN) criteria. Significant fibrosis was defined by the presence of a histological fibrosis score higher than F≥2. Patients with and without evidence of IR were compared concerning clinical, laboratory, and histological characteristics.ResultsOf the 263 patients with biopsy-proven NAFLD, 53 (20.2%) patients had no evidence of IR. Patients without IR were younger [IR (-): 42 (22–65) years versus IR (+): 49 (22−71) years, p=0.001] and had a higher prevalence of men [IR (-): 39 (73.6%) versus IR (+): 113 (53.8%), p=0.009]. Moreover, they were characterized by a lower body mass index [IR (-): 30.06±3.61 kg/m2 versus IR (+): 33.19±5.06 kg/m2, p=0.000] and lower frequencies of metabolic risk factors–including the metabolic syndrome, diabetes, hypertension, hyperlipidemia, and lower waist/hip circumference. Liver histology was generally less severe in patients without IR; specifically, they showed a lower prevalence of NASH [IR (-): 38 (71.7%) versus IR (+): 190 (90.5%), p=0.000] and significant fibrosis [IR (-): 9 (17.0%) versus IR (+): 106 (50.5%), p=0.000] than did patients with IR. Multivariate analysis identified obesity [odds ratio (OR): 9.321, 95% confidence interval (CI): 1.031−84.261, p<0.05] and an international normalized ratio >1.1 (OR: 10.116, 95% CI: 1.325−77.225, p<0.05) as independent predictors of significant fibrosis in patients with NAFLD and no IR.ConclusionPatients with NAFLD and no IR has less severe liver histology than patients with IR. However, obesity appears to be independently associated with significant fibrosis in this patient group.

Prenatal alcohol exposure programmes offspring disease: insulin resistance in adult males in a rat model of acute exposure.

Prenatal alcohol exposure has the potential to affect fetal development and programme chronic disease in offspring. Previous preclinical models typically use high, chronic doses of alcohol throughout pregnancy to examine effects on offspring, particularly on the brain and behaviour. In this study we use a rat model of moderate, acute, prenatal alcohol exposure to determine if this can be detrimental to maintenance of glucose homeostasis in adolescent and adult offspring. Although female offspring were relatively unaffected, there was evidence of insulin resistance in 6-month-old male offspring exposed to prenatal alcohol, suggestive of a pre-diabetic state. This result suggests that even a relatively low-dose, acute exposure to alcohol during pregnancy can still programme metabolic dysfunction in a sex-specific manner. Alcohol consumption is highly prevalent amongst women of reproductive age. Given that approximately 50% of pregnancies are unplanned, alcohol has the potential to affect fetal development and programme chronic disease in offspring. We examined the effect of an acute but moderate prenatal alcohol exposure (PAE) on glucose metabolism, lipid levels and dietary preference in adolescent and/or adult rat offspring. Pregnant Sprague-Dawley rats received an oral gavage of ethanol (1gkg-1 maternal body weight, n=9 dams) or an equivalent volume of saline (control, n=8 dams) at embryonic days 13.5 and 14.5. PAE resulted in a blood alcohol concentration of 0.05-0.06% 1h post-gavage in dams. Fasting blood glucose concentration was not affected by PAE in offspring at any age, nor were blood glucose levels during a glucose tolerance test (GTT) in 6-month-old offspring (P>0.5). However, there was evidence of insulin resistance in PAE male offspring at 6months of age, with significantly elevated fasting plasma insulin (P=0.001), a tendency for increased first phase insulin secretion during the GTT and impaired glucose clearance following an insulin challenge (P=0.007). This was accompanied by modest alterations in protein kinase B (AKT) signalling in adipose tissue. PAE also resulted in reduced calorie consumption by offspring compared to controls (P=0.04). These data suggest that a relatively low-level, acute PAE programmes metabolic dysfunction in offspring in a sex-specific manner. These results highlight that alcohol consumption during pregnancy has the potential to affect the long-term health of offspring.