Severe Insulin Resistance Research Articles

OR18-01 Massively Parallel Functional Assay Of Extracellular Insulin Receptor Variants

Abstract Disclosure: V. Aslanzadeh: None. G. Brierley: None. G. Kudla: None. R.K. Semple: None. Loss-of-function mutations in the gene for the human insulin receptor, INSR, cause either autosomal dominant or autosomal recessive severe insulin resistance. Biallelic mutations produce extreme insulin resistance which is commonly fatal in infancy or childhood. A wide and growing number of mutations have been associated with disease, with few recurring mutations, and only a small subset have been studied functionally to date. Discriminating loss-of-function pathogenic alleles from insignificant variants is an important barrier to diagnosis and translational studies of novel candidate treatments. Such candidate therapies include a variety of antibody, peptide and small molecule ligands that activate the receptor in a manner distinct to insulin. These show potential to activate mutant receptors that are expressed but show impaired insulin binding or responsiveness. To address this barrier to translation we have now used massively multiplexed, Flow-Seq-based assays simultaneously to determine the effects of 14,000 human INSR extracellular domain missense variants. We assayed receptor cell surface expression, insulin binding and signal transduction using heterologous expression of mutants in mouse embryonic cells in which endogenous Insr and Igf1r genes had been knocked out or knocked down. Preliminary analysis reliably discriminates A. variants that reduce or abolish receptor cell surface expression when measured with two different monoclonal anti-receptor antibodies B. variants with preserved cell surface expression but selectively impaired binding of insulin and C. an overlapping group of variants with severely impaired signalling response to insulin but preserved response to antibody. Our assay confirmed previously studied attributes of a panel of disease-causing variants, and shows strong agreement with prior alanine scanning mutagenesis studies and structural predictions. We thus provide a rich sequence-function map for INSR variant interpretation. A prediction tool trained on known pathogenic INSR alleles is currently being developed for access by the community both to accelerate confident molecular diagnosis of newly identified rare INSR variants, and also to aid stratification of mutations according to potential for activation by non canonical INSR ligands. Presentation: Saturday, June 17, 2023

Senescence-associated inflammation and inhibition of adipogenesis in subcutaneous fat in Werner syndrome.

Werner syndrome (WS) is a hereditary premature aging disorder characterized by visceral fat accumulation and subcutaneous lipoatrophy, resulting in severe insulin resistance. However, its underlying mechanism remains unclear. In this study, we show that senescence-associated inflammation and suppressed adipogenesis play a role in subcutaneous adipose tissue reduction and dysfunction in WS. Clinical data from four Japanese patients with WS revealed significant associations between the decrease of areas of subcutaneous fat and increased insulin resistance measured by the glucose clamp. Adipose-derived stem cells from the stromal vascular fraction derived from WS subcutaneous adipose tissues (WSVF) showed early replicative senescence and a significant increase in the expression of senescence-associated secretory phenotype (SASP) markers. Additionally, adipogenesis and insulin signaling were suppressed in WSVF, and the expression of adipogenesis suppressor genes and SASP-related genes was increased. Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), alleviated premature cellular senescence, rescued the decrease in insulin signaling, and extended the lifespan of WS model of C. elegans. To the best of our knowledge, this study is the first to reveal the critical role of cellular senescence in subcutaneous lipoatrophy and severe insulin resistance in WS, highlighting the therapeutic potential of rapamycin for this disease.

Rabson–Mendenhall Syndrome with Severe Insulin Resistance Type A: The Need to Act Faster than the Disease

Abstract Introduction Rabson–Mendenhall syndrome (RMS) is an autosomal disorder where severe insulin resistance is observed. Insulin levels decrease over time and suppress gluconeogenesis in the liver. Fatty acid oxidation is affected, leading to frequent episodes of ketoacidosis. The changes in RMS are much faster than in patients with type 2 diabetes. RMS patients have a significantly reduced life expectancy and may die during adolescence or early adulthood. Case Presentation A 15-year-old girl presented with poorly controlled diabetes. She was diagnosed with RMS at the age of 50 days, and her genetic study showed a homozygous mutation for R141W in the INSR gene. Her insulin level was high at 737 μIU/mL, insulinoma antigen 2 and glutamic acid decarboxylase antibodies were negative, and C-peptide was > 18 ng/mL. There is a strong family history of RMS on her mother's side. Her hyperglycemia was treated with an insulin pump (requiring up to 300 units of insulin/day) and oral rosiglitazone for the first 6 years. Rosiglitazone was replaced by oral insulin-like growth factor 1 (IGF1). Over the last 3 years, she had four further episodes of diabetic ketoacidosis triggered by infections and severe lipodystrophy. A trial of leptin and subcutaneous IGF1 has failed. The patient has a closed-loop insulin pump MiniMed 780G with a total daily dose of 261 units (4.6 U/kg/day). Results During the past 15 years, the patient suffered many health, psychological, family, and school issues. These issues were due to RMS itself, complications of diabetes, side effects of medications, and technology failure. Our multidisciplinary team tackled all issues by providing the most appropriate care, mediation, and technology. Conclusion To act faster than the disease progression, we need to know the whole list of issues our patient could face, as this will help us to look at the entire picture rather than treating different pieces separately. Effective cooperation between the teams is crucial and needs to be organized through a family physician or by the team involved the most in patient care. Although technology has limitations, it still helps when used appropriately.

Influence of Atherosclerotic Risk Factors on the Effectiveness of Therapeutic Ultrasound Cavitation for Flow Augmentation

Shear created by inertial cavitation of microbubbles by ultrasound augments limb and myocardial perfusion and can reverse tissue ischemia. Our aim was to determine whether this therapeutic bioeffect is attenuated by atherosclerotic risk factors that are known to impair shear-mediated vasodilation and adversely affect microvascular reactivity. In mice, lipid-stabilized decafluorobutane microbubbles (2×108) were administered intravenously while exposing a proximal hind limb to ultrasound (1.3MHz, 1.3 mechanical index, pulsing interval 5seconds) for 10 minutes. Murine strains included wild-type mice and severely hyperlipidemic mice at 15, 35, or 52 weeks of age as a model of aging and elevated cholesterol, and obese db/db mice (≈15weeks) with severe insulin resistance. Quantitative contrast-enhanced ultrasound perfusion imaging was performed to assess microvascular perfusion in the control and ultrasound-exposed limb. An in situ electrochemical probe and invivo biophotonic imaging were used to assess limb nitric oxide (NO) and adenosine triphosphosphate concentrations, respectively. Microvascular perfusion was significantly increased by several fold in the cavitation-exposed limb versus control limb for all murine strains and ages (P<.001). In wild-type and hyperlipidemic mice, hyperemia from cavitation was attenuated in the 2 older age groups (P<.01). In young mice (15weeks), perfusion in cavitation-exposed muscle was less in both the hyperlipidemic mice and the obese db/db mice compared with corresponding wild-type mice. Using young hyperlipidemic mice as a model for flow impairment, limb NO production after cavitation was reduced but adenosine triphosphosphate production was unaltered when compared with age-matched wild-type mice. In mice, ultrasound cavitation of microbubbles increases limb perfusion by several fold even in the presence of traditional atherosclerotic risk factors. However, older age, hyperlipidemia, and insulin resistance modestly attenuate the degree of flow augmentation, which could impact the degree of flow response in current clinical trials in patients with critical limb ischemia.

Atypical Adolescent Presentation of Novel INSR Mutation with Hyperglycemia

The human Insulin Receptor (INSR) mutation can result in inherited insulin resistance syndrome. Severe Insulin Resistance (IR) results secondary INSR mutations have been reported in adult, adolescent and children manifesting with Hyperinsulinemic Hypoglycaemia (HH). Rabson-Mendenhall Syndrome and Donohue’s Syndrome, Type A insulin resistance syndrome are resultant of the INSR mutation. We report a case of an adolescent boy who presented with very high blood sugars requiring high doses of insulin, with a novel heterozygous INSR mutation.

NEFA Dynamics in Adults With Severe Obesity and Insulin Resistance: No Coupling to the rs9939609 FTO Risk Allele.

The FTO gene is highly expressed in adipose tissues; however, whether nonesterified fatty acids (NEFA) dynamics are impacted by FTO has not been rigorously tested for in a uniformly obese study population comprising both sexes. To test for associations of the rs9939609 FTO risk allele with NEFA suppression. We investigated 97 subjects with severe obesity but without diabetes, having genotype TT (n = 32), AT (n = 31), or AA (n = 34) in a cross-sectional observation study. NEFA suppression was assessed from a low-dose hyperinsulinemic euglycemic clamp with glucose-tracer as well as from the response to a standardized meal. Insulin sensitivity was assessed by hepatic and total insulin sensitivity measurements in the clamp and by the Matsuda index during the meal. Variables of possible importance for NEFA dynamics were primarily assessed by linear regression. No genotype associations with fasting or suppressed NEFA were found, whether in the clamp or meal situation (P > .7 for all comparisons). Independent of genotype, higher fasting concentrations of NEFA and larger NEFA suppression were found in female compared with male subjects. Fasting NEFA or degree of suppression were not associated with total fat mass or body mass index. The respiratory quotient was negatively associated with NEFA suppression. In a gender-mixed adult population of obese individuals, an FTO obesity-risk allele did not affect fasting NEFA nor suppression thereof. These negative results on NEFA dynamics appear strengthened by the documentation of gender influence and associations with parameters reflective of insulin resistance.

P31-074-23 Lack of Maternal Exposure to Somatostatin Negatively Impacts the Development of Pancreas Islets Inducing Severe Insulin and Leptin Resistance in Offspring Fed a High-Fat Diet

P31-074-23 Lack of Maternal Exposure to Somatostatin Negatively Impacts the Development of Pancreas Islets Inducing Severe Insulin and Leptin Resistance in Offspring Fed a High-Fat Diet

1851-PUB: Intractable Diabetic Ketoacidosis with Enfortumab Vedotin

Enfortumab Vedotin (EV) is an antibody-drug conjugate for metastatic urothelial carcinoma. Hyperglycemia and diabetic ketoacidosis (DKA) have been reported in patients using EV. The incidence increases with higher BMI. The one case report available on the association between EV and DKA resulted in development of multiorgan failure and death. This case, however, describes a positive outcome with recovery from DKA. We present a case of a 59 year-old Caucasian woman with morbid obesity, prediabetes and recurrent metastatic urothelial cell carcinoma who presented with hyperglycemia after 2 doses of EV. Labs were indicative of DKA without an infectious etiology. She was admitted to the ICU for intravenous insulin drip treatment. Hyperglycemia and ketosis persisted despite using a maximum insulin drip rate of 60 units/hour. Starvation ketosis was a factor, so a diet was started. On day 2, NPH insulin and prandial lispro were added along with the insulin drip, resulting in a total daily insulin dose of 1660 units. Nevertheless, hyperglycemia persisted. U-500 regular insulin was initiated and by day 4, the patient received a total of 2940 units of insulin in one day with normalized serum ketones. Insulin drip requirements decreased with blood glucose controlled solely on subcutaneous insulin. She remained euglycemic, so U-500 insulin was switched to daily glargine. Eventually, she was off all insulin and maintained blood glucose below 130 mg/dL. Work up for insulin resistance included a C-peptide of 42.6 ng/mL (normal 1.1-4.4) with glucose of 230 mg/dL, negative glutamic acid decarboxylase 65 and insulin antibodies, and a glucagon level of 213 pg/mL (normal ≤80) with glucose of 220 mg/dL. Although the mechanism by which EV causes hyperglycemia is not known, this case illustrates that hyperglycemia was due to severe insulin resistance associated with EV. Understanding this, along with glycemic effects of targeted therapies with Vedotin are necessary to investigate the causal mechanism and treatment for EV related hyperglycemia/DKA. Disclosure A.Elahi: None. J.Duron: None. T.Porter: None.

1338-P: Characteristics of Patients with Type 2 Diabetes without Nonalcoholic Fatty Liver Disease (NAFLD)

About 70% of patients with type 2 diabetes mellitus (T2DM) have NAFLD which is a risk factor for cirrhosis and hepatocellular carcinoma. Many factors may be associated with more severe disease (i.e., insulin resistance, obesity). However, the metabolic profile of T2DM patients spared from having NAFLD and liver fibrosis is unclear. To this end, we recruited 266 patients with a history of T2DM without a known history of NAFLD (age: 59 ± 10 years; female 58.3 %; BMI: 33.0 ± 6.3 kg/m2, A1c: 7.0 ± 1.4 %) attending the outpatient university clinics. We performed a medical history, physical exam and measured routine/metabolic laboratories, liver fat (by CAP score ≥ 274 dB/m) and fibrosis (by liver stiffness measurement or LSM ≥7.0 kPa or F≥1) by elastography. A total of 32% patients did not have NAFLD, but when compared to NAFLD patients there were no differences in terms of age, gender, or race. Those without NAFLD had a lower mean BMI ± SD (29.6 ± 5.2 vs. 34.6 ± 6.2 kg/m2) and better glycemic control (mean A1c: 6.7 ± 1.3% vs. 7.2 ± 1.4%, both p&amp;lt;0.05). Patients without NAFLD had lower plasma ALT levels (mean 21 ± 12 vs. 28 ± 19 U/L; p&amp;lt;0.05). Patients with NAFLD had more severe (hepatic) insulin resistance (IR) (HOMA-IR: 3.0 ± 2.3 vs. 4.9 ± 3.2, p&amp;lt;0.05), with more people having a HOMA-IR ≥3.0 (35% vs. 72%, p&amp;lt;0.05). In multiple regression analysis, with a 95% CI, obesity (OR 4.0, 2.3-7.1), HOMA-IR (OR 3.1, 1.0-5.7), and worse glycemic control (A1c) (OR 1.7, 1.1-2.9) accounted for most of the difference between subjects with vs. without NAFLD. In NAFLD patients, comparing those with vs. without fibrosis, obesity (OR 2.8, 1.6-4.9) and elevated aminotransferases (OR 2.1, 1.3-3.2) accounted for most of the difference among patient. Conclusion: Patients with type 2 diabetes mellitus without NAFLD are usually more insulin sensitive and have a more favorable cardiometabolic profile than those with NAFLD. This highlights the role of insulin resistance and lipotoxicity in the development of NAFLD in this population. Disclosure E.Valdez saenz: None. D.Barb: None. M.J.Gurka: None. A.Sharma: None. K.Cusi: Consultant; Poxel SA, Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, 89bio, Inc., Bristol-Myers Squibb Company, Lilly, Madrigal Pharmaceuticals, Inc., Merck &amp; Co., Inc., Medscape, Myovant, Novo Nordisk, ProSciento, Quest Diagnostics, Sagimet, Sonic Incytes, Terns, Research Support; Echosens, Inventiva, LabCorp, Zydus. E.Godinez leiva: None. R.Lomonaco: None. S.A.Marangi: None. S.Kalavalapalli: None. M.A.Gonzalez: None. X.Chi: None. A.Ortiz rocha: None. Y.Mohseni: None. Funding National Institutes of Health (R01120331-01A1)

1529-P: Hypothalamic FGF1 Regulates Systemic Glucose and Energy Homeostasis

Systemic glucose and energy homeostasis is maintained by interorgan communication networks and the hypothalamus plays a key part in this process. Many research are being conducted to investigate the hypothalamus as a therapeutic target for metabolic diseases such as diabetes and obesity. Recent studies demonstrate that a single intracerebroventricular (icv) injection of FGF1 causes sustained glucose remission in diabetic rodent models (Scarlett et al.), and further study is being conducted. However, there are limited findings about how metabolic status affects endogenous brain FGF1 expression and how brain FGF1 plays in energy homeostasis. A study published in 2012 (Jonker et al.) found severe insulin resistance and a defect in adipose tissue remodeling in HFD-fed FGF1 null-mice. However, these investigations have a limitation in that it is not obvious which tissue/organ mediates insulin resistance due to FGF1 depletion. We found that CNS-deletion of FGF1 (BKO) shows impaired glucose sensing and decreased ERK/STAT3 signaling in ventromedial hypothalamus (VMH) and arcuate nucleus (ARC). This decreased leptin sensitivity leads to decreased muscle glucose uptake following glucose intolerance. We evaluated FGF1 expression in hypothalamus in several metabolic states such as fasting-feeding or other postprandial stimuli to discover which hypothalamic area mediates endogenous FGF1 activity. Interestingly, FGF1 expression in the VMH, but not other brain regions, are increased upon feeding or glucose administration and this induction of FGF1 does not require leptin or insulin. Acute FGF1 deletion in adult VMH causes glucose intolerance as well as increased body weight gain due to reduced leptin sensitivity and brown fat dysfunction, which leads to decreased energy expenditure. In keeping with this finding, germ-line ablation of FGF1 in VMH neurons results in increased adiposity. We propose that endogenous brain FGF1 regulates glucose and energy homeostasis through modulating VMH leptin sensitivity. Disclosure H.Shin: None. J.Suh: None.

1738-P: Instrument-Free Single-Cell Resolution of Transcriptome in Mouse Pancreatic Islet Cells

Type 1 diabetes is characterized by an almost complete depletion of insulin-producing beta cells. Thus, regeneration of beta cells through beta-cell neogenesis represents a major therapeutic strategy to cure the disease. We previously reported a mouse model of severe insulin resistance that leads to high insulin secretion and massive beta-cell neogenesis. To understand the origins of the newly formed beta cells and the genic programs involved in high insulin secretion, we aimed at defining the pancreatic islet cells transcriptome at high resolution cell by cell. Here, we tested the compatibility of the novel instrument-free 3’ single-cell RNA-sequencing benchtop kit Asteria™, recently released by Scipio bioscience (Paris, France), on pancreatic islet cells isolated from adult mice, which underwent cell dissociation by trypsin treatment. In the Asteria™ procedure, differently from the microfluidic-based single-cell one, coupling of solid polymer-barcoded beads and cells occurs in homogenous phase in a reversible hydrogel named RevGel™. Such conditions are claimed by the vendor to be causing less mechanical stress to cells for an expected more preserved transcriptome. Successive steps were classic molecular biology and bioinformatic analysis using Scipio bioscience’s data analysis cloud-based software Cytonaut™. We profiled the transcriptome of 938 single cells from healthy mice and identified a total of 12 cell subtypes. SingleR annotation based on reference data revealed all the major cell types commonly described in the literature, including a well-represented beta cell population and some rare cell types such as ductal and stellate cells. We demonstrate 3’ single-cell RNA-sequencing using Scipio bioscience’s kit Asteria™ as an effective strategy to dissect the heterogeneity and the complexity of mouse pancreatic islets and identify the gene expression signatures of each cell. Disclosure D.G.Dimitrova: None. A.Liboz: None. S.Lipin: None. C.Beaupere: None. N.Roblot: None. J.Komatsu: None. G.Guillemain: None. B.Blondeau: None.

189-OR: FGF21-Mediated Signaling Defects and Their Effects on Insulin Resistance in Insulin-Mediated Pseudoacromegaly

Insulin-mediated pseudoacromegaly (IMPA) is a rare, severe insulin resistance syndrome linked to digenic mutations in FGFR1 and KLB. These proteins form the receptor complex for FGF21, a hepatokine that plays a critical role in adipose tissue insulin sensitivity. Patients with IMPA have normal growth hormone and IGF-1. However, they have markedly increased insulin levels, tall stature, and obesity. To assess the pathogenicity of these mutations, we isolated iPSC from the proband with IMPA. We used CRISPR gene editing to correct the FGFR1 and KLB mutations and differentiated the iPSC lines into adipocytes. Western immunoblotting demonstrated that the uncorrected (mutant) cells demonstrated decreased levels of FGFR1 and pERK1/2 in response to insulin and/or FGF21 compared to corrected (wild-type) cells. Additionally, mutant adipocytes demonstrated significantly larger lipid droplets when stained with BODIPY. To complement the iPSC work, a humanized transgenic knock-in mouse line was created using CRISPR gene editing. When exposed to a high fat diet (HFD), female mice harboring variants in FGFR1 and KLB (DM - Double Mutant) developed significant weight gain compared to wild-type (WT) littermates. The difference in body weight was attributed to a difference in body fat. Similar to the human phenotype, the DM mice experience intermittent hyperglycemia and significant hyperinsulinemia. Explants of gonadal white adipose tissue demonstrated decreased lipolysis and pAKT and pERK. Mac-2 staining of white adipose tissue demonstrated abundant adipose tissue macrophages forming crown-like structures, suggesting adipose tissue inflammation. Additionally, we measured gene expression in brown adipose tissue, and noting that Ucp1 expression in DM mice was 37% when compared to WT. These results suggest pathogenic mechanisms in which FGFR1 and KLB mutations lead to IMPA via decreased FGF21-mediated signaling in the adipose tissue. Disclosure N.Phan: None. D.M.Ornitz: None. S.I.Stone: None. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21HD098872); National Institute of Diabetes and Digestive and Kidney Diseases (K08 DK124574, P30DK020579, P30DK056341); National Center for Advancing Translational Sciences

Potential impact of metabolic syndrome on cognitive function in US firefighters.

Among US firefighters, sudden cardiac arrest and psychological stress (i.e., PTSD) are the leading cause of on-duty death. Metabolic syndrome (MetSyn) may influence both cardiometabolic and cognitive health. Here, we examined differences in cardiometabolic disease risk factors, cognitive function, and physical fitness in US firefighters with vs. without MetSyn. One hundred fourteen male firefighters, aged 20 to 60 years, participated in the study. US firefighters with MetSyn vs. non-MetSyn were divided by AHA/NHLBI criteria. Of them, we performed a paired-match analysis with respect to the age and BMI of firefighters with (n = 18) vs. without MetSyn (n = 18). The cardiometabolic disease risk factors included blood pressure, fasting glucose, blood lipid profiles [HDL-C, triglyceride (TG)], and surrogate markers of insulin resistance [TG/HDL-C, TG glucose index (TyG)]. The cognitive test included a psychomotor vigilance task as a measure of reaction time and a delayed-match-to-sample task (DMS) as a measure of memory, using the computer-based Psychological Experiment Building Language Version 2.0 program. The differences between MetSyn and non-MetSyn groups in US firefighters were analyzed using an independent t-test adjusted for age and BMI. In addition, Spearman correlation and stepwise multiple regression were conducted. US firefighters with MetSyn exhibited severe insulin resistance estimated by TG/HDL-C and TyG (Cohen's d > 0.8, all p < 0.01) compared with their age- and BMI-matched counterparts without MetSyn. In addition, US firefighters with MetSyn exhibited higher DMS total time and reaction time compared with non-MetSyn (Cohen's d > 0.8, all p < 0.01). In stepwise linear regression, HDL-C predicted DMS total time (β = - 0.440, R2 = 0.194, p < 0.05), and TyG (β = 0.432, R2 = 0.186, p < 0.05) predicted DMS reaction time. US firefighters with vs. without MetSyn were predisposed to metabolic risk factors, surrogate markers of insulin resistance, and cognitive function, even when matched for age and BMI, and there was a negative association between metabolic characteristics and cognitive function in US firefighters. The findings of this study suggest that the prevention of MetSyn may be beneficial to supporting firefighters' safety and occupational performance.

A machine learning-based classification of adult-onset diabetes identifies patients at risk of liver-related complications

Diabetes mellitus is a major risk factor for fatty liver disease development and progression. A novel machine learning method identified five clusters of patients with diabetes, with different characteristics and risk of diabetic complications using six clinical and biological variables. We evaluated whether this new classification could identify individuals with an increased risk of liver-related complications. We used a prospective cohort of patients with a diagnosis of type 1 or type 2 diabetes without evidence of advanced fibrosis at baseline recruited between 2000 and 2020. We assessed the risk of each diabetic cluster of developing liver-related complications (i.e. ascites, encephalopathy, variceal haemorrhage, hepatocellular carcinoma), using competing risk analyses. We included 1,068 patients, of whom 162 (15.2%) were determined to be in the severe autoimmune diabetes subgroup, 266 (24.9%) had severe insulin-deficient diabetes, 95 (8.9%) had severe insulin-resistant diabetes (SIRD), 359 (33.6%) had mild obesity-related diabetes, and 186 (17.4%) were in the mild age-related diabetes subgroup. In multivariable analysis, patients in the SIRD cluster and those with excessive alcohol consumption at baseline had the highest risk for liver-related events. The SIRD cluster, excessive alcohol consumption, and hypertension were independently associated with clinically significant fibrosis, evaluated by liver biopsy or transient elastography. Using a simplified classification, patients assigned to the severe and mild insulin-resistant groups had a three- and twofold greater risk, respectively, of developing significant fibrosis compared with those in the insulin-deficient group. A novel clustering classification adequately stratifies the risk of liver-related events in a population with diabetes. Our results also underline the impact of the severity of insulin resistance and alcohol consumption as key prognostic risk factors for liver-related complications. Diabetes represents a major risk factor for NAFLD development and progression. This study examined the ability of a novel machine-learning approach to identify at-risk diabetes subtypes for liver-related complications. Our results suggest that patients that had severe insulin resistance had the highest risk of liver-related outcomes and fibrosis progression. Moreover, excessive alcohol consumption at the diagnosis of diabetes was the strongest risk factor for developing liver-related events.

Hepatic mTORC2 compensates for loss of adipose mTORC2 in mediating energy storage and glucose homeostasis.

Mammalian target of rapamycin complex 2 (mTORC2) is a protein kinase complex that plays an important role in energy homeostasis. Loss of adipose mTORC2 reduces lipogenic enzyme expression and de novo lipogenesis in adipose tissue. Adipose-specific mTORC2 knockout mice also display triglyceride accumulation in the liver. However, the mechanism and physiological role of hepatic triglyceride accumulation upon loss of adipose mTORC2 are unknown. Here, we show that loss of adipose mTORC2 increases the expression of de novo lipogenic enzymes in the liver, thereby causing accumulation of hepatic triglyceride and hypertriglyceridemia. Simultaneous inhibition of lipogenic enzymes in adipose tissue and liver by ablating mTORC2 in both tissues prevented accumulation of hepatic triglycerides and hypertriglyceridemia. However, loss of adipose and hepatic mTORC2 caused severe insulin resistance and glucose intolerance. Thus our findings suggest that increased hepatic lipogenesis is a compensatory mechanism to cope with loss of lipogenesis in adipose tissue, and further suggest that mTORC2 in adipose tissue and liver plays a crucial role in maintaining whole body energy homeostasis.NEW & NOTEWORTHY Loss of adipose and hepatic mTORC2 causes diabetes.

Clinical utility of GnRH analogues in female androgen excess due to severe insulin resistance

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

The sociodemographic and metabolic factors associated with severe insulin resistance in individuals with type 2 diabetes mellitus

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Microvascular and macrovascular complications prevalence, mortality rate in type 2 diabetes patients with severe insulin resistance: A case-control study

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

The Metabolic Syndrome Puzzles; Possible Pathogenesis and Management.

Metabolic syndrome is a multifactorial pathophysiological process with complicated homeostatic disorders that arise from various systematic metabolic defects. Various theories underlie the development of metabolic syndrome but are fully not understood. Revising PubMed and Scopus literature data on metabolic syndrome pathogenesis and management. The most accepted hypothesis is that a cluster of risk factors combined to obtain a truly metabolic syndrome. The pathophysiology of the metabolic syndrome depends on the underlying development path due to insulin resistance or chronic inflammation and is usually combined with neurohormonal disturbance. Meanwhile, these defects can be inherited via loss of function of certain genes that lead to severe obesity, early diabetes, or severe insulin resistance (with or without lipodystrophy). Chronic inflammation is also a driver of metabolic syndrome. Lifestyle is still the therapy of choice in managing metabolic syndrome, but unfortunately, during the lockdown, most people could not reserve a healthy regime; therefore, it can also be referred to as a pandemic with COVID-19. This powerful illustration shows how defects in specific encoded proteins located predominantly in the brain, pancreatic beta-cell, muscle, or fat give rise to these distinct components of the metabolic syndrome. Primarily, obesity and its sequela are the initiators of metabolic syndrome. The presence of metabolic syndrome increases the risk and severity of other pathologies' emergence, even in non-related metabolic syndrome diseases such as COVID-19. The article provides new insights into the pathogeneses and management of the metabolic syndrome.

Aggravated pneumonia and diabetes in SARS-CoV-2 infected diabetic mice

ABSTRACT Multiple clinical and epidemiological studies have shown an interconnection between coronavirus disease 2019 (COVID-19) and diabetes, but experimental evidence is still lacking. Understanding the interplay between them is important because of the global health burden of COVID-19 and diabetes. We found that C57BL/6J mice were susceptible to the alpha strain of SARS-CoV-2. Moreover, diabetic C57BL/6J mice with leptin receptor gene deficiency (db/db mice) showed a higher viral load in the throat and lung and slower virus clearance in the throat after infection than C57BL/6J mice. Histological and multifactor analysis revealed more advanced pulmonary injury and serum inflammation in SARS-CoV-2 infected diabetic mice. Moreover, SARS-CoV-2 infected diabetic mice exhibited more severe insulin resistance and islet cell loss than uninfected diabetic mice. By RNA sequencing analysis, we found that diabetes may reduce the collagen level, suppress the immune response and aggravate inflammation in the lung after infection, which may account for the greater susceptibility of diabetic mice and their more severe lung damage after infection. In summary, we successfully established a SARS-CoV-2 infected diabetic mice model and demonstrated that diabetes and COVID-19 were risk factors for one another.