Development Of Insulin Resistance Research Articles

Comparative analysis of the drugs efficacy for carbohydrate metabolism early disorders (prediabetes) treatment: A review

In the contemporary reality pharmacological correction of the early carbohydrate metabolism disorders is the main method for the type 2 diabetes prevention. Taking into account the main role of insulin resistance in the prediabetes development it can be supposed that pharmacological agents directly activating the insulin receptor are the pathogenic-base therapy for prediabetes treatment. Such kind of this pathogenic therapy is Subetta® – a representative of the class of biological drugs created using the based graduated technology. Due to the absent of the direct comparative trials of Subetta® versus metformin in the efficacy of the type 2 diabetes prevention in prediabetes patients, was performed an analysis of the effectiveness of these two drugs using the adjusted indirect comparison method of the results of the randomized double-blind placebo-controlled clinical trial of Subetta® efficacy and safety in impaired glucose tolerance patients with the results of several metformin studies similar in inclusion and efficacy criteria. The results indicate greater Subetta® efficacy in the treatment of glucose intolerance and metformin's – in the impaired fasting glucose treatment, which can be explained by the differences in the action mechanisms of these two drugs for prediabetes treatment.

Body Fat Distribution Contributes to Defining the Relationship between Insulin Resistance and Obesity in Human Diseases.

The risk for metabolic and cardiovascular complications of obesity is defined by body fat distribution rather than global adiposity. Unlike subcutaneous fat, visceral fat (including hepatic steatosis) reflects insulin resistance and predicts type 2 diabetes and cardiovascular disease. In humans, available evidence indicates that the ability to store triglycerides in the subcutaneous adipose tissue reflects enhanced insulin sensitivity. Prospective studies document an association between larger subcutaneous fat mass at baseline and reduced incidence of impaired glucose tolerance. Case-control studies reveal an association between genetic predisposition to insulin resistance and a lower amount of subcutaneous adipose tissue. Human peroxisome proliferator-activated receptorgamma (PPAR-γ) promotes subcutaneous adipocyte differentiation and subcutaneous fat deposition, improving insulin resistance and reducing visceral fat. Thiazolidinediones reproduce the effects of PPAR-γ activation and therefore increase the amount of subcutaneous fat while enhancing insulin sensitivity and reducing visceral fat. Partial or virtually complete lack of adipose tissue (lipodystrophy) is associated with insulin resistance and its clinical manifestations, including essential hypertension, hypertriglyceridemia, reduced HDL-c, type 2 diabetes, cardiovascular disease, and kidney disease. Patients with Prader Willi syndrome manifest severe subcutaneous obesity without insulin resistance. The impaired ability to accumulate fat in the subcutaneous adipose tissue may be due to deficient triglyceride synthesis, inadequate formation of lipid droplets, or defective adipocyte differentiation. Lean and obese humans develop insulin resistance when the capacity to store fat in the subcutaneous adipose tissue is exhausted and deposition of triglycerides is no longer attainable at that location. Existing adipocytes become large and reflect the presence of insulin resistance.

StarD5 levels of expression correlate with onset and progression of steatosis and liver fibrosis.

Insufficient expression of steroidogenic acute regulatory lipid transfer protein 5 (StarD5) on liver cholesterol/lipid homeostasis is not clearly defined. The ablation of StarD5 was analyzed in mice on a normal or western diet (WD) to determine its importance in hepatic lipid accumulation and fibrosis compared to wild type (WT) mice. Rescue experiments in StarD5-/- mice and hepatocytes were performed. In addition to increased hepatic triglyceride/cholesterol levels, global StarD5-/- mice fed a normal diet displayed reduced plasma triglycerides and liver VLDL secretion as compared with WT counterparts. Insulin levels and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) scoring were elevated, demonstrating developing insulin resistance (IR). WD fed StarD5-/- mice up-regulated TAZ expression with accelerated liver fibrosis when compared to WD-fed WT mice. CYP7B1's suppression coupled with chronic accumulation of toxic oxysterol levels correlated with presentation of fibrosis. 'Hepatocyte selective' StarD5 overexpression in StarD5-/- mice restored expression, reduced hepatic triglycerides, and improved HOMA-IR. Observations in 2 additional mouse and one human NASH model were supportive. StarD5's downregulation with hepatic lipid excess is a previously unappreciated physiologic function appearing to promote lipid storage for future needs. Conversely, StarD5's lingering downregulation with prolonged lipid/cholesterol excess accelerates fatty liver's transition to fibrosis; mediated via dysregulation in the oxysterol signaling pathway.

Mechanism of muscle atrophy in a normal-weight rat model of type 2 diabetes established by using a soft-pellet diet

Dietary factors such as food texture affect feeding behavior and energy metabolism, potentially causing obesity and type 2 diabetes. We previously found that rats fed soft pellets (SPs) were neither hyperphagic nor overweight but demonstrated glucose intolerance, insulin resistance, and hyperplasia of pancreatic β-cells. In the present study, we investigated the mechanism of muscle atrophy in rats that had been fed SPs on a 3-h time-restricted feeding schedule for 24 weeks. As expected, the SP rats were normal weight; however, they developed insulin resistance, glucose intolerance, and fat accumulation. In addition, skeletal muscles of SP rats were histologically atrophic and demonstrated disrupted insulin signaling. Furthermore, we learned that the muscle atrophy of the SP rats developed via the IL-6–STAT3–SOCS3 and ubiquitin–proteasome pathways. Our data show that the dietary habit of consuming soft foods can lead to not only glucose intolerance or insulin resistance but also muscle atrophy.

Rab18 maintains homeostasis of subcutaneous adipose tissue to prevent obesity-induced metabolic disorders.

Metabolically healthy obesity refers to obese individuals who do not develop metabolic disorders. These people store fat in subcutaneous adipose tissue (SAT) rather than in visceral adipose tissue (VAT). However, the molecules participating in this specific scenario remain elusive. Rab18, a lipid droplet (LD)-associated protein, mediates the contact between the endoplasmic reticulum (ER) and LDs to facilitate LD growth and maturation. In the present study, we show that the protein level of Rab18 is specifically upregulated in the SAT of obese people and mice. Rab18 adipocyte-specific knockout (Rab18 AKO) mice had a decreased volume ratio of SAT to VAT compared with wildtype mice. When subjected to high-fat diet (HFD), Rab18 AKO mice had increased ER stress and inflammation, reduced adiponectin, and decreased triacylglycerol (TAG) accumulation in SAT. In contrast, TAG accumulation in VAT, brown adipose tissue (BAT) or liver of Rab18 AKO mice had a moderate increase without ER stress stimulation. Rab18 AKO mice developed insulin resistance and systematic inflammation. Rab18 AKO mice maintained body temperature in response to acute and chronic cold induction with a thermogenic SAT, similar to the counterpart mice. Furthermore, Rab18-deficient 3T3-L1 adipocytes were more prone to palmitate-induced ER stress, indicating the involvement of Rab18 in alleviating lipid toxicity. Rab18 AKO mice provide a good animal model to investigate metabolic disorders such as impaired SAT. In conclusion, our studies reveal that Rab18 is a key and specific regulator that maintains the proper functions of SAT by alleviating lipid-induced ER stress.

Exploring the impacts of ketogenic diet on reversible hepatic steatosis: initial analysis in male mice.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common chronic liver disease. Ketogenic diet (KD), a diet with very low intake in carbohydrates, gained popularity as a weight-loss approach. However, in mice models, it has been reported that an excess exposition of dietary fat induces hepatic insulin resistance and steatosis. However, data published is inconsistent. Herein, we investigated in a mouse model, the metabolic effects of KD and its contribution to the pathogenesis of NALFD. Mice were exposed to KD or CHOW diet for 12 weeks while a third group was exposed to KD for also 12 weeks and then switched to CHOW diet for 4 weeks to determine if we can rescue the phenotype. We evaluated the effects of diet treatments on fat distribution, glucose, and insulin homeostasis as well as hepatic steatosis. Mice fed with KD developed glucose intolerance but not insulin resistance accompanied by an increase of inflammation. KD-fed mice showed an increase of fat accumulation in white adipose tissue and liver. This effect could be explained by an increase in fat uptake by the liver with no changes of catabolism leading to MAFLD. Interestingly, we were able to rescue the phenotype by switching KD-fed mice for 4 weeks on a CHOW diet. Our studies demonstrate that even if mice develop hepatic steatosis and glucose intolerance after 12 weeks of KD, they do not develop insulin resistance and more importantly, the phenotype can be reversed by switching the mice from a KD to a CHOW.

Interacting and joint effects of triglyceride-glucose index (TyG) and body mass index on stroke risk and the mediating role of TyG in middle-aged and older Chinese adults: a nationwide prospective cohort study

BackgroundIndividuals who are overweight or obese often develop insulin resistance, mediation of the association between body mass index (BMI) and stroke risk through the triglyceride-glucose index (TyG) seems plausible but has not been investigated. This study aims to examine whether TyG mediates associations of BMI with stroke risk and the extent of interaction or joint relations of TyG and BMI with stroke outcome.MethodsThe China Health and Retirement Longitudinal Study, initiated in 2011, is a nationally representative, ongoing prospective cohort study involving 8 231 middle-aged and older Chinese adults without a stroke history at baseline. Exposures examined include BMI and the TyG, the latter being the logarithmized product of fasting triglyceride and glucose concentrations. The primary study outcome is stroke incidence, as determined through self-reports, with a follow-up period extending from June 1, 2011, to June 30, 2018.ResultsOf the 8 231 participants, 3 815 (46.3%) were men; mean (SD) age was 59.23 (9.32) years. During a median follow-up of 7.1 years, 585 (7.1%) participants developed stroke. The TyG was found to mediate the association between BMI and incident stroke, proportions mediated were 16.3% for BMI in the 24.0–27.9 kg/m2 group and 53.8% for BMI ≥ 28.0 kg/m2 group. No significant multiplicative and additive interactions were found between BMI and TyG on incident stroke (Additive: RERI = 1.78, 95% CI − 1.29–4.86; Multiplicative, HR = 1.40, 95% CI 0.86–2.27). HRs for individuals with BMI ≥ 28.0 kg/m2 and quartile 4 of TyG compared with those with BMI < 24.0 kg/m2 and quartile 1 of TyG were 2.05 (95% CI 1.37–3.06) for incident stroke. Combining BMI and TyG enhanced predictive performance for stroke when compared to their individual (AUCBMI+TyGvs AUCBMIvs AUCTyG, 0.602 vs 0.581 vs 0.583).ConclusionsTyG appeared to be associated with stroke risk and mediates more than 50% of the total association between BMI and stroke in middle-aged and older Chinese adults. Public health efforts aiming at the reduction of body weight might decrease the stroke risk due to insulin resistance and the burden of stroke.

Tryptophanylation of insulin receptor by WARS attenuates insulin signaling.

Increased circulating amino acid levels have been linked to insulin resistance and development of type 2 diabetes (T2D), but the underlying mechanism remains largely unknown. Herein, we show that tryptophan modifies insulin receptor (IR) to attenuate insulin signaling and impair glucose uptake. Mice fed with tryptophan-rich chow developed insulin resistance. Excessive tryptophan promoted tryptophanyl-tRNA synthetase (WARS) to tryptophanylate lysine 1209 of IR (W-K1209), which induced insulin resistance by inhibiting the insulin-stimulated phosphorylation of IR, AKT, and AS160. SIRT1, but not other sirtuins, detryptophanylated IRW-K1209 to increase the insulin sensitivity. Collectively, we unveiled the mechanisms of how tryptophan impaired insulin signaling, and our data suggested that WARS might be a target to attenuate insulin resistance in T2D patients.

Social media for obesity education: a general overview for the novice creator.

Rates of obesity continue to rise in the United States and across the globe. Obesity is a risk factor for developing insulin resistance, type 2 diabetes, and cardiovascular disease. For clinicians, other health care providers, and educators, providing patients with accurate and meaningful information about obesity, including lifestyle (diet and exercise) interventions and symptom monitoring, is challenging because of infrequent contact, methods of communication, a lack of effective patient education resources, and inefficient patient feedback methods. Evidence suggests that significantly more patients are now getting their health care information online from general medical websites, disease-specific network communities, and social media. Thus, harnessing the power of technologies, including personal computers and smartphones, with attention to social media may equip health care providers with methods to serve their patients better by addressing challenges, improving indirect patient contact, and enhancing health outcomes. This article aims to provide an overview of technology with a focus on social media use in obesity education and outreach. Practical information is provided related to creating content, delivering content, and managing the social media space for the novice creator.NEW & NOTEWORTHY Rates of obesity continue to increase. Health care providers have a limited time to cover the nuances of obesity. Technology and social media are tools that can help health care workers provide obesity education to a large audience. This article provides the foundations for obesity education content generation and delivery for the novice creator.

Primordial Drivers of Diabetes Heart Disease: Comprehensive Insights into Insulin Resistance.

Insulin resistance has been regarded as a hallmark of diabetes heart disease (DHD). Numerous studies have shown that insulin resistance can affect blood circulation and myocardium, which indirectly cause cardiac hypertrophy and ventricular remodeling, participating in the pathogenesis of DHD. Meanwhile, hyperinsulinemia, hyperglycemia, and hyperlipidemia associated with insulin resistance can directly impair the metabolism and function of the heart. Targeting insulin resistance is a potential therapeutic strategy for the prevention of DHD. Currently, the role of insulin resistance in the pathogenic development of DHD is still under active research, as the pathological roles involved are complex and not yet fully understood, and the related therapeutic approaches are not well developed. In this review, we describe insulin resistance and add recent advances in the major pathological and physiological changes and underlying mechanisms by which insulin resistance leads to myocardial remodeling and dysfunction in the diabetic heart, including exosomal dysfunction, ferroptosis, and epigenetic factors. In addition, we discuss potential therapeutic approaches to improve insulin resistance and accelerate the development of cardiovascular protection drugs.

RNA-seq analysis reveals modulation of inflammatory pathways by an enriched-triterpene natural extract in mouse and human macrophage cell lines

Chronic inflammation is crucial in developing insulin resistance and type 2 diabetes. Previous studies have shown that a leaf extract of Eucalyptus tereticornis, with ursolic acid (UA), oleanolic acid (OA), and ursolic acid lactone (UAL) as the main molecules (78 %) mixed with unknown minor metabolites (22 %), provided superior anti-inflammatory, hypoglycemic, and hypolipidemic effects than reconstituted triterpenoid mixtures in macrophage cell lines and a pre-diabetic mouse model. Further identification of the molecular mechanisms of action of this mixture of triterpenes is required. This study aims to analyse the RNA expression profiles of mouse and human macrophage cell lines treated with the natural extract and its components. Activated macrophage cell lines were treated with the natural extract, UA, OA, UAL or a triterpene mixture (M1). RNA was extracted and sequenced using the DNBseq platform and the EnrichR software to perform gene enrichment analysis using the Gene Ontology database, Kyoto Encyclopedia of Genes and Genomes, and Reactome. To conduct clustering analysis, we standardised the normalised counts of each gene and applied k-means clustering. The combination of molecules in the natural extract has an additive or synergic effect that affects the expression of up-regulated genes by macrophage activation. Triterpenes (M1) regulated 76 % of human and 68 % of mouse genes, while uncharacterised minority molecules could regulate 24 % of human and 32 % of mouse genes. The extract inhibited the expression of many cytokines (IL6, IL1, OSM), chemokines (CXCL3), inflammatory mediators (MMP8 and MMP13) and the JAK-STAT signalling pathway in both models. The natural extract has a more powerful immunomodulatory effect than the triterpene mixture, increasing the number of genes regulated in mouse and human models. Our study shows that Eucalyptus tereticornis extract is a promising option for breaking the link between inflammation and insulin resistance.

Janus kinase-signal transducer and activator of transcription signaling pathway in the ocular cells of rat fetuses exposed to maternal saturated fat ingestion.

The aim of this study was to analyze possible alterations (morphological and inflammatory) in the ocular cells of fetuses from mothers with insulin resistance exposed to saturated fatty acids through the period of pregnancy. Wistar female rats were induced to develop insulin resistance before pregnancy. Fetuses' skulls were collected on the 20th day of intrauterine life. The rats were separated on the first day of management into two groups according to the diet applied: control group (C): diet containing soybean oil as a source of fat; and saturated fatty acid group (S): diet containing butter as a source of fat. Histological and immunohistochemical analyses have been conducted. The immunohistochemical analyses of interleukin 6, suppressor of cytokine signaling, 3 and signal transducer and activator of transcription 3 did not demonstrate alterations in the expression of proteins in the fetuses of mothers fed with a saturated fatty diet. Moreover, no histopathological changes were noticed between groups. The saturated fatty diet does not induce tissue changes or activate the Janus kinase/signal transducer and activator of transcription signaling pathway during eye development in the fetuses of mothers with insulin resistance.

High dietary intake of unsaturated fatty acids is associated with improved insulin resistance – a cross-sectional study based on the NHANES database

BackgroundA moderate intake of unsaturated fatty acids (UFA) is associated positively with improved insulin resistance. The aim of this study was to investigate the relationship between the dietary intake of unsaturated fatty acids/total fats (UFA/TF) and insulin resistance.Methods15,560 participants were selected from the National Health and Nutrition Examination Survey (NHANES) database enrolled between March 2017 and 2020, and excluded those under 20 years of age, pregnant, or with missing data for key research items. Finally, 7,630 participants were included in the study. R software was used for data analysis that included: (1) general descriptive statistics; (2) comparison of differences in baseline information of three UFA/TF groups, namely low, medium, and high ratios; (3) calculation of the correlation between the UFA/TF ratio and markers of insulin resistance: triglyceride-glucose index (TyG) and homeostatic model assessment for insulin resistance (HOMA-IR); (4) stratification of the study subjects into two groups, with or without insulin resistance, using a cut-off value of HOMA-IR ≥ 2, followed by logistic regression analysis to examine the relationship between UFA/TF and insulin resistance status in the two groups; and (5) further stratification of the subjects according to age, gender, body mass index (BMI), race, total energy intake, total protein, total carbohydrate, total sugars, total dietary fiber, total fat, alcohol consumption, diabetes, hypercholesterolemia to analyze the impact of UFA/TF on insulin resistance status in different subgroups.Results(1) A high UFA/TF level was associated with a low TyG index and HOMA-IR [β (vs. TyG index) = -0.559, 95% CI: (-0.821~-0.297), P < 0.001; β (vs. HOMA-IR) = -0.742, 95% CI: (-1.083~-0.402), P < 0.001]. This negative relationship became more pronounced when UFA/TF exceeded 57.9% (i.e., the higher group). (2) Logistic regression analysis showed that a higher UFA/TF level was associated with a lower risk of developing insulin resistance [Q3 vs. Q1: 0.838 (95%CI: 0.709 ~ 0.991); P for trend = 0.038]. After adjusting for covariates such as gender, age, and BMI, this protective effect remained significant (P value < 0.05). (3) Analysis also showed that increased UFA/TF intake reduced the risk of developing insulin resistance (OR = 0.266, 95% CI: (0.075 ~ 0.946), P = 0.041). Subgroup analysis showed that although elevated UFA/TF intake showed no statistically significant difference in its effect in most subgroups, the large study population in this study provides valuable insights on potential changes. Increased UFA/TF intake may confer relatively greater benefits within specific subgroups, particularly among the elderly [Q3 age group, OR = 0.114, 95%CI: (0.012 ~ 1.078), P = 0.058], females [OR = 0.234, 95%CI: (0.041 ~ 1.333), P = 0.102], those with a BMI ≤ 25 kg/m²[OR = 0.191, 95%CI: (0.016 ~ 2.344), P = 0.196], and individuals without hypercholesterolemia [OR = 0.207, 95%CI: (0.042 ~ 1.013), P = 0.0519]. The impact of high UFA/TF levels within subgroups based on the presence or absence of coronary heart disease and stroke displayed contrasting trends. In those without coronary heart disease, there was a significant protective effect against insulin resistance [OR = 0.254, 95% CI: (0.07 ~ 0.929), P = 0.0384], while in the stroke subgroup, a significantly protective effect against insulin resistance was observed [OR = 0.002, 95%CI: (0 ~ 0.695), P = 0.0376].ConclusionA high dietary intake of UFA relative to total fat consumption could be a protective factor against the risk of developing insulin resistance.

Metabolic Syndrome‐Associated Oligodendrocyte Dysfunction and Cognitive Impairment

AbstractBackgroundOne in nine people aged 65 and older in the United States suffer from cognitive decline, including dementias such as Alzheimer’s disease (AD) and AD‐related Dementias (ADRD). A major risk factor for cognitive impairment is midlife metabolic syndrome (MetS). MetS‐associated cognitive impairment progresses in a non‐cell autonomous manner and implicates a breakdown in metabolic support. This breakdown in metabolic support is likely due to disruption of metabolic crosstalk between neurons and glia, especially oligodendrocytes. Our aim was therefore to elucidate midlife MetS effects on oligodendrocytes and subsequent impact on oligodendrocyte metabolism and cognition.MethodTo accomplish this aim, middle‐aged mice (12‐month old) were fed either standard diet (SD, 10% fat) or high‐fat diet (HFD, 60% fat) for 13 weeks, followed by full assessment of metabolic parameters and cognitive function. Oligodendrocytes were then isolated for single cell RNA‐sequencing (scRNA‐seq), and protein expression of monocarboxylate transporters (MCTs).ResultWe observed that, as expected, HFD mice gained more weight and had higher blood glucose and fat mass versus SD controls. Middle‐aged HFD mice also performed worse in puzzle box and social recognition tests, reflecting impaired executive function and impaired short‐ and long‐term memory responses. scRNA‐seq analysis identified multiple oligodendrocyte clusters. One cluster of interest contained genes involved in cognition (Fam171a2, Nrsn1, Dlgap4) and metabolism (Ldhb, Slc25a5, Cox7c, Cox17), which were differentially expressed in HFD versus SD mice. This was coupled with downregulated MCT1 protein expression in HFD mouse oligodendrocytes versus oligodendrocytes from their SD counterparts. In vitro, human oligodendrocytes treated with palmitate to mimic MetS developed insulin resistance and had downregulated MCT1 protein expression.ConclusionCollectively, these results suggest that midlife MetS impairs oligodendrocyte metabolic function, suggesting a novel mechanism underlying MetS‐associated cognitive impairment.

The impact of microalbuminuria and insulin resistance as prognostic biomarker for nephropathy in obese persons: a systematic review

Background: The progression of weight gain over the normal level is accompanied by an increase in renovascular damage markers, such as microalbuminuria. Microalbuminuria could be an indication of vascular disturbances caused by obesity. The global pandemic of renal disease has something to do with the link between obesity and type-2 diabetes. Furthermore, microalbuminuria can also be a possible factor for developing insulin resistance syndrome and high blood pressure. The goal of this research is to analyze the impact that insulin resistance, as well as microalbuminuria, play in predicting the severity of nephropathy among obese individuals and also look into these markers in identifying patients with this condition. Methods: The selected studies (updated to November 2022) were evaluated using the Electronic PubMed database. Based on our selection criteria only those that included high-quality investigations on the relevance of insulin resistance and microalbuminuria as markers of nephropathy in obese people were included. We evaluated this link using odds ratios with a confidence interval of 95%. Results: Overall, 15 studies, including over 10,000 obese individuals, were evaluated for this study. The summative results revealed that microalbuminuria and insulin may be strong indicators for the advancement of nephropathy in individuals with diabetes mellitus and obese individuals. In support of this, more studies need to be carried out on obese individuals with nephropathy in the absence of diabetes to confirm the relevance of these biomarkers as a prevention measure. Conclusions: Understanding the importance of the impact microalbuminuria and resistance to insulin play as biomarkers in the health of obese individuals may be very important to prevent nephropathy progression and premature death in both diagnosed and undiagnosed situations. A limitation of this review is that it didn't focus on other anomalies related to obesity such as cardiovascular disease or diabetes.

Relationship of Glucagon-like Peptide 1 and Peptide YY with Catch-up Growth in Children Born Small for Gestational Age

Children born small for gestational age (SGA) are at a greater risk of developing insulin resistance, type 2 diabetes, and cardiovascular disease in adulthood. Gastrointestinal peptides, some secreted by intestinal L cells, regulate glucose and lipid metabolism and act on the hypothalamus to regulate energy homeostasis. The aim of this study was to explore whether gastrointestinal peptides are involved in metabolic disorders in SGA, which remains unclear. The secretion of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) were investigated in prepubertal children born SGA, the differences between catch-up growth and persistent short stature were compared, and correlation with glucose and lipid metabolism was analyzed. GLP-1, PYY, insulin-like growth factor 1, glucose, insulin, and lipid concentrations were analyzed in prepubertal children aged 4-10 years, stratified into three groups: short-SGA (SGA-s), catch-up growth SGA, and normal growth appropriate for gestational age (AGA). Fasting GLP-1 and PYY concentrations were significantly lower in the SGA group than in the AGA group (p<0.05), and the GLP-1 level in infants born SGA with catch-up growth was lower than that in the SGA-s group (p<0.05). In the SGA population, GLP-1 showed a weak negative correlation with catch-up growth (r=-0.326) and positive correlation with fasting insulin (r=0.331). Lower GLP-1 concentrations may be associated with abnormal glucose metabolism in prepubertal children born SGA with catch-up growth. This is indirect evidence that impaired intestinal L cell function may be involved in the development of metabolic complications in SGA children.

A high-sugar diet, but not obesity, reduces female fertility in Drosophila melanogaster.

Obesity is linked to reduced fertility in various species, from Drosophila to humans. Considering that obesity is often induced by changes in diet or eating behavior, it remains unclear whether obesity, diet, or both reduce fertility. Here, we show that Drosophila females on a high-sugar diet become rapidly obese and less fertile as a result of increased death of early germline cysts and vitellogenic egg chambers (or follicles). They also have high glycogen, glucose and trehalose levels and develop insulin resistance in their fat bodies (but not ovaries). By contrast, females with adipocyte-specific knockdown of the anti-obesity genes brummer or adipose are obese but have normal fertility. Remarkably, females on a high-sugar diet supplemented with a separate source of water have mostly normal fertility and glucose levels, despite persistent obesity, high glycogen and trehalose levels, and fat body insulin resistance. These findings demonstrate that a high-sugar diet affects specific processes in oogenesis independently of insulin resistance, that high glucose levels correlate with reduced fertility on a high-sugar diet, and that obesity alone does not impair fertility.

Type 2 Diabetes Mellitus Serum Biomarker Levels and Associated Single Nucleotide Polymorphisms in a South African Population

Type 2 diabetes mellitus (T2DM) is a metabolic disorder with multiple causes. The prevalence of T2DM is on the rise, however, on the African continent, nearly 70% of all T2DM cases go undiagnosed. T2DM places a great burden on the already stretched healthcare systems. Current tests do not provide predictive measures in terms of the possible onset of the disease. Biomarker and gene analysis have been used to predict the onset of the disease, but this has seen very limited use in the African population groups. Identification of variances in biomarkers and subsequent genetic aberrations at early diagnosis could enable clinical focus on patients more likely to develop insulin resistance. The aim of the study was to compare T2DM-associated biomarker levels between T2DM patients and non-T2DM participants and identify genetic variances in single nucleotide polymorphisms (SNPs) associated with the biomarkers. Two cohorts (n = 78) were screened for associated biomarkers using a commercially available enzyme-linked immunosorbent assay (ELISA) kit. The results of this analysis were used to select SNPs in genes associated with the screened biomarkers. The molecular genotyping was completed using quantitative polymerase chain reaction (qPCR) assays. The biomarker analysis revealed significant statistical differences between four of the ten screened biomarkers: Glucose-dependent insulinotropic polypeptide (GIP) (p = 0.0004), resistin (p = 0.0398), visfatin (p = 0.0009), and glucagon (p = 0.0034). The SNPs selected for molecular genotyping were rs6235 in proprotein convertase subtilisin/kexin type 1 (PCSK1) and rs2208203 in proprotein convertase subtilisin/kexin type 2 (PCSK2). Both these genes are involved in the biosynthesis of various biomarkers that were screened. The results from the molecular genotyping failed to show any significant difference between the control and T2DM case groups. While some biomarkers were shown to have significant statistical differences between the two study cohorts, more work needs to be conducted to understand the role of each biomarker in T2DM.

THU312 The Type 1 Diabetes Susceptible LEW.1WR1 Rat Develops Insulin Resistance And Severe Non-alcoholic Fatty Liver Disease

Abstract Disclosure: S.T. Love-Rutledge: None. M. Wimalarathne: None. L.D. Mercado: None. A. Smiley: None. C. Apperson: None. Q.C. Vidal: None. A subpopulation of type 1 diabetes patients develop the pathophysiological parameters to be termed double diabetes. This patient population often develops obesity, non-alcoholic fatty liver disease, and other hallmarks of insulin resistance. The LEW.1WR1 rat is a type 1 diabetes susceptible rodent with hyperinsulinemia that has shown signs of fatty liver infiltration1,2. We hypothesized that LEW.1WR1 rats would develop insulin resistance and severe nonalcoholic fatty liver disease due to its increased circulating insulin and predisposition to autoimmune disease. LEW.1WR1 rats and Wistar Furth rats were used for the 18-week long experiment. Peripheral insulin sensitivity was evaluated using insulin tolerance tests at weeks 11 and 17 showing worsening insulin sensitivity as evidenced by the gradual slope compared to the steep slope of the Wistar Furth rats. HOMA-IR values support LEW.1WR1 rats develop worsening insulin sensitivity and are insulin resistant at week 23 of the experiment (2.613± 0.796, p &amp;lt; 0.0001). Terminal liver mass confirmed increased liver mass normalized to body mass and liver triglyceride levels suggested increased ectopic lid accumulation in the liver (Liver Mass 2.65% ±0.32 p = 0.0005 and triglyceride levels 192.8 ± 21.85 mg/dL, p = 0.034). The H&amp;E-stained digital liver slides were scored for liver ballooning, steatosis, and markers of inflammation. Fibrosis and terminal circulating cytokines were also measured to assess severity of condition. While both groups showed increased steatosis and injury ballooning, trichrome blue staining and inflammatory cytokines verify the severity of disease in the LEW.1WR1 rats. LEW rats have increased fibrosis area and high serum TNF-α, IFN-, MCP-1 levels. As hypothesized, we observed that LEW.1WR1 rats show characteristics of insulin resistance and malignant nonalcoholic fatty liver disease development.

FRI047 Clinical Characteristics Of Patients With Morbid Obesity With Semaphorines (SEMA3D,E,G) And PLXNA3&amp;4 Gene Variants

Abstract Disclosure: M. Berra: None. A. Khattab: None. S.B. Ten: None. A.S. Bhangoo: None. Aim of the study: To describe the clinical characteristics of patients with morbid obesity with SEMA3D,E,G and PLXNA3&amp;4 gene variants. Introduction: Heterozygous variants of SEMA3s and their receptors PLXNA3 and 4 were described in cases of morbid obesity (Ref1). SEMA3 genes encodes a member of the semaphorin III family of secreted signaling proteins that are involved in axon guidance during neuronal development. SEMA3s signaling pathway is important for POMC neurons projections from the arcuate to the paraventricular nucleus. Methods: Patients with morbid obesity underwent genetic testing at the Prevention Genetics after obtaining consent. Results: Heterozygous gene variants were found in 8 cases, 3 males, 5 females, from 2 to 22 yrs., average BMI 33.3±8.6 kg/m2, 5 Hispanics, 2 Caucasians, 1 Asian. All cases presented with early morbid obesity from 2-4 yrs. of age, hyperphagia. Leptin was measured in 4 cases and was low for the degree of obesity (5.8-7.8 ng/ml). They had fatty liver, elevated triglycerides 168±33; had HDL 41.7±6.9 (data presented as avg±SDS).16 yrs. old female, BMI 31.2, PLXN3, c.1556G&amp;gt;A, p.Arg519His variant. Father had morbid obesity, treated with bariatric surgery lap band procedure.8 yrs. old girl, BMI 28.7, PLXN3, c.1733C&amp;gt;T, p.Ala578Val variant. Maternal aunt had bariatric surgery.22 yrs. old female, BMI 53, PLXNA4, c.1982C&amp;gt;T, p.Ser661Leu variant. She had impaired glucose tolerance, PCOS, a nodular goiter, impaired glucose tolerance, 2 sisters and a brother had bariatric surgery.16 yrs. old boy, BMI 35.5, SEMA3D, c.1048T&amp;gt;C, p.Ser350Pro variant. He had anxiety, panic attacks, depression. His PGF and paternal uncle has morbid obesity. 16 yrs. old girl, BMI 30.9, SEMA3G, c.2305&amp;gt;G variant. She had impaired fasting glucose, elevated prolactin and amenorrhea. Mother and MGM had morbid obesity. 2 year old male with BMI of 30.1, SEMA3E, c.1443A&amp;gt;T, p.Glu481Asp variant. Mother had morbid obesity.4 year old female with BMI of 23.7, SEMA3G, c.2086GA, p.Gly696Arg variant. She has autism, epilepsy and motor delay. Mother and maternal aunt had morbid obesity.11 year old male, BMI 33.6, PLXNA4, c.4896CA, p.Asp1632Glu variant. MGF had morbid obesity. Conclusion: Clinical phenotype of patients with heterozygous variants of Semaphorins and its receptors shows presence of severe obesity from a young age of 2-4 yrs. All had a very strong family history of morbid obesity. These children developed insulin resistance with elevated TG and fatty liver from a young age. Leptin levels in few were low for the degree of obesity. Ref1. van der Klaauw AA, Farooqi IS et.al. Human Semaphorin 3 Variants Link Melanocortin Circuit Development and Energy Balance. Cell. 2019 Feb 7;176(4):729-742.e18. doi: 10.1016/j.cell.2018.12.009. PMID: 30661757. Presentation: Friday, June 16, 2023