Decline In Insulin Sensitivity Research Articles

Disentangling Dual Threats: Premature Coronary Artery Disease and Early-Onset Type 2 Diabetes Mellitus in South Asians.

South Asian individuals (SAs) face heightened risks of premature coronary artery disease (CAD) and early-onset type 2 diabetes mellitus (T2DM), with grave health, societal, and economic implications due to the region's dense population. Both conditions, influenced by cardiometabolic risk factors such as insulin resistance, hypertension, and central adiposity, manifest earlier and with unique thresholds in SAs. Epidemiological, demographic, nutritional, environmental, sociocultural, and economic transitions in SA have exacerbated the twin epidemic. The coupling of premature CAD and T2DM arises from increased obesity due to limited adipose storage, early-life undernutrition, distinct fat thresholds, reduced muscle mass, and a predisposition for hepatic fat accumulation from certain dietary choices cumulatively precipitating a decline in insulin sensitivity. As T2DM ensues, the β-cell adaptive responses are suboptimal, precipitating a transition from compensatory hyperinsulinemia to β-cell decompensation, underscoring a reduced functional β-cell reserve in SAs. This review delves into the interplay of these mechanisms and highlights a prediabetes endotype tied to elevated vascular risk. Deciphering these mechanistic interconnections promises to refine stratification paradigms, surpassing extant risk-prediction strategies.

Basal-bolus advisor for type 1 diabetes (T1D) patients using multi-agent reinforcement learning (RL) methodology

This study presents in-silico design and verification of an advanced multi-agent reinforcement learning (RL) strategy for personalized glucose regulation in individuals diagnosed with type 1 diabetes (T1D). The proposed framework realizes a closed-loop system, encompassing a blood glucose (BG) metabolic model acting as virtual patient, and a sophisticated multi-agent soft actor–critic RL controller serving as the basal-bolus advisor. The efficacy of the RL agents in meeting the recommended glycemic targets is benchmarked against traditional therapeutic approaches and rigorously assessed across three distinct scenarios: (A) nominal, three meals per day, (B) robustness against meal disturbances, and (C) robustness against insulin sensitivity disturbances. Key evaluation metrics are minimum, maximum and mean values of glucose concentrations, the temporal distribution across various BG intervals, and the daily averages of both bolus and basal insulin administrations. Empirical results underscore the superior performance of the RL-driven basal-bolus advisor, manifesting in diminished glycemic fluctuations and an augmented duration within the optimal range of 70–180 mg/dL. Specifically, in scenarios A, B, and C, the time within this desired range witnessed a surge from 66.66±34.97% to 92.55±4.05%, 64.13±33.84% to 93.91±6.03%, and 58.85±34.67% to 78.34±13.28%, respectively. The RL paradigm also exhibited a marked proficiency in curtailing severe hyperglycemia incidents (p ≤0.05) and diminishing hypoglycemia occurrences. In scenarios A and B, hypoglycemic incidents were curtailed from 14.2% ±32.27% to 3.77% ±4.01% and 16.59% ±32.42% to 2.63% ±4.09%, respectively. Intriguingly, scenario C recorded zero hypoglycemic incidents for both methodologies, attributed to a decline in insulin sensitivity. Additionally, a statistically significant decrement in the mean daily basal insulin dosage was observed with the RL agent in comparison to traditional therapy (p ≤0.05). Collectively, the outcomes accentuate the potential of the multi-agent RL strategy in enhancing glucose regulation and minimizing the peril of severe hyperglycemia for T1D patients.

Impact of Initiation of Insulin Therapy on Serum Prolactin and Cortisol Levels in Type 2 Diabetic Male Patients

Background Type 2 Diabetes Mellitus is a common metabolic disease characterized by a decline in insulin sensitivity and relative insulin insufficiency-induced hyperglycemia. In type 2 diabetic patients who have failed to achieve target glycemic control goals on oral anti-diabetic drug therapy, Initiating insulin therapy significantly improved overall glycemic control. Objective To assess Impact of Initiation of Insulin Therapy on Serum Prolactin and Cortisol levels In Type 2 Diabetic Male Patients. Subjects and Methods It was conducted on thirty (30) male patients who were diagnosed to have type 2 diabetes attending diabetes clinic at Ain- Shams University Hospital from 1 Jan. to 1 July 2018. Their ages range from 40 to 60 years old. Results On studying the Correlation between cortisol and prolactin with other laboratory findings showed that: There were no significant correlations between cortisol a.m. and prolactin with FBS, 2HPPBG and HbA1C (P > 0.05) in the first and third visits in group I. And no significant correlations between cortisol a.m. and prolactin with FBS and 2HPPBG (P > 0.05) in the second visit in group I. But there was a significant positive correlation between cortisol with FBS (P = 0.028) and HbA1C (P = 0.033) in group II. And a significant positive correlation between cortisol with FBS (P = 0.034) and 2HPPBG (P = 0.041) in group III. There was a highly significant positive correlation between cortisol and FBS (P = 0.001) in group III. And there was a highly significant positive correlation between prolactin with 2HPPBG (P = 0.008) in group II. Conclusion We conclude from this study that initiation of insulin therapy in poorly controlled diabetic patients achieves a highly significant reduction in blood glucose level. Also, insulin therapy in diabetic patients has impact on other hormones regulating blood glucose level as it reduces serum prolactin and cortisol levels. Also we conclude that prolactin is a diabetogenic hormone.

1515-P: Effect of Aging on Insulin Clearance in Mice

Aging is commonly linked with hyperinsulinemia and insulin resistance. Age-related hyperinsulinemia results from increased insulin secretion and/or decreased insulin clearance as compensatory mechanisms to peripheral insulin resistance. Several studies have reported reduced β-cell function in elderly rodents and humans. Earlier reports on decreased insulin clearance due to aging suggest that hyperinsulinemia in elderly could be explained predominantly by a reduction in insulin clearance. Hence, we aim to better understand the role of aging on insulin clearance following fat infusion. To investigate the aging effect, 3 months and 10-14 months old C57BL6 mice were infused with ethylpalmitate for 48h (hydrolyzed to palmitate and ethanol in plasma), to achieve elevated circulating FFA in a non-toxic manner. Mice were then subjected to hyperglycemic clamp, and during the clamp plasma C-peptide and insulin were measured to evaluate insulin clearance. Glucose infusion rate (GINF), insulin sensitivity index (SI) and disposition index (DI) were also assessed during clamp analysis. GINF is a measure of glucose tolerance whereas DI evaluates β-cell function. Whereas insulin secretion did not increase, insulin clearance was reduced in the aging mice, as indicated by the lower C-peptide/insulin molar ratio, observed during hyperglycemic clamp. No significant changes were observed in GINF between old and young mice; however, SI and DI were lower in elderly group. These results collectively suggest that with advancing age, β-cells may lose their ability to maintain a higher insulin secretion and that reduced hepatic insulin clearance plays a more dominant role to compensate for age-related decline in insulin sensitivity. Disclosure S.Rahman: None. S.Zaidi: Other Relationship; BullFrog AI. H.T.Muturi: None. S.M.Najjar: None. A.Giacca: None.

Neuronostatin accts as a counterregulatory factor to protect against hypoglycemia

Neuronostatin (NST) is a 13-amino acid hormone derived from the somatostatin (SST) preprohormone that exerts metabolic and cardiovascular actions in many tissue types. In transformed alpha cell lines and isolated rat islets neuronostatin enhanced low glucose-stimulated proglucagon transcription and glucagon secretion1. Additionally, neuronostatin inhibited high glucose-stimulated insulin secretion from isolated rat islets, which was mirrored in vivo in rats subjected to an intra-arterial glucose tolerance test. Rats that received a bolus injection of neuronostatin followed by infusion glucose exhibited delayed glucose disposal and impaired insulin release, causing an increased peak blood glucose1. We, therefore hypothesized the ability of neuronostatin to act as a counterregularoty factor to protect against hypoglycemia. We found that Neuronostatin administered prior to an insulin tolerance test significantly reduced hypoglycemia compared to the saline control. In addition, we found that administration of exogenous Insulin significantly reduced Neuronostatin plasma levels. These data suggest Neuronostatin may act as a counterregulatory factor in adult, male rats to prevent hypoglycemia. However, after menopause or OVX, a precipitous decline in insulin sensitivity parallels an increase in fat mass, suggesting estrogens at physiological concentrations may maintain insulin action and glucose tolerance. We therefore investigated the neuronostatin-induced blood glucose changes in conscious, cycling females. We found blood glucose levels following neuronostatin administration decreased on diestrus, when both estrogen and progesterone levels are low, but not on proestrus or estrus. From these data we conclude that the metabolic actions of Neuronostatin are modulated by sex hormone status. Further studies are required to determine the contributions of chromosomal sex and individual sex hormones to these metabolic effects of Neuronostatin.1. Salvatori AS, Elrick MM, Samson WK, Corbett JA, Yosten GL. Neuronostatin inhibits glucose-stimulated insulin secretion via direct action on the pancreatic alpha-cell. Am J Physiol Endocrinol Metab. 2014;306:E1257–E1263. Saint Louis University Internal Funds This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Inflammation and Oxidative Stress in Frailty and Metabolic Syndromes-Two Sides of the Same Coin.

In developed countries, aging is often seen as typical, but it is made complicated by many disorders and co-morbidities. Insulin resistance seems to be an underlying pathomechanism in frailty and metabolic syndromes. The decline in insulin sensitivity leads to changes in the oxidant-antioxidant balance and an accelerated inflammatory response, especially by adipocytes and macrophages in adipose tissue, as well as muscle mass density. Thus, in the pathophysiology of syndemic disorders-the metabolic syndrome and frailty syndrome-an extremely important role may be played by increased oxidative stress and pro-inflammatory state. Papers included in this review explored available full texts and the reference lists of relevant studies from the last 20 years, before the end of 2022; we also investigated the PubMed and Google Scholar electronic databases. The online resources describing an elderly population (≥65 years old) published as full texts were searched for the following terms: "oxidative stress and/or inflammation", "frailty and/or metabolic syndrome". Then, all resources were analyzed and narratively described in the context of oxidative stress and/or inflammation markers which underlie pathomechanisms of frailty and/or metabolic syndromes in elderly patients. So far, different metabolic pathways discussed in this review show that a similar pathogenesis underlies the development of the metabolic as well as frailty syndromes in the context of increased oxidative stress and acceleration of inflammation. Thus, we argue that the syndemia of the syndromes represents two sides of the same coin.

Prediabetes as a risk factor for new-onset atrial fibrillation: the propensity-score matching cohort analyzed using the Cox regression model coupled with the random survival forest

BackgroundThe glycemic continuum often indicates a gradual decline in insulin sensitivity leading to an increase in glucose levels. Although prediabetes is an established risk factor for both macrovascular and microvascular diseases, whether prediabetes is independently associated with the risk of developing atrial fibrillation (AF), particularly the occurrence time, has not been well studied using a high-quality research design in combination with statistical machine-learning algorithms.MethodsUsing data available from electronic medical records collected from the National Taiwan University Hospital, a tertiary medical center in Taiwan, we conducted a retrospective cohort study consisting 174,835 adult patients between 2014 and 2019 to investigate the relationship between prediabetes and AF. To render patients with prediabetes as comparable to those with normal glucose test, a propensity-score matching design was used to select the matched pairs of two groups with a 1:1 ratio. The Kaplan–Meier method was used to compare the cumulative risk of AF between prediabetes and normal glucose test using log-rank test. The multivariable Cox regression model was employed to estimate adjusted hazard ratio (HR) for prediabetes versus normal glucose test by stratifying three levels of glycosylated hemoglobin (HbA1c). The machine-learning algorithm using the random survival forest (RSF) method was further used to identify the importance of clinical factors associated with AF in patients with prediabetes.ResultsA sample of 14,309 pairs of patients with prediabetes and normal glucose test result were selected. The incidence of AF was 11.6 cases per 1000 person-years during a median follow-up period of 47.1 months. The Kaplan–Meier analysis revealed that the risk of AF was significantly higher in patients with prediabetes (log-rank p < 0.001). The multivariable Cox regression model indicated that prediabetes was independently associated with a significant increased risk of AF (HR 1.24, 95% confidence interval 1.11–1.39, p < 0.001), particularly for patients with HbA1c above 5.5%. The RSF method identified elevated N-terminal natriuretic peptide and altered left heart structure as the two most important risk factors for AF among patients with prediabetes.ConclusionsOur study found that prediabetes is independently associated with a higher risk of AF. Furthermore, alterations in left heart structure make a significant contribution to this elevated risk, and these structural changes may begin during the prediabetes stage.

Etiology, risk factors and complications of exercise induced muscle injury

Healthy lifestyle includes physical activity as the basic component however, exercises with eccentricity have been associated to a higher risk of muscle injury and slower recovery. The development of exercise-induced muscle injury is a phenomenon that results from atypical or unaccustomed activity; the intensity of the pain and the extent of the damage steadily deteriorate over time, and when the exercise session contains an eccentric component, they may last for several days. Increasing levels of muscle-specific circulating protein are present, along with increased levels of muscular pain and decreased muscle strength. The extent of severity of the symptoms following eccentric exercise varies greatly. Exercise-induced muscle injury is influenced by a number of factors including intensity, duration, mode, muscle group, age, gender, genetics, and dietary state. Numerous scientific studies illustrate the circumstances under which exercise causes muscle injury. It is widely acknowledged that exercise that is unfamiliar, particularly exercise that involves eccentric contractions, causes damage. exercise-induced muscle injury is accompanied by an inflammatory response involving numerous mediators, including the production of muscle-specific creatine kinase and interleukins and interleukins receptor antagonist and acute phase proteins. Complications of exercise-induced muscle injury include temporary muscle inflammation, loss of strength, muscle discomfort, restricted range of motion, elevated passive tension, discomfort, and a momentary decline in insulin sensitivity and can also lead to rhabdomyolysis. The purpose of this research is to review the available information about an etiology, risk factors and complications of exercise-induced muscle injury.

Pyroptosis and Insulin Resistance in Metabolic Organs.

Skeletal muscle serves as the optimal effective organ to balance glucose homeostasis, but insulin resistance (IR) in skeletal muscle breaks this balance by impeding glucose uptake and causes metabolic disorders. IR in skeletal muscle is caused by multiple factors, and it has been reported that systemic low-grade inflammation is related to skeletal muscle IR, though its molecular mechanisms need to be ulteriorly studied. Pyroptosis is a novel inflammatory-mediated type of cell death. It has recently been reported that pyroptosis is associated with a decline in insulin sensitivity in skeletal muscle. The appropriate occurrence of pyroptosis positively eliminates pathogenic factors, whereas its excessive activation may aggravate inflammatory responses and expedite disease progression. The relationship between pyroptosis and IR in skeletal muscle and its underlined mechanism need to be further illustrated. The role of pyroptosis during the process of IR alleviation induced by non-drug interventions, such as exercise, also needs to be clarified. In this paper, we review and describe the molecular mechanisms of pyroptosis and further comb the roles of its relevant key factors in skeletal muscle IR, aiming to propose a novel theoretical basis for the relationship between pyroptosis and muscle IR and provide new research targets for the improvement of IR-related diseases.

1330-P: Longitudinal Multiyear Prospective Study in 87 Diabetic Primates: Lack of Support for a Mechanistic Basis for the Disposition Index

Cross-sectional studies of individuals before, during, and after the development of overt type 2 diabetes (ADA definition) , as well as those in which 3 to 5 subgroups have been analyzed, typically have applied DM progression analyses using the parameters of the Disposition Index (DI) . In such correlation-based analyses, the inferences drawn do not reflect the relationships we and others have drawn from longitudinal analyses of the same data obtained within-subject across time during the development of diabetes. The problems with the DI and its interpretation have been a subject of concern for many years, but, nevertheless, its assumptions and interpretations have dominated the diabetes scientific literature. As recently noted by Arreola, et al 2022, the form of the relationship between two measures, insulin sensitivity as measured by the “gold standard” euglycemic hyperinsulinemic clamp and beta-cell responsiveness based on the intravenous glucose tolerance test induced Acute Insulin Response (AIR, 0 to min) is clearly nonlinear, and likely is not hyperbolic. In our longitudinal laboratory study of adult nonhuman primates, 87 developed overt type 2 diabetes[LS1] while under study. The laboratory provided standard monkey chow ad libitum to all individually caged Macaca mulatta rhesus monkeys throughout the study. We found that ß cell function was not a result of or associated with a decline in insulin sensitivity as measured by a euglycemic hyperinsulinemic clamp. Furthermore, hyperglycemia is clearly not the stimulus for nor cause of hypersecretion of insulin, the latter significantly preceding the development of impaired glucose tolerance followed by progression to overt DM. We conclude that the disposition index failed to predict the natural progression from normal to overt type 2 diabetes mellitus in this longitudinal data analysis, and its value is best considered only in the context of an epidemiological study using cross-sectional data. Disclosure L.Shiver: None. C.Bellido: None. A.Rosado: None. B.C.Hansen: None. Funding National Institutes of Health (NO1 AG3 1012)

Metabolic Syndrome and Myocardial Infarction in Women.

Metabolic syndrome (MetS) represents a cluster of metabolic disorders that arise from insulin resistance (IR) and adipose tissue dysfunction. As a consequence, there is an increased risk for type 2 diabetes mellitus and atherosclerotic cardiovascular disease (CVD). MetS is associated with a 2-fold increase in cardiovascular outcomes. Earlier population analyses showed a lower prevalence of MetS in women (23.9%) in comparison to men (27.8%), while later analyses suggest significantly reduced difference due to an increase in the prevalence in women aged between 20 and 39. However, the prevalence of MetS in specific populations of women, such as in women with polycystic ovary syndrome, ranges from 16% to almost 50% in some geographical regions. Abdominal fat accumulation and IR syndrome are recognized as the most important factors in the pathogenesis of MetS. After menopause, a decline in insulin sensitivity corresponds to an increase in fat mass, circulating fatty acids, low-density lipoproteins, and triglycerides. Prevalence of MetS in acute coronary syndrome (ACS) is significantly more present in women (55.9%-66.3%) than in men (40.2%-47.3%) in different cohorts. Younger women with ACS had a higher mortality rate than younger men. Acute myocardial infarction (AMI) remains a leading cause of death in aging women. Women with AMI had significantly higher rates of prior congestive heart failure, hypertension history, and diabetes. The role of androgens in CVD pathogenesis in women has not yet been clarified. The current review aims to provide an insight into the role of MetS components and inflammation for the development of atherosclerosis, CVD, and AMI in women.

Feline comorbidities: Pathophysiology and management of the obese diabetic cat.

Up to 40% of the domestic feline population is overweight or obese. Obesity in cats leads to insulin resistance via multiple mechanisms, with each excess kilogram of body weight resulting in a 30% decline in insulin sensitivity. Obese, insulin-resistant cats with concurrent beta-cell dysfunction are at risk of progression to overt diabetes mellitus. In cats that develop diabetes, appropriate treatment includes dietary modification to achieve ideal body condition (for reduction of insulin resistance), and optimization of diet composition and insulin therapy (for glycemic control and the chance of diabetic remission). Initially, as many obese cats that become diabetic will have lost a significant amount of weight and muscle mass by the time of presentation, some degree of diabetic control should be attempted with insulin before initiating any caloric restriction. Once body weight has stabilized, if further weight loss is needed, a diet with ≤ 12-15% carbohydrate metabolizable energy (ME) and >40% protein ME should be fed at 80% of resting energy requirement for ideal weight, with the goal of 0.5-1% weight loss per week. Other approaches may be necessary in some cats that need either substantial caloric restriction or do not find low carbohydrate diets palatable. Long-acting insulins are preferred as initial choices and oral antidiabetic drugs can be used in combination with diet if owners are unable or unwilling to give insulin injections. Glucagon-like peptide-1 (GLP-1) agonists have recently been investigated for use as adjunctive treatment in diabetic cats and sodium-glucose cotransporter-2 (SGLT2) inhibitors are currently being evaluated in clinical trials. The information in this review is drawn from: epidemiological studies on obesity prevalence; prospective longitudinal studies of development of insulin resistance with obesity; randomized controlled studies; and expert opinion regarding the effect of diet on diabetes management in cats.

170-OR: Hypothalamic Gliosis Predicts Decline in Insulin Sensitivity over One Year in People with Obesity

Studies demonstrate evidence of gliosis in the mediobasal hypothalamus (MBH) of people with obesity and T2D or impaired glucose tolerance (IGT), but whether MBH gliosis predicts worsening glucose homeostasis is unknown. The study evaluated 38 subjects with obesity (68% female, 76% White). Mean age was 47±11 y and BMI was 35±3.9 kg/m2. MRI, DXA, and 75 g OGTT were performed at baseline and DXA and OGTT repeated at 1y. Mean bilateral T2 relaxation time (ms) in the MBH and 3 control regions was measured as a marker of gliosis. Serial blood samples from OGTT were used to calculate glucose area under the curve (incremental [iAUC] and total [totalAUC]) and to model insulin sensitivity (OGIS) and beta-cell function (beta-cell glucose sensitivity). Generalized estimating equations tested associations and interactions by region. On average, measures of glucose tolerance (iAUC and totalAUC), OGIS, and beta-cell glucose sensitivity were stable over 1 y. Baseline bilateral mean MBH T2 relaxation time was not associated with changes in glucose tolerance (Δ iAUC β: -5.8 ms, 95% CI -21.0, 9.4, P=0.45; Δ totalAUC β: 1.3 ms, 95% CI -33.5, 36.0, P=0.94, adjusted for sex, age) or change in glucose sensitivity (β: 0.3 ms, 95% CI -1.0, 1.6, P=0.66) nor were interactions present. Change in OGIS over 1y was significantly negatively associated with bilateral mean MBH T2 relaxation time at baseline (β: -0.94 ms, 95% CI -1.7, -0.2, P=0.02, adjusted for sex, age); subjects with longer MBH T2 relaxation times at baseline reduced OGIS over 1 y. A formal interaction by region was not significant (chi2(7)=7.11, Pint=0.42). The relationship within the MBH was attenuated when also adjusted for change in fat mass (β: -0.70 ms 95% CI -1.4, 0.02, P=0.056). Subjects with greater radiologic evidence for MBH gliosis exhibited declines in insulin sensitivity over 1 y which were not fully accounted for by changes in adiposity. These longitudinal findings are consistent with a role for MBH gliosis in T2D pathogenesis in people with obesity. Disclosure J. L. Rosenbaum: None. S. Schoen: None. S. J. Melhorn: None. M. De leon: None. M. Webb: None. K. Utzschneider: None. E. Schur: None. Funding American Diabetes Association (1-17-ICTS-085 to E.S.)

Effects of High-Fat Diet at Two Energetic Levels on Fecal Microbiota, Colonic Barrier, and Metabolic Parameters in Dogs.

Increased consumption of energy-rich foods is a key factor in overweight, obesity, and associated metabolic disorders. This would be, at least in part, related to microbiota disturbance. In rodent models of obesity, microbiota disruption has been associated with alteration of the intestinal barrier, endotoxemia, inflammation grade, and insulin sensitivity. The aim of the present study was to assess the effects of a high-fat diet (HFD), fed at two energetic levels, on microbiota, intestinal barrier, and inflammatory and metabolic parameters in dogs. A HFD (33% fat as fed, 4,830 kcal/kg) was given to 24 healthy Beagle dogs at 100% (HF-100; n = 8) and at 150% (HF-150; n = 16) of their maintenance energy requirements for 8 weeks. Analysis of similarity revealed a significant difference in gut microbiota β-diversity following the diet compared to week 0 in both groups while α-diversity was lower only in the HF-150 group. Firmicutes/Bacteroidetes ratio was higher in the HF-150 group compared to the HF-100 group at weeks 2 and 8. A reduction in insulin sensitivity was observed over time in the HF150 group. Neither endotoxemia nor inflammation was observed in either group, did not find supporting data for the hypothesis that the microbiota is involved in the decline of insulin sensitivity through metabolic endotoxemia and low-grade inflammation. Colonic permeability was increased at week 4 in both groups and returned to initial levels at week 8, and was associated with modifications to the expression of genes involved in colonic barrier function. The increase in intestinal permeability may have been caused by the altered intestinal microbiota and increased expression of genes encoding tight junction proteins might indicate a compensatory mechanism to restore normal permeability. Although simultaneous changes to the microbiota, barrier permeability, inflammatory, and metabolic status have not been observed, such a causal link cannot be excluded in dogs overfed on a HFD. Further studies are necessary to better understand the link between HFD, intestinal microbiota and the host.

Integrative Analysis of Glucometabolic Traits, Adipose Tissue DNA Methylation, and Gene Expression Identifies Epigenetic Regulatory Mechanisms of Insulin Resistance and Obesity in African Americans.

Decline in insulin sensitivity due to dysfunction of adipose tissue (AT) is one of the earliest pathogenic events in type 2 diabetes. We hypothesize that differential DNA methylation (DNAm) controls insulin sensitivity and obesity by modulating transcript expression in AT. Integrating AT DNAm profiles with transcript profile data measured in a cohort of 230 African Americans (AAs) from the African American Genetics of Metabolism and Expression cohort, we performed cis-expression quantitative trait methylation (cis-eQTM) analysis to identify epigenetic regulatory loci for glucometabolic trait-associated transcripts. We identified significantly associated cytosine-guanine dinucleotide regions for 82 transcripts (false discovery rate [FDR]-P < 0.05). The strongest eQTM locus was observed for the proopiomelanocortin (POMC; ρ = -0.632, P = 4.70 × 10-27) gene. Epigenome-wide association studies (EWAS) further identified 155, 46, and 168 cytosine-guanine dinucleotide regions associated (FDR-P < 0.05) with the Matsuda index, SI, and BMI, respectively. Intersection of EWAS, transcript level to trait association, and eQTM results, followed by causal inference test identified significant eQTM loci for 23 genes that were also associated with Matsuda index, SI, and/or BMI in EWAS. These associated genes include FERMT3, ITGAM, ITGAX, and POMC In summary, applying an integrative multiomics approach, our study provides evidence for DNAm-mediated regulation of gene expression at both previously identified and novel loci for many key AT transcripts influencing insulin resistance and obesity.

Glucagon-Like Peptide 1 Attenuates Lipotoxicity-Induced Islet Dysfunction in ApoE-/- Mice.

AimGlucagon-like peptide-1 (GLP1) is known to decrease glucagon release and may be beneficial for the reduction of elevated blood glucose. However, its role and mechanism of action in diabetes remain elusive. This study aimed to examine the function of GLP1 and analyze the mechanism of effect that GLP1exerts on inducible nitric oxide synthase (iNOS) in diabetic mice.MethodsA diabetes model was established in ApoE–/– mice fed a high-fat diet and treated with GLP1 and/or lentivirus-expressing PARP1. PARP1, iNOS, and inflammatory factors in islets were detected by Western blot and ELISA. Islet α cells and β cells and CD8+ T lymphocytes were detected by immunostaining. Islet-cell apoptosis was detected by TUNEL.ResultsGLP1 inhibited the expression of PARP1 and iNOS in islets, alleviated decrease in β cells, and suppressed cell apoptosis induced by the high-fat diet. Moreover, GLP1 recovered the decline in insulin sensitivity and glucose tolerance in ApoE–/– mice fed the high-fat diet, and the effects of GLP1 were related to the inhibition of COX2 and NFκB expression.ConclusionGLP1 significantly alleviated the decrease in β-cell numbers, suppressed β-cell apoptosis induced by the high-fat diet, inhibited the expression of iNOS, and alleviated inflammatory islet injury via inhibiting the COX2–NFκB pathway.

243-OR: Integrative Multiomics Analysis of Glucometabolic Traits, Adipose Tissue DNA Methylation, and Gene Expression Identifies Epigenetic Regulatory Mechanisms of Insulin Resistance and Obesity in African Americans

Decline in insulin sensitivity due to dysfunction of adipose tissue (AT) is one of the earliest pathogenic events in type 2 diabetes. We hypothesize that differential DNA methylation (DNAm) in regulatory regions of a subset of genes controls insulin sensitivity and obesity by modulating transcript expression in AT. Integrating reduced representation bisulfite sequencing-derived AT DNAm profiles for 1,054,719 CpG sites and 200,800 CpG regions with AT transcript profile data in 230 African Americans, we performed cis-expression quantitative trait methylation (cis-eQTM) analysis focused on 6,774 glucometabolic trait-associated transcripts to identify local epigenetic regulatory loci for these transcripts. We identified significantly associated CpG regions for 140 transcripts (FDR-P&amp;lt;0.1). The strongest eQTM locus was observed for the proopiomelanocortin (POMC; ρ= -0.632, P = 4.70X10-27) gene at the chr2:25,384,001-25,385,000 region covering a CpG island in the gene. Epigenome-wide association studies (EWAS) further examined the association of DNAm levels of CpG sites/regions with insulin sensitivity (Matsuda index and SI) and BMI. EWAS identified 520, 154, and 482 CpG regions associated (FDR-P &amp;lt;0.1) with Matsuda index, SI and BMI, respectively. We jointly analyzed the EWAS, transcript level to trait association, and eQTM data and identified significant eQTM loci for 26, 15 and 25 genes that were also associated with Matsuda index, SI and BMI, respectively in EWAS. These associated genes include fructose-2,6-biphosphatase 3 (PFKFB3), integrin alpha M (ITGAM), integrin alpha X (ITGAX), and POMC. In summary, applying an integrative multi-omics approach, our study provides evidence for DNAm-mediated regulation of gene expression at both previously identified and novel loci for many key AT transcripts influencing insulin resistance and obesity. Disclosure N.K. Sharma: None. M. Comeau: None. D.J. Montoya: None. M. Pellegrini: None. T. Howard: None. C.D. Langefeld: None. S.K. Das: None. Funding American Diabetes Association (1-18-ICTS-113 to S.K.D.); National Institutes of Health (R01DK090111)

Electroacupuncture improves inflammatory reaction and insulin sensitivity in insulin-resistant obese rats

To observe the effect of electroacupuncture (EA) on inflammatory reaction and insulin sensitivity in insulin-resistant obese (OIR) rats. Thirteen male Wistar rats were randomly selected as the control group and fed with common diet. The other 39 rats were fed with high-fat diet for 8 weeks to establish OIR model and then randomized into model, EA and sham EA groups. EA (2 Hz, 1 mA) was applied to unilateral "Zusanli" (ST36), "Fenglong" (ST40), "Zhongwan" (CV12) and "Guanyuan" (CV4) for 15 min, once every other day for 8 weeks, and sham EA was applied to unilateral 4 control spots about 5 mm lateral to the aforementioned 4 acupoints after shallowly inserting acupuncture needles, but without electric current output. After 8 weeks' intervention, the body weight was recorded and the glucose infusion rate (GIR) measured using hyperinsulinemic-euglycemic clamp technique. At the 6th week of intervention, glucose contents of intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tole-rance test (IPITT) were measured. The levels of serum insulin (INS) and inflammatory factors as C-reactive protein (CRP), IL-6 and TNF-α were measured by using ELISA at the end of the treatment. The expression levels of IL-6, TNF-α, monocyte chemoattractant protein-1(MCP-1), IL-10 and IL-1β proteins and mRNAs in the abdominal adipose tissues were detected by Western blot and quantitative real time-PCR, separately. The CD68 expression (displaying infiltration of macrophages) of adipose tissue was detected using immunohistochemistry. After modeling, the contents of glucose of IPGTT at 30, 60 and 120 min and those of IPITT at 15, 30, 60 and 120 min, serum INS, CRP, IL-6 and TNF-α, as well as the expression levels of IL-6, TNF-α, IL-1β and MCP-1 proteins and mRNAs and CD68 protein were significantly increased (P<0.01, P<0.05), while the levels of GIR and IL-10 protein and mRNA were obviously decreased in the model group in comparison with those of the control group (P<0.01), suggesting an increase of inflammation and a decline of INS sensitivity. Following the interventions, the increased contents of glucose of IPGTT and IPITT, serum INS, CRP, IL-6 and TNF-α, expression levels of IL-6, TNF-α, IL-1β and MCP-1 proteins and mRNAs and CD68 protein, and the decreased levels of GIR and IL-10 protein and mRNA were evidently reversed in the EA group compared with the model group (P<0.01, P<0.05) rather than those in the sham EA group (P>0.05). EA can reduce the level of inflammation and improve insulin sensitivity in OIR rats.

Evaluating the Effect of Acarbose Treatment on Insulin Secretion and Sensitivity in Early Diabetes Using a Novel Interpretation of the Disposition Index Equation

Background and Hypothesis: In pathologic states such as obesity and insulin resistance, there is a progressive decline in insulin sensitivity requiring greater insulin secretion to maintain normoglycemia. The inverse relationship between insulin sensitivity and secretion is mathematically defined by the Disposition Index (DI), a measure of βcell function adjusted for insulin sensitivity. We are working to generalize the DI equation to allow direct physiologic interpretation of the DI term, and of the slope relating insulin secretion with insulin sensitivity. We tested study treatment effects hypotheses using these new analytic methods.&#x0D; Background and Hypothesis: In pathologic states such as obesity and insulin resistance, there is a progressive decline in insulin sensitivity requiring greater insulin secretion to maintain normoglycemia. The inverse relationship between insulin sensitivity and secretion is mathematically defined by the Disposition Index (DI), a measure of βcell function adjusted for insulin sensitivity. We are working to generalize the DI equation to allow direct physiologic interpretation of the DI term, and of the slope relating insulin secretion with insulin sensitivity. We tested study treatment effects hypotheses using these new analytic methods.&#x0D; Results: These analyses revealed statistically significant 1-year changes in DI, in secretion-sensitivity coupling slopes, and in the joint changes in secretion and sensitivity. However, these treatment effects did not differ by randomized treatment group, suggesting an on-study effect beyond the randomized treatments.&#x0D; Conclusion and Potential Impact: &#x0D; We have applied a novel analytic approach to evaluate the secretion-sensitivity relationship modeled by the disposition index equation to investigate the effect of randomized therapy on β-cell function in a placebo-controlled randomized clinical trial. These analyses revealed study effects on the secretion-sensitivity relationship that have not been previously described, suggesting that this novel approach will have value in clinical studies of β-cell dysfunction and treatment effects.&#x0D;

Lower Insulin Clearance Parallels a Reduced Insulin Sensitivity in Obese Youths and Is Associated With a Decline in β-Cell Function Over Time.

We examined the relationship between insulin clearance, insulin sensitivity, and β-cell function and the longitudinal effect of insulin clearance on β-cell function in lean and obese insulin-sensitive and insulin-resistant adolescents. A hyperinsulinemic-euglycemic and a hyperglycemic clamp were performed in 110 youths to quantify hepatic and peripheral clearance, insulin sensitivity, and β-cell function (disposition index, DIh-clamp). Participants underwent an oral glucose tolerance test at baseline and after 2 years to assess glucose tolerance and oral β-cell function (oDIcpep) and were sorted into four groups (lean and obese normal glucose tolerance, insulin sensitive, insulin resistant, and impaired glucose tolerance). Insulin sensitivity was defined based on the median of insulin stimulated glucose disposal (M) measured during the hyperinsulinemic-euglycemic clamp. Lean and obese insulin-sensitive participants did not differ with respect to hepatic and peripheral clearance or for insulin sensitivity. Insulin sensitivity was linearly correlated with whole-body insulin clearance. Hepatic insulin extraction at baseline acted as an independent determinant of β-cell function at follow-up. The decline in insulin sensitivity, even in the absence of an impairment of glucose tolerance, is associated with lowering of hepatic insulin clearance in obese youth, which in turn may contribute to the decline in β-cell function over time.