Role In Insulin Sensitivity Research Articles

Interplay of FXN expression and lipolysis in white adipocytes plays a critical role in insulin sensitivity in Friedreich’s ataxia mouse model

Frataxin (FXN) is required for iron-sulfur cluster biogenesis, and its loss causes the early-onset neurodegenerative disease Friedreich ataxia (FRDA). Loss of FXN is a susceptibility factor in the development of diabetes, a common metabolic complication after myocardial hypertrophy in patients with FRDA. The underlying mechanism of FXN deficient-induced hyperglycemia in FRDA is, however, poorly understood. In this study, we confirmed that the FXN deficiency mouse model YG8R develops insulin resistance in elder individuals by disturbing lipid metabolic homeostasis in adipose tissues. Evaluation of lipolysis, lipogenesis, and fatty acid β-oxidation showed that lipolysis is most severely affected in white adipose tissues. Consistently, FXN deficiency significantly decreased expression of lipolytic genes encoding adipose triglyceride lipase (Atgl) and hormone-sensitive lipase (Hsl) resulting in adipocyte enlargement and inflammation. Lipolysis induction by fasting or cold exposure remarkably upregulated FXN expression, though FXN deficiency lessened the competency of lipolysis compared with the control or wild type mice. Moreover, we found that the impairment of lipolysis was present at a young age, a few months earlier than hyperglycemia and insulin resistance. Forskolin, an activator of lipolysis, or pioglitazone, an agonist of PPARγ, improved insulin sensitivity in FXN-deficient adipocytes or mice. We uncovered the interplay between FXN expression and lipolysis and found that impairment of lipolysis, particularly the white adipocytes, is an early event, likely, as a primary cause for insulin resistance in FRDA patients at later age.

Revisiting the Effect of Leptin on Alzheimer Disease and Parkinson Disease: The Role of Insulin Sensitivity.

Studies have indicated a link between leptin, Alzheimer disease (AD), and Parkinson disease (PD). However, the causal relationship among them remains not well established due to confounders and reverse causation. This Mendelian randomization (MR) study was performed to evaluate the impact and potential mechanism of leptin and its soluble receptor on AD and PD. Utilizing genome-wide association studies summary-level data, a comprehensive MR was conducted to assess the causal effect of leptin and soluble leptin receptor (sLEPR) on AD and PD. Additionally, we also explored the role of body mass index (BMI) and insulin sensitivity index (ISI) in using the multivariable MR. The primary analysis was performed using the inverse variance-weighted method. Pooled estimates showed that genetically proxied higher leptin levels was significantly associated with a decreased risk of AD (OR 0.838, 95% CI 0.741-0.948, P = .005), but not PD. In contrast, no significant associations were observed between sLEPR levels, AD, and PD. Moreover, the effect of leptin on AD was attenuated to null after adjustment of ISI (OR 0.879, 95% CI 0.758-1.018, P = .086), but not BMI. There was no causal impact of AD and PD on circulating levels of leptin and sLEPR, indicating the absence of reverse causation. Sensitivity analyses confirmed the robustness of these associations, with no obvious pleiotropy and heterogeneity. The study offers evidence supporting a potential protective effect of leptin in AD, but not PD, via the enhancement of insulin sensitivity. Our findings underscore the distinct roles of leptin in AD and PD.

Molecular dynamic of omega-3 compounds as an anti-obesity agent into GPR-120 receptor

Obesity is a cause of comorbid diseases such as type 2 diabetes mellitus, dyslipidemia, hypertension which is based on low-level chronic inflammation. The GPR-120 receptor plays a role in insulin sensitization which is related to diabetes mellitus which is a comorbid obesity. Omega-3 fatty acids are believed to possess anti-inflammatory properties, hence potentially serving as a preventive measure against obesity-related comorbidities. The aim of this study is to do a stability analysis of the binding affinity between nine specific chemicals derived from omega-3 and the active site of the human GPR120 receptor using molecular dynamics simulations. Docking analysis was performed using Discovery Studio Visualizer, AutoDock Tools 1.5.6, and molecular dynamic simulation with AMBER 16. In this study, we used neurotensin 8–13 as a natural ligand to bind with the neurotensin receptor. Based on the neurotensin receptor docking results, the ΔG values for the following compounds are close to the values for neurotensin 8–13 -6.41 kcal/mol; docosahexaenoic acid -8.96 kcal/mol; eicosapentaenoic acid -7.41 kcal/mol; and heneicosapentaenoic acid -6.34 kcal/mol. Neurotensin 8–13 forms hydrogen bonds with TYR146, ARG213, and PHE344 of the neurotensin receptor, whereas docosahexaenoic acid forms hydrogen bonds with TYR146. Meanwhile, the average RMSD fluctuations for each system, namely docosahexaenoic acid, eicosapentaenoic acid, and heneicosapentaenoic acid, were 0.672, 0.437, and 0.650, respectively. The SASA of the neurotensin receptor-ligand complex showed similar fluctuations, with the average values for docosahexaenoic acid, eicosapentaenoic acid, and heneicosapentaenoic acid being 230.40, 229.89, and 230.20 nm2.

Binding of Per- and Polyfluoroalkyl Substances (PFAS) to the PPARγ/RXRα-DNA Complex.

Nuclear receptors are the fundamental building blocks of gene expression regulation and the focus of many drug targets. While binding to DNA, nuclear receptors act as transcription factors, governing a multitude of functions in the human body. Peroxisome proliferator-activator receptor γ (PPARγ) and the retinoid X receptor α (RXRα) form heterodimers with unique properties and have a primordial role in insulin sensitization. This PPARγ/RXRα heterodimer has been shown to be impacted by per- and polyfluoroalkyl substances (PFAS) and linked to a variety of significant health conditions in humans. Herein, a selection of the most common PFAS (legacy and emerging) was studied utilizing molecular dynamics simulations for PPARγ/RXRα. The local and global structural effects of PFAS binding on the known ligand binding pockets of PPARγ and RXRα as well as the DNA binding domain (DBD) of RXRα were inspected. The binding free energies were predicted computationally and were compared between the different binding pockets. In addition, two electronic structure approaches were utilized to model the interaction of PFAS within the DNA binding domain, density functional theory (DFT) and domain-based pair natural orbital coupled cluster with perturbative triples (DLPNO-CCSD(T)) approaches, with implicit solvation. Residue decomposition and hydrogen-bonding analysis were also performed, detailing the role of prominent residues in molecular recognition. The role of l-carnitine is explored as a potential in vivo remediation strategy for PFAS interaction with the PPARγ/RXRα heterodimer. In this work, it was found that PFAS can bind and act as agonists for all of the investigated pockets. For the first time in the literature, PFAS are postulated to bind to the DNA binding domain in a nonspecific manner. In addition, for the PPARγ ligand binding domain, l-carnitine shows promise in replacing smaller PFAS from the pocket.

ZNF259 rs964184 genetic variant is associated with metabolic syndrome in a Portuguese population

Abstract Background Zinc finger protein (ZPR1) encoded by the ZNF259 gene has been associated with defects in transcription and cell cycle progression. Additionally, the promoter site of ZPR1 binds to peroxisome proliferator-activated receptor gamma (PPARG), which plays a crucial role in insulin sensitivity and obesity. It's not consensual in its association with Metabolic Syndrom (MetS). Aim To estimate the influence of the ZNF259 rs964184 variant in MetS appearance. Methods A case-control study was performed with 3134 subjects (mean age 52.8 ± 8.1 years, 76.4% male) recruited from the Research Unit database, a regional quality clinical registry of hospital admissions. 1756 were patients with MetS and 1378 controls without MetS. MetS was diagnosed according to the International Diabetes Federation (IDF) criteria. The ZNF259 rs964184 C>G was genotyped with the TaqMan PCR assay (Applied Biosystems 7300 Real-Time). The bivariate analysis evaluated the genotypic and allelic distribution in the two groups, with and without MetS. Multivariate Logistic Regression assessed the variables independently associated with MetS. Results There were significant differences in genotype and allele distributions for the ZNF259 C>G variant between patients with MetS and without MetS. Wild-type genotype CC was increased in the non-MetS group, whereas the risk GG was higher in patients with MetS (P=0.008). Similarly, C allele frequencies were significantly higher in the non-MetS group, while the G allele was highly present MetS population (P=0.002). After multivariate logistic regression, GC genotype (OR=1.23; 95%CI:1.05–1.45; p=0.011) and GG genotype (OR=1.59; 95%CI:1.01–2.50; p=0.047) remained as independent risk factors for Metabolic Syndrome. Conclusions This study presents novel data and findings that may have important implications for assessing MetS risk in our population. For the first time in a Portuguese population, we demonstrated that ZNF259 genetic changes are significantly associated with more than 60% increased probability of having Metabolic Syndrome.

A-046 Investigating the Role of RNase L in Metabolic Syndrome

Abstract Background Metabolic syndrome is closely associated with the incidence of heart disease, type 2 diabetes, and stroke. Though the exact cause of metabolic syndrome is not known, many features of the metabolic syndrome are caused by insulin resistance. Recent years, accumulating evidence has shown that dysregulation of insulin signaling leads to insulin resistance. Interestingly, we have observed that RNase L affects the insulin signaling pathway by regulating the activation of insulin receptor subtrate-1 (IRS-1) in primary mouse embryonic fibroblasts (MEFs) and primary mouse hepatocyte. RNase L is an enzyme that plays a critical role in interferon function against viral infection and cellular proliferation. How RNase L affects the insulin signaling pathway is still unknown. Methods Age-matched C57BL/6 background RNase L wild type (WT) and knockout (KO) mice (n = 6–8) were fed on a chow diet. Metabolic tolerance tests including glucose tolerance test (GTT) and insulin tolerance test (ITT) were conducted on mice between 12 and 16 weeks old. Mice were subjected to either a morning (4 h) or an overnight (12 h) fast, then intraperitoneally injected with glucose (1.5 g/kg body weight) in PBS, pH 7.4, for GTT and insulin (1.0I U/kg body weight) for ITT. Blood was collected via tail vein at different time intervals over a span of 2 h and blood glucose was measured using a glucometer. Results We found that RNase L KO mice displayed significantly increased glucose tolerance in compared to RNase L WT mice as measured in the intraperitoneal glucose tolerance test. The glucose level in RNase L KO mice was 150% higher than that in RNase L WT mice after IP injection of glucose in 60 min. In the ITT experiment, the glucose level in RNase L KO mice was 130% higher than that in WT mice in 60 min post injection. Taken together, the results in GTT and ITT indicated that RNase L mediates the metabolism of glucose in vivo. Further investigation of molecular mechanisms is currently being conducted. Conclusion Our results suggests that RNase L plays a role in insulin sensitivity, which affects glucose metabolism.

The Rho guanine dissociation inhibitor α inhibits skeletal muscle Rac1 activity and insulin action

The molecular events governing skeletal muscle glucose uptake have pharmacological potential for managing insulin resistance in conditions such as obesity, diabetes, and cancer. With no current pharmacological treatments to target skeletal muscle insulin sensitivity, there is an unmet need to identify the molecular mechanisms that control insulin sensitivity in skeletal muscle. Here, the Rho guanine dissociation inhibitor α (RhoGDIα) is identified as a point of control in the regulation of insulin sensitivity. In skeletal muscle cells, RhoGDIα interacted with, and thereby inhibited, the Rho GTPase Rac1. In response to insulin, RhoGDIα was phosphorylated at S101 and Rac1 dissociated from RhoGDIα to facilitate skeletal muscle GLUT4 translocation. Accordingly, siRNA-mediated RhoGDIα depletion increased Rac1 activity and elevated GLUT4 translocation. Consistent with RhoGDIα's inhibitory effect, rAAV-mediated RhoGDIα overexpression in mouse muscle decreased insulin-stimulated glucose uptake and was detrimental to whole-body glucose tolerance. Aligning with RhoGDIα's negative role in insulin sensitivity, RhoGDIα protein content was elevated in skeletal muscle from insulin-resistant patients with type 2 diabetes. These data identify RhoGDIα as a clinically relevant controller of skeletal muscle insulin sensitivity and whole-body glucose homeostasis, mechanistically by modulating Rac1 activity.

1098-P: Association of Sleep with ß-Cell Response and Insulin Sensitivity in Youth

Poor sleep may be associated with reduced β-cell response or decreased insulin sensitivity in youth. We explored whether sleep duration, sleep quality or obstructive sleep apnea (OSA) risk factors were associated with measures of β-cell response or insulin sensitivity in youth. At baseline, 88 youth (10-19 yrs of age) with recently diagnosed T2D or prediabetes completed validated questionnaires (Sleep Disturbances Scale and Cleveland Adolescent Sleepiness) in the Restoring Insulin Secretion (RISE) Study. Hyperglycemic clamps measured insulin sensitivity (steady state glucose infusion rate/insulin [M/I]) and β-cell responses: acute (0-10 min) C-peptide response to glucose (ACPRg), steady-state C-peptide at a glucose of 11.1 mmol/L (SSCP), and arginine-stimulated maximum C-peptide responses at glucose >25 mmol/L (ACPRmax). Linear regression models explored the independent association between sleep variables and clamp measures, adjusted for age, race/ethnicity, sex, Tanner stage, metformin use and BMI. Models including β-cell responses were adjusted for M/I to account for the role of insulin sensitivity in β-cell function. The cohort was 70% female, 28% white, 25% black, 36% Hispanic; age 14.3±2.0 yrs and BMI 36.9±6.4 kg/m2 (mean±SD). Using ADA criteria, 60% had prediabetes and 40% had T2D; 27% reported metformin use. Sleep duration <8 h was reported in 59%; 57% reported daytime sleepiness; 28% reported poor sleep quality; 29% had high risk for OSA. Low sleep duration (<8 h) was associated with a trend for lower ACPRg (p=0.069). No sleep variables (sleep duration or quality, OSA risk) were associated with clamp-derived outcomes in unadjusted or adjusted linear regression models. In youth with prediabetes or T2D, subjective measures of sleep quantity, sleep quality and OSA risk were not independently associated with β-cell response or insulin sensitivity. Further research using objective measures of sleep may better delineate the relationship between sleep and β-cell function in youth. Disclosure K.A.Temple: None. A.H.Tjaden: None. S.Manchanda: Advisory Panel; Inspire. D.Ehrmann: None. K.J.Nadeau: None. S.Edelstein: None. T.S.Hannon: Advisory Panel; Eli Lilly and Company. B.Mokhlesi: None. Rise consortium: n/a. Funding American Diabetes Association (1-20-RISE-01 to S.E.); National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute

Role for insulin sensitivity in the cerebrovascular response to hyperinsulinemia in young adults

Objective: Cerebral blood flow is highly regulated and cerebrovascular responsiveness to vasodilatory stimuli is predictive of brain health. In preclinical animal models, insulin elicits cerebrovascular dilation and subsequent increases in cerebral blood flow. Contrary to this, preliminary data from our group in a large cohort of healthy humans indicate surrogate measures of cerebral blood flow remain at baseline levels during hyperinsulinemia – although responses were highly variable. In the peripheral circulation, insulin-stimulated vasodilation is closely associated with markers of insulin sensitivity (e.g., elevated fasting glucose, insulin, HOMA-IR); whether these associations translate to the cerebral circulation remains unclear. With this information in mind, we hypothesized the degree of insulin-mediated increases in cerebral blood flow would correlate with indices of peripheral insulin sensitivity.Methods: Middle cerebral artery blood velocity (MCAv) was measured with transcranial Doppler ultrasound in 17 adults (11M/6F, 28±2 yrs, 24±1 kg/m 2 ) at baseline and following a 60-min hyperinsulinemic (40 mU/m 2 body surface area/min), euglycemic infusion. Correlations between MCAv and indices of peripheral insulin sensitivity [i.e., fasting glucose, insulin, HOMA-IR, glucose infusion rate, weight, body mass index (BMI), age, physical activity] were determined. Results: Intravenous insulin infusion increased plasma insulin concentrations (6±1 to 49±3 μIU/mL, p<0.001) with blood glucose maintained (73±4 to 82±6 mg/dL, p=0.196). There was no net change in MCAv during hyperinsulinemia (60±4 to 60±4 cm/s, p=0.930). We observed negative associations between the change in MCAv during hyperinsulinemia (Δ=Insulin–Baseline) and both body weight (R=-0.49, p=0.047) and BMI (R=-0.50, p=0.040). No correlations between ΔMCAv and fasting glucose (p=0.435), insulin (p=0.733), HOMA-IR (p=0.960), age (p=0.132), physical activity (p=0.179), or glucose infusion rate (p=0.599) were observed. Conclusions: As previously shown in these participants, hyperinsulinemia in young adults elicits no net change in MCAv. Any increases in MCAv during hyperinsulinemia occur primarily in individuals with lower body weight and lower BMI. Future studies are needed to translate results to disease states (e.g., diabetes). Margaret W. Mangel Faculty Research Catalyst Fund (JP, JKL), NIH HL137769 (JP), NIH HL130339 (JKL) 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.

Associations of Serum Total 25OHD, 25OHD3, and epi-25OHD3 with Insulin Resistance: Cross-Sectional Analysis of the National Health and Nutrition Examination Survey, 2011-2016.

Background: Vitamin D may have a role in insulin sensitivity. However, the data on the association between various metabolites of Vitamin D and insulin-related parameters have been limited. Methods: We identified 6026 adults aged 20–80 years who participated in the 2011–2016 National Health and Nutrition Examination Survey (NHANES). Serum total 25OHD, 25OHD3, and epi-25OHD3, fasting glucose, insulin, and HOMA2-IR were obtained from the NHANES data. The association between serum Vitamin D-related values and insulin resistance was analyzed using a generalized linear model. For risk analysis, multifactorial logistic regression was used. Results: The median total 25-hydroxyvitamin D level, 25-hydroxyvitamin D3 level, and 3-epi-25-hydroxyvitamin D3 level were 62.5 nmol/L, 58.8 nmol/L, and 3.3 nmol/L, respectively. After adjustment for sex, age, race, ethnicity, and education status, the ORs for the insulin resistance of participants of total 25-hydroxyvitamin D, 25-hydroxyvitamin D3, and 3-epi-25-hydroxyvitamin D3 were 0.32 (95% CI 0.24, 0.43), 0.34 (95% CI 0.26, 0.44), and 0.64 (95% CI 0.53, 0.77), respectively. After an adjustment for body mass index, diabetes, and drinking and smoking, the ORs for the insulin resistance of the participants for total 25-hydroxyvitamin D, 25-hydroxyvitamin D3, and 3-epi-25-hydroxyvitamin D3 were 0.56 (95% CI 0.40, 0.78), 0.63 (95% CI 0.46, 0.85), and 0.99 (95% CI 0.80, 1.24), respectively. Conclusions: Our study provides suggestive evidence for the association between Vitamin D concentrations and a lower risk of insulin resistance. Evidence from larger and more adequately powered cohort studies is needed to confirm our results.

Artemisia annua L. Extracts Improved Insulin Resistance via Changing Adiponectin, Leptin and Resistin Production in HFD/STZ Diabetic Mice.

ObjectivesInsulin resistance (IR) is major cause of type 2 diabetes (T2D), and adipokines (e.g., adiponectin, leptin, and resistin) play an important role in insulin sensitivity. Medicinal plants are frequently used for T2D treatment. This study investigates the effect of Artemisia annua L. (AA) extracts on adipokines in mice with high-fat-diet (HFD)/streptozotocin (STZ)-induced T2D.MethodsWe divided 60 mice into 12 groups (n = 5 per group) control, untreated T2D, treated T2D, and 9 other groups. T2D was induced in all groups, except controls, by 8 weeks of HFD and STZ injection. The treated T2D group was administered 250 mg/kg of metformin (MTF), while the nine other groups were treated with 100, 200, and 400 mg/kg of hot-water extract (HWE), cold-water extract (CWE), and alcoholic extract (ALE) of AA (daily oral gavage) along with 250 mg/kg of MTF for 4 weeks. The intraperitoneal glucose tolerance test (IPGTT) was performed, and the homeostasis model assessment of adiponectin (HOMA-AD) index and blood glucose and serum insulin, leptin, adiponectin, and resistin levels were measured.ResultsSimilar to MTF, all three types of AA extracts (HWEs, CWEs, and ALEs) significantly (p < 0.0001) decreased the area under the curve (AUC) of glucose during the IPGTT, the HOMA-AD index, blood glucose levels, and serum insulin, leptin, and resistin levels and increased serum adiponectin levels in the MTF group compared to the T2D group (p < 0.0001). The HWEs affected adipokine release, while the CWEs and ALEs decreased leptin and resistin production.ConclusionWater and alcoholic AA extracts have an antihyperglycemic and antihyperinsulinemic effect on HFD/STZ diabetic mice. In addition, they decrease IR by reducing leptin and resistin production and increasing adiponectin secretion from adipocytes.

Computational Study of Asian Propolis Compounds as Potential Anti-Type 2 Diabetes Mellitus Agents by Using Inverse Virtual Screening with the DIA-DB Web Server, Tanimoto Similarity Analysis, and Molecular Dynamic Simulation.

Propolis contains a wide range of pharmacological activities because of their various bioactive compounds. The beneficial effect of propolis is interesting for treating type-2 diabetes mellitus (T2DM) owing to dysregulation of multiple metabolic processes. In this study, 275 of 658 Asian propolis compounds were evaluated as potential anti-T2DM agents using the DIA-DB web server towards 18 known anti-diabetes protein targets. More than 20% of all compounds could bind to more than five diabetes targets with high binding affinity (<−9.0 kcal/mol). Filtering with physicochemical and pharmacokinetic properties, including ADMET parameters, 12 compounds were identified as potential anti-T2DM with favorable ADMET properties. Six of those compounds, (2R)-7,4′-dihydroxy-5-methoxy-8-methylflavone; (RR)-(+)-3′-senecioylkhellactone; 2′,4′,6′-trihydroxy chalcone; alpinetin; pinobanksin-3-O-butyrate; and pinocembrin-5-methyl ether were first reported as anti-T2DM agents. We identified the significant T2DM targets of Asian propolis, namely retinol-binding protein-4 (RBP4) and aldose reductase (AKR1B1) that have important roles in insulin sensitivity and diabetes complication, respectively. Molecular dynamic simulations showed stable interaction of selected propolis compounds in the active site of RBP4 and AKR1B1. These findings suggest that Asian propolis compound may be effective for treatment of T2DM by targeting RBP4 and AKR1B1.

Comparison of insulin sensitivity indices for detection of double diabetes in Indian adolescents with type 1 diabetes.

The role of insulin sensitivity (IS) in the development and progression of metabolic syndrome (MS) in subjects with type-1 diabetes (T1D) is being increasingly recognized. As patients with T1D lack endogenous insulin secretion, measurement of insulin concentration by immunoassay or by indices such as homeostasis model of assessment for insulin resistance (HOMA-IR) is not helpful in assessing IS. Hence, some equations have been developed and validated against data from euglycemic-hyper-insulinemic clamp tests (the gold standard) to estimate IS. 1) To assess IS using available equations (EDC, SEARCH and CACTI) and relationship of IS with MS and microalbuminuria in adolescents with T1D, (2) To compare the predictive value of these equations for detection of MS and derive a cut-off to predict the future risk of development of MS and microalbuminuria and (3) To identify the most accurate non-invasive and easy-to-use equation for detecting patients with double diabetes (DD) in a clinical setting. This cross-sectional study included 181 adolescents aged 12-18years with T1D. Demographic data and laboratory measurements were performed using standard protocols. IS was calculated using following equations:(1) EDC=24.31-12.22×(WHR)-3.29×(hypertension)-0.57×(HbA1c), (2) SEARCH=exp(4.64725-0.02032(waist)-0.09779(HbA1c)-0.00235(Triglycerides), (3)CACTI-exA=exp(4.1075-0.01299×(waist)-1.05819×(insulin dose)-0.00354×(Triglycerides)-0.00802×(DBP)). IS determined by all three methods had significant negative correlation (p<0.05) with MS as well as with microalbuminuria. The cut-off value of 5.485mg/kg/min by SEARCH method for determining IS had the highest sensitivity and specificity in identifying MS. IS by SEARCH equation may be used in routine clinical practice to detect DD in Indian adolescents with T1D at risk of developing metabolic as well as microvascular complications.

1363-P: Remission of Type 2 Diabetes and Improvement in Incretins, Cardiovascular Risk Factors, and Weight Loss with a High-Protein Diet

The incretins GLP-1 and GIP have important roles in insulin sensitivity and have been shown to be effective in pharmacological treatment of type 2 diabetes (T2D) . Therefore, we studied these incretin level changes with remission of T2D and weight loss using a high protein (HP) diet in 12 obese women and men with T2D. Our studies have shown that subjects with T2D on a 6 month HP diet (30%protein,30%fat, 40%CHO) had 100% remission of T2D compared to only 33% on a HC diet (15%protein,30%fat, 55%CHO) . Effects of HP and HC diets on ghrelin levels were determined since HP subjects had increased satiety compared to HC diet. GLP-1, GIP, and Ghrelin levels were determined with a Meal Tolerance Test (MTT) at baseline and after 6 mo on HP and HC diets where all food was provided. Since cardiovascular risk factors (CVRF) decreased more in the HP than the HC diet, we determined if the B-Type Natriuretic Peptide (BNP) released from the heart was affected by either diet. As shown in Table, HP diet had a greater increase in GLP-1 and GIP than the HC diet. BNP decrease demonstrates improvement in heart tissue with the HP diet having a greater effect than the HC diet. Weight loss was similar (9.8% in HP vs. 11.3% in HC, p=0.692) . this study demonstrates that the HP diet increases GLP-1 and GIP which may be responsible in part for the improved insulin sensitivity and decreased BNP with greater improvement in CVRF with remission of T2D Disclosure F.B.Stentz: None. A.Ammons: None. J.V.Christman: None. Funding AD Baskin Research Grant

The Efficacy of Plant-Based Dietary Program in Patients with Diabetes: A Pilot Study

Dietary choices play a key role in insulin sensitivity among diabetes patients. An 8-week pilot study was conducted to evaluate whether a mostly plant-based dietary program will lead to improvement in biochemical markers in adults with diabetes. The dietary program included educational presentations, weekly cooking demonstrations and small group discussions. A sample of thirty-two adults with diabetes (types 1 and 2) were recruited and seventeen (53%) completed the study. Matched-pair tests and Fishers exact tests were used to compare the changes in means and proportion of the participants’ responses. There were changes in HbA1c, lipids, CRP (mg/L), cholesterol (mg/dL), HDL (mg/dL), triglycerides (mg/dL), LDL (mg/dL), non-HDL (mg/dL), Insulin (uIU/mL), AST (U/L), ALT (U/L), weight (lbs), systolic blood pressure (mmHg), diastolic (mmHg). The mean (std) age for the matched pair participant is 60.5 (11.35). Five type 1 and twelve type 2 diabetes patients showed a significant improvement in HbA1c (p = 0.001), weight (p = 0.002), intake of vegetables per day (p-value = 0.003), intake of plant-based protein (p-value &lt; 0.001) and self-reported reduction in fatigue and improvement in energy levels. Our 8-week dietary program showed an improvement in biochemical markers and positive attitudes toward the adoption of plant-based diets.

A Computational approach of phytochemicals from Bacopa monnieri in contrast to DPP-4 and peroxisome proliferator-activated receptors gamma as a Target for type-1 diabetes

Affecting the vast majority of the population, diabetes has become one of the major causes of death in India and the world. With the growing number of diabetic people in India, one in six people in the world with diabetes is from India. Bacopa monnieri is a wonder herb having many pharmacological applicaions. Traditionally, Brahmi is used to improve memory and concentration. Asthma, bronchitis, gastric ulcers, irritable bowel syndrome, anxiety, etc. DDP-4 inhibitors cause antihyperglycemic effect and regulates blood glucose. PPARs effectively regulates blood glucose levels and reduce triglycerides. The isoform of PPARs i.e., PPARγ plays a vital role in insulin sensitivity. The role of these protein receptors in treating T1DM is under research. Though few instances prove their effectiveness to treat T1DM, its efficacy is questionable and requires more research input. Branched chain and aromatic amino acids like tyrosine and glutamine have their functional role in regulating blood glucose level and onset of diabetic conditions. Bioactive ligands like Jujubogenin, bacogenin and luteolin are selected based on their interactions and binding affinity. T1DM mainly affects children and prediabetic period before the onset of T1DM provides us the golden opportunity to treat or suppress the condition through medical interventions. Thus, the ligand-macromolecule interaction and their efficacy in controlling Type-1 diabetes mellitus is the basis of this study.

Plasma epoxyeicosatrienoic acids and dihydroxyeicosatrieonic acids, insulin, glucose and risk of diabetes: The strong heart study

BackgroundEpoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid with multiple biological functions. Rodent experiments suggest EETs play a role in insulin sensitivity and diabetes, but evidence in humans is limited. To address this knowledge gap, we conducted a case-cohort study in the Strong Heart Family Study, a prospective cohort among American Indians. MethodsWe measured 4 EET species and 4 species of corresponding downstream metabolites, dihydroxyeicosatrieonic acids (DHETs), in plasma samples from 1161 participants, including 310 with type 2 diabetes. We estimated the associations of total (esterified and free) EETs and DHETs with incident diabetes risk, adjusting for known risk factors. We also examined cross-sectional associations with plasma fasting insulin and glucose in the case-cohort and in 271 participants without diabetes from the older Strong Heart Study cohort, and meta-analyzed the results from the 2 cohorts. FindingsWe observed no significant association of total EET or DHET levels with incident diabetes. In addition, plasma EETs were not associated with plasma insulin or plasma glucose. However, higher plasma 14,15-DHET was associated with lower plasma insulin and lower plasma glucose. InterpretationIn this first prospective study of EETs and diabetes, we found no evidence for a role of total plasma EETs in diabetes. The novel associations of 14,15-DHET with insulin and glucose warrant replication and exploration of possible mechanisms. FundingUS National Institutes of Health

High Expression Level of PPARγ in CD24 Knockout Mice and Gender-Specific Metabolic Changes: A Model of Insulin-Sensitive Obesity.

Background: The heat-stable HSA/CD24 gene encodes a protein that shows high expression levels in adipocyte precursor cells but low levels in terminally differentiated adipocytes. Its high expression in many types of human cancer suggests an association between cancer, diabetes, and obesity, which is currently unclear. In addition, peroxisome proliferator-activated receptor gamma (PPARγ) is a regulator of adipogenesis that plays a role in insulin sensitivity, lipid metabolism, and adipokine expression in adipocytes. Aim: To assess gender-dependent changes in CD24 KO and its association with PPARγ expression. Experimental approach: WT and CD24 KO mice were monitored from birth up to 12 months, and various physiological and molecular characteristics were analysed. Mean body weight and adipose mass were higher in KO mice than in WT mice. Male, but not female, KO mice showed increased insulin sensitivity, glucose uptake, adipocyte size, and PPARγ expression than WT mice. In addition, enteric bacterial populations, assessed through high-throughput sequencing of stool 16S rRNA genes, were significantly different between male KO and WT mice. Conclusions: CD24 may negatively regulate PPARγ expression in male mice. Furthermore, the association between the CD24 and insulin sensitivity suggests a possible mechanism for diabetes as a cancer risk factor. Finally, CD24 KO male mice may serve as a model of obesity and insulin hyper-sensitivity.

Current treatment paradigms and emerging therapies for NAFLD/NASH.

Non-alcoholic fatty liver disease (NAFLD) is one the fastest emerging manifestations of the metabolic syndrome worldwide. Non-alcoholic steatohepatitis (NASH), the progressive form of NAFLD, may culminate into cirrhosis and hepatocellular cancer (HCC) and is presently a leading cause of liver transplant. Although a steady progress is seen in understanding of the disease epidemiology, pathogenesis and identifying therapeutic targets, the slowest advancement is seen in the therapeutic field. Currently, there is no FDA approved therapy for this disease and appropriate therapeutic targets are urgently warranted. In this review we discuss the role of lifestyle intervention, pharmacological agents, surgical approaches, and gut microbiome, with regard to therapy for NASH. In particular, we focus the role of insulin sensitizers, thyroid hormone mimetics, antioxidants, cholesterol lowering drugs, incretins and cytokines as therapeutic targets for NASH. We highlight these targets aiming to optimize the future for NASH therapy.

Prokineticin receptor 1 ameliorates insulin resistance in skeletal muscle.

Type 2 diabetes mellitus may result from insulin resistance in skeletal muscle. Prokineticin receptor 1 (Prokr1) improves metabolic phenotype in adipose tissue and the cardiovascular system; however, its effects on skeletal muscle have not been investigated. We investigated the Prokr1 signaling pathways and its metabolic function in murine myoblast, satellite cells, and their differentiated myotubes. We measured the expression levels of Prokr1 in the skeletal muscle of mice as well as human skeletal muscle cell-derived myotubes. Prokineticin 2 (PROK2), a ligand of PROKR1, induced calcium mobilization in a dose-dependent manner and altered the mRNA levels of 578 genes in PROKR1-overexpressed HEK293T cells. Functional enrichment of differentially expressed genes revealed that PROKR1 activated Gq-mediated PI3K/AKT and MAPK/ERK signaling pathways in skeletal muscle cells. Prokr1 significantly activated the PI3K/AKT signaling pathway in myotubes derived from C2C12 and satellite cells, regardless of the presence or absence of insulin. Prokr1 also promoted the translocation of glucose transporter 4 (GLUT4) into the plasma membrane. In palmitate-induced insulin-resistant myotubes, Prokr1 enhanced insulin-stimulated AKT phosphorylation, GLUT4 translocation, and glucose uptake. mRNA and protein levels of Prokr1 were significantly decreased in skeletal muscle and white adipose tissue of diet-induced obese mice, and the amount of PROKR1 protein was significantly decreased in human skeletal muscle cell-derived myotubes under insulin resistance conditions. Taken together, these results demonstrate that Prokr1 plays an important role in insulin sensitivity and is a potential therapeutic target to ameliorate insulin resistance in skeletal muscle.