Increased Insulin Sensitivity Research Articles

Optimal exercise combinations for patients with diabetes.

Exercise is a key way to control the blood glucose, which can improve blood lipids and blood pressure, reduce glycated hemoglobin levels, and increase insulin sensitivity. It is of great significance for maintaining blood glucose homeostasis. This study aims to explore the optimal exercise combinations suitable for diabetic patients, and to provide scientific and effective personalized exercise guidance for diabetic patients. The physical examination data and questionnaire results of were collected from the Third Xiangya Hospital of Central South University. The study was involved in 3 867 diabetes from January, 2020 to December, 2021. The basic information and living habits were obtained through questionnaires. The fasting blood samples were collected to measure the levels of total cholesterol (TCh), triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and fasting blood glucose. Physical measurements included height, weight, waistline, hipline, and blood pressure. Categorical variables were tested using chi-square tests, and continuous variables were tested using non-parametric Kruskal-Wallis test. Multiple linear regression model was used to analyze the relationship between exercise behaviors (frequency, duration, and intensity), years of exercise, diet habits, medicine, and fasting blood glucose. The relationship between different exercise behaviors and various indexes (BMI, blood pressure, blood lipids, blood glucose) was analyzed by multiple rising sun rose plots. The polar thermal diagram showed the relationship of exercise behaviors with the best expected effect. Non-parametric Kruskal-Wallis test showed that there were significant differences in other indexes except LDL-C (P=0.681) among groups with different exercise behaviors (all P<0.01). The multiple rising sun rose plots showed that diabetic patients who did moderate to high intensity exercise more than 5 times a week for more than 30 min each time had a healthier BMI, blood lipid levels, blood glucose levels, and blood pressure. Polar thermal diagram showed that low-intensity exercise once or twice a week requires 30 to 60 min or more of exercise to achieve the desired results. Multiple linear regression analysis showed that frequency (β=-0.208, 95% CI -0.356 to -0.059, P=0.006), duration (β=-0.227, 95% CI -0.387 to -0.066, P=0.006), intensity of exercise (β=-0.110, 95% CI -0.218 to -0.002, P=0.046), diet habits (β=0.462, 95% CI 0.295 to 0.556, P<0.001) and medicine (β=-0.520, 95% CI -0.720 to -0.312, P<0.001) were correlated with fasting blood glucose. Moderate to high intensity exercise for more than 30 min and 5 times a week is the most beneficial combination for diabetes. Low exercise intensity should be combined with higher exercise frequency and longer exercise time to achieve the desired effect. With the increase of exercise intensity, the relationship between low exercise frequency and long exercise time is weakened.

Anti-diabetics and the Prevention of Dementia: A Systematic Review.

Type 2 diabetes mellitus (T2DM) is a worldwide epidemic that is only increasing as the years progress, and as of 2019, affecting over 37 million. T2DM is a chronic condition caused by reduced insulin secretion and increased insulin resistance. Due to insulin not operating at optimal conditions, blood glucose rises and remains high, thus disturbing metabolic hemostasis. Many complications can arise from T2DM, such as coronary vascular disease, kidney damage, eye damage, and, quite significantly, dementia. It is theorized that dementia from T2DM stems from the fact that the brain is susceptible to hyperglycemic conditions, which are promoted by the increase in insulin resistance of target cells in the central nervous system. This directly affects cognitive processes and memory, which correlates to decreased temporal and front lobes volume. The risk of diabetic complications can be minimized with therapeutic interventions such as oral-antidiabetic (OAD) agents and insulin. Several OADs are on the market, but the first-line agent is metformin, a biguanide that decreases glucose production and increases insulin sensitivity. This paper aims to determine if currently prescribed OADs can help slow cognitive decline and reduce the risk and incidence of dementia as a complication of T2DM. Studies found that, for the most part, all OADs except sulfonylureas (SU) significantly slowed the decline of cognitive function and reduced the risk and incidence of dementia. SU's were shown to increase the risk of dementia in most studies. Of all the OADs, thiazolidinediones may be the most beneficial drug class for reducing the risk of dementia in T2DM patients. Future research should focus on whether early intervention with specific classes of OADs can not only improve glycemic control, leading to decreased hyperglycemia but also prevent the build-up of damaged brain tissue and help to reduce the risk and incidence of dementia in patients with T2DM.

Analysing uric acid levels to assess the effectiveness of dapagliflozin

Sodium-glucose cotransporter-2 inhibitors are an innovative diabetes treatment that lowers blood sugar levels without insulin. A growing body of evidence suggests that blood sugar levels are tightly correlated with uric acid levels in their blood and urine. To alleviate type 2 diabetes (T2DM) suffering, we tested dapagliflozin on serum and urinary uric acid levels of patients with T2DM and measured its efficacy in reducing uric acid levels. A study was conducted on 60 people with T2DM. Patients were treated with Dapagliflozin doses of 10mg daily for 3 months. Three months later, we measured body weight, fasting, and postprandial blood glucose levels, Hemoglobin A1C (HbA1c), serum lipids, renal function tests, routine urine, and serum uric acid. A number of clinical parameters of T2DM patients were compared to those of healthy subjects of the same age group. A comprehensive analysis of all parameters was conducted to evaluate dapagliflozin's impact. After 90 days of dapagliflozin treatment, serum uric acid levels dropped significantly from 9.0 to 8mg/dL in the dapagliflozin group, as well as uric acid percentage in urine changed from 16.1 to 23.6%. After three months of treatment, HbA1C levels decreased from 9.8% to 8.5%. Following treatment with dapagliflozin, the patients' Homeostatic Model Assessment for Insulin Resistance decreased to 4.0. Further, multivariate correlation analysis showed a correlation of serum uric acid with glycemic profile positively. In conclusion, dapagliflozin lowers uric acid levels and increases insulin sensitivity in diabetic patients to improve their glycemic control.

Browning of white adipose tissue may be an appropriate adaptive response to critical illness.

Both the baseline amount of brown adipose tissue (BAT) and the capacity to stimulate browning of white adipose tissue (WAT) may provide a protective effect to the patient in a critical care setting. Critical illness is associated with reduced mitochondrial volume and function resulting in the increased production of reactive oxygen species, greater demand for adenosine triphosphate, a switch to uncoupled fat metabolism, and hibernation of the organelle, which all contribute to multiple organ failure. Increasing insulin resistance, decreasing fatty acid oxidation, and dependence on carbohydrate metabolism result. Browning of WAT may oppose many of these adverse effects. The presence of BAT and the changes associated with browning may help dissipate oxidative stress, increase consumption and utilization of metabolites, and reduce pro-inflammatory actions. The number of mitochondria increases, and there is greater infiltration of macrophages into adipose tissue. A shift occurs in macrophage expression from the M1 to M2 phenotype, an effect which further dampens inflammation, increases insulin sensitivity, and improves tissue healing and remodeling. Any benefit from these responses may be lost in the disease states of chronic hypermetabolism (such as burns or cancer cachexia) in which the persistence of these physiologic effects may become detrimental, contributing to excessive weight loss, adipose wasting, and loss of lean body mass. This paper discusses the plasticity of adipose tissue and whether shifts in its physiology provide clinical advantages in the intensive care unit.

Antioxidant and Hypoglycemic Potential of Essential Oils in Diabetes Mellitus and Its Complications.

Since the earliest times, essential oils (EOs) have been utilized for medicinal and traditional purposes. However, in recent decades, an increasing interest has developed due to the need to rediscover herbal remedies and adjuvant therapies for the management of various diseases, particularly chronic ones. The present narrative review examines the potential for EOs to exert hypoglycemic and antioxidant effects in diabetes mellitus, analyzing the main publications having evaluated plant species with potentially beneficial effects through their phytocompounds in diabetes mellitus and its complications. Numerous species have shown promising characteristics that can be used in diabetes management. The hypoglycemic effects of these EOs are attributed to their capacity to stimulate glucose uptake, suppress glucose production, and increase insulin sensitivity. Moreover, EOs can alleviate the oxidative stress by manifesting their antioxidant effects via a variety of mechanisms, including the scavenging of free radicals, the regulation of antioxidant enzymes, and the decreasing of lipid peroxidation, due to their diverse chemical composition. These findings demonstrate the possible benefits of EOs as adjuvant therapeutic agents in the management of diabetes and its complications. The use of EOs in the treatment of diabetes shows good potential for the development of natural and effective strategies to enhance the health outcomes of people with this chronic condition, but additional experimental endorsements are required.

Planting a path to kidney health: The vegetarian diet and diabetic nephropathy

Abstract About 40% of people with diabetes experience diabetic nephropathy (DN), which is the main cause of renal problems. The aberrant urine albumin excretion rate, diabetic glomerular lesions, and a reduction in glomerular filtration rate are its defining characteristics. Numerous studies have found a strong link between eating animal protein and conditions like glucagon activation, insulin resistance, proteinuria, microalbuminuria, and the worsening of kidney problems in diabetic individuals. A vegan diet, which forgoes all animal products including leather and other non-edibles like fish, shellfish, and insects as well as dairy, eggs, and honey, has demonstrated significant benefits. It has been connected to enhanced insulin sensitivity, less glucagon activation, a decreased risk of developing chronic kidney disease (CKD), and a slowed rate of DN progression. According to several studies, avoiding animal products and switching to plant-based protein sources can be a better nutritional plan than simply limiting dietary protein. This change may prove very helpful in reducing the risk of kidney and cardiovascular illnesses, especially for those who have diabetes and severe insulin resistance in addition to CKD. A vegan diet contains considerable benefits for those with diabetes and CKD, acting as a brake on the advancement of DN and renal failure, according to the literature evaluation done for this study. Nevertheless, more interventional studies involving humans are needed to elucidate the processes underlying the increased insulin sensitivity brought on by vegan diets. It is also advised to conduct more research to fully explore the effectiveness and security of vegan diets in people with diabetes and DN.

Single anastomosis duodeno-ileal bypass with sleeve gastrectomy generates sustained improvement of glycemic control compared with sleeve gastrectomy in the diet-induced obese rat model.

Bariatric surgery has become a recognized and effective procedure for treating obesity and type 2 diabetes (T2D). Our objective was to directly compare the caloric intake-independent effects of sleeve gastrectomy (SG) and single anastomosis duodenoileal bypass with SG (SADI-S) on glucose tolerance in rats with diet-induced obesity (DIO) and to elucidate the differences between bariatric surgery and caloric restriction.A total of 120 adult male Wistar rats with DIO and insulin resistance were randomly assigned to surgical (sham operation, SG, and SADI-S) and dietary (pair-feeding the amount of food eaten by animals undergoing the SG or SADI-S surgeries) interventions. Body weight and food intake were weekly monitored, and 6weeks after interventions, fasting plasma glucose, oral glucose and insulin tolerance tests, plasma insulin, adiponectin, GIP, GLP-1, and ghrelin levels were determined.The body weight of SADI-S rats was significantly (p < 0.001) lower as compared to the sham-operated, SG, and pair-fed groups. Furthermore, SADI-S rats exhibited decreased whole body fat mass (p < 0.001), lower food efficiency rates (p < 0.001), and increased insulin sensitivity, as well as improved glucose and lipid metabolism compared to that of the SG and pair-fed rats.SADI-S was more effective than SG, or caloric restriction, in improving glycemic control and metabolic profile, with a higher remission of insulin resistance as well as long-term weight loss.

A Propolis-Derived Small Molecule Tectochrysin Ameliorates Type 2 Diabetes in Mice by Activating Insulin Receptor β.

Propolis has been found to decrease glucose levels and increase insulin sensitivity in type 2 diabetes. However, the active ingredient responsible for these effects and its regulating mechanism are not fully understood. To address this, molecular docking screening is used to screen the effective hypoglycemic ingredient in propolis and found that tectochrysin (TEC) has a high affinity to the insulin receptor (IR), highlighting its potential for glycemic control. In vivo tests show that TEC decreases glucose levels and enhances insulin sensitivity in db/db mice. By hyperinsulinemic euglycemic clamp test, this study further finds that TEC promotes glucose uptake in adipose tissue and skeletal muscle, as well as inhibits hepatic gluconeogenesis. Moreover, it finds that TEC promotes glucose uptake and adipocytes differentiation in 3T3-L1 cells like insulin, suggesting that TEC exerts an insulin mimetic effect. Mechanistically, pharmacology inhibition of IRβ abolishes the effects of TEC on glucose uptake and the phosphorylation of IR. The study further demonstrates that TEC binds to and activates IRβ by targeting its E1077 and M1079. Therefore, this study sheds light on the mechanism underlying propolis' potential for ameliorating type 2 diabetes, offering a natural food-derived compound as a promising therapeutic option.

Vitamin B12-Induced Autophagy Alleviates High Glucose-Mediated Apoptosis of Islet β Cells.

High glucose levels can lead to the apoptosis of islet β cells, while autophagy can provide cytoprotection and promote autophagic cell death. Vitamin B12, a water-soluble B vitamin, has been shown to regulate insulin secretion and increase insulin sensitivity. However, the precise mechanism of action remains unclear. In this study, we investigated the influence of vitamin B12 on high glucose-induced apoptosis and autophagy in RIN-m5F cells to elucidate how vitamin B12 modulates insulin release. Our results demonstrate that exposure to 45 mM glucose led to a significant increase in the apoptosis rate of RIN-m5F cells. The treatment with vitamin B12 reduced the apoptosis rate and increased the number of autophagosomes. Moreover, vitamin B12 increased the ratio of microtubule-associated protein 1 light chain 3 beta to microtubule-associated protein 1 light chain 3 alpha (LC3-II/LC3-I), while decreasing the amount of sequestosome 1 (p62) and inhibiting the phosphorylation of p70 ribosomal protein S6 kinase (p70S6K) under both normal- and high-glucose conditions. The additional experiments revealed that vitamin B12 inhibited high glucose-induced apoptosis. Notably, this protective effect was attenuated when the autophagy inhibitor 3-methyladenine was introduced. Our findings suggest that vitamin B12 protects islet β cells against apoptosis induced by high glucose levels, possibly by inducing autophagy.

Lunasin ameliorates glucose utilization in C2C12 myotubes and metabolites profile in diet-induced obese mice benefiting metabolic disorders

AimsObesity is the main cause of low-grade inflammation and oxidation, resulting in insulin resistance. This study aimed to investigate the effects of a seed peptide lunasin on glucose utilization in C2C12 myotubes and the metabolite profiles in obese mice. Main methodsC2C12 myotubes were challenged by palmitic acid (PA) to mimic the obese microenvironment and inflammation, cell vitality, and glucose utilization were determined. C57BL6/j mice were divided into low-fat diet (LF), high-fat diet (HF), and HF with intraperitoneally injected lunasin (HFL) groups. Glucose intolerance and metabolite profiles of the tissues were analyzed. Key findingsIn vitro, C2C12 myotubes treated with lunasin showed decreased proinflammatory cytokines and increased cell vitality under palmitic acid conditions. Lunasin improved glucose uptake and glucose transporter 4 expression by activating insulin receptor substrate-1 and AKT phosphorylation. Next-generation sequencing revealed that lunasin regulates genes expression by promoting insulin secretion and decreasing oxidative stress. In vivo, HF mice showed increased tricarboxylic acid cycle and uric acid metabolites but decreased bile acids metabolites and specific amino acids. Lunasin intervention improved glucose intolerance and modulated metabolites associated with increased insulin sensitivity and decreased metabolic disorders. SignificanceThis study is the first to reveal that lunasin is a promising regulator of anti-inflammation, anti-oxidation, and glucose utilization in myotubes and ameliorating glucose uptake and metabolite profiles in obese mice, contributing to glucose homeostasis and benefiting metabolic disorders.

Exploration of the main active metabolites from Tinospora crispa (L.) Hook. f. & Thomson stem as insulin sensitizer in L6.C11 skeletal muscle cell by integrating in vitro, metabolomics, and molecular docking

Ethnopharmacological relevanceTinospora crispa (L.) Hook. f. & Thomson stem (TCS) has long been used as folk medicine for the treatment of diabetes mellitus. Previous study revealed that TCS possesses multi-ingredients and multi-targets characteristic potential as insulin sensitizer activity. However, its mechanisms of action and molecular targets are still obscure. Aim of the studyIn the present study, we investigated the effects of TCS against insulin resistance in muscle cells through integrating in vitro experiment and identifying its active biomarker using metabolomics and in molecular docking validation. Materials and methodsWe used centrifugal partition chromatography (CPC) to isolate 33 fractions from methanolic extract of TCS, and then used UHPLC-Orbitrap-HRMS to identify the detectable metabolites in each fraction. We assessed the insulin sensitization activity of each fraction using enzyme-linked immunosorbent assay (ELISA), and then used confocal immunocytochemistry microscopy to measure the translocation of glucose transporter 4 (GLUT4) to the cell membrane. The identified active metabolites were further simulated for its molecular docking interaction using Autodock Tools. ResultsThe polar fractions of TCS significantly increased insulin sensitivity, as measured by the inhibition of phosphorylated insulin receptor substrate-1 (pIRS1) at serine-312 residue (ser312) also the increasing number of translocated GLUT4 and glycogen content. We identified 58 metabolites of TCS, including glycosides, flavonoids, alkaloids, coumarins, and nucleotides groups. The metabolomics and molecular docking simulations showed the presence of minor metabolites consisting of tinoscorside D, higenamine, and tinoscorside A as the active compounds. ConclusionsOur findings suggest that TCS is a promising new treatment for insulin resistance and the identification of the active metabolites in TCS could lead to the development of new drugs therapies for diabetes that target these pathways.

SAT415 Development Of A Novel, Preclinical Swine Model Of Transgender Men To Assess Testosterone Impact On Insulin Sensitivity And Whole-Body Metabolism

Abstract Disclosure: N. Mahabir: None. I. Ahmad: None. T. Wright: None. G. Ten Have: None. N. Deutz: None. A.E. Newell-Fugate: None. The effects oftestosterone therapy on peripheral insulin sensitivity in transgender men areequivocal due to heterogeneity of the population, short term patientfollow-up, and small cohort sizes. Most research has found testosterone therapyto decrease or have no effect on insulin sensitivity, but in one studytransgender men had increased insulin sensitivity. We have found thatshort-term, virilizing doses of testosterone in female pigs suppress circulatinginsulin levels. The objective of the current study was to develop a long-term,preclinical model of transgender men to assess insulin sensitivity and whole-bodymetabolism. A swine model of transgender men is superior to other models,because pigs closely mimic human cardiometabolic physiology and their largebody size permits longitudinal sampling and interventional procedures. Togenerate stable, long-term serum testosterone (TEST) concentrations in femalepigs, we fabricated testosterone silastic implants at the following doses:placebo (30 mm, n=1) or 15 mm (n=2), 30 mm (n=2), 60 mm (n=2), or 120 mm (n=1)TEST. Eight sexually mature female pigs were administered 14 days of progestin(Altrenogest) which was withdrawn on day 15. On day 16, 400 I.U. of pregnantmare serum gonadotropin and 200 I.U of human chorionic gonadotropin (PG600®,Merck Animal Health) were administered intramuscularly to stimulatefolliculogenesis and ovulation. Pigs had estrus detection performed dailythroughout the study and came into estrus 3-7 days post PG600® injection.Twenty-four hours post-estrus, implants were surgically placed subcutaneously,blood was taken, and biopsies of subcutaneous white adipose tissue werecollected from the incision site for baseline assessment of mitochondrialoxygen flux (Oroboros) and proteomic measurement of mitochondrial and insulinpathway abundance. After implant placement, fasted blood was collected at 24,48, 72 hours and every three days thereafter for six weeks. During weeks 2-6post-implantation, continuous glucose monitoring was performed (Freestyle Libre3). Twenty-four hours prior to study completion, a catheter was placed in thecranial vena cava and an intravenous glucose tolerance test was performed (0,5, 10, 20, 30, 40, 50, 60 min). The next morning fasted blood was collected (time0) and a stable isotopic tracer bolus was administered to measure whole bodyproduction of glycerol, branched chain amino acids, branched chain keto acids, and β-hydroxyβ-methylbutyric acid. After tracer bolus, blood was collected at 10, 20, 40, 60and 120 minutes. At 120 minutes post-bolus, tissues were collected for isotopiccompound measurement, mitochondrial function assays, and insulin signalingpathway assessment. This translational swine model will help uncover themechanistic effects of testosterone therapy on insulin sensitivity and whole-bodymetabolism in female to male transitioning patients. Presentation: Saturday, June 17, 2023

THU128 Transcription Factor ETV5 In POMC Neurons Regulate Energy And Glucose Homeostasis

Abstract Disclosure: S. Gahlot: None. A. Caron: None. S. Lee: None. J.K. Elmquist: None. Pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARH) are critical for the regulation of energy balance and glucose homeostasis. Pomc gene transcription is regulated by the Erythrocyte Transformation Specific (ETS)-domain transcription factors, including Etv1, Etv2, Etv4, and Etv5. Large-scale genome-wide association studies have identified ETV5 genetic variants linked with human obesity and body mass index. Histological studies in adult mouse pituitaries also show the co-localization of ETV5 with POMC and POMC-derived peptides: adrenocorticotropic hormone (ACTH) and alpha-melanocyte stimulating hormone (α-MSH). Furthermore, whole-body Etv5 knockout mice are lean, severely glucose intolerant and hypoinsulinaemic. While these findings suggest a potential role for Etv5 in the control of energy and glucose balance, the role of Etv5 remains unknown. This study aims to determine whether ETV5 binds to the Pomc promoter to alter its expression and regulate energy balance and glucose homeostasis. To assess whether ETV5 binds to the Pomc promoter, we performed chromatin immunoprecipitation with quantitative real-time PCR (ChIP-qPCR) in C57BL/6J mice. ChIP-qPCR determined that Etv5 directly binds to the Pomc promoter. We further performed luciferase reporter assay in mouse neuroblastoma N2a cell lysates to measure the Pomc promoter activity after Etv5 knockdown or overexpression. Luciferase assay revealed that Etv5 knockdown increased, while Etv5 overexpression reduced the Pomc promoter activity in N2a cells. Also, Etv5 overexpression blocked the leptin-induced POMC activation. Further, to determine the role of Etv5 in POMC neurons to regulate energy balance and glucose homeostasis, we used the Cre/loxP system to selectively delete Etv5 from POMC neurons both prenatally and postnatally. Mice were fed either a standard chow or a 60% high-fat diet (HFD), followed by serial body weight, food intake, body composition, metabolic assessment, glucose tolerance and insulin tolerance test measurements. We found that mice with a prenatal deletion of Etv5 in POMC neurons had reduced body weight, reduced lean mass, and were protected from HFD-induced insulin resistance. Similarly, postnatal deletion of Etv5 in POMC neurons resulted in reduced body weight, lean mass and fat mass, and increased insulin sensitivity and energy expenditure in mice of 8 weeks age. We also performed electrophysiological recordings in hypothalamic slices from these mice to assess POMC neuron excitability. We found that loss of Etv5 increased the activity and electrical excitability of POMC neurons. These findings highlight a previously unrecognized role of Etv5 in POMC neurons in the regulation of energy balance and glucose homeostasis. These results also point to the potential therapeutic applications for Etv5 against obesity. Presentation: Thursday, June 15, 2023

THU512 Elevated Insulin Like Growth Factor Binding Protein 2 Levels Are Associated With Muscle Wasting And Increased Insulin Sensitivity In Cancer Patients

Abstract Disclosure: L. Caeiro: None. L.J. Anderson: None. H. Liu: None. K. Krumm: None. J.M. Garcia: None. Cancer-associated weight loss is a complex metabolic syndrome characterized by a loss of skeletal muscle mass and function. Insulin resistance is present in cancer but its role in cancer-related muscle wasting is poorly understood. Recent data from in vitro and animal models show that tumor-derived insulin-like growth factor binding protein (IGFBP)-2 can lead to skeletal muscle wasting and insulin resistance in cancer. We hypothesized that muscle mass and function would be inversely associated with IGFBP-2 levels and insulin resistance in circulation. IGFBP-2, physical function, body composition, insulin and glucose (to calculate HOMA-IR), quality of life (QOL), and cytokines were assessed in male cancer patients with (CWL, n=25) or without (CWS, n=47) weight loss. Physical Function was assessed by hand grip strength (HGS), stair climb power (SCP), and one repetition maximum (1RM) tests of the major muscle groups. Body composition was measured by bioimpedance (BIA) and CT scans and QOL by Karnofsky and ECOG scores. Blood samples were obtained after an overnight fast to measure IGFBP-2, insulin, glucose, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in plasma. CWL had higher plasma IGFBP2 levels (p = 0.01) and lower skeletal muscle index (SMI) (p = 0.03) and body mass index (BMI) (p = 0.007) when compared to CWS, but no differences were found with SCP, HGS, 1RM tests, or with HOMA-IR. IGFBP2 was negatively correlated with SMI (N = 65, R² = -.58, P = &amp;lt;0.001), BMI (N=73, R² = -.54, P = &amp;lt;0.001), CT-derived muscle mass (N = 48, R² = -.56, P = &amp;lt;0.001), BIA fat percent, (N = 25, R² = -.56, P = 0.005), 6 month weight change (N = 73, R² = -.27, P = 0.020), 12 month weight change (N = 73, R² = -.24, P = 0.044), insulin (N = 53, R² = -.48, P = &amp;lt;0.001) ,and HOMA IR (N = 53, R² = -.51, P = &amp;lt;0.001) and positively correlated with IL-6 (N = 72, R² = .33, P = 0.005) and TNF-α (N = 72, R² = .27, P = 0.021) in cancer patients. HOMA-IR was positively correlated with SMI (N = 31, R² = .39, P = 0.029), CT-derived muscle mass (N = 31, R² = .38, P = 0.036), and BIA fat percent (N = 21, R² = .62, P = 0.003). No association was found with IGFBP2 and QOL, SCP, HGS or the other functional parameters with exception of Knee Extension (N = 26, R² = .39, P = 0.049). In conclusion, cancer weight losing patients have increased IGFBP2 levels that were associated with muscle wasting, decreased fat mass, weight loss, and elevated IL-6 and TNF-α. HOMA-IR was negatively correlated with IGFBP2 and positively correlated with muscle mass. We postulate that a decrease in fat mass seen in weight-losing cancer patients leads to an increase in insulin sensitivity. More studies are needed to test this hypothesis and establish the role of IGFBP-2 as a mediator of muscle wasting in cancer. Presentation: Thursday, June 15, 2023

FRI417 An Interdisciplinary Program Promoting The Adoption Of A Healthy Lifestyle Increases Insulin Sensitivity In Women With Obesity And Infertility

Abstract Disclosure: A. Forget-Renaud: None. M. Belan: None. F. Jean-Denis: None. M. Pesant: None. J. Baillargeon: Grant Recipient; Self; Ferring Pharmaceuticals, JPB received an unrestricted investigator-initiated grant from Ferring Canada, which was not for the reported study. Introduction Obesity increases the risk of ovulatory and anovulatory infertility in women, mainly through the development of polycystic ovary syndrome (PCOS). Insulin resistance contributes to the pathogenesis of PCOS and may play a role in the infertility of PCOS and non-PCOS women with overweight or obesity. Lifestyle modifications are recommended as a first-line therapy in women with PCOS or those with obesity and infertility, as it was associated with improvement in menstrual pattern and fertility outcomes. We therefore hypothesized that a lifestyle intervention may increase insulin sensitivity in women with obesity and infertility. Methods Women with obesity and infertility were randomly allocated to usual fertility care (control group, CG) or to an interdisciplinary intervention promoting the adoption of a healthy lifestyle (LSG) alone for 6 months and then combined with usual care. Insulin resistance was estimated during fasting (HOMA-IR) and a 75-g oral glucose test (Matsuda Insulin Sensitivity Index, ISI(M)), and β-cell function was estimated using the Insulin Secretion-Sensitivity Index (ISSI-2) in women not taking medication affecting insulin sensitivity (except metformin). Data were collected at baseline, 6, 12 and 18 months, and as soon as possible when the participant knew she was pregnant. We estimated the integrated change in insulin sensitivity during follow-up using the incremental area-under-the-curve of ISI(M) divided by time (iAUC-ISI(M)/time). Results Among 130 randomized participants, 105 had available data (LSG=51, CG=54). PCOS was diagnosed using the Rotterdam criteria in 63.2% of participants, equally distributed between the groups. As compared to CG, women in the LSG improved significantly more their ISI(M) after 6 months (+0.24 [IQR: -0.48 - +0.94] vs 0.16 [-1.32 - +0.53], p=0.039, n=90), as well as their iAUC-ISI(M)/time during follow-up (+0.18±0.84 vs -0.21±0,93, p=0.035, n=104). All these results remained statistically significant after correction for baseline BMI, age and use of folic acid. Increases in iAUC-ISI(M)/time in the intervention vs control groups were significantly more important (p for interaction=0.045) in participants with baseline ISI(M) above the median (LSG: +0.10±1.13, n=24, vs CG: -0.62±1.13, n=27, p=0.028) than in those below the median (LSG: +0.26±0.48, n=27, vs CG: +0.21±0.35, n=26, p=0.71). Interactions with PCOS status and other subgroups were not statistically significant. There was no impact on HOMA-IR or ISSI-2. Conclusion An interdisciplinary program promoting the adoption of a healthy lifestyle significantly increases whole-body insulin sensitivity in women with infertility and obesity, mainly in those with higher baseline insulin sensitivity. It may be explained in part by the weight loss associated with the intervention and may have a role in improving fertility in this population. Presentation: Friday, June 16, 2023

THU637 The Effects Of Polyphenol On Insulin Resistance And Hormonal Parameters On Women With Polycystic Ovary Syndrome: A Systematic Review And Meta-analysis Of Randomized Controlled Trials

Abstract Disclosure: C.A. Balieiro: None. L.C. Hespanhol: None. M. Araújo Freitas: None. L. Lima de Oliveira: None. Introduction: Polycystic ovary syndrome (PCOS) is an endocrinopathy with a high prevalence in women of reproductive age. This syndrome is characterized by ovarian cysts, anovulation, infertility, skin disorders, increased Body Mass Index (BMI), insulin resistance, and altered hormone levels. The most commonly affected hormones include testosterone, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and insulin. Different treatments have been tested to increase insulin sensitivity and hormone regulation, and recently polyphenols have emerged as a promising option for these women. We aimed to perform a systematic review and meta-analysis of randomized clinical trials (RCTs) comparing polyphenols to placebo in women with PCOS. Methods: The PubMed, Cochrane, and Embase databases were searched for RCTs comparing polyphenols to placebo. Data were extracted from published reports, and quality assessment was performed according to PRISMA guidelines. Endpoints included were: changes in levels of serum insulin, changes in BMI, LH, and testosterone levels. We used a random-effects model to calculate the Mean Difference (MD), Standardized Mean Difference (SMD), and 95% confidence interval (CI). Heterogeneity was examined with the Cochrane Q test and I² statistics: p values inferior to 0.05 and I² &amp;gt; 25% were considered significant for heterogeneity. Results: A total of 15 studies involving 916 patients were included. Of all participants, 445 (49%) received polyphenols. Polyphenols resulted in a significant decrease in serum insulin level (MD -2.49 [-3.72, -1.25] 95% CI; p &amp;lt; 0.0001, I² = 64%), in comparison to placebo. In addition, BMI levels were significantly reduced in patients treated with polyphenols when compared to placebo (MD -0.12 [-0.18, -0.06] 95% CI; p = 0.0002, I² = 0%). There was a reduction in LH levels in the intervention group, when compared with the baseline levels to the final levels (MD -0.87 [-1.54, 0.20] 95% CI; p = 0.01, I² = 46%). The decrease in testosterone levels was not significantly different when comparing polyphenols and placebo (SMD -0.14 [-0.53, 0.25] 95% CI; p = 0.48, I² = 73%). Conclusion: This meta-analysis provided evidence of the effectiveness of polyphenols in reducing serum insulin, LH and BMI in women with polycystic ovary syndrome compared to placebo. There was no statistically significant difference in the reduction of testosterone levels between polyphenols and placebo. This study represents the most current evidence on this promising treatment. Presentation: Thursday, June 15, 2023

SAT092 A Case Of Mature Onset Diabetes Of The Young

Abstract Disclosure: L. Beshay: None. A. Thakkar: None. Background: Maturity onset diabetes of the young (MODY) is a disorder characterized by noninsulin-dependent diabetes diagnosed at a young age (&amp;lt;25 years) with autosomal dominant inheritance and lack of autoantibodies. It accounts for 2 to 5 percent of diabetes cases. Several different genetic abnormalities have been identified causing disruption in pancreatic beta cells development and function leading to impaired insulin secretion. Mutations in hepatocyte nuclear factor-1-alpha (HNF1A) is the most commonly identified mutation occurring in 52 to 65 of MODY cases. Case Description: A 21 year old female with a history of diabetes and recurrent skin abscesses presented to the emergency room with right lower quadrant epidermal abscess. Endocrinology was consulted for evaluation of her diabetes. She was diagnosed at age 14 when she presented with weight loss, polyuria, polydipsia, BG 406 without diabetic ketoacidosis. She reported a history of type 2 diabetes in mother. Her medications included metformin, lantus and humalog. It was noted that her diabetes was never controlled with an A1c persistently &amp;gt;10%. Patient reported skin swelling with insulin injections and working two jobs which limited her ability to take more than one injection per day. Her BMI is 23 kg/m2. Labs this admission showed HbA1c 13.7%, GAD 65 Ab and IA-2 Ab negative, c-peptide 1.1 ng/ml, with a glucose of 209 mg/dl. MODY was suspected due to her age, intact c-peptide, and lack of DM1 antibodies. The patient was discharged on Trulicity 0.75 mg weekly, Lantus 12U nightly, Glipizide 2.5mg daily. On follow up, a MODY genetic panel confirmed a HNF1A missense variant with AD inheritance. Since initiation of sulfonylurea, she has had improved control of diabetes. Glipizide dose is being titrated up with concomitant decrease in insulin dose with plan to discontinue basal insulin once her blood sugars are at goal. Conclusion: The HNF1A gene on chromosome 12 is a weak transactivator of the insulin gene in beta cells. Mutations of HNF1A can lead to abnormal insulin secretion and a low renal threshold for glucose. These patients are at risk for micro- and macrovascular complications of diabetes. In terms of treatment, they exhibit increased insulin sensitivity and marked sensitivity to the hypoglycemic effects of sulfonylureas compared with patients with type 2 diabetes. Thus, patients can be successfully treated with sulfonylurea monotherapy, and in one clinical study, approximately 70 percent of patients previously treated with insulin successfully switched to sulfonylureas. Thus, it is important to evaluate etiology of diabetes, as detection of MODY variants in which sulfonylureas are used for treatment simplifies management and improves outcomes as demonstrated in this case. Presentation: Saturday, June 17, 2023

Esculin ameliorates obesity-induced insulin resistance by improving adipose tissue remodeling and activating the IRS1/PI3K/AKT/GLUT4 pathway

Ethnopharmacological relevanceCortex fraxini (also known as qinpi)—the bark of Fraxinus rhynchophylla Hance (Oleaceae)—is widely used as a Chinese traditional medicinal for its anti-inflammatory and anti-hyperuricemic activities. Aim of the studyObesity-induced insulin resistance (IR) is driving the rising incidence of type 2 diabetes mellitus and is related to pathological adipose tissue remodeling. Esculin, a major active component of Cortex fraxini, has anti-diabetic effects. However, whether esculin improves obesity-induced IR by regulating adipose tissue remodeling is unclear. The aims of the present study were to assess the effects of esculin on obesity-induced IR and to explore the underlying mechanisms. Materials and methodsObese IR C57BL/6J mice were treated with esculin (40 or 80 mg/kg/day) for 4 weeks. Oral glucose tolerance tests were used to assess insulin sensitivity. Histological analyses were performed to analyze the number and size distribution of adipocytes. Glucose uptake was assessed using 2-NBDG. ResultsEsculin had no effect on body weight gain but reduced fasting blood glucose, improved oral glucose tolerance, and increased insulin sensitivity. Esculin reduced adipocyte size and the expression levels of collagen 4A1 and tumor necrosis factor α and increased the number of adipocytes and the expression of vascular endothelial growth factor A. Esculin promoted the differentiation of 3T3-L1 cells and upregulated the mRNA expression of CCAAT/enhancer-binding protein α and peroxisome proliferator-activated receptor-γ, activated the insulin receptor substrate 1 (IRS1)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, and enhanced the translocation of glucose transporter type 4 (GLUT4) and glucose uptake in adipocytes treated with palmitic acid. ConclusionsThese data suggest that esculin increases insulin sensitivity by improving adipose tissue remodeling and activating the IRS1/PI3K/AKT/GLUT4 pathway.

Status and physiological significance of circulating adiponectin in the very old and centenarians: an observational study.

High levels of circulating adiponectin are associated with increased insulin sensitivity, low prevalence of diabetes, and low body mass index (BMI); however, high levels of circulating adiponectin are also associated with increased mortality in the 60-70 age group. In this study, we aimed to clarify factors associated with circulating high-molecular-weight (cHMW) adiponectin levels and their association with mortality in the very old (85-89 years of age) and centenarians. The study included 812 (women: 84.4%) for centenarians and 1498 (women: 51.7%) for the very old. The genomic DNA sequence data were obtained by whole-genome sequencing or DNA microarray-imputation methods. Least Absolute Shrinkage and Selection Operator (LASSO) and multivariate regression analyses were used to evaluate cHMW adiponectin characteristics and associated factors. All-cause mortality was analyzed in three quantile groups of cHMW adiponectin levels using Cox regression. The cHMW adiponectin levels were increased significantly beyond 100 years of age, were negatively associated with diabetes prevalence, and were associated with SNVs in CDH13 (p=2.21 × 10-22) and ADIPOQ (p=5.72 × 10-7). Multivariate regression analysis revealed that genetic variants, BMI, and high-density lipoprotein cholesterol (HDLC) were the main factors associated with cHMW adiponectin levels in the very old, whereas the BMI showed no association in centenarians. The hazard ratios for all-cause mortality in the intermediate and high cHMW adiponectin groups in very old men were significantly higher rather than those for all-cause mortality in the low-level cHMW adiponectin group, even after adjustment with BMI. In contrast, the hazard ratios for all-cause mortality were significantly higher for high cHMW adiponectin groups in very old women, but were not significant after adjustment with BMI. cHMW adiponectin levels increased with age until centenarians, and the contribution of known major factors associated with cHMW adiponectin levels, including BMI and HDLC, varies with age, suggesting that its physiological significance also varies with age in the oldest old. This study was supported by grants from the Ministry of Health, Welfare, and Labour for the Scientific Research Projects for Longevity; a Grant-in-Aid for Scientific Research (No 21590775, 24590898, 15KT0009, 18H03055, 20K20409, 20K07792, 23H03337) from the Japan Society for the Promotion of Science; Keio University Global Research Institute (KGRI), Kanagawa Institute of Industrial Science and Technology (KISTEC), Japan Science and Technology Agency (JST) Research Complex Program "Tonomachi Research Complex" Wellbeing Research Campus: Creating new values through technological and social innovation (JP15667051), the Program for an Integrated Database of Clinical and Genomic Information from the Japan Agency for Medical Research and Development (No. 16kk0205009h001, 17jm0210051h0001, 19dk0207045h0001); the medical-welfare-food-agriculture collaborative consortium project from the Japan Ministry of Agriculture, Forestry, and Fisheries; and the Biobank Japan Program from the Ministry of Education, Culture, Sports, and Technology.

The roles of FGF21 and GDF15 in mediating the mitochondrial integrated stress response.

Various models of mitochondrial stress result in induction of the stress-responsive cytokines fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15). This is an adaptive mechanism downstream of the mitochondrial integrated stress response frequently associated with improvements in systemic metabolic health. Both FGF21 and GDF15 have been shown to modulate energy balance and glucose homeostasis, and their pharmacological administration leads to promising beneficial effects against obesity and associated metabolic diseases in pre-clinical models. Furthermore, endogenous upregulation of FGF21 and GDF15 is associated with resistance to diet-induced obesity (DIO), improved glucose homeostasis and increased insulin sensitivity. In this review, we highlight several studies on transgenic mouse models of mitochondrial stress and will compare the specific roles played by FGF21 and GDF15 on the systemic metabolic adaptations reported in these models.