Alpha lipoic acid administration improved both peripheral sensitivity to insulin and liver clearance of insulin reducing potential risk of diabetes and nonalcoholic fatty liver disease in overweight/obese PCOS patients.

OBJECTIVE: To evaluate the effects of alpha lipoic acid (ALA) on hormonal and metabolic parameters in a group of overweight/obese Polycystic Ovary Syndrome (PCOS) patients. METHODS: This was a retrospective study in which thirty-two overweight/obese patients with PCOS (n = 32) not requiring hormonal treatment were selected from the database of the ambulatory clinic of the Gynecological Endocrinology Center at the University of Modena and Reggio Emilia, Italy. The hormonal profile, routine exams and insulin and C-peptide response to oral glucose tolerance test (OGTT) were evaluated before and after 12 weeks of complementary treatment with ALA (400 mg/day). Hepatic Insulin Extraction (HIE) index was also calculated. RESULTS: ALA administration significantly improved insulin sensitivity and decreased ALT and AST plasma levels in all subjects, though no changes were observed on reproductive hormones. When PCOS patients were subdivided according to the presence or absence of familial diabetes background, the higher effects of ALA were observed in the former group that showed AST and ALT reduction and greater HIE index decrease. CONCLUSION: ALA administration improved insulin sensitivity in overweight/obese PCOS patients, especially in those with familial predisposition to diabetes. ALA administration improved both peripheral sensitivity to insulin and liver clearance of insulin. Such effects potentially decrease the risk of nonalcoholic fat liver disease and diabetes in PCOS patients.

Probiotic co-supplementation with absorbent smectite for pancreatic beta-cell function in type 2 diabetes: a secondary-data analysis of a randomized double-blind controlled trials.

Introduction: There is growing evidence from animal and clinical studies suggesting probiotics can positively affect type 2 diabetes (T2D). In a previous randomized clinical study, we found that administering a live multistrain probiotic and absorbent smectite once a day for eight weeks to patients with T2D could reduce chronic systemic inflammatory state, insulin resistance, waist circumference and improve the glycemic profile. However, there is a lack of evidence supporting the efficacy of probiotic co-supplementation with absorbent smectite on pancreatic ß-cell function in T2D. Aim: This secondary analysis aimed to assess the effectiveness of an alive multistrain probiotic co-supplementation with absorbent smectite vs placebo on ß-cell function in T2D patients. Material and methods: We performed a secondary analysis on a previously published randomized controlled trial (NCT04293731, NCT03614039) involving 46 patients with T2D. The main inclusion criteria were the presence of ß-cell dysfunction (%B<60%) and insulin therapy alone or combined with oral anti-diabetic drugs. The primary outcome was assessing ß-cell function as change C-peptide and %B. Results: We observed only a tendency for improving ß-cell function (44.22 ± 12.80 vs 55.69 ± 25.75; р=0.094). The effectiveness of the therapy probiotic-smectite group was confirmed by fasting glycemia decreased by 14% (p=0.019), HbA1c - 5% (p=0.007), HOMA-2 - 17% (p=0.003) and increase of insulin sensitivity by 23% (p=0.005). Analysis of the cytokine profile showed that statistical differences after treatment were in the concentration of both pro-inflammatory cytokines: IL-1ß (22.83 ± 9.04 vs 19.03 ± 5.57; p=0.045) and TNF-α (31.25 ± 11.32 vs 26.23 ± 10.13; p=0.041). Conclusion: Adding a live multistrain probiotic and absorbent smectite supplement slightly improved ß-cell function and reduced glycemic-related parameters in patients with T2D. This suggests that adjusting the gut microbiota could be a promising treatment for diabetes and warrants further investigation through more extensive studies.

Combination therapy of metformin and morin attenuates insulin resistance, inflammation, and oxidative stress in skeletal muscle of high-fat diet-fed mice.

Lipid accumulation, inflammation, and oxidative stress are the most important causes of muscle insulin resistance. The aim of this study was to investigate the single and combined treatment effects of metformin (MET) and morin (MOR) on lipid accumulation, inflammation, and oxidative stress in the skeletal muscle of mice fed a high-fat diet. The mice were supplemented with MET (230 mg/kg diet), MOR (100 mg/kg diet), and MET + MOR for 9 weeks. Our results revealed that single treatment with MET or MOR, and with a stronger effect of MET + MOR combined treatment, reduced body weight gain, improved glucose intolerance and enhanced Akt phosphorylation in the muscle tissue. In addition, plasma and muscle triglyceride levels were decreased after treatment with MET and MOR. The expression of genes involved in macrophage infiltration and polarization and pro-inflammatory cytokines showed that MET + MOR combined treatment, significantly reduced inflammation in the muscle. Furthermore, combined treatment of MET + MOR with greater efficacy than the single treatment improved several oxidative stress markers in the muscle. Importantly, combined treatment of MET and MOR could increase the expression of nuclear factor erythroid 2-related factor 2, the master regulator of the antioxidant response. These findings suggest that combination of MET with MOR might ameliorate insulin resistance, inflammation, and oxidative stress in the skeletal muscle of mice fed high-fat diet.

The Effect of Magnesium Supplementation on Insulin Resistance and Metabolic Profiles in Women with Polycystic Ovary Syndrome: a Randomized Clinical Trial.

Due to the definitive known effect of magnesium on insulin resistance and the fact that insulin resistance is a main etiology in polycystic ovary syndrome (PCOS), it is assumed the use of magnesium supplements can improve insulin resistance, lipid profiles, and glucose and thus may also play a role in improving the clinical condition of patients with PCOS. We aimed to assess the effects of magnesium supplements on anthropometric, clinical, and metabolic parameters in women suffering from PCOS. This triple-blind randomized clinical trial study was conducted on women aged 15-35 years with PCOS. The patients were randomly assigned to receive a magnesium oxide supplement (250 mg/day for 2 months) or a placebo. The study parameters were evaluated and compared between two groups before as well as 2 months and 5 months after the initial assessment. In total, 40 cases (20 in each group) were recruited in the study. A significant reduction in the serum insulin level (P-value = 0.036) and insulin resistance (p-value = 0.032) was observed in the case group. Prescribing magnesium supplements could also lead to lowering total cholesterol, low-density lipoprotein, and fasting blood sugar along with increasing the level of high-density lipoprotein. We could not find any significant difference in anthropometric parameters as well as the mean systolic and diastolic blood pressures before and after intervention between the two groups. Although the rate of oligomenorrhea significantly decreased in the two study groups, it was no different across the two groups before and also after the intervention. The use of magnesium supplements in patients with PCO, regardless of the etiology or progression of the disease, can greatly improve the metabolic status of these patients by improving insulin resistance and modulating the level of lipid profile.

Electroacupuncture ameliorates hepatic defects in a rat model of polycystic ovary syndrome induced by letrozole and a high-fat diet.

BACKGROUND: This study was designed to evaluate the effects of low-frequency electroacupuncture (EA) on glucose and lipid disturbances in a rat model of polycystic ovary syndrome (PCOS) characterized by insulin resistance (IR) and hepatic steatosis. METHODS: The PCOS rat model was induced by continuous administration of letrozole (LET) combined with a high-fat diet (HFD). Female Sprague-Dawley rats were divided into the following four groups: control, control + EA, LET + HFD and LET + HFD + EA. EA was administered five or six times a week with a maximum of 20 treatment sessions. Body weight, estrous cyclicity, hormonal status, glucose and insulin tolerance, lipid profiles, liver inflammation factors, liver morphology and changes in the phosphatidylinositol 3-kinase (PI3-K)/Akt (protein kinase B) pathway were evaluated. RESULTS: The rat model presented anovulatory cycles, increased body weight, elevated testosterone, abnormal glucose and lipid metabolism, IR, liver inflammation, hepatic steatosis and dysregulation of the insulin-mediated PI3-K/Akt signaling axis. EA reduced fasting blood glucose, fasting insulin, area under the curve for glucose, homeostasis model assessment of IR indices, triglycerides and free fatty acids, and alleviated hepatic steatosis. Furthermore, low-frequency EA downregulated mRNA expression of tumor necrosis factor (TNF)-α and interleukin (IL)-6, upregulated mRNA expression of peroxisome proliferator-activated receptor (PPAR)-α, increased protein expression of phosphorylated (p)-Akt (Ser473), p-glycogen synthase kinase (GSK) 3ß (Ser9) and glucose transporter 4 (GLUT4), increased the ratio of p-GSK3ß to GSK3ß and downregulated protein expression of GSK3ß. CONCLUSION: An obese PCOS rat model with IR and hepatic steatosis was successfully established by the combination of LET and HFD. EA improved dysfunctional glucose and lipid metabolism in this PCOS-IR rat model, and the molecular mechanism appeared to involve regulation of the expression of key molecules of the PI3-K/Akt insulin signaling pathway in the liver.

Fish oil minimises feed intake and improves insulin sensitivity in Zucker fa/fa rats.

Long-chain n-3 PUFA (LC n-3 PUFA) prevent, in rodents, insulin resistance (IR) induced by a high-fat and/or fructose diet but not IR induced by glucocorticoids. In humans, contrasting effects have also been reported. We investigated their effects on insulin sensitivity, feed intake (FI) and body weight gain in genetically insulin resistant male obese (fa/fa) Zucker (ZO) rats during the development of obesity. ZO rats were fed a diet supplemented with 7 % fish oil (FO) + 1 % corn oil (CO) (wt/wt) (ZOFO), while the control group was fed a diet containing 8 % fat from CO (wt/wt) (ZOCO). Male lean Zucker (ZL) rats fed either FO (ZLFO) or CO (ZLCO) diet were used as controls. FO was a marine-derived TAG oil containing EPA 90 mg/g + DHA 430 mg/g. During an oral glucose tolerance test, glucose tolerance remained unaltered by FO while insulin response was reduced in ZOFO only. Liver insulin sensitivity (euglycaemic-hyperinsulinaemic clamp + 2 deoxyglucose) was improved in ZOFO rats, linked to changes in phosphoenolpyruvate carboxykinase expression, activity and glucose-6-phosphatase activity. FI in response to intra-carotid insulin/glucose infusion was decreased similarly in ZOFO and ZOCO. Hypothalamic ceramides levels were lower in ZOFO than in ZOCO. Our study demonstrates that LC n-3 PUFA can minimise weight gain, possibly by alleviating hypothalamic lipotoxicity, and liver IR in genetically obese Zucker rats.

Astaxanthin supplementation impact on insulin resistance, lipid profile, blood pressure, and oxidative stress in polycystic ovary syndrome patients: A triple-blind randomized clinical trial.

Astaxanthin (ASX) is a natural carotenoid compound found in several of microorganisms and seafood. It may have numerous therapeutic benefits for polycystic ovarian syndrome (PCOS) patients. The aim of this study was to investigate the effect of ASX on lipid profile, insulin resistance (IR), blood pressure (BP), and oxidative stress (OS) levels in infertile PCOS patients. Overall, 58 infertile women with diagnosed PCOS participated in this triple-blind randomized clinical trial. They were randomly assigned to two groups, taking either a placebo or ASX (2 × 6 mg/day) for 8 weeks. Blood serum samples were collected from patients before and after the intervention. Fasting Insulin (FI), fasting blood glucose (FBS), OS markers (malondialdehyde [MDA], superoxide dismutase [SOD], and total antioxidant capacity [TAC]), and lipid profiles were evaluated in serum. Moreover, based on the relevant formula, several indices associated with IR were calculated. BP was also assessed at the start and end of the study. After 8 weeks of ASX consumption, a significant reduction was observed in fasting blood sugar, HOMA-IR, FI, MDA, low-density lipoprotein-cholesterol, and TC/HDL-C. Conversely, ASX significantly increased TAC, HDL-C, and QUICKI. After adjusting the analysis for the baseline values of age, body mass index, and biochemical parameters, non-significant values were obtained for QUICKI and FI, along with no changes in other findings. Overall, ASX appears to be an effective and safe supplement that alleviates insulin metabolism, lipid profile parameters, and OS in infertile PCOS patients.

Tea seed saponin­reduced extract ameliorates palmitic acid­induced insulin resistance in HepG2 cells.

Tea (Camellia sinensis) seed cake is a potential resource that contains a wealth of bioactive compounds. However, the high toxicity of tea saponins in tea seed cake restricts its applications. The present study aimed to i) develop a method of extracting bioactive compounds and reducing tea saponins during the process of tea seed cake extraction and ii) investigate the anti­insulin resistance effect of tea seed saponin­reduced extract (TSSRE) in a palmitic acid (PA)­induced insulin resistance HepG2­cell model. The concentration of tea saponins in TSSRE was ~10­fold lower than that in tea seed crude extract (TSCE) after the saponin­reduction process. In addition, TSSRE cytotoxicity was significantly lower than that of TSCE in HepG2 cells. TSSRE treatment improved glucose consumption as well as glucose transporter (GLUT) 2 and GLUT4 expression levels in PA­stimulated HepG2 cells. Moreover, TSSRE enhanced the phosphorylation of the insulin receptor substrate 1/protein kinase B/forkhead box protein O1/glycogen synthase kinase 3ß and inhibited the elevated expression of phosphoenolpyruvate carboxykinase in PA­exposed HepG2 cells. The effect of TSSRE on the mediation of the insulin signaling pathway was attributed to the inhibition of PA­induced mitogen­activated protein kinase activation. The findings of the present study indicated that TSSRE ameliorates hepatic insulin resistance by ameliorating insulin signaling and inhibiting inflammation-related pathways.

Optimal vitamin D supplement dosage for improving insulin resistance in children and adolescents with overweight/obesity: a systematic review and network meta-analysis.

PURPOSE: We conducted a network meta-analysis which aims to evaluate the comparative efficacy of different supplementation dosages of vitamin D on cardiometabolic and bone-metabolic indicators as well as insulin resistance in children and adolescents with overweight/obesity. METHODS: Eligible studies published before December 10, 2022 were retrieved from PubMed, EMBASE, Cochrane Library, and Web of Science. Mean difference and 95% confidence interval (CI) were used to express pooled estimates. Network meta-analysis of multiple doses, including low (< 1000 IU/day, LDS), medium (1000-2000 IU/day, MDS), high (2000-4000 IU/day, HDS), and extremely high (> 4000 IU/day, EHDS) dosage strategy, was conducted using STATA/MP 14.0. RESULTS: Our network meta-analysis of 15 RCTs suggested that, compared with placebo and LDS, EHDS was increased 25-(OH)-D, with a pooled MD of 8.65 (95% CI 4.72-12.58) and 7.66 (95% CI 0.91-14.41), respectively. Meanwhile, EHDS also decreased ho meostasis model assessment-insulin resistance (HOMA-IR) (MD: - 0.74; 95% CI: - 1.45 to - 0.04) and C-reactive protein (CRP) (MD: - 18.99; 95% CI - 21.60 to - 16.38), and EHDS was also better than LDS (MD: - 18.47; 95% CI - 20.66 to - 16.28) and MDS (MD: - 19.69; 95% CI - 22.17 to - 17.21) in decreasing CRP. Ranking probability suggested that EHDS ranked best for increasing 25-(OH)-D, and decreasing HOMA-IR and CRP, with a probability of 86.1%, 83.1%, and 76.6%, respectively. CONCLUSIONS: The results of our network meta-analysis suggest that EHDS may be the best strategy for vitamin D supplementation to reduce inflammatory responses as well as improve insulin resistance in children and adolescents with overweight/obesity. PROSPERO REGISTRATION NUMBER: CRD42023387775.

A prospective guide for clinical implementation of selected OGTT- derived surrogate indices for the evaluation of ß- cell function and insulin sensitivity in patients with transfusion-dependent ß- thalassaemia.

The gold standard for the measurement of insulin secretion is the hyperglycemic clamp and for insulin sensitivity the hyperinsulinemic euglycemic clamp, respectively. A number of surrogate indices, derived from plasma glucose and insulin levels at a fasting state or after oral glucose load, have been proposed to estimate ß-cell response, and the ability of ß-cells to compensate for changes of insulin sensitivity by modulating insulin secretion (disposition index). Starting from the current recommendations for the annual screening of glucose dysregulation in patients with transfusion dependent ß-thalassemia (ß-TDT), this article summarizes the most frequently used indirect indices of insulin secretion and resistance derived from the oral glucose tolerance test (OGTT) and discusses the strengths and weaknesses of selected indices and the basic concepts underlying each method for the appropriate evaluation of glucose regulation. Basal indices for ß-cell function and insulin sensitivity, albeit simple and cheap, have limited usefulness due to a high coefficient variation and the lack of data about response to glucose load. Therefore, measurement of indices during an OGTT, despite being costly and time-consuming, is suggested since it can detect, even subtle, dynamic changes in insulin secretion and glucose handling. In patients with ß-TDT, the indices derived from OGTT may offer an additional factor to evaluate the efficiency of iron chelation therapy and detect patients who may need intensification of iron chelation therapy and/or pharmacological intervention.

Reducing Dietary Polyunsaturated to Saturated Fatty Acids Ratio Improves Lipid and Glucose Metabolism in Obese Zucker Rats.

We investigated the influence of varying dietary polyunsaturated fatty acid (PUFA)/saturated fatty acids (SFA) ratios on insulin resistance (IR), fatty acid metabolism, N-acylethanolamine (NAE) bioactive metabolite levels, and mitochondrial function in lean and obese Zucker rats in a model designed to study obesity and IR from overnutrition. We provided diets with 7% fat (w/w), with either a low PUFA/SFA ratio of 0.48, predominantly comprising palmitic acid (PA), (diet-PA), or the standard AIN-93G diet with a high PUFA/SFA ratio of 3.66 (control, diet-C) over eight weeks. In obese rats on diet-PA versus diet-C, there were reductions in plasma triglycerides, cholesterol, glucose, insulin concentrations and improved muscle mitochondrial function, inflammatory markers and increased muscle N-oleoylethanolamine (OEA), a bioactive lipid that modulates lipid metabolism and metabolic flexibility. Elevated palmitic acid levels were found exclusively in obese rats, regardless of their diet, implying an endogenous production through de novo lipogenesis rather than from a dietary origin. In conclusion, a reduced dietary PUFA/SFA ratio positively influenced glucose and lipid metabolism without affecting long-term PA tissue concentrations. This likely occurs due to an increase in OEA biosynthesis, improving metabolic flexibility in obese rats. Our results hint at a pivotal role for balanced dietary PA in countering the effects of overnutrition-induced obesity.

The relationship between vitamin K and T2DM: a systematic review and meta-analysis.

Background: Previous studies have shown the potential role of vitamin K supplementation in the prevention and treatment of many diseases. However, the effect of vitamin K supplementation on blood glucose remains controversial. The purpose of this study was to assess the effects of vitamin K supplementation on glycemia-related indicators, including Fasting Blood Sugar (FBS), Fasting Insulin (FINS) and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). The potential association between vitamin K and type 2 diabetes mellitus (T2DM) risk was also evaluated. Methods: Up to April 2023, Cochrane, PubMed, Web of Science, Medline and EMBASE databases were searched to assess the effects of vitamin K on blood glucose and the risk of developing T2DM. Results: A meta-analysis of seven studies (813 participants) found vitamin K supplementation significantly reduced FBS (SMD = -0.150 mg dl-1, 95% CI = -0.290, -0.010 mg dl-1) and HOMA-IR (SMD = -0.200, 95% CI = -0.330, -0.060), but not FINS. Five studies with a total of 105 798 participants were included in the meta-analysis of the association between vitamin K and T2DM. The results showed that vitamin K was associated with the reduced risk of developing T2DM (HR = 0.79, 95% CI [0.71-0.88], P < 0.001). Conclusion: The meta-analysis demonstrated that vitamin K supplementation had a significant effect on the regulation of FBS and HOMA-IR in the population. Moreover, vitamin K was associated with the reduced risk of developing T2DM. Considering some limitations found in this study, additional data from large clinical trials are needed.

High-fat diet during pregnancy promotes fetal skeletal muscle fatty acid oxidation and insulin resistance in an ovine model.

Maternal diet during pregnancy is associated with offspring metabolic risk trajectory in humans and animal models, but the prenatal origins of these effects are less clear. We examined the effects of a high-fat diet (HFD) during pregnancy on fetal skeletal muscle metabolism and metabolic risk parameters using an ovine model. White-faced ewes were fed a standardized diet containing 5% fat wt/wt (CON), or the same diet supplemented with 6% rumen-protected fats (11% total fat wt/wt; HFD) beginning 2 wk before mating until midgestation (GD75). Maternal HFD increased maternal weight gain, fetal body weight, and low-density lipoprotein levels in the uterine and umbilical circulation but had no significant effects on circulating glucose, triglycerides, or placental fatty acid transporters. Fatty acid (palmitoylcarnitine) oxidation capacity of permeabilized hindlimb muscle fibers was >50% higher in fetuses from HFD pregnancies, whereas pyruvate and maximal (mixed substrate) oxidation capacities were similar to CON. This corresponded to greater triacylglycerol content and protein expression of fatty acid transport and oxidation enzymes in fetal muscle but no significant effect on respiratory chain complexes or pyruvate dehydrogenase expression. However, serine-308 phosphorylation of insulin receptor substrate-1 was greater in fetal muscle from HFD pregnancies along with c-jun-NH2 terminal kinase activation, consistent with prenatal inhibition of skeletal muscle insulin signaling. These results indicate that maternal high-fat feeding shifts fetal skeletal muscle metabolism toward a greater capacity for fatty acid over glucose utilization and favors prenatal development of insulin resistance, which may predispose offspring to metabolic syndrome later in life.NEW & NOTEWORTHY Maternal diet during pregnancy is associated with offspring metabolic risk trajectory in humans and animal models, but the prenatal origins of these effects are less clear. This study examined the effects of a high-fat diet during pregnancy on metabolic risk parameters using a new sheep model. Results align with findings previously reported in nonhuman primates, demonstrating changes in fetal skeletal muscle metabolism that may predispose offspring to metabolic syndrome later in life.

Insulin resistance and adipose tissue interactions as the cornerstone of metabolic (dysfunction)-associated fatty liver disease pathogenesis.

The relationship between metabolic derangements and fatty liver development are undeniable, since more than 75% of patients with type 2 diabetes mellitus present with fatty liver. There is also significant epidemiological association between insulin resistance (IR) and metabolic (dysfunction)-associated fatty liver disease (MAFLD). For little more than 2 years, the nomenclature of fatty liver of non-alcoholic origin has been intended to change to MAFLD by multiple groups. While a myriad of reasons for which MAFLD is thought to be of metabolic origin could be exposed, the bottom line relies on the role of IR as an initiator and perpetuator of this disease. There is a reciprocal role in MAFLD development and IR as well as serum glucose concentrations, where increased circulating glucose and insulin result in increased de novo lipogenesis by sterol regulatory element-binding protein-1c induced lipogenic enzyme stimulation; therefore, increased endogenous production of triglycerides. The same effect is achieved through impaired suppression of adipose tissue (AT) lipolysis in insulin-resistant states, increasing fatty acid influx into the liver. The complementary reciprocal situation occurs when liver steatosis alters hepatokine secretion, modifying fatty acid metabolism as well as IR in a variety of tissues, including skeletal muscle, AT, and the liver. The aim of this review is to discuss the importance of IR and AT interactions in metabolic altered states as perhaps the most important factor in MAFLD pathogenesis.

Preventive nutritional supplementation with furan fatty acid in a DIO mouse model increases muscle mass and reduces metabolic disorders.

The increase in obesity has become a major global health problem and is associated with numerous metabolic dysfunctions. Furan fatty acids (FuFAs) are minor lipids present in our diet. Recently we showed that FuFA-F2 extracted from Hevea brasiliensis latex stimulates muscle anabolism in mice in vitro and in vivo, mimicking in part physical activity. While skeletal muscle is essential for energy metabolism and is the predominant site of insulin-mediated glucose uptake in the post prandial state, our results suggested that FuFA-F2 could have favorable effects against obesity. The aim of this work was therefore to study whether a preventive nutritional supplementation with FuFA-F2 (40 mg or 110 mg/day/kg of body weight) in a diet-induced obesity (DIO) mouse model may have beneficial effects against obesity and liver and skeletal muscle metabolic dysfunction. We showed that 12 weeks of FuFA-F2 supplementation in DIO mice decreased fat mass, increased lean mass and restored normal energy expenditure. In addition, we found that FuFA-F2 improved insulin sensitivity. We revealed that FuFA-F2 increased muscle mass but had no effect on mitochondrial function and oxidative stress in skeletal muscle. Furthermore, we observed that FuFA-F2 supplementation reduced liver steatosis without impact on mitochondrial function and oxidative stress in liver. Our findings demonstrated for the first time that a preventive nutritional supplementation with a furan fatty acid in DIO mice reduced metabolic disorders and was able to mimic partly the positive effects of physical activity. This study highlights that nutritional FuFA-F2 supplementation could be an effective approach to treat obesity and metabolic syndrome.

Insulin sensitization by Feronia elephantum in fructose-induced hyperinsulinemic rats: Insights from computational and experimental pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Feronia elephantum corr. (synonym: Feronia limonia, Murraya odorata, Schinus Limonia, or Limonia acidissima; common names: Bela, Kath, Billin, and Kavitha), belonging to the family Rutaceae has been known for clinical conditions such as pruritus, diarrhea, impotence, dysentery, heart diseases, and is also used as a liver tonic. However, the effect of the fruit pulp of F. elephantum on insulin resistance has yet not been reported. AIM OF THE STUDY: The present study aimed to assess the effect of hydroalcoholic extract/fraction of F. elephantum fruit pulp on fasting blood glucose, oral glucose tolerance test, and glucose uptake in fructose-induced insulin-resistant rats and predict the gene-set enrichment of lead hits of F. elephantum with targets related to insulin resistance. MATERIAL AND METHODS: System biology tools were used to predict the best category of fraction and propose a possible mechanism. Docking was carried out with adiponectin and its receptor (hub genes). Further, fructose supplementation was used for the induction of insulin resistance. Later, three doses of extract (400, 200, and 100 mg/kg) and a flavonoid-rich fraction (63 mg/kg) were used for treatment along with metformin as standard. The physical parameters like body weight, food intake, and water intake were measured along with oral glucose tolerance test, insulin tolerance test, glycogen content in skeletal muscles and liver, glucose uptake by rat hemidiaphragm, lipid profiles, anti-oxidant biomarkers, and histology of the liver and adipose tissue. RESULTS: Network pharmacology reflected the potency of F. elephantum to regulate adiponectin which may promote the reversal of insulin resistance and inhibit α-amylase and α-glucosidase. Vitexin was predicted to modulate the most genes associated with diabetes mellitus. Further, F. elephantum ameliorated the exogenous glucose clearance, promoted insulin sensitivity, reduced oxidative stress, and improved glucose and lipid metabolism. HPLC profiling revealed the presence of apigenin and quercetin in the extract for the first time. CONCLUSION: The fruit pulp of F. elephantum reverses insulin resistance by an increase in glucose uptake and a decrease in gluconeogenesis which may be due to the regulation of multiple proteins via multiple bio-actives.

Towards an adiposity-related disease framework for the diagnosis and management of obesities.

Obesity is a complex disease that relapses frequently and associates with multiple complications that comprise a worldwide health priority because of its rising prevalence and association with numerous complications, including metabolic disorders, mechanic pathologies, and cancer, among others. Noteworthy, excess adiposity is accompanied by chronic inflammation, oxidative stress, insulin resistance, and subsequent organ dysfunction. This dysfunctional adipose tissue is initially stored in the visceral depot, overflowing subsequently to produce lipotoxicity in ectopic depots like liver, heart, muscle, and pancreas, among others. People living with obesity need a diagnostic approach that considers an exhaustive pathophysiology and complications assessment. Thus, it is essential to warrant a holistic diagnosis and management that guarantees an adequate health status, and quality of life. The present review summarizes the different complications associated with obesity, at the same time, we aim to fostering a novel framework that enhances a patient-centered approach to obesity management in the precision medicine era.

Triazine herbicides exposure, natural immunoglobulin M antibodies, and fasting plasma glucose changes: Association and mediation analyses in general Chinese urban adults.

The effects of triazine herbicides on glucose metabolism remain unclear. In this study, we aimed to assess the associations between serum triazine herbicides and glycemia-related risk indicators in general adults, and to evaluate the mediating role of natural immunoglobulin M antibodies (IgM) in the above associations among uninfected participants. We measured the concentrations of atrazine, cyanazine, and IgM in serum, as well as fasting plasma glucose (FPG), and fasting plasma insulin in 4423 adult participants from the Wuhan-Zhuhai cohort baseline population, enrolled in 2011-2012. Generalized linear models were used to evaluate the associations of serum triazine herbicides with glycemia-related risk indicators, and mediation analyses were performed to evaluate the mediating role of serum IgM in the above associations. The median levels of serum atrazine and cyanazine were 0.0237 µg/L and 0.0786 µg/L, respectively. Our study found significant positive associations of serum atrazine, cyanazine, and Σtriazine with FPG levels, risk of impaired fasting glucose (IFG), abnormal glucose regulation (AGR), and type 2 diabetes (T2D). Additionally, serum cyanazine and Σtriazine were found to be significant positive associated with the homeostatic model assessment of insulin resistance (HOMA-IR) levels. Significant negative linear relationships were observed in associations of serum IgM with serum triazine herbicides, FPG, HOMA-IR levels, the prevalence of T2D, and AGR (P < 0.05). Furthermore, we observed a significant mediating role by IgM in the associations of serum triazine herbicides with FPG, HOMA-IR, and AGR, with the proportions ranging from 2.96% to 7.71%. To ensure the stability of our findings, we conducted sensitivity analyses in normoglycemic participants and found that the association of serum IgM with FPG and the mediating role by IgM remained stable. Our results suggest that triazine herbicides exposure is positively associated with abnormal glucose metabolism, and decreasing serum IgM may partly mediate these associations.

Regulation of Insulin Resistance, Lipid Profile and Glucose Metabolism Associated with Polycystic Ovary Syndrome by Tinospora cordifolia.

Background: The plant Tinospora cordifolia (TC), traditionally known as guduchi or giloy, is used for a number of health conditions as a nutritional supplement and rejuvenation medicine. Its nutritional supplementary products are traditionally recommended for a wide range of health issues, including diabetes, menstruation discomfort, fever, obesity, inflammation, and more. Unfortunately, there has not been extensive research into its effectiveness in treating or managing insulin resistance, lipid and carbohydrate metabolism, hormonal imbalance, and metabolic syndrome-associated polycystic ovary syndrome (PCOS). Methods: Consequently, the present study was designed to induce insulin resistance, dyslipidemia, hormonal abnormality, hyperglycemia, and menstrual disturbance of PCOS using dehydroepiandrosterone (DHEA) in mice and study the effect of oral TC extracts on these factors by using ancient and modern technologies. During the 21-day study, 6 mg/100 g/day of DHEA was given to female mice. Levels of glucose, insulin, lipids, and hormones were estimated. In addition to being seen with the naked eye, the morphological and microscopic changes were also observed on histology slides. Results: The study outcomes show that pretreatment with TC preparations significantly improved biochemical and histological abnormalities in female mice. Diestrus phase was only observed in DHEA-treated animals, while cornified epithelial cells were present in TC-treated mice. Pretreatment with TC satva showed significant (p < 0.001) reductions in body weight compared to placebo. Fasting blood glucose, 1-h OGTT, and 2-h OGTT levels were all significantly lower in TC satva- and oil-treated animals in comparison to the disease control group (p < 0.001). Treatment with TC extracts resulted in a normalization of estradiol, progesterone, and testosterone levels (p < 0.05). Treatment with TC extract improved lipid profiles (p < 0.001), LH/FSH ratios (p < 0.01), fasting insulin levels (p < 0.001), HOMA-IR (p < 0.001), HOMA-Beta (p < 0.001), and QUICKI (p < 0.001). Both macroscopic and microscopic alterations were seen to be restored after TC extract treatment. After being treated with TC satva, oil, and hydroalcoholic extract, the severity of PCOS decreased by 54.86%. Conclusions: These findings lead us to the conclusion that TC extracts and satva as nutritional supplements are useful for treating PCOS and associated symptoms. It is recommended that additional research be conducted to determine the molecular mechanism of action of TC nutritional supplements on PCOS-related changes in metabolic profiles. We also recommend further clinical studies to explore the clinical efficacy and effectiveness of TC nutritional supplements in treating and/or managing PCOS.

Peeling the onion: another layer in the regulation of insulin secretion.

Insulin secretion by pancreatic ß cells is a dynamic and highly regulated process due to the central importance of insulin in enabling efficient utilization and storage of glucose. Multiple regulatory layers enable ß cells to adapt to acute changes in nutrient availability as well as chronic changes in metabolic demand. While epigenetic factors have been well established as regulators of chronic ß cell adaptations to insulin resistance, their role in acute adaptations in response to nutrient stimulation has been relatively unexplored. In this issue of the JCI, Wortham et al. report that short-term dynamic changes in histone modifications regulated insulin secretion and acute ß cell adaptations in response to fasting and feeding cycles. These findings highlight the importance of investigating whether other epigenetic mechanisms may contribute to acute physiologic adaptations in ß cells.