Insulin Stimulation Research Articles

The effects of sucrose and arsenic on muscular insulin signaling pathways differ between the gastrocnemius and quadriceps muscles.

Insulin resistance in muscle can originate from a sedentary lifestyle, hypercaloric diets, or exposure to endocrine-disrupting pollutants such as arsenic. In skeletal muscle, insulin stimulates glucose uptake by translocating GLUT4 to the sarcolemma. This study aimed to evaluate the alterations induced by sucrose and arsenic exposure in vivo on the pathways involved in insulinstimulated GLUT4 translocation in the quadriceps and gastrocnemius muscles. Male Wistar rats were treated with 20% sucrose (S), 50 ppm sodium arsenite (A), or both (A+S) in drinking water for 8 weeks. We conducted an intraperitoneal insulin tolerance (ITT) test on the seventh week of treatment. The quadriceps and gastrocnemius muscles were obtained after overnight fasting or 30 min after intraperitoneal insulin injection. We assessed changes in GLUT4 translocation to the sarcolemma by cell fractionation and abundance of the proteins involved in GLUT4 translocation by Western blot. Male rats consuming S and A+S gained more weight than control and Atreated animals. Rats consuming S, A, and A+S developed insulin resistance assessed through ITT. Neither treatments nor insulin stimulation in the quadriceps produced changes in GLUT4 levels in the sarcolemma and Akt phosphorylation. Conversely, A and A+S decreased protein expression of Tether containing UBX domain for GLUT4 (TUG), and A alone increased calpain-10 expression. All treatments reduced this muscle's protein levels of VAMP2. Conversely, S and A treatment increased basal GLUT4 levels in the sarcolemma of the gastrocnemius, while all treatments inhibited insulin-induced GLUT4 translocation. These effects correlated with lower basal levels of TUG and impaired insulin-stimulated TUG proteolysis. Moreover, animals treated with S had reduced calpain-10 protein levels in this muscle, while A and A+S inhibited insulin-induced Akt phosphorylation. Arsenic and sucrose induce systemic insulin resistance due to defects in GLUT4 translocation induced by insulin. These defects depend on which muscle is being analyzed, in the quadriceps there were defects in GLUT4 retention and docking while in the gastrocnemius the Akt pathway was impacted by arsenic and the proteolytic pathway was impaired by arsenic and sucrose.

The effects of sucrose and arsenic on muscular insulin signaling pathway differ between gastrocnemius and quadriceps muscles

Background: Muscle insulin resistance can originate from a sedentary lifestyle, hypercaloric diets or, the exposure to endocrine-disrupting pollutants such as arsenic. In skeletal muscle, insulin stimulates glucose uptake by translocating GLUT4 to the sarcolemma. This study aimed to evaluate the alterations induced by sucrose and arsenic exposure in vivo on the pathways involved in insulin-stimulated GLUT4 translocation in the quadriceps and gastrocnemius muscles. Methods: Male Wistar rats were treated with 20 % sucrose (S), 50 mg/L sodium arsenite (A), or both (A+S) in drinking water for 8 weeks. The intraperitoneal insulin tolerance (ITT) test was on the seventh week of treatment. Quadriceps and gastrocnemius muscles were obtained after overnight fasting or after 30 min of intraperitoneal insulin injection. We assessed changes in GLUT4 translocation to the sarcolemma by cell fractionation and abundance of the proteins involved in GLUT4 translocation by Western blot. Results: Male rats consuming S and A+S gained more weight than control and A-treated animals. Rats consuming S, A, and A+S developed insulin resistance assessed through ITT. Neither treatments nor insulin stimulation in the quadriceps produced changes in GLUT4 levels in sarcolemma and Akt phosphorylation. Conversely, A and A+S decreased protein expression of Tether containing Ubx domain for GLUT4 (TUG), and A alone increased calpain-10 expression. All treatments reduced this muscle's protein levels of VAMP2. Conversely, S and A-treatment increased basal GLUT4 levels in the sarcolemma of the gastrocnemius, while all treatments inhibited insulin-induced GLUT4 translocation. These effects correlated with lower basal levels of TUG and impaired insulin-stimulated TUG proteolysis. Moreover, animals treated with S had reduced capn10 protein levels in this muscle, while A and A+S inhibited insulin-induced Akt phosphorylation. Conclusion: Arsenic and sucrose act through different pathways to impair GLUT4 trafficking, and the effects differ between the quadriceps and gastrocnemius. CONACYT-Fronteras #568492, DGAPA-PAPIIT-UNAM #IN20872 and DGAPA-PAPIIT-UNAM #IN205621 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.

Neutral Effect of Skeletal Muscle Mineralocorticoid Receptor on Glucose Metabolism in Mice.

The mineralocorticoid receptor (MR) is able to regulate the transcription of a number of genes in the myotube, although its roles in skeletal muscle (SM) metabolism still await demonstration. SM represents a major site for glucose uptake, and its metabolic derangements play a pivotal role in the development of insulin resistance (IR). The aim of this study was to investigate the contribution of SM MR in mediating derangements of glucose metabolism in a mouse model of diet-induced obesity. We observed that mice fed a high-fat diet (HFD mice) showed impaired glucose tolerance compared to mice fed a normal diet (ND mice). Mice fed a 60% HFD treated with the MR antagonist Spironolactone (HFD + Spiro) for 12 weeks revealed an improvement in glucose tolerance, as measured with an intraperitoneal glucose tolerance test, compared with HFD mice. To investigate if blockade of SM MR could contribute to the favorable metabolic effects observed with pharmacological MR antagonism, we analyzed MR expression in the gastrocnemius, showing that SM MR protein abundance is downregulated by HFD compared to ND mice and that pharmacological treatment with Spiro was able to partially revert this effect in HFD + Spiro mice. Differently from what we have observed in adipose tissue, where HDF increased adipocyte MR expression, SM MR protein was down-regulated in our experimental model, suggesting a completely different role of SM MR in the regulation of glucose metabolism. To confirm this hypothesis, we investigated the effects of MR blockade on insulin signaling in a cellular model of IRin C2C12 myocytes, which were treated with or without Spiro. We confirmed MR protein downregulation in insulin-resistant myotubes. We also analyzed Akt phosphorylation upon insulin stimulation, and we did not observe any difference between palmitate- and palmitate + Spiro-treated cells. These results were confirmed by in vitro glucose uptake analysis. Taken together, our data indicate that reduced activity of SM MR does not improve insulin signaling in mouse skeletal myocytes and does not contribute to the favorable metabolic effects on glucose tolerance and IR induced by systemic pharmacological MR blockade.

Increased let-7d-5p in non-alcoholic fatty liver promotes insulin resistance and is a potential blood biomarker for diagnosis.

The molecular mechanisms driving non-alcoholic fatty liver disease (NAFLD) are poorly understood; however, microRNAs might play a key role in these processes. We hypothesize that let-7d-5p could contribute to the pathophysiology of NAFLD and serve as a potential diagnostic biomarker. We evaluated let-7d-5p levels and its targets in liver biopsies from a cross-sectional study including patients with NAFLD and healthy donors, and from a mouse model of NAFLD. Moreover, the induction of let-7d-5p expression by fatty acids was evaluated in vitro. Further, we overexpressed let-7d-5p in vitro to corroborate the results observed in vivo. Circulating let-7d-5p and its potential as a NAFLD biomarker was determined in isolated extracellular vesicles from human plasma by RT-qPCR. Our results demonstrate that hepatic let-7d-5p was significantly up-regulated in patients with steatosis, and this increase correlated with obesity and a decreased expression of AKT serine/threonine kinase (AKT), insulin-like growth factor 1 (IGF1), IGF-I receptor (IGF1R) and insulin receptor (INSR). These alterations were corroborated in a NAFLD mouse model. In vitro, fatty acids increased let-7d-5p expression, and its overexpression decreased AKT, IGF-IR and IR protein expression. Furthermore, let-7d-5p hindered AKT phosphorylation in vitro after insulin stimulation. Finally, circulating let-7d-5p significantly decreased in steatosis patients and receiver operating characteristic (ROC) analyses confirmed its utility as a diagnostic biomarker. Our results highlight the emerging role of let-7d-5p as a potential therapeutic target for NAFLD since its overexpression impairs hepatic insulin signalling, and also, as a novel non-invasive biomarker for NAFLD diagnosis.

Comparing the responses of grain fed feedlot cattle under moderate heat load and during subsequent recovery with those of feed restricted thermoneutral counterparts: metabolic hormones

We set out to determine the impact of moderate heat load on the plasma concentrations of a suite of hormones involved in regulating energy metabolism and feed intake. The responses of the thermally challenged (TC) feedlot steers were compared to those of feed restricted thermoneutral (FRTN) steers. Two sequential cohorts of twelve 518 ± 23 kg Black Angus steers on finisher grain ration were housed in climate-controlled rooms (CCR) for 18 days and returned to outdoor pens for 40 days. The TC group was subjected to a diurnal range of 28–35 °C for 7 days (Challenge) but held in thermoneutral conditions beforehand (PreChallenge), and in Recovery (after Challenge). The FRTN group was held in thermoneutral conditions and feed restricted throughout. Blood was collected over the three periods in CCR and two periods in outdoor pens for 40 days (PENS and Late PENS). Plasma concentrations of prolactin, thyroid stimulating hormone, insulin, leptin, adiponectin and thyroxine (T4) were determined during the five periods. Whilst the pituitary hormones were relatively stable, there were differences in plasma leptin, adiponectin and T4 between the two groups during Challenge and Recovery, and occasionally in PENS. The interaction of the plasma hormone concentrations and rumen temperature and DMI were also investigated. Whilst the positive relationship between DMI and leptin was confirmed, we found a strong negative relationship between adiponectin and rumen temperature, and a strong positive relationship between adiponectin and dry matter intake (DMI) in the TC steers only.

Nose-to-brain delivery of insulin nanoparticles for diabetes management: A review

Hyperglycemia and the onset of insulin resistance or deficiency, or both, are the hallmarks of the group of diseases known as diabetes. Ultimately, insulin subcutaneous injection is the most effective treatment for diabetic patients. However, most patients must self-administer insulin at least twice daily for the rest of their lives, as this form of administration is frequently uncomfortable and inconvenient. Infections, insulin precipitation, lipoatrophy, or lipohypertrophy are commonly observed at the injection site. To date, nasal, pulmonary, and oral methods of insulin administration have been explored. Although insulin stimulation is the ideal method for diabetic patients, there are several obstacles to overcome, such as rapid insulin degradation in the stomach and limited oral bioavailability. Various strategies have been approved to improve these parameters, including the use of enzyme inhibitors, mucoadhesive polymeric agents, absorption-enhancing agents, and chemical modifications. Insulin-loaded nanocarriers can bypass numerous physiological limitations. The current review discusses the approach of nanotechnology in nose-to-brain delivery of nanoparticles for diabetes management.

Insulin signaling in skeletal muscle during inflammation and/or immobilisation

BackgroundThe decline in the downstream signal transduction pathway of anabolic hormone, insulin, could play a key role in the muscle atrophy and insulin resistance observed in patients with intensive care unit acquired weakness (ICUAW). This study investigated the impact of immobilisation via surgical knee and ankle fixation and inflammation via Corynebacterium parvum injection, alone and in combination, as risk factors for altering insulin transduction and, therefore, their role in ICUAW.ResultsMuscle weight was significantly decreased due to immobilisation [estimated effect size (95% CI) − 0.10 g (− 0.12 to − 0.08); p < 0.001] or inflammation [estimated effect size (95% CI) − 0.11 g (− 0.13 to − 0.09); p < 0.001] with an additive effect of both combined (p = 0.024). pAkt was only detectable after insulin stimulation [estimated effect size (95% CI) 85.1-fold (76.2 to 94.0); p < 0.001] irrespective of the group and phosphorylation was not impaired by the different perturbations. Nevertheless, the phosphorylation of GSK3 observed in the control group after insulin stimulation was decreased in the immobilisation [estimated effect size (95% CI) − 40.2 (− 45.6 to − 34.8)] and inflammation [estimated effect size (95% CI) − 55.0 (− 60.4 to − 49.5)] groups. The expression of phosphorylated GS (pGS) was decreased after insulin stimulation in the control group and significantly increased in the immobilisation [estimated effect size (95% CI) 70.6-fold (58.8 to 82.4)] and inflammation [estimated effect size (95% CI) 96.7 (85.0 to 108.5)] groups.ConclusionsBoth immobilisation and inflammation significantly induce insulin resistance, i.e., impair the insulin signaling pathway downstream of Akt causing insufficient GSK phosphorylation and, therefore, its activation which caused increased glycogen synthase phosphorylation, which could contribute to muscle atrophy of immobilisation and inflammation.

The Role of Inositols in the Hyperandrogenic Phenotypes of PCOS: A Re-Reading of Larner's Results.

Polycystic ovarian syndrome (PCOS) is the most common endocrinological disorder in women, in which, besides chronic anovulation/oligomenorrhea and ovarian cysts, hyperandrogenism plays a critical role in a large fraction of subjects. Inositol isomers-myo-Inositol and D-Chiro-Inositol-have recently been pharmacologically effective in managing many PCOS symptoms while rescuing ovarian fertility. However, some disappointing clinical results prompted the reconsideration of their specific biological functions. Surprisingly, D-Chiro-Ins stimulates androgen synthesis and decreases the ovarian estrogen pathway; on the contrary, myo-Ins activates FSH response and aromatase activity, finally mitigating ovarian hyperandrogenism. However, when the two isomers are given in association-according to the physiological ratio of 40:1-patients could benefit from myo-Ins enhanced FSH and estrogen responsiveness, while taking advantage of the insulin-sensitizing effects displayed mostly by D-Chiro-Ins. We need not postulate insulin resistance to explain PCOS pathogenesis, given that insulin hypersensitivity is likely a shared feature of PCOS ovaries. Indeed, even in the presence of physiological insulin stimulation, the PCOS ovary synthesizes D-Chiro-Ins four times more than that measured in control theca cells. The increased D-Chiro-Ins within the ovary is detrimental in preserving steroidogenic control, and this failure can easily explain why treatment strategies based upon high D-Chiro-Ins have been recognized as poorly effective. Within this perspective, two factors emerge as major determinants in PCOS: hyperandrogenism and reduced aromatase expression. Therefore, PCOS could no longer be considered a disease only due to increased androgen synthesis without considering the contemporary downregulation of aromatase and FSH receptors. Furthermore, these findings suggest that inositols can be specifically effective only for those PCOS phenotypes featured by hyperandrogenism.

The Effect of Breadfruit Leaf Extract (Artocarpus Altilis) on Fasting Blood Sugar Levels among Diabetes Mellitus (DM) Type 2 Outpatient at Biru Public Health Center of Bone Regency, Indonesia

Diabetes is a disease that can reduce the quality of life of patients and lead to death. Based on Indonesian Basic Health research, the prevalence of diabetes mellitus has increased over several years. Breadfruit leaves contain antioxidant compounds that can lower blood sugar by inhibiting glucose transport in the gastrointestinal tract and stimulating insulin secretion in pancreatic beta cells. The study aimed to assess the effect of giving Breadfruit Leaf Extract on reducing Fasting Blood Sugar among type 2 Diabetes Mellitus Patients. The study used a quasi-experiment study with a randomized pretest-posttest, design with the control group. It involved 39 outpatients for type 2 diabetes mellitus at Biru Public Health Center of Bone Regency, who had suffered from Diabetes for 1-4 years. The sample was divided into 2 groups by simple random sampling, 19 respondents for the intervention group and 20 respondents for the control group. Data collected were the socio-demographic characteristics and fasting blood sugar levels. In the intervention group, breadfruit leaf capsules were given at a dose of 500 mg 1x1 for 21 days, while the control group was only given health education. The data were analyzed using the Chi-Square test, paired t-test, independent t-test, Wilcoxon Signed Rank Test, and Mann-Whitney. The majority of respondents aged 46-55 years were 53.8% in both groups, 74.4% were female, while the majority of BMI status had normal nutritional status as much as 41%. There was a change in FBS levels in the intervention group before (263.31 ± 134.43) and after (174.84 ± 84.99) intervention (p-value = 0.000). there was a change in FBS levels in the group before (181.35±91.36) and after (147.45 ±79.25) intervention (p-value = 0.001). it is known that there is a significant difference in changes in fasting blood sugar levels of patients with diabetes mellitus in the intervention group (-88.47±88.01) and the control group (-33.90±53.53) with (p-value = 0.024). The test results show that the content of flavonoids and other non-nutritive substances in breadfruit leaves has an effect on lowering the FBS of patients with diabetes mellitus and can be used as an alternative medicine in patients with diabetes mellitus.

ETNPPL modulates hyperinsulinemia-induced insulin resistance through the SIK1/ROS-mediated inactivation of the PI3K/AKT signaling pathway in hepatocytes.

Hyperinsulinemia is a critical risk factor for the pathogenesis of insulin resistance (IR) in metabolic tissues, including the liver. Ethanolamine phosphate phospholyase (ETNPPL), a newly discovered metabolic enzyme that converts phosphoethanolamine (PEA) to ammonia, inorganic phosphate, and acetaldehyde, is abundantly expressed in liver tissue. Whether it plays a role in the regulation of hyperinsulinemia-induced IR in hepatocytes remains elusive. Here, we established an in vitro hyperinsulinemia-induced IR model in the HepG2 human liver cancer cell line and primary mouse hepatocyte via a high dose of insulin treatment. Next, we overexpressed ETNPPL by using lentivirus-mediated ectopic to investigate the effects of ETNPPL per se on IR without insulin stimulation. To explore the underlying mechanism of ETNPPL mediating hyperinsulinemia-induced IR in HepG2, we performed genome-wide transcriptional analysis using RNA sequencing (RNA-seq) to identify the downstream target gene of ETNPPL. The results showed that ETNPPL expression levels in both mRNA and protein were significantly upregulated in hyperinsulinemia-induced IR in HepG2 and primary mouse hepatocytes. Upon silencing ETNPPL, hyperinsulinemia-induced IR was ameliorated. Under normal conditions without IR in hepatocytes, overexpressing ETNPPL promotes IR, reactive oxygen species (ROS) generation, and AKT inactivation. Transcriptome analysis revealed that salt-inducible kinase 1 (SIK1) is markedly downregulated in the ETNPPL knockdown HepG2 cells. Moreover, disrupting SIK1 prevents ETNPPL-induced ROS accumulation, damage to the PI3K/AKT pathway and IR. Our study reveals that ETNPPL mediates hyperinsulinemia-induced IR through the SIK1/ROS-mediated inactivation of the PI3K/AKT signaling pathway in hepatocyte cells. Targeting ETNPPL may present a potential strategy for hyperinsulinemia-associated metabolic disorders such as type 2 diabetes.

The Insulin Receptor Substrate 2 Mediates the Action of Insulin on HeLa Cell Migration via the PI3K/Akt Signaling Pathway.

Insulin signaling plays an important role in the development and progression of cancer since it is involved in proliferation and migration processes. It has been shown that the A isoform of the insulin receptor (IR-A) is often overexpressed, and its stimulation induces changes in the expression of the insulin receptor substrates (IRS-1 and IRS-2), which are expressed differently in the different types of cancer. We study the participation of the insulin substrates IRS-1 and IRS-2 in the insulin signaling pathway in response to insulin and their involvement in the proliferation and migration of the cervical cancer cell line. Our results showed that under basal conditions, the IR-A isoform was predominantly expressed. Stimulation of HeLa cells with 50 nM insulin led to the phosphorylation of IR-A, showing a statistically significant increase at 30 min (p ≤ 0.05). Stimulation of HeLa cells with insulin induces PI3K and AKT phosphorylation through the activation of IRS2, but not IRS1. While PI3K reached the highest level at 30 min after treatment (p ≤ 0.05), AKT had the highest levels from 15 min (p ≤ 0.05) and remained constant for 6 h. ERK1 and ERK2 expression was also observed, but only ERK2 was phosphorylated in a time-dependent manner, reaching a maximum peak 5 min after insulin stimulation. Although no effect on cell proliferation was observed, insulin stimulation of HeLa cells markedly promoted cell migration.

Ganglioside GM3 prevents high fat diet-induced hepatosteatosis via attenuated insulin signaling pathway.

Gangliosides, sialic acid-containing glycosphingolipids, are widely involved in regulations of signal transductions to control cellular functions. It has been suggested that GM3, the simplest structure among gangliosides, is involved in insulin resistance, whereas it remains unclear whether insulin signaling diminished by GM3 actually aggravates the pathological conditions in metabolic disorders. Moreover, the functional roles of gangliosides in the regulation of insulin signaling have not yet been fully elucidated in liver or hepatocytes despite that it is one of the major insulin-sensitive organs. To understand physiological roles of GM3 in metabolic homeostasis in liver, we conducted a high fat diet (HFD) loading experiment using double knockout (DKO) mice of GM2/GD2 synthase and GD3 synthase, which lack all gangliosides except GM3, as well as wild-type (WT) mice. DKO mice were strikingly resistant to HFD-induced hepatosteatosis, and hepatic lipogenesis-related molecules including insulin signaling components were down-regulated in HFD-fed DKO. Furthermore, we established primary hepatocyte cultures from DKO and WT mice, and examined their responses to insulin in vitro. Following insulin stimulation, DKO hepatocytes expressing GM3 showed attenuated expression and/or activations in the downstream components compared with WT hepatocytes expressing GM2. While insulin stimulation induced lipogenic proteins in hepatocytes from both genotypes, their expression levels were lower in DKO than in WT hepatocytes after insulin treatment. All our findings suggest that the modified gangliosides, i.e., a shift to GM3 from GM2, might exert a suppressive effect on lipogenesis by attenuating insulin signaling at least in mouse hepatocytes, which might result in protection of HFD-induced hepatosteatosis.

H2S- and Redox-State-Mediated PTP1B S-Sulfhydration in Insulin Signaling.

Because hydrogen sulfide (H2S) is classified as a gaseous signaling molecule, protein S-sulfhydration is known to be one of the mechanisms by which H2S signals are conducted. PTP1B, a negative regulator in insulin signaling, has been found to be S-sulfhydrated at Cys215-SH to form Cys215-SSH in response to endoplasmic reticulum (ER) stress. Therefore, we aimed to understand the change in PTP1B S-sulfhydration and cellular redox homeostasis in response to insulin stimulation. We demonstrated a feasible PEG-switch method to determine the levels of PTP1B S-sulfhydration. According to the results obtained from HEK293T and MDA-MB-231 cells, insulin induced a change in PTP1B S-sulfhydration that was similar to the change in Insulin receptor substrate 1 (IRS1) phosphorylation in both cell lines. However, insulin-induced PTP1B S-sulfhydration and IRS1 phosphorylation were only significantly affected by metformin in HEK293T cells. Insulin also induced an increase in reactive oxygen species (ROS) in both cell lines. However, the level of H2S, GSH, and GSSG was only significantly affected by insulin and metformin in HEK293T cells. HEK293T cells maintained high levels of H2S and cysteine, but low levels of GSSG and GSH in general compared to MDA-MB-231 cells. From these findings, we suggest that PTP1B activity is modulated by H2S and redox-regulated S-sulfhydration during insulin signaling.

Sex differences in muscle SIRT1 and SIRT3 and exercise + weight loss effects on muscle sirtuins.

The sirtuins, SIRT1 and SIRT3, are involved in the control of cellular processes to maintain metabolic homeostasis. The purpose of this study was to determine the effects of a 6-month aerobic training + weight loss program and hyperinsulinemia on SIRT1 and SIRT3 expression in skeletal muscle and to compare their expression between men and women. Thirty-five adult men (n = 18) and postmenopausal women (n = 17), (X ± SEM, age: 61 ± 1 years, BMI: 31.3 ± 0.7 kg/m2) completed 6 months 3×/week of aerobic exercise and 1×/week dietary instruction to induce weight loss (EX + WL). Participants had a VO2max test, vastus lateralis muscle biopsies at baseline and 2 h into a hyperinsulinemic-euglycemic clamp, a total body dual-energy X-ray absorptiometry scan, and abdominal computed tomography scan. Skeletal muscle SIRT1, SIRT3, and PGC1-α mRNA expression were quantified by qRT-PCR. Skeletal muscle SIRT1 and SIRT3 mRNA expression are higher in women than men (P < 0.005). Body weight, body fat, and abdominal obesity decreased and VO2max and glucose utilization (M) increased after EX + WL (P < 0.001). Basal SIRT1 decreased following EX + WL (P < 0.05). This change in basal SIRT1 was not related to changes in VO2max, M or fat mass, nor was it different by gender. Insulin stimulation increased SIRT1 expression (P < 0.001) and PGC1-α expression (P < 0.01) following EX + WL (insulin-basal post). Sex differences in the levels of these sirtuins did not affect changes with EX + WL. Skeletal muscle SIRT1 decreases after a long-term combined exercise and weight loss program in middle-aged and older adults.

Glipizide ameliorates human poly(Q) mediated neurotoxicity by upregulating insulin signalling in Drosophila disease models

Increasing reports suggest insulin signalling pathway as a putative drug target against polyglutamine [poly(Q)] disorders, such as Huntington's disease (HD), Spinocerebellar ataxias (SCA) 1, 2, 3 etc. However, studies on drug-based stimulation of insulin signalling cascade to mitigate poly(Q) pathogenesis are lacking. In our study, we adopted an evidence-based approach to examine if some established insulin stimulating drug can be utilized to restrict poly(Q) aetiology in Drosophila disease models. For the first time, we report that glipizide, an FDA approved anti-diabetic drug upregulates insulin signalling in poly(Q) expressing tissues and restricts formation of inclusion bodies and neurodegeneration. Moreover, it reinstates the chromatin architecture by improving histone acetylation, which is otherwise abrogated due to poly(Q) toxicity. In view of the functional conservation of insulin signalling pathway in Drosophila and humans, our finding strongly suggests that glipizide can be repurposed as an effective treatment strategy against the neurodegenerative poly(Q) disorders. Also, with appropriate validation studies in mammalian disease models, glipizide could be subsequently considered for the clinical trials in human patients.

Molecular mechanisms of antidiabetic effect of betulinic acid in lotus rhizome.

To explain the bio-physiological mechanisms of the antidiabetic effect of betulinic acid in Lotus rhizome. Even though Sri Lankan native medicine uses Lotus rhizome as a medicinal food for diabetes mellitus, its antidiabetic property has not been scientifically explained yet. It is found to compose several medicinally active components with antidiabetic properties, including Betulinic acid. A narrator review was conducted with a literature search in PubMed and Google Scholar databases using the search terms "Nelumbo nucifera rhizome", "Lotus rhizome", "phytochemicals", "antidiabetic effect", "hypoglycaemic effect" "Betulinic acid", and "molecular mechanism". The triterpenoid, Betulinic acid exerts its antidiabetic effect via seven bio-physiological mechanisms including, inhibiting α-glucosidase and α-amylase, upregulating the expression of peroxisome proliferator-activated receptor gamma coactivator-1 α, enhancing AS160 protein phosphorylation, stimulating adenosine monophosphate-activated protein kinase activation, stimulating Glucose transporter type 4 synthesis and translocation, inhibiting Protein Tyrosine Phosphatase 1 B activity preventing dephosphorylation of insulin receptor and stimulating Takeda-G-protein-receptor-5 resulting in an increased release of insulin from insulin-containing granulesCONCLUSION: The available scientific knowledge explains that betulinic acid in Lotus rhizome can improve glucose homeostasis contributing to the antidiabetic effect of this root (Tab. 1, Fig. 6, Ref. 29).

Therapeutic Effect of Tinospora cordifolia (Willd) Extracts on Letrozole-Induced Polycystic Ovarian Syndrome and its Complications in Murine Model.

Tinosopora cordifolia (Willd) (TC) is commonly used in Ayurvedic medicine since long time for number of ailments and its preparations are also considered by food safety and standards authority of India as nutritional supplement. However the scientific evidence on its possible safety and efficacy in polycystic ovarian syndrome and associated complications was not studied in detail. The purpose of this investigation is to examine whether or not TC can have therapeutic effects on letrozole induced PCOS and related complications such as body weight, dyslipidaemia, glucose tolerance, hormonal regulation, insulin resistance and sensitivity, severity of PCOS and histopathological changes in ovary using mice animal model. Present study is a preclinical study involving laboratory animals. After verifying the absence of PCOS, the animals began receiving Letrozole, which lasted for 21 days. Fasting blood glucose (FBG), the oral glucose tolerance test (OGTT), triglycerides, cholesterol, and weight were recorded. The levels of hormones like oestrogen, progesterone, insulin, testosterone, luteinising hormone (LH) and follicle stimulating hormone (FSH), histopathology was carried out. The Institutional Animal Ethics Committee at DITU gave its clearance to the animal experimentation on July 10, 2021 (DITU/IAEC/21-22/07-06). The majority of cornified epithelial cells were seen in groups treated with TC extract during the estrous phase of the cycle. Mice exposed to TC retained normal body weight. FBG, 1- and 2-hour OGTT, triglyceride and cholesterol levels were all significantly improved by extracts. Estradiol, progesterone, testosterone, insulin, LH and FSH concentration were all corrected in TC-treated animals. The HOMA-IR, HOMA-Beta and QUICKI values were also corrected with TC extracts. The morphological and microscopic features of the ovary were also greatly enhanced. Based on these findings, we conclude that treating PCOS mice with TC extracts significantly ameliorates the disease and severity down to nil-to-moderate levels by reducing hyperinsulinemia, hyperandrogenism, dyslipidaemia, enhancing insulin sensitivity, correcting oestrogen, progesterone, LH and FSH levels via enhanced ovarian function. Further molecular and cellular level of study is recommended for further elaboration of mechanism of action. • Tinospora cordifolia satva, oil and hydroalcoholic extract were studied in letrozole-induced PCOS in mice model• Anti PCOS efficacy of 3 preparations studied with respect to their mechanism of action in detail• For the first time proposing method of calculating severity of PCOS in animal model• Tinospora cordifolia oil preparation completely reversed PCOS effect of letrozole and made them normal• Histopathological and morphological studies support the biochemical claims.

The use of cinnamon supplementation in diabetes: Research evidence and expert opinion

Dietary supplements have increasingly used in the prevention and treatment of a variety of chronic conditions, During the previous decades, cinnamon have been reported to have a beneficial effects diabetes mellitus patients, and in experimental diabetic animals. The aim of this paper is to review cinnamon research findings relevant to its supplementary use in diabetes. Conclusion: There is convincing research evidence suggesting that cinnamon has at least a weak hypoglycemic effect and an insulin stimulation effect that can contribute to improving insulin sensitivity and reducing serum glycosylated hemoglobin (HbA1C) in type 2 diabetes. Its antioxidant effect can reduce the risks contributing to the development of diabetes.

Combined Arginine and Insulin Stimulation Elicits a Robust and Consistent Copeptin Response in Short Children

Introduction: Copeptin, co-secreted with arginine vasopressin, is regulated by osmotic and volume stimuli but also responds to intravenous arginine and insulin-induced hypoglycemia. The serum copeptin response to the latter agents has been studied in adults but only to a limited extent in children. The objective of this study was to describe the copeptin response to combined arginine and insulin in children with normal posterior pituitary function. Methods: We conducted a prospective, single-arm assessment of serum copeptin concentrations in children (age 7–16 years, n = 38) undergoing growth hormone stimulation testing with an arginine-insulin tolerance test (AITT) for short stature or growth deceleration in a tertiary referral center. After overnight fasting, arginine (500 mg/kg) was administered between 0 and 30 min intravenously (IV) followed by insulin (0.1 units/kg IV) at 60 min. Copeptin serum concentrations were measured at baseline (0 min), at the post-arginine peak (60 min), and at the post-insulin peak (90 min; 30 min post-insulin), respectively. The main outcome was the peak copeptin concentration. Results: Mean ± SD copeptin concentrations increased from 9.9 ± 5.0 pmol/L at 0 min to 13.2 ± 5.8 pmol/L at 60 min (p < 0.0001 vs. 0 min) and 27.7 ± 14.2 pmol/L at 90 min (p < 0.0001 vs. 0 and 60 min). There was no significant correlation between copeptin concentrations and age, BMI, pubertal status, cortisol, growth hormone, or glucose concentrations. Discussion/Conclusion: Arginine and insulin appear to have an additive and consistent effect resulting in significant stimulation of copeptin secretion in children. The AITT may be a useful tool to evaluate for normal posterior pituitary function in this age-group, with potential implications for the evaluation of polyuria-polydipsia syndrome.

The dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance

Insulin receptor (IR) signaling is central to normal metabolic control and is dysregulated in metabolic diseases such as type 2 diabetes. We report here that IR is incorporated into dynamic clusters at the plasma membrane, in the cytoplasm and in the nucleus of human hepatocytes and adipocytes. Insulin stimulation promotes further incorporation of IR into these dynamic clusters in insulin-sensitive cells but not in insulin-resistant cells, where both IR accumulation and dynamic behavior are reduced. Treatment of insulin-resistant cells with metformin, a first-line drug used to treat type 2 diabetes, can rescue IR accumulation and the dynamic behavior of these clusters. This rescue is associated with metformin’s role in reducing reactive oxygen species that interfere with normal dynamics. These results indicate that changes in the physico-mechanical features of IR clusters contribute to insulin resistance and have implications for improved therapeutic approaches.