Glycemic Homeostasis Research Articles

Vitamin K2 supplementation improves impaired glycemic homeostasis and insulin sensitivity for type 2 diabetes through gut microbiome and fecal metabolites

BackgroundThere is insufficient evidence for the ability of vitamin K2 to improve type 2 diabetes mellitus symptoms by regulating gut microbial composition. Herein, we aimed to demonstrate the key role of the gut microbiota in the improvement of impaired glycemic homeostasis and insulin sensitivity by vitamin K2 intervention.MethodsWe first performed a 6-month RCT on 60 T2DM participants with or without MK-7 (a natural form of vitamin K2) intervention. In addition, we conducted a transplantation of the MK-7-regulated microbiota in diet-induced obesity mice for 4 weeks. 16S rRNA sequencing, fecal metabolomics, and transcriptomics in both study phases were used to clarify the potential mechanism.ResultsAfter MK-7 intervention, we observed notable 13.4%, 28.3%, and 7.4% reductions in fasting serum glucose (P = 0.048), insulin (P = 0.005), and HbA1c levels (P = 0.019) in type 2 diabetes participants and significant glucose tolerance improvement in diet-induced obesity mice (P = 0.005). Moreover, increased concentrations of secondary bile acids (lithocholic and taurodeoxycholic acid) and short-chain fatty acids (acetic acid, butyric acid, and valeric acid) were found in human and mouse feces accompanied by an increased abundance of the genera that are responsible for the biosynthesis of these metabolites. Finally, we found that 4 weeks of fecal microbiota transplantation significantly improved glucose tolerance in diet-induced obesity mice by activating colon bile acid receptors, improving host immune-inflammatory responses, and increasing circulating GLP-1 concentrations.ConclusionsOur gut-derived findings provide evidence for a regulatory role of vitamin K2 on glycemic homeostasis, which may further facilitate the clinical implementation of vitamin K2 intervention for diabetes management.Trial registrationThe study was registered at https://www.chictr.org.cn (ChiCTR1800019663).

Progesterone Has No Impact on the Beneficial Effects of Estradiol Treatment in High-Fat-Fed Ovariectomized Mice

In recent decades, clinical and experimental studies have revealed that estradiol contributes enormously to glycemic homeostasis. However, the same consensus does not exist in women during menopause who undergo replacement with progesterone or conjugated estradiol and progesterone. Since most hormone replacement treatments in menopausal women are performed with estradiol (E2) and progesterone (P4) combined, this work aimed to investigate the effects of progesterone on energy metabolism and insulin resistance in an experimental model of menopause (ovariectomized female mice-OVX mice) fed a high-fat diet (HFD). OVX mice were treated with E2 or P4 (or both combined). OVX mice treated with E2 alone or combined with P4 displayed reduced body weight after six weeks of HFD feeding compared to OVX mice and OVX mice treated with P4 alone. These data were associated with improved glucose tolerance and insulin sensitivity in OVX mice treated with E2 (alone or combined with P4) compared to OVX and P4-treated mice. Additionally, E2 treatment (alone or combined with P4) reduced both hepatic and muscle triglyceride content compared with OVX control mice and OVX + P4 mice. There were no differences between groups regarding hepatic enzymes in plasma and inflammatory markers. Therefore, our results revealed that progesterone replacement alone does not seem to influence glucose homeostasis and ectopic lipid accumulation in OVX mice. These results will help expand knowledge about hormone replacement in postmenopausal women associated with metabolic syndrome and non-alcoholic fatty liver disease.

Carbohydrates for glycemic control: functional and microbiome aspects.

Glycemia goals are used as indicators of control and progression in prediabetes and diabetes. Adopting healthy eating habits is essential. It is worth considering the quality of carbohydrates to help with dietary glycemic control. The present article aims to review recent meta-analyses published in the years 2021-2022 on the effects of dietary fiber and low glycemic index/load (LGI/LGL) foods on glycemic control and how gut microbiome modulation contributes to glycemic control. Data involving more than 320 studies were reviewed. The evidence allows us to infer that LGI/LGL foods, including dietary fiber intake, are associated with reduced fasting glycemia and insulinemia, postprandial glycemic response, HOMA-IR, and glycated hemoglobin, which are more evident in soluble dietary fiber. These results can be correlated with changes in the gut microbiome. However, the mechanistic roles of microbes or metabolites implicated in these observations continue to be explored. Some controversial data highlight the need for more homogeneity between studies. The properties of dietary fiber are reasonably well established for their glycemic homeostasis effects, including the fermentation aspects. Findings of gut microbiome correlations with glucose homeostasis can be incorporated into clinical nutrition practice. Target dietary fiber interventions on microbiome modulation can offer options to improve glucose control and contribute to personalized nutritional practices.

Irisin administration restores beta-cell functional mass in a mouse model of type 2 diabetes

Aim: Irisin is a hormone secreted by skeletal muscle able to improve metabolic homeostasis. Serum irisin levels are reduced in type 2 diabetes (T2D), while exogenous irisin administration improves glycemic control in diabetic mice. We have previously demonstrated that irisin promotes beta-cell survival and function both in vitro and in vivo in healthy wild type mice. We have also demonstrated that irisin restores the defective glucose-stimulated insulin secretion (GSIS) and reduces apoptosis in human pancreatic islets from patients with T2D. Nevertheless, the beta-cellular effects of in vivo irisin administration to T2D mice are still unknown. Methods: C57Bl/6 mice (n = 8) were fed a high-fat diet (HFD, 60% of energy deriving from fat) for 10 weeks and then intraperitoneally injected with streptozotocin (STZ, 100 mg/kg) to induce diabetes. Four standard diet (SD)-fed mice were used as control. HFD/STZ mice were treated with 0.5 μg/g irisin (n = 4) or vehicle (n = 4), for 14 days. Fasting glycemia, insulinemia, body weight, glucose tolerance, and pancreatic islet function were assessed. Pancreatic islet architecture was also evaluated through immunofluorescence analyses. Results: Compared to SD mice, HFD/STZ mice showed higher fasting glycemia and body weight, glucose intolerance, and reduced GSIS; in addition, HFD/STZ mice showed reduced islet volume (-78%), beta-cell area (-35%), and insulin content (-60%), and increased alpha-cell area (+54%). Irisin administration significantly restored glycemia (-31%), body weight (-13%), glucose tolerance (-27%), GSIS (+23%), islet volume (+61%), beta-cell area (+34%) and alpha-cell area (-49%), and insulin content (+36%). Of note, irisin induced a 9-fold increase in beta-cell proliferation rate. Conclusions: These results show that irisin improves glycemic homeostasis and restores the functional beta-cell mass when administered in vivo to diabetic mice, probably by promoting beta-cell proliferation.

Bempedoic Acid: An Emerging Therapy for Uncontrolled Low-Density Lipoprotein (LDL) Cholesterol

Atherosclerotic cardiovascular disease (ASCVD) is a silent epidemic, which is progressing relentlessly across the globe. Developing countries such as India have a high prevalence of dyslipidemia and consequently a huge burden of coronary artery disease (CAD) and ASCVD. Low-density lipoprotein is regarded as the primary culprit in the genesis of ASCVD, and statins are the first line therapy for LDL-C lowering. Statin therapy has unequivocally demonstrated the benefit of lowering LDL-C in patients across the spectrum of CAD and ASCVD. Muscle symptoms and worsening of glycemic homeostasis could be challenges with statin therapy, especially with the use of high doses. A large fraction of patients are also unable to achieve their LDL goals with statins alone in clinical practice. Moreover, LDL-C goals have become aggressive over years, necessitating a combination of lipid lowering therapies. PCSK-9 inhibitors and Inclisiran have emerged as robust and safe lipid-lowering agents, but parenteral administration and high cost precludes their widespread use. Bempedoic acid is a novel lipid-lowering agent working upstream of statins by inhibiting the enzyme ATP citrate lyase (ACL). The drug produces an average LDL lowering of 22-28% in statin-naïve patients and 17-18% when given to preexisting statin users. Because skeletal muscles lack the ACL enzyme, there is minimal risk of muscle-related symptoms. In combination with ezetimibe, the drug synergistically reduced LDL-C by 39%. Moreover, the drug has no adverse effect on glycemic parameters and lowers hsCRP (inflammation) like statin. The series of four randomized CLEAR trials, involving >4000 patients, have shown consistent LDL lowering across the spectrum of ASCVD patients with or without background therapy. The large and only cardiovascular outcome trial of the drug (CLEAR Outcomes) has recently demonstrated a 13% reduction of MACE at 40 months. Rise in levels of uric acid (four times) and acute gout (three times) are more common compared to placebo with the drug, owing to competitive renal transportation by OAT 2. In a nutshell, Bempedoic acid represents a value addition to the inventory of dyslipidemia management.

Short-chain fatty acids are associated with adiposity, energy and glucose homeostasis among different metabolic phenotypes in the Nutritionists' Health Study.

The gut microbiome is associated with obesity, mainly mediated by bacteria-produced short-chain fatty acids (SCFAs). It is unknown how SCFA concentrations are associated with the phenotypes metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy obese/overweight (MHO), and metabolically unhealthy obese/overweight (MUO). We compared plasma and fecal SCFA concentrations among adult women categorized according to the metabolic phenotypes mentioned above and examined associations between SCFA and adiposity and components of energy and glucose homeostasis. This was a cross-sectional study involving 111 participants. Body composition was assessed by DEXA. Energy and glycemic homeostasis were assessed by the standard mixed-meal tolerance test coupled with indirect calorimetry. SCFAs were quantified by gas chromatography and mass spectrometry. Only plasma propionate was increased in the MHNW phenotype compared to the MHO and MUO phenotypes [p < 0.05]. Fecal propionate and butyrate concentrations and plasma propionate concentrations were inversely associated with total and visceral adiposity [p < 0.05]. Fecal and plasma SCFA concentrations were associated with reduced glucose, insulin and HbA1c levels, increased fasting and postprandial GLP-1 levels; and more preserved beta-cell function [p < 0.05]. Fecal and plasma SCFA concentrations were positively correlated with resting energy expenditure and lipid oxidation rate and inversely correlated with the oxidation rate of carbohydrates [p < 0.05]. These findings reinforce the concept that fecal and plasma SCFA concentrations are linked to specific components of energy and glucose homeostasis; and body adiposity. However, it was not possible to discriminate the different metabolic phenotypes of adiposity based on the determination of fecal SCFA concentrations.

The early use of glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes and high cardiovascular risk

Patients with type 2 diabetes mellitus are at an increased risk of cardiovascular disease and microvascular and macrovascular complications. Although multiple classes of antidiabetic drugs are currently available, cardiovascular complications of diabetes still cause considerable morbidity and premature cardiovascular mortality in diabetic patients. The development of new drugs represented a conceptual breakthrough in the treatment of patients with type 2 diabetes mellitus. In addition to improving glycemic homeostasis, these new treatments have consistently demonstrated relevant cardiovascular and renal benefits due to their multiple pleiotropic effects. The aim of this review is to analyze the direct and indirect mechanisms by which glucagon-like peptide 1 receptor agonists favorably impact cardiovascular outcome and report current indications for their implementation in clinical practice based on national and international guidelines.

Outcomes of laparoscopic SG and laparoscopic one-anastomosis gastric bypass in terms of improvement in the lipid profile

Introduction Obesity is associated with an increased mortality rate, particularly of cardiovascular origin, due to the close association between obesity and cardiovascular risk factors such as dyslipidemia. The efficacy of different bariatric Surgeries in weight reduction and in glycemic homeostasis improvement has been widely described. In contrast, little is known about the effects of bariatric surgery on lipid profile. Few studies have compared the effect of different surgical techniques on lipid profile changes. So, we aim at assessing and comparing the effect of SG and OAGB in terms of improvement in the lipid profile. Patients and methods This is a prospective comparative study that included 46 morbidly obese patients. Patients were divided into two groups: SG group (23 patients), and OAGB group (23 patients). Preoperative and 3 months post-operative cholesterol levels, triglycerides, LDL (Low-density lipoprotein), and HDL (High-density lipoprotein) were measured. The results were documented, analyzed, and correlated to baseline results, and results from the two groups were compared together. Results This study revealed that most of our patients who were candidates for bariatric surgeries either SG or OAGB presented with elevated mean LDL, Cholesterol, and triglyceride and decreased mean HDL. The results showed a significant improvement of lipid profile after both SG and OAGB over a 3-month interval. There was a statistically significant difference between the two operations in the decrease of cholesterol over 3 months postoperatively in favour of the OAGB operation; hence the significant difference is observed in the change of the cardiovascular risk and improvement of quality of life of those patients underwent OAGB. Conclusion Obese patients have shown an association with elevated LDL, Cholesterol, and triglyceride and decreased HDL. SG and OAGB both result in a significant decrease in LDL, Cholesterol and triglyceride and an increase in HDL.

Bisphenol F induced hyperglycemia via activation of oxidative stress-responsive miR-200 family in the pancreas

Bisphenol F (BPF), BPS and BPAF are gaining popularity as main substitutes to BPA, but there is no clear evidence that these compounds disrupt glycemic homeostasis in the same way. In this study, four bisphenols were administered to C57BL/6 J mice, and showed that the serum insulin was elevated in the BPA and BPS exposed mice, whereas BPF exposed mice exhibited lower serum insulin and higher blood glucose. BPF decreased oxidized glutathione/reduced glutathione ratio (GSSG/GSH) and N6–methyladenosine (m6A) levels, which was responsible for pancreatic apoptosis in mice. Additionally, the downregulation of Nrf2 and the aberrant regulation of the p53-lncRNA H19 signaling pathway further increased miR-200 family in the BPF-exposed pancreas. The miR-200 family directly suppressed Mettl14 and Xiap by targeting their 3' UTR, leading to islet apoptosis. Antioxidant treatment not only elevated m6A levels and insulin contents but also suppressed the miR-200 family in the pancreas, ultimately improving BPF-induced hyperglycemia. Taken together, miR-200 family could serve as a potential oxidative stress-responsive regulator in the pancreas. And moreover, we demonstrated a novel toxicological mechanism in that BPF disrupted the Keap1-Nrf2 redox system to upregulate miR-141/200b/c which controlled pancreatic insulin production and apoptosis via Mettl14 and Xiap, respectively. As the major surrogates of BPA in various applications, BPF was also diabetogenic, which warrants attention in future research.

Hydrophobicity Regulation of Energy Acceptors Confined in Mesoporous Silica Enabled Reversible Activation of Optogenetics for Closed-Loop Glycemic Control.

Optogenetics-based synthetic biology holds great promise as a cell-based therapy strategy for many clinical incurable diseases; however, precise control over genetic expression strength and timing through disease state-related closed-loop regulation remains a challenge due to the lack of reversible probes to indicate real-time metabolite fluctuations. Here, based on a novel mechanism of analyte-induced hydrophobicity regulation of energy acceptors confined in mesoporous silica, we developed a smart hydrogel platform comprising glucose reversible responsive upconversion nanoprobes and optogenetic engineered cells, in which the upconverted blue light strength was adaptively tuned through blood glucose levels to control optogenetic expressions for insulin secretion. The intelligent hydrogel system enabled convenient maintenance of glycemic homeostasis through simple near-infrared illuminations without any additional glucose concentration monitoring, which efficiently avoided genetic overexpression-induced hypoglycemia. This proof-of-concept strategy efficiently combines diagnostics with optogenetics-based synthetic biology for mellitus therapy, opening up a new avenue for nano-optogenetics.

Cinnamaldehyde supplementation acts as an insulin mimetic compound improving glucose metabolism during adolescence, but not during adulthood, in healthy male rats.

Adolescence is a critical period of increased vulnerability to nutritional modifications, and adolescents may respond differently from adults to dietary intake and nutraceuticals. Cinnamaldehyde, a major bioactive compound of cinnamon, improves energy metabolism, as has been shown in studies conducted primarily in adult animals. We hypothesized that cinnamaldehyde treatment may have a higher impact on the glycemic homeostasis of healthy adolescent rats than on healthy adult rats. Male adolescent (30 days) or adult (90 days) Wistar rats received cinnamaldehyde (40 mg/kg) for 28 days by gavage. The oral glucose tolerance test (OGTT), liver glycogen content, serum insulin concentration, serum lipid profile, and hepatic insulin signaling marker expression were evaluated. Cinnamaldehyde-treated adolescent rats showed less weight gain (P = 0.041), improved OGTT (P = 0.004), increased expression of phosphorylated IRS-1 (P = 0.015), and a trend to increase phosphorylated IRS-1 (P = 0.063) in the liver of adolescent rats in the basal state. None of these parameters was modified after treatment with cinnamaldehyde in the adult group. Cumulative food intake, visceral adiposity, liver weight, serum insulin, serum lipid profile, hepatic glycogen content, and liver protein expression of IRβ, phosphorylated IRβ, AKT, phosphorylated AKT, and PTP-1B in the basal state were similar between both age groups. In a healthy metabolic condition, cinnamaldehyde supplementation affects glycemic metabolism in adolescent rats while promoting no changes in adult rats.

Exercise training restores weight gain and attenuates hepatic inflammation in a rat model of non-celiac gluten sensitivity.

Gluten intolerance is associated with several disorders in the body. Although research has grown in recent years, the understanding of its impact on different tissues and the effects of physical exercise in mitigating health problems in the condition of gluten intolerance are still limited. Therefore, our objective was to test whether gliadin would affect metabolism and inflammation in liver tissue and whether aerobic physical exercise would mitigate the negative impacts of gliadin administration in rodents. Wistar rats were divided into exercised gliadin, gliadin, and control groups. Gliadin was administered by gavage from birth to 60 days of age. The rats in the exercised gliadin group performed an aerobic running exercise training protocol for 15 days. At the end of the experiments, physiological, histological, and molecular analyzes were performed in the study. Compared to the control group, the gliadin group had impaired weight gain and increased gluconeogenesis, lipogenesis, and inflammatory biomarkers in the liver. On the other hand, compared to the gliadin group, animals in the exercise-gliadin group had a recovery in body weight, improved insulin sensitivity, and a reduction in some gluconeogenesis, lipogenesis, and inflammatory biomarkers in the liver. In conclusion, our results revealed that the administration of gliadin from birth impaired weight gain and induced an increase in hepatic inflammatory cytokines, which was associated with an impairment of glycemic homeostasis in the liver, all of which were attenuated by adding aerobic exercise training in the gliadin group.

Metabolic effects of coenzyme Q10, magnesium and vitamin D in cardiovascular diseases: a systematic review

Introduction: Cardiovascular diseases (CVD) are the main causes of death in the population. According to data from the World Health Organization for 2020, of the 20.8 million deaths from these diseases, 9.2 million are due to atherosclerotic coronary disease. In this context, the beneficial metabolic effects of magnesium, vitamin D, and coenzyme Q10 can be highlighted. Objective: It was to scientifically analyze, through clinical and experimental studies, the influence of the three elements Magnesium, Vitamin D, and Coenzyme Q10 concerning cardiovascular diseases and metabolic syndrome, highlighting the improvement of metabolic disorders and heart failure. Methods: The systematic review rules of the PRISMA Platform were followed. The research was carried out from September to November 2022 in Scopus, PubMed, Science Direct, Scielo, and Google Scholar databases. The quality of the studies was based on the GRADE instrument and the risk of bias was analyzed according to the Cochrane instrument. Results and Conclusion: A total of 154 articles were found, and 80 articles were evaluated and 78 were included in this systematic review. Considering the Cochrane tool for risk of bias, the overall assessment resulted in 18 studies with a high risk of bias and 26 studies that did not meet GRADE. Most studies showed homogeneity in their results, with I2 =95.7% &gt;50%. It was concluded that magnesium plays a fundamental role in glucose metabolism, insulin, and glycemic homeostasis, in the synthesis of adenosine triphosphate, proteins, and nucleic acids. However, further studies are needed to better clarify the role of magnesium in the prevention and treatment of cardiovascular diseases, especially concerning higher concentrations and increased treatment time. Vitamin D plays important roles in innate and adaptive immune responses, cell cycle, and metabolic processes, evidenced by the reported relationship between its deficiency and the prevalence of immune-mediated disorders, cancer, and cardiometabolic diseases. Coenzyme Q10 exerts an important protective antioxidant action. Clinical studies carried out showed that pathologies such as acute myocardial infarction, arterial hypertension, myopathies induced by statins, physical fatigue inherent to physical exercise, male infertility, pre-eclampsia, Parkinson's disease, periodontal diseases, and migraines had low plasma concentrations of Q10. In addition, Coenzyme Q10 reduces the amount of lipid peroxide found in atherosclerotic lesions. Thus, Q10 protects the lipids present in cell membranes, as well as plasma lipoproteins.

Identification of Genipin as a Potential Treatment for Type 2 Diabetes.

The prevalence of type 2 diabetes (T2D) has been rising dramatically in many countries around the world. The main signatures of T2D are insulin resistance and dysfunction of β-cells. While there are several pharmaceutical therapies for T2D, no effective treatment is available for reversing the functional decline of pancreatic β-cells in T2D patients. It has been well recognized that glucagon-like peptide-1 (GLP-1), which is an incretin hormone secreted from intestinal L-cells, plays a vital role in regulating glycemic homeostasis via potentiating glucose-stimulated insulin secretion and promoting β-cell function. We found that genipin, a natural compound from Elli, can directly target intestinal L-cells, leading to the secretion of GLP-1. Incubation of the cells with genipin elicited a rapid increase in intracellular Ca2+. Inhibition of PLC ablated genipin-stimulated Ca2+ increase and GLP-1 secretion, suggesting that genipin-induced GLP-1 release from cells is dependent on the PLC/Ca2+ pathway. In vivo, acute administration of genipin stimulated GLP-1 secretion in mice. Chronically, treatment with genipin via oral gavage at 50 mg/kg/day for 6 weeks reversed hyperglycemia and insulin resistance in high-fat-diet (HFD)-induced obese mice. Moreover, genipin alleviated the impaired lipid metabolism and decreased lipid accumulation in the liver of obese mice. These results suggest that naturally occurring genipin might potentially be a novel agent for the treatment of T2D and diet-induced fatty liver disease.

Role of leisure sedentary behavior on type 2 diabetes and glycemic homeostasis: a Mendelian randomization analysis.

Utilize Mendelian randomization (MR) to examine the impact of leisure sedentary behavior (LSB) on the prevalence of type 2 diabetes mellitus (T2D) and glycemic homeostasis impairment, as well as to identify potential mediating pathways involved in these associations. We chose genetic variants linked to LSB from a large genome-wide association study (GWAS) to use as instrumental variables (IVs). Then, we used a two-sample MR study to investigate the link between LSB and T2D and glycemic homeostasis. Multivariate MR (MVMR) and mediation analysis were also used to look at possible mediating paths. MR analysis showed a genetical link between leisure TV watching and T2D (OR 1.64, 95% CI 1.39-1.93, P< 0.001) and impaired Glycemic Homeostasis, while leisure computer use seemed to protect against T2D prevalence (OR 0.65, 95% CI 0.50-0.84, P< 0.001). It was found that leisure TV watching increases the risk of T2D through higher BMI (mediation effect 0.23, 95% CI 0.11-0.35, P< 0.001), higher triglycerides (mediation effect 0.07, 95% CI 0.04-0.11, P< 0.001), and less education (mediation effect 0.16, 95% CI 0.08-0.24, P< 0.001). Sensitivity and heterogeneity analyses further substantiated the robustness of these findings. Reverse MR analysis did not yield significant results. This study shows LSB is linked to a higher rate of T2D and impaired glycemic homeostasis through obesity, lipid metabolism disorders, and reduced educational attainment.

Investigation into the Intake of Edible Mushroom &amp;lt;i&amp;gt;Pleurotus ostreatus&amp;lt;/i&amp;gt; (Aqueous Extract Oyster Mushroom) on Biochemical Indices of Female Wistar Rats

Pleurotus ostreatus, popularly known as oyster mushroom, has nutraceutical properties that include hypocholesterolemic, hypoglycemic, antioxidant, anti-inflammatory, antitumor, hepatoprotective and hypotensive activities. Aqueous Extract Oyster Mushroom (AEOM) containing lyophilized P. ostreatus reconstituted in 0.9% saline solution was evaluated for its effect on body weight, biochemical indices and pancreas morphometry. Twelve healthy Wistar female rats were assigned to Control and AEOM groups, consisting of rats that received 0.9% saline solution and AEOM (100 mg/kg/day), respectively, administered by oral gavage at 3 mL/kg of body weight for 15 days. The animals had free access to commercial feed and water ad libitum. Blood was obtained by cardiac puncture and serum was used to biochemical determinations. Pancreas was excised, weighed and fixed in 4% neutral buffered formalin for histopathological examination. Initial and final body weights, and absolute and relative weights of pancreas did not differ between the groups. Total cholesterol, HDL-c, albumin and uric acid were lower in the AEOM group compared to the control group. The serum concentration of total proteins, glucose, triglycerides, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, creatinine and urea were similar in the groups. Pancreas of rats treated with AEOM exhibited an increase in the size of pancreatic islet. Thus, the use of AEOM is relatively safe at the dose studied and produces hypertrophy of the pancreatic islets without altering glycemic homeostasis.

Single-cell RNA sequencing combined with single-cell proteomics identifies the metabolic adaptation of islet cell subpopulations to high-fat diet in mice.

Islets have complex heterogeneity and subpopulations. Cell surface markers representing alpha, beta and delta cell subpopulations are urgently needed for investigations to explore the compositional changes of each subpopulation in obesity progress and diabetes onset, and the adaptation mechanism of islet metabolism induced by a high-fat diet (HFD). Single-cell RNA sequencing (scRNA-seq) was applied to identify alpha, beta and delta cell subpopulation markers in an HFD-induced mouse model of glucose intolerance. Flow cytometry and immunostaining were used to sort and assess the proportion of each subpopulation. Single-cell proteomics was performed on sorted cells, and the functional status of each alpha, beta and delta cell subpopulation in glucose intolerance was deeply elucidated based on protein expression. A total of 33,999 cells were analysed by scRNA-seq and clustered into eight populations, including alpha, beta and delta cells. For alpha cells, scRNA-seq revealed that the Ace2low subpopulation had downregulated expression of genes related to alpha cell function and upregulated expression of genes associated with beta cell characteristics in comparison with the Ace2high subpopulation. The impaired function and increased fragility of ACE2low alpha cells exposure to HFD was further suggested by single-cell proteomics. As for beta cells, the CD81high subpopulation may indicate an immature signature of beta cells compared with the CD81low subpopulation, which had robust function. We also found differential expression of Slc2a2 in delta cells and a potentially stronger cellular function and metabolism in GLUT2low delta cells than GLUT2high delta cells. Moreover, an increased proportion of ACE2low alpha cells and CD81low beta cells, with a constant proportion of GLUT2low delta cells, were observed in HFD-induced glucose intolerance. We identified ACE2, CD81 and GLUT2 as surface markers to distinguish, respectively, alpha, beta and delta cell subpopulations with heterogeneous maturation and function. The changes in the proportion and functional status of islet endocrine subpopulations reflect the metabolic adaptation of islets to high-fat stress, which weakened the function of alpha cells and enhanced the function of beta and delta cells to bring about glycaemic homeostasis. Our findings provide a fundamental resource for exploring the mechanisms maintaining each islet endocrine subpopulation's fate and function in health and disease. The scRNA-seq analysis datasets from the current study are available in the Gene Expression Omnibus (GEO) repository under the accession number GSE203376.

Glucose-responsive microneedle patch for closed-loop dual-hormone delivery in mice and pigs

Insulin and glucagon secreted from the pancreas with dynamic balance play a vital role in regulating blood glucose levels. Although distinct glucose-responsive insulin delivery systems have been developed, the lack of a self-regulated glucagon release module limits their clinical applications due to the potential risk of hypoglycemia. Here, we describe a transdermal polymeric microneedle patch for glucose-responsive closed-loop insulin and glucagon delivery to achieve glycemic regulation with minimized risk of hypoglycemia. The glucose-responsive phenylboronic acid units can bind to glucose to reversibly shift the net charge (from positive to negative) of the entire polymeric matrix within microneedles. Therefore, the release ratio of the negatively charged insulin and the positively charged glucagon analog from the patch can be dynamically tuned upon the fluctuation of blood glucose levels to realize glycemic homeostasis. In both chemically induced type 1 diabetic mouse and minipig models, this glucose-responsive dual-hormone microneedle patch demonstrated tight long-term regulation in blood glucose levels (>24 hours in minipigs).

Sex differences in endocannabinoids during 3 years of Mediterranean diet intervention: Association with insulin resistance and weight loss in a population with metabolic syndrome.

Excess circulating endocannabinoids (eCBs) and imbalanced N-acylethanolamines (NAEs) related eCBs abundance could influence dietary weight loss success. We aimed to examine sex differences in the impact of a 3-years Mediterranean diet (MedDiet) intervention on circulating eCBs, NAEs and their precursor fatty acids, and to analyze the interplay between changes in eCBs or NAEs ratios, insulin resistance and the achievement of clinically meaningful weight reductions. Prospective cohort study in a subsample of N = 105 participants (54.3% women; 65.6 ± 4.6 years) with overweight or obesity and metabolic syndrome that underwent a 3-years MedDiet intervention (PREDIMED-Plus study). Plasma eCBs and NAEs, including 2-arachidonoylglycerol (2-AG), anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), fatty acids, diet, glycemic homeostasis (including the assessment of insulin resistance-HOMA-IR), and cardiovascular risk markers were monitored (at 0-6-12-36 months). Mediterranean diet adherence increased in both sexes and remained high during the 3 years of follow-up. Reductions in body weight, glycemic and cardiovascular parameters were larger in men than in women. Women presented higher concentrations of NAEs than men throughout the study. In both sexes, AEA and other NAEs (including OEA, and PEA) decreased after 6 months (for AEA: -4.9%), whereas the ratio OEA/AEA increased after 1 year (+5.8%). Changes in 2-AG (-3.9%) and the ratio OEA/PEA (+8.2%) persisted over the 3 years of follow-up. In women, 6-months changes in AEA (OR = 0.65) and the ratio OEA/AEA (OR = 3.28) were associated with the achievement of 8% weight reductions and correlated with HOMA-IR changes (r = 0.29 and r = -0.34). In men, OEA/PEA changes were associated with 8% weight reductions (OR = 2.62) and correlated with HOMA-IR changes (r = -0.32). A 3-years MedDiet intervention modulated plasma concentrations of eCBs and NAEs. Changes in AEA and in the relative abundance of NAEs were associated with clinically meaningful weight reductions. However, marked sex differences were identified in eCBs and NAEs, as well as in the efficacy of the intervention in terms of glycemic and cardiovascular parameters, which could be related to post-menopause alterations in glucose metabolism. These findings support a sex-balanced research strategy for a better understanding of the mechanisms underlying the regulation of body weight loss.

The effects of N-acetylcysteine administration on metabolic status and serum adiponectin levels in patients with metabolic syndrome: A randomized, double-blind, placebo-controlled trial

• NAC administration to patients with MetS improved antioxidative defense system and inflammatory status. • NAC administration to patients with MetS ameliorated glycemic control and serum HDL-cholesterol levels. • NAC prescription may be a new strategy for the amelioration of metabolic parameters in patients with MetS. This study examined the impact of N-acetylcysteine (NAC) administration on metabolic parameters and serum adiponectin levels in individuals with metabolic syndrome (MetS). This randomized clinical trial included 76 people with MetS, aged 25–75 years. Participants were randomly assigned to receive either 1800 mg/day NAC (n = 38) or matched placebo (n = 38) for 12 weeks. Fasting blood samples were collected at the onset and at the end of 12-week intervention to quantify metabolic parameters. NAC significantly reduced fasting plasma glucose (P = 0.02), fasting serum insulin (P = 0.006), insulin resistance index (P = 0.005), and serum C-reactive protein (P = 0.003), and increased serum HDL-cholesterol (P = 0.001) and plasma total glutathione (P < 0.001) versus the placebo group. NAC administration did not alter adiponectin, blood pressure, other lipid indices, malondialdehyde, and total antioxidant capacity. Overall, 1800 mg/day NAC consumption for 12 weeks in MetS subjects had positive impacts on the parameters of glycemic homeostasis, HDL-cholesterol, inflammatory status, and body antioxidative defense system. NAC prescription may be a new strategy for the amelioration of metabolic parameters in individuals with MetS. Clinical Trial Registration: This clinical trial was prospectively registered in the Iranian website for registration of clinical trials ( https://www.irct.ir/trial/44284 ).