Regulation Of Glucose Homeostasis Research Articles

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

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

FRI617 Targeting Unc119b For Insulin Sensitization

Abstract Disclosure: A. Mittal: None. P. Buscaglia: None. J.A. Sebag: None. Using high-throughput screening, we identified a new insulin sensitizer, C59, which enhances insulin-stimulated GLUT4 translocation and glucose uptake in glucose storage tissues. C59 treatment improves glucose tolerance in rodent models of insulin resistance. Using Proteome Integral Stability Assay we identified Unc119B as the molecular target of C59. Interaction of C59 with Unc119 was further confirmed by solving the crystal structure of C59 bound Unc119. Unc119B, a protein involved in intracellular trafficking of lapidated cargos, has not previously been implicated in the regulation of glucose homeostasis. Here, we show that deletion of Unc119B protects mice from high fat diet induced insulin resistance compared to DIO WT mice despite similar weight gain, thus, further suggesting an important role of this protein in glucose handling. To understand the mechanism through which Unc119b may inhibit insulin-stimulated GLUT4 translocation, we tested its interaction with TC10α, a prenylated small G-protein that plays a critical role in GLUT4 translocation. Co-immunoprecipitation in CHO cells revealed that Unc119B forms a complex with TC10α. Our results identify Unc119B as a new important regulator of GLUT4 translocation and suggest that it may be acting through the regulation of TC10α activity. This work also identifies Unc119b as a new promising target for the treatment of pre-diabetes and type II diabetes. Presentation: Friday, June 16, 2023

SAT034 Exploring The Role Of Zfp664 In Hepatic Glucose Regulation

Abstract Disclosure: A. Tsay: None. J. Wang: None. Genome wide association studies (GWAS) identify the association between variants at genomic loci and common diseases. These variants consist of single nucleotide polymorphisms (SNPs), which can be localized within coding or non-coding regions. The former could affect the functions of proteins encoded by these genes. The latter could modulate the expression of genes contained or localized nearby these SNPs. Several SNPs associated with metabolic disease such as diabetes, obesity, and dyslipidemia are found in and nearby the human ZNF664 gene, which encodes a zinc finger protein that is predicted to be a transcriptional regulator. The mouse homolog of ZNF664 is Zfp664, whose amino acid sequence is identical to ZNF664. To learn whether Zfp664 contains a transcriptional activation or repression function, the expression plasmid harboring the cDNA of full length or deletion mutants of mouse Zfp664 fused to yeast GAL4 DNA binding domain (DBD) was transfected into HEK293T cells along with a luciferase reporter plasmid containing 5 copies of the GAL4 binding sites. We saw decreased luciferase activity in cells overexpressing the GAL4 DBD and full length Zfp664 fusion protein. Thus, Zfp664 acts as a transcriptional repressor. The deletion analysis identified that amino acid 7 to 95 of Zfp664 was required for its transcriptional repressive activity. To test the metabolic function of hepatic Zfp664, 8 weeks old male C57Bl/6J mice were infected with adeno-associated virus (AAV) expressing either scramble small hairpin RNA (shRNA, as a control) or shRNA targeting Zfp664 and then fed a normal chow diet or western diet (42% kcal from fat, 0.2% total cholesterol) for 12 weeks. We found that mice infected with AAV expressing Zfp664 shRNA had a lower expression of Zfp664 in the liver but not in epididymal white adipose tissue and gastrocnemius muscle. Under chow diet feeding, not only did hepatic Zfp664 knockdown not affect glucose tolerance and insulin sensitivity, but it also did not affect fasting glucose, insulin, triglyceride, and total cholesterol levels. In contrast, in mice fed a western diet, hepatic Zfp664 knockdown worsened glucose tolerance and elevated fasting insulin levels. Moreover, the expression of hepatic gluconeogenic genes, such as phosphoenolpyruvate carboxykinase (Pck1) and the catalytic subunit of glucose-6-phosphatase (G6pc), was increased. The fasting plasma triglyceride and total cholesterol levels were not affected by hepatic Zfp664 knockdown in western diet fed mice. Overall, these results discover the novel role of Zfp664 in the regulation of hepatic glucose homeostasis. Presentation: Saturday, June 17, 2023

Transcription factor EB: A potential integrated network regulator in metabolic-associated cardiac injury.

With the worldwide pandemic of metabolic diseases, such as obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD), cardiometabolic disease (CMD) has become a significant cause of death in humans. However, the pathophysiology of metabolic-associated cardiac injury is complex and not completely clear, and it is important to explore new strategies and targets for the treatment of CMD. A series of pathophysiological disturbances caused by metabolic disorders, such as insulin resistance (IR), hyperglycemia, hyperlipidemia, mitochondrial dysfunction, oxidative stress, inflammation, endoplasmic reticulum stress (ERS), autophagy dysfunction, calcium homeostasis imbalance, and endothelial dysfunction, may be related to the incidence and development of CMD. Transcription Factor EB (TFEB), as a transcription factor, has been extensively studied for its role in regulating lysosomal biogenesis and autophagy. Recently, the regulatory role of TFEB in other biological processes, including the regulation of glucose homeostasis, lipid metabolism, etc. has been gradually revealed. In this review, we will focus on the relationship between TFEB and IR, lipid metabolism, endothelial dysfunction, oxidative stress, inflammation, ERS, calcium homeostasis, autophagy, and mitochondrial quality control (MQC) and the potential regulatory mechanisms among them, to provide a comprehensive summary for TFEB as a potential new therapeutic target for CMD.

Gender-specific Reference Range for Serum Leptin in Omani Population.

Leptin is a hormone that contributes to glucose homeostasis and food intake regulation via its action on the hypothalamus. Leptin level increases with obesity and overfeeding and decreases with energy deficiency. Serum leptin levels vary between different ethnic groups with no reports of its reference range in the Arabic population. We sought to determine gender-specific reference ranges for serum leptin in a cohort of the Arabic population and identify the cut-off value for different metabolic derangements. The study data were obtained from the records of 1198 subjects included in the Oman Family Study. The percentile method was used in the estimation reference range and the receiver operating characteristic to identify cut-off points for multiple metabolic derangements. The reference range of serum leptin was 0.5-90.6 ng/mL, and it was not correlated with the age of the subjects. Higher leptin was observed in females compared to males (p < 0.001), and the reference range for serum leptin in females was 4.9-96.3 ng/mL compared to 0.25-48.8 ng/mL in males. The optimum cut-off value for leptin ranged between 24.1-28.9 ng/mL for metabolic syndrome, obesity, central obesity, and type 2 diabetes. We identified gender-specific reference ranges for serum leptin in a large cohort of Arabs. The optimum cut-off value for serum leptin to determine metabolic derangement with the highest sensitivity and specificity was 24.1-28.9 ng/mL. Future studies are needed to study the relative risk of higher serum leptin using prospective studies.

Insulin Preferentially Regulates the Activity of Parasympathetic Preganglionic Neurons over Sympathetic Preganglionic Neurons.

Insulin is a peptide hormone that regulates post-prandial physiology, and it is well known that insulin controls homeostasis at least in part via the central nervous system. In particular, insulin alters the activity of neurons within the autonomic nervous system. However, currently available data are mostly from unidentified brainstem neurons of the dorsal motor nucleus of the vagus nerve (DMV). In this study, we used several genetically engineered mouse models to label distinct populations of neurons within the brainstem and the spinal cord for whole-cell patch clamp recordings and to assess several in vivo metabolic functions. We first confirmed that insulin directly inhibited cholinergic (parasympathetic preganglionic) neurons in the DMV. We also found inhibitory effects of insulin on both the excitatory and inhibitory postsynaptic currents recorded in DMV cholinergic neurons. In addition, GABAergic neurons of the DMV and nucleus tractus solitarius were inhibited by insulin. However, insulin had no effects on the cholinergic sympathetic preganglionic neurons of the spinal cord. Finally, we obtained results suggesting that the insulininduced inhibition of parasympathetic preganglionic neurons may not play a critical role in the regulation of glucose homeostasis and gastrointestinal motility. Our results demonstrate that insulin inhibits parasympathetic neuronal circuitry in the brainstem, while not affecting sympathetic neuronal activity in the spinal cord.

Neuronal AR regulates glucose homeostasis and energy expenditure in lean female mice with androgen excess.

Hyperandrogenemia and polycystic ovarian syndrome are a result of the imbalance of androgen levels in females. Androgen receptor (Ar) mediates the effect of androgen, and this study examines how neuronal Ar in the central nervous system (CNS) mediates metabolism under normal and increased androgen conditions in female mice. The neuron specific ARKO mouse (SynARKO) was created from female (Ar fl/wt; synapsin promoter driven Cre) and male (Ar fl/y) mice. Glucose tolerance test revealed impaired glucose tolerance that was partially alleviated in the SynARKO-DHT mice compared to Con-DHT mice after 4-months of DHT treatment. Heat production and food intake was higher in Con-DHT mice compared to Con-veh mice; these effects were not altered between SynARKO-veh and SynARKO-DHT mice, indicating that excess androgens may partially alter calorie intake and energy expenditure in females via the neuronal AR. The pAkt/Akt activity was higher in the hypothalamus in Con-DHT mice compared to the Con-veh mice, and this effect was attenuated in the SynARKO-DHT mice. Western blot studies show that markers of inflammation and microglia activation, such as NF-kB p-65 and IBA1, increased in the hypothalamus of Con-DHT mice compared to Con-veh. These studies suggest that neuronal Ar mediates the metabolic impacts of androgen excess in females.

ADGRL1 is a glucose receptor involved in mediating energy and glucose homeostasis

Aims/hypothesisThe brain is a major consumer of glucose as an energy source and regulates systemic glucose as well as energy balance. Although glucose transporters such as GLUT2 and sodium−glucose cotransporter 2 (SGLT2) are known to regulate glucose homeostasis and metabolism, the identity of a receptor that binds glucose to activate glucose signalling pathways in the brain is unknown. In this study, we aimed to discover a glucose receptor in the mouse hypothalamus.MethodsHere we used a high molecular mass glucose–biotin polymer to enrich glucose-bound mouse hypothalamic neurons through cell-based affinity chromatography. We then subjected the enriched neurons to proteomic analyses and identified adhesion G-protein coupled receptor 1 (ADGRL1) as a top candidate for a glucose receptor. We validated glucose–ADGRL1 interactions using CHO cells stably expressing human ADGRL1 and ligand–receptor binding assays. We generated and determined the phenotype of global Adgrl1-knockout mice and hypothalamus-specific Adgrl1-deficient mice. We measured the variables related to glucose and energy homeostasis in these mice. We also generated an Adgrl1Cre mouse model to investigate the role of ADGRL1 in sensing glucose using electrophysiology.ResultsAdgrl1 is highly expressed in the ventromedial nucleus of the hypothalamus (VMH) in mice. Lack of Adgrl1 in the VMH in mice caused fasting hyperinsulinaemia, enhanced glucose-stimulated insulin secretion and insulin resistance. In addition, the Adgrl1-deficient mice had impaired feeding responses to glucose and fasting coupled with abnormal glucose sensing and decreased physical activity before development of obesity and hyperglycaemia. In female mice, ovariectomy was necessary to reveal the contribution of ADGRL1 to energy and glucose homeostasis.Conclusions/interpretationAltogether, our findings demonstrate that ADGRL1 binds glucose and is involved in energy as well as glucose homeostasis in a sex-dependent manner. Targeting ADGRL1 may introduce a new class of drugs for the treatment of type 2 diabetes and obesity.Graphical

Thymoquinone attenuates olanzapine-induced metabolic disorders in rats.

Olanzapine (OLZ) is an atypical antipsychotic agent for psychotic disorders. Evidence has shown that OLZ is related to metabolic side effects, including obesity, hypertension, and insulin resistance. Thymoquinone (TQ) is the principal bioactive component of Nigella sativa. Several studies have been conducted to investigate the effectiveness of TQ in alleviating metabolic abnormalities. In the current research work, the protective effects of TQ on metabolic disorders induced by OLZ and possible underlying mechanisms were investigated. Wistar rats were exposed to TQ alone (10mg/kg), OLZ (5mg/kg), or OLZ plus TQ (2.5, 5, or 10mg/kg) given daily by intraperitoneal injection. After the treatment, variations in body weight, food intake, systolic blood pressure, serum leptin, biochemical factors, liver malondialdehyde (MDA), and glutathione (GSH) content were evaluated. Protein expression of AMPK in the liver was also measured by a western blotting test. OLZ increased body weight, food intake, MDA levels, and blood pressure. OLZ also elevated glucose, triglyceride, low-density lipoprotein cholesterol, and leptin serum levels. It decreased GSH. In the western blot, decreased AMPK protein level was obtained. These changes were attenuated by TQ co-administration. The present study demonstrates the effectiveness of TQ on OLZ-induced metabolic abnormalities related to its antioxidant activity and regulation of glucose homeostasis and lipid metabolism.

Olfr78, a novel short‐chain fatty acid receptor, regulates glucose homeostasis and gut GLP‐1 secretion in mice

AbstractOlfr78, which is a novel receptor for short‐chain fatty acid (SCFA) acetate and propionate, plays essential roles in some cellular processes. The present study aimed to investigate the role of olfr78 in regulating energy metabolism and delineate the underlying mechanisms using olfr78−/− mice. Deletion of olfr78 did not influence the adiposity of mice fed either normal chow or a high‐fat diet (HFD). However, olfr78−/− mice exhibited glucometabolic dysfunction, as evidenced by increased fasting blood glucose levels, decreased serum insulin levels, and impaired oral glucose tolerance under HFD feeding. When compared to wild‐type (WT) mice, olfr78 deficiency enhanced HFD‐induced gluconeogenesis and increased the mRNA expression of key gluconeogenic genes in the liver and kidney. Quantitative real‐time PCR results revealed that olfr78 expression was higher in the colon compared with other tissues in WT mice. Analysis of the gut microbiota in the feces of olfr78−/− mice using 16S rRNA gene sequencing revealed altered relative abundances of some representative SCFAs producers along with decreased levels of SCFAs, including propionic, isobutyric, 2‐methylbutyric, valeric, isovaleric, and 4‐methylvaleric acids. Importantly, mice lacking olfr78 had low circulating levels of glucagon‐like peptide 1 (GLP‐1). In the STC‐1 enteroendocrine cell line, propionate and acetate induced the secretion of the gut hormone GLP‐1, and this effect was partially abolished by olfr78 siRNA‐mediated knockdown. Together, these results suggest a previously undescribed, specific regulatory role for gut olfr78 in glucose homeostasis and highlight olfr78 as a potential target for diabetes treatment.

Efficacy and safety of HIMABERB® Berberine on glycemic control in patients with prediabetes: double-blind, placebo-controlled, and randomized pilot trial

BackgroundPrediabetes and diabetes involve alterations in glucose homeostasis, including increased fasting blood glucose and impaired glucose tolerance. Berberine has been identified as a potential regulator of glucose homeostasis with implications on the management of type 2 diabetes mellitus (DM). Given a paucity of data on berberine in prediabetes, evaluation of its effect in individuals with prediabetes may prove clinically valuable.ObjectiveThe present pilot study aimed to investigate the effect of daily oral berberine on markers of glycemic control and insulin resistance among individuals with prediabetes.MethodsA randomized, double-blinded, placebo-controlled trial was conducted for 12 weeks among 34 individuals with prediabetes as defined by the American Diabetes Association (fasting plasma glucose (FPG) between 5.6 and 6.9 mmol/L, glycosylated hemoglobin (HbA1c) between 5.7% and 6.4%, or 2-hour 75-gram oral glucose tolerance test (2 h-OGTT) between 7.8 and 11.1 mmol/L). HIMABERB® 500 mg was given three times daily to the treatment group, and placebo was administered three times daily to the control group. Glycemic control markers and physical parameters were evaluated for both groups on days 0, 28, 56, and 84. The glycemic control markers assessed included FPG, fasting insulin (FI), 2 h-OGTT, HbA1c, and homeostatic model assessment-insulin resistance (HOMA-IR). The observed outcomes were analyzed using independent t-test statistics to determine the significance of differences over time after treatment initiation and between treatment and control groups.ResultsSignificant decreases in all markers of glycemic control were observed in the treatment group at intermediate time points and the endpoint of the study compared to baseline levels and to the control group. For the treatment group, FPG decreased from 6.75 ± 0.23 mmol/L to 5.33 ± 0.28 mmol/L, FI from 9.81 ± 0.36 to 7.88 ± 0.52 mmol/L, 2 h-OGTT from 10.44 ± 0.52 to 8.12 ± 0.40 mmol/L, HbA1c from 6.40% ± 0.20–5.43% ± 0.21%, and HOMA-IR from 3.61 ± 0.31 to 2.41 ± 0.14. The decreases in glycemic control markers compared to the control group were clinically and statistically significant (p<10− 5). No severe adverse effects, kidney or liver toxicity were detected.ConclusionAfter 12 weeks, berberine (HIMABERB®) intervention in individuals with prediabetes significantly reduced glycemic control markers, with mean FPG and 2 h-OTGG being reduced to below prediabetic thresholds, supporting the investigation of the use of HIMABERB® for delaying progression to diabetes mellitus.Trial registrationhttp://ctri.nic.in(CTRI/2021/12/038751) (20/12/2021).

Evaluation of postprandial total triglycerides within the TIGG model for characterizing postprandial response of glucose, insulin, and GLP-1.

The TIGG model is the first model to integrate glucose and insulin regulation, incretin effect, and triglyceride (TG) response in the lipoprotein subclasses of chylomicrons and VLDL-V6. This model described the response following a high-fat meal in individuals who are lean, obese, and very obese and provided insights into the possible regulation of glucose homeostasis in the extended period following a meal. Often, total TGs are analyzed within clinical studies, instead of lipoprotein subclasses. We extended the existing TIGG model to capture the observed total TGs and determined if this model could be used to predict the postprandial TG response of chylomicron and VLDL-V6 when only total TGs are available. To assess if the lipoprotein distinction was important for the model, a second model (tTIGG) was developed using only the postprandial response in total TGs, instead of postprandial TG response in chylomicrons and VLDL-V6. The two models were compared on their predictability to characterize the postprandial response of glucose, insulin, and active GLP-1. Both models were able to characterize the postprandial TG response in individuals who are lean, obese, or very obese following a high-fat meal. The extended TIGG model resulted in a better model fit of the glucose data compared to the tTIGG model, indicating that chylomicron and VLDL-V6 provided additional information compared to total TGs. Furthermore, the expanded TIGG model was able to predict the postprandial TG response of chylomicrons and VLDL-V6 using the total TGs and could therefore be used in studies where only total TGs were collected.

Identification of myokines susceptible to improve glucose homeostasis after bariatric surgery.

The identification of myokines susceptible to improve glucose homeostasis following bariatric surgery could lead to new therapeutic approaches for type 2 diabetes. Changes in the Homeostasis Model Assessment (HOMA) test were assessed in patients before and 3 months after bariatric surgery. Changes in myokines expression and circulating levels were assessed using RT-qPCR and ELISA. Myokines known to regulate glucose homeostasis were identified using literature (Targeted study) and putative myokines using RNA-Sequencing (Untargeted study). A linear regression analysis adjusted for age and sex was used to search for associations between changes in the HOMA test and changes in myokines. In the targeted study, BDNF expression was upregulated (+30%, p=0.006) while BDNF circulating levels were decreased (-12%, p=0.001). Upregulated BDNF expression was associated with decreased HOMA-IR (adjusted estimate [95%CI]: -0.51 [-0.88; -0.13], p=0.010). Decreased BDNF serum levels were associated with decreased HOMA-B (adjusted estimate [95%CI] = 0.002 [0.00002-0.0031], p=0.046). In the untargeted study, upregulated putative myokines included XYLT1 (+64%, p<0.001), LGR5 (+57, p<0.001), and SPINK5 (+46%, p<0.001). Upregulated LGR5 was associated with decreased HOMA-IR (adjusted estimate -0.50 [-0.86; -0.13], p=0.009). Upregulated XYLT1 and SPINK5 were associated with increased HOMA-S (respectively, adjusted estimate [95%CI]: 109.1 [28.5; 189.8], p=0.009 and 16.5 [0.87; 32.19], p=0.039). Improved glucose homeostasis following bariatric surgery is associated with changes in myokines expression and circulating levels. In particular, upregulation of BDNF, XYLT1, SPINK5, and LGR5 is associated with improved insulin sensitivity. These results suggest that these myokines could contribute to improved glucose homeostasis following bariatric surgery.

The role of sex in the relationship between fasting adipokines levels, maximal fat oxidation during exercise, and insulin resistance in young adults with excess adiposity

AimPrevious evidence suggest that a sexual dimorphism in exercise fat oxidation and adipokines levels may explain a lower risk of cardio-metabolic disorders in women. Therefore, we investigated the role of sex in the relationship between adipokines levels, maximal fat oxidation (MFO) during exercise and insulin resistance. MethodsFifty young adults with excess adiposity (31 women; body fat: 38.7 ± 5.3%) were included in this study. The fasting levels of leptin, adiponectin, glucose and insulin were determined from blood samples and the homeostatic model assessment of insulin resistance index (HOMA-IR) subsequently calculated. Body fat percentage and visceral adipose tissue (VAT) were assessed through dual-energy X-ray absorptiometry whereas MFO was estimated during an incremental-load exercise test after an overnight fasting through indirect calorimetry. ResultsMen had lower levels of body fat (d = 1.80), adiponectin (d = 1.35), leptin (d = 0.43) and MFO (d = 1.25) than women. Conversely, men showed higher VAT (d = 0.85) and fasting glucose levels (d = 0.89). No sex differences were observed in HOMA-IR (d = 0.34). Adipokines levels were not associated with MFO in both sexes (r < 0.30), whereas adiponectin levels were inversely related with HOMA-IR in both men (r = −0.58) and women (r = −0.50). Leptin concentration was associated to HOMA-IR only in men (r = 0.41), while no statistically significant relationships were observed between MFO and HOMA-IR in both sexes (r < 0.44). ConclusionInsulin resistance was similar between sexes regardless of superior levels of adipokines and MFO during exercise in women. Therefore, adiponectin and leptin may regulate glucose homeostasis without altering whole body fat oxidation rate during exercise.

Low-Calorie Ketogenic Diet: Potential Application in the Treatment of Polycystic Ovary Syndrome in Adolescents.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Hyperandrogenism, hyperinsulinism and insulin resistance (IR) are the main drivers of clinical, metabolic and reproductive phenotypes of PCOS. In adolescence, the cornerstones of PCOS treatment are lifestyle and dietary interventions. In particular, the quality and quantity of carbohydrates introduced with the diet play a crucial role in the benefits of diet on PCOS. Recently, the ketogenic diet (KD) has attracted significant interest for the treatment of IR and for the control of carbohydrate metabolism, which has proven to be beneficial for several dysmetabolic conditions, including PCOS. The goal of the KD is to induce a fasting-like metabolism with production of chetonic bodies. Ketosis is a good regulator of calorie intake and mimics the starvation effect in the body, leading to body weight control and consequent metabolism. Additionally, during ketogenesis, insulin receptor sensitivity is also promoted. We proposed a broad overview of the available literature regarding KD indications and considered its metabolic benefits useful for improving PCOS management. The reported data support that a low-calorie ketogenic diet (LCKD) plays a positive role as a regulator of control weight, IR, glucose and lipid homeostasis and hormonal profile. Unfortunately, the evidence concerning the benefits of the very LCKD in adolescents with PCOS and excessive body weight is still numerically scarce. Further studies are necessary to understand whether these effects are due to weight loss or to the nutritional characteristics of this diet. Considering the long-term consequences of PCOS, it is crucial to detect the prospects of nutritional interventions to protect fertility, starting in adolescence.

Obesity-associated microglial inflammatory activation paradoxically improves glucose tolerance

Hypothalamic gliosis associated with high-fat diet (HFD) feeding increases susceptibility to hyperphagia and weight gain. However, the body-weight-independent contribution of microglia to glucose regulation has not been determined. Here, we show that reducing microglial nuclear factor κB (NF-κB) signaling via cell-specific IKKβ deletion exacerbates HFD-induced glucose intolerance despite reducing body weight and adiposity. Conversely, two genetic approaches to increase microglial pro-inflammatory signaling (deletion of an NF-κB pathway inhibitor and chemogenetic activation through a modified Gq-coupled muscarinic receptor) improved glucose tolerance independently of diet in both lean and obese rodents. Microglial regulation of glucose homeostasis involves a tumor necrosis factor alpha (TNF-α)-dependent mechanism that increases activation of pro-opiomelanocortin (POMC) and other hypothalamic glucose-sensing neurons, ultimately leading to a marked amplification of first-phase insulin secretion via a parasympathetic pathway. Overall, these data indicate that microglia regulate glucose homeostasis in a body-weight-independent manner, an unexpected mechanism that limits the deterioration of glucose tolerance associated with obesity.

Regulation of plasma glucose levels by central dopamine D2 receptors is impaired in type 1 but not type 2 diabetic mouse models

Glucose metabolism is reported to be regulated by the central nervous system, but it is unclear whether this regulation is altered in diabetes. We investigated whether regulation of glucose metabolism by central dopamine D2 receptors is altered in type 1 and type 2 diabetic models. Intracerebroventricular injections of both the dopamine D2 receptor agonist quinpirole and the antagonist l-sulpiride induced hyperglycemia in control mice, but not in streptozotocin (STZ)-induced diabetic mice, a type 1 diabetic model. Hyperglycemia induced by quinpirole or l-sulpiride was diminished following fasting and these drugs did not affect hyperglycemia in the pyruvate tolerance test. In addition, both quinpirole and l-sulpiride increased hepatic glucose-6-phosphatase (G6Pase) mRNA. In STZ-induced diabetic mice, dopamine and dopamine D2 receptor mRNA in the hypothalamus, which regulates glucose homeostasis, were decreased. Hepatic glycogen and G6Pase mRNA were also decreased in STZ-induced diabetic mice. Neither quinpirole nor l-sulpiride increased hepatic G6Pase mRNA in STZ-induced diabetic mice. In diet-induced obesity mice, a type 2 diabetic model, both quinpirole and l-sulpiride induced hyperglycemia, and hypothalamic dopamine and dopamine D2 receptor mRNA were not altered. These results indicate that (i) stimulation or blockade of dopamine D2 receptors causes hyperglycemia by increasing hepatic glycogenolysis, and (ii) stimulation or blockade of dopamine D2 receptors does not affect glucose levels in type 1 but does so in type 2 diabetic models. Moreover, hypothalamic dopaminergic function and hepatic glycogenolysis are decreased in the type 1 diabetic model, which reduces hyperglycemia induced by stimulation or blockade of dopamine D2 receptors.

Insulin and the kidneys: a contemporary view on the molecular basis.

Insulin is a hormone that is composed of 51 amino acids and structurally organized as a hexamer comprising three heterodimers. Insulin is the central hormone involved in the control of glucose and lipid metabolism, aiding in processes such as body homeostasis and cell growth. Insulin is synthesized as a large preprohormone and has a leader sequence or signal peptide that appears to be responsible for transport to the endoplasmic reticulum membranes. The interaction of insulin with the kidneys is a dynamic and multicenter process, as it acts in multiple sites throughout the nephron. Insulin acts on a range of tissues, from the glomerulus to the renal tubule, by modulating different functions such as glomerular filtration, gluconeogenesis, natriuresis, glucose uptake, regulation of ion transport, and the prevention of apoptosis. On the other hand, there is sufficient evidence showing the insulin receptor's involvement in renal functions and its responsibility for the regulation of glucose homeostasis, which enables us to understand its contribution to the insulin resistance phenomenon and its association with the progression of diabetic kidney disease.

Short-chain fatty acids, secondary bile acids and indoles: gut microbial metabolites with effects on enteroendocrine cell function and their potential as therapies for metabolic disease.

The gastrointestinal tract hosts the largest ecosystem of microorganisms in the body. The metabolism of ingested nutrients by gut bacteria produces novel chemical mediators that can influence chemosensory cells lining the gastrointestinal tract. Specifically, hormone-releasing enteroendocrine cells which express a host of receptors activated by these bacterial metabolites. This review will focus on the activation mechanisms of glucagon-like peptide-1 releasing enteroendocrine cells by the three main bacterial metabolites produced in the gut: short-chain fatty acids, secondary bile acids and indoles. Given the importance of enteroendocrine cells in regulating glucose homeostasis and food intake, we will also discuss therapies based on these bacterial metabolites used in the treatment of metabolic diseases such as diabetes and obesity. Elucidating the mechanisms gut bacteria can influence cellular function in the host will advance our understanding of this fundamental symbiotic relationship and unlock the potential of harnessing these pathways to improve human health.

Platelet-derived lipids promote insulin secretion of pancreatic β cells.

Hyperreactive platelets are commonly observed in diabetic patients indicating a potential link between glucose homeostasis and platelet reactivity. This raises the possibility that platelets may play a role in the regulation of metabolism. Pancreatic β cells are the central regulators of systemic glucose homeostasis. Here, we show that factor(s) derived from β cells stimulate platelet activity and platelets selectively localize to the vascular endothelium of pancreatic islets. Both depletion of platelets and ablation of major platelet adhesion or activation pathways consistently resulted in impaired glucose tolerance and decreased circulating insulin levels. Furthermore, we found platelet-derived lipid classes to promote insulin secretion and identified 20-Hydroxyeicosatetraenoic acid (20-HETE) as the main factor promoting β cells function. Finally, we demonstrate that the levels of platelet-derived 20-HETE decline with age and that this parallels with reduced impact of platelets on β cell function. Our findings identify an unexpected function of platelets in the regulation of insulin secretion and glucose metabolism, which promotes metabolic fitness in young individuals.