Control Of Glucose Homeostasis Research Articles

Autophagy regulator ATG5 preserves cerebellar function by safeguarding its glycolytic activity.

Dysfunctions in autophagy, a cellular mechanism for breaking down components within lysosomes, often lead to neurodegeneration. The specific mechanisms underlying neuronal vulnerability due to autophagy dysfunction remain elusive. Here we show that autophagy contributes to cerebellar Purkinje cell (PC) survival by safeguarding their glycolytic activity. Outside the conventional housekeeping role, autophagy is also involved in the ATG5-mediated regulation of glucose transporter 2 (GLUT2) levels during cerebellar maturation. Autophagy-deficient PCs exhibit GLUT2 accumulation on the plasma membrane, along with increased glucose uptake and alterations in glycolysis. We identify lysophosphatidic acid and serine as glycolytic intermediates that trigger PC death and demonstrate that the deletion of GLUT2 in ATG5-deficient mice mitigates PC neurodegeneration and rescues their ataxic gait. Taken together, this work reveals a mechanism for regulating GLUT2 levels in neurons and provides insights into the neuroprotective role of autophagy by controlling glucose homeostasis in the brain.

The impact of Serum Amylin on Body mass index in Children with type1 Diabetes Mellitus newly diagnosis

Background: Pancreatic β cells' inability to synthesize insulin is the defining feature of type 1 diabetes mellitus (T1DM), an endocrine illness. This action involves the peptide hormone amylin, which is co-secreted with insulin and plays a key role in controlling glucose homeostasis and appetite. It also influences body weight, calorie intake, stomach emptying, glucagon release suppression, and satiety. Subjects, Material, and Method: This study included 120 pediatric individuals aged between( 2-14) years. They were divided into four groups. Group one contains 40 lean patients with T1DM, with a BMI≥85 percentile, and group two contains 40 underweight patients with (T1DM) with a BMI≥5 percentile. The Group contains 40 healthy pediatrics and ages matched with the patients subdivided into (group three, lean control with a BMI less than 85 percentile. The group numbered 22, and four groups, underweight control with BMI≥5 percentile, consisted of 18 pediatric underweight healthy as controls. They were analyzed for fasting serum glucose, amylin, and HbA1c. Results: The levels of Amylin in the control group(lean and underweight) were higher than in the patients with diabetes mellitus(lean and underweight). Also, fast blood glucose( FBG) was found in the Lean DM group. Similarly, the Underweight DM group was higher than those observed in the Lean Control and Underweight Control groups. For HbA1c%, the Lean DM group. The Underweight DM group exhibited a higher mean HbA1c%. In contrast, the Lean Control and Underweight Control groups had significantly lower mean HbA1c% values. Conclusion: The control group had higher Amylin levels, a potential biomarker for metabolic status in children with T1DM, and could inform therapeutic strategies to optimize glycemic control and body weight management. In comparison, the patient group had higher FBG values. The Lean DM group had higher HbA1c% values, while the Underweight DM group had slightly higher values. Both control groups had significantly lower HbA1c% values.

Antidiabetic Effect of Bifidobacterium animalis TISTR 2591 in a Rat Model of Type 2 Diabetes.

This study investigated the beneficial effects of probiotic Bifidobacterium animalis TISTR 2591 on the regulation of blood glucose and its possible mechanisms in a rat model of type 2 diabetes. The type 2 diabetic-Sprague Dawley rats were established by the combination of a high-fat diet and a low dose of streptozotocin. After 4weeks of treatment with 2 × 108CFU/ml of B. animalis TISTR 2591, fasting blood glucose (FBG), oral glucose tolerance, serum insulin, and pancreatic and hepatic histopathology were determined. Liver lipid accumulation, glycogen content, and gluconeogenic protein expression were evaluated. Oxidative stress and inflammatory status were determined. B. animalis TISTR 2591 significantly reduced FBG levels and improved glucose tolerance and serum insulin in the diabetic rats. Structural damage of the pancreas and liver was ameliorated in the B. animalis TISTR 2591-treated diabetic rats. In addition, significant decreases in hepatic fat accumulation, glycogen content, and phosphoenolpyruvate carboxykinase-1 protein expression were found in the diabetic rats treated with B. animalis TISTR 2591. The diabetic rats showed a significant reduction of inflammation following B. animalis TISTR 2591 supplementation, as demonstrated by decreasing hepatic NF-κB protein expression and serum and liver TNF-α levels. The B. animalis TISTR 2591 significantly decreased MDA levels and increased antioxidant SOD and GPx activities in the diabetic rats. In conclusion, B. animalis TISTR 2591 was shown to be effective in controlling glucose homeostasis and improving glucose tolerance in the diabetic rats. These beneficial activities were attributed to reducing oxidative and inflammatory status and modulating hepatic glucose metabolism.

Adipose Tissue: A Novel Target of the Incretin Axis? A Paradigm Shift in Obesity-Linked Insulin Resistance.

Adipose tissue (AT) represents a plastic organ that can undergo significant remodeling in response to metabolic demands. With its numerous checkpoints, the incretin system seems to play a significant role in controlling glucose homeostasis and energy balance. The importance of the incretin hormones, namely the glucagon-like peptide-1 (GLP-1) and the glucose-dependent insulinotropic peptide (GIP), in controlling the function of adipose cells has been brought to light by recent studies. Notably, a "paradigm shift" in reevaluating the role of the incretin system in AT as a potential target to treat obesity-linked metabolic disorders resulted from the demonstration that a disruption of the GIP and GLP-1 signaling axis in fat is associated with adiposity-induced insulin-resistance (IR) and/or type 2 diabetes mellitus (T2D). We will briefly discuss the (patho)physiological functions of GLP-1 and GIP signaling in AT in this review, emphasizing their potential impacts on lipid storage, adipogenesis, glucose metabolism and inflammation. We will also address the conundrum with the perturbation of the incretin axis in white or brown fat tissue and the emergence of metabolic disorders. In order to reduce or avoid adiposity-related metabolic complications, we will finally go over a potential scientific rationale for suggesting AT as a novel target for GLP-1 and GIP receptor agonists and co-agonists.

BCAAs acutely drive glucose dysregulation and insulin resistance: role of AgRP neurons

BackgroundHigh-protein diets are often enriched with branched-chain amino acids (BCAAs) known to enhance protein synthesis and provide numerous physiological benefits, but recent studies reveal their association with obesity and diabetes. In support of this, protein or BCAA supplementation is shown to disrupt glucose metabolism while restriction improves it. However, it is not clear if these are primary, direct effects of BCAAs or secondary to other physiological changes during chronic manipulation of dietary BCAAs.MethodsThree-month-old C57Bl/6 mice were acutely treated with either vehicle/BCAAs or BT2, a BCAA-lowering compound, and detailed in vivo metabolic phenotyping, including frequent sampling and pancreatic clamps, were conducted.ResultsUsing a catheter-guided frequent sampling method in mice, here we show that a single infusion of BCAAs was sufficient to acutely elevate blood glucose and plasma insulin. While pre-treatment with BCAAs did not affect glucose tolerance, a constant infusion of BCAAs during hyperinsulinemic–euglycemic clamps impaired whole-body insulin sensitivity. Similarly, a single injection of BT2 was sufficient to prevent BCAA rise during fasting and markedly improve glucose tolerance in high-fat-fed mice, suggesting that abnormal glycemic control in obesity may be causally linked to high circulating BCAAs. We further show that chemogenetic over-activation of AgRP neurons in the hypothalamus, as present in obesity, significantly impairs glucose tolerance that is completely normalized by acute BCAA reduction. Interestingly, most of these effects were demonstrated only in male, but not in female mice.ConclusionThese findings suggest that BCAAs per se can acutely impair glucose homeostasis and insulin sensitivity, thus offering an explanation for how they may disrupt glucose metabolism in the long-term as observed in obesity and diabetes. Our findings also reveal that AgRP neuronal regulation of blood glucose is mediated through BCAAs, further elucidating a novel mechanism by which brain controls glucose homeostasis.

Circadian desynchrony and glucose metabolism.

The circadian timing system controls glucose metabolism in a time-of-day dependent manner. In mammals, the circadian timing system consists of the main central clock in the bilateral suprachiasmatic nucleus (SCN) of the anterior hypothalamus and subordinate clocks in peripheral tissues. The oscillations produced by these different clocks with a period of approximately 24-h are generated by the transcriptional-translational feedback loops of a set of core clock genes. Glucose homeostasis is one of the daily rhythms controlled by this circadian timing system. The central pacemaker in the SCN controls glucose homeostasis through its neural projections to hypothalamic hubs that are in control of feeding behavior and energy metabolism. Using hormones such as adrenal glucocorticoids and melatonin and the autonomic nervous system, the SCN modulates critical processes such as glucose production and insulin sensitivity. Peripheral clocks in tissues, such as the liver, muscle, and adipose tissue serve to enhance and sustain these SCN signals. In the optimal situation all these clocks are synchronized and aligned with behavior and the environmental light/dark cycle. A negative impact on glucose metabolism becomes apparent when the internal timing system becomes disturbed, also known as circadian desynchrony or circadian misalignment. Circadian desynchrony may occur at several levels, as the mistiming of light exposure or sleep will especially affect the central clock, whereas mistiming of food intake or physical activity will especially involve the peripheral clocks. In this review, we will summarize the literature investigating the impact of circadian desynchrony on glucose metabolism and how it may result in the development of insulin resistance. In addition, we will discuss potential strategies aimed at reinstating circadian synchrony to improve insulin sensitivity and contribute to the prevention of type 2 diabetes.

Clinical investigation of glucokinase activators for the restoration of glucose homeostasis in diabetes.

As a sensor, glucokinase (GK) controls glucose homeostasis, which progressively declines in patients with diabetes. GK maintains the equilibrium of glucose levels and regulates the homeostatic system set points. Endocrine and hepatic cells can both respond to glucose cooperatively when GK is activated. GK has been under study as a therapeutic target for decades due to the possibility that cellular GK expression and function can be recovered, hence restoring glucose homeostasis in patients with type 2 diabetes. Five therapeutic compounds targeting GK are being investigated globally at the moment. They all have distinctive molecular structures and have been clinically shown to have strong antihyperglycemia effects. The mechanics, classification, and clinical development of GK activators are illustrated in this review. With the recent approval and marketing of the first GK activator (GKA), dorzagliatin, GKA's critical role in treating glucose homeostasis disorder and its long-term benefits in diabetes will eventually become clear.

The 26RFa (QRFP)/GPR103 Neuropeptidergic System: A Key Regulator of Energy and Glucose Metabolism.

Obesity and type 2 diabetes are strongly associated pathologies, currently considered as a worldwide epidemic problem. Understanding the mechanisms that drive the development of these diseases would enable to develop new therapeutic strategies for their prevention and treatment. Particularly, the role of the brain in energy and glucose homeostasis has been studied for 2 decades. In specific, the hypothalamus contains well-identified neural networks that regulate appetite and potentially also glucose homeostasis. A new concept has thus emerged, suggesting that obesity and diabetes could be due to a dysfunction of the same, still poorly understood, neural networks. The neuropeptide 26RFa (also termed QRFP) belongs to the family of RFamide regulatory peptides and has been identified as the endogenous ligand of the human G protein-coupled receptor GPR103 (QRFPR). The primary structure of 26RFa is strongly conserved during vertebrate evolution, suggesting its crucial roles in the control of vital functions. Indeed, the 26RFa/GPR103 peptidergic system is reported to be involved in the control of various neuroendocrine functions, notably the control of energy metabolism in which it plays an important role, both centrally and peripherally, since 26RFa regulates feeding behavior, thermogenesis and lipogenesis. Moreover, 26RFa is reported to control glucose homeostasis both peripherally, where it acts as an incretin, and centrally, where the 26RFa/GPR103 system relays insulin signaling in the brain to control glucose metabolism. This review gives a comprehensive overview of the role of the 26RFa/GPR103 system as a key player in the control of energy and glucose metabolism. In a pathophysiological context, this neuropeptidergic system represents a prime therapeutic target whose mechanisms are highly relevant to decipher.

A combination of virtual screening, molecular dynamics simulation, MM/PBSA, ADMET, and DFT calculations to identify a potential DPP4 inhibitor

DPP4 inhibitors can control glucose homeostasis by increasing the level of GLP-1 incretins hormone due to dipeptidase mimicking. Despite the potent effects of DPP4 inhibitors, these compounds cause unwanted toxicity attributable to their effect on other enzymes. As a result, it seems essential to find novel and DPP4 selective compounds. In this study, we introduce a potent and selective DPP4 inhibitor via structure-based virtual screening, molecular docking, molecular dynamics simulation, MM/PBSA calculations, DFT analysis, and ADMET profile. The screened compounds based on similarity with FDA-approved DPP4 inhibitors were docked towards the DPP4 enzyme. The compound with the highest docking score, ZINC000003015356, was selected. For further considerations, molecular docking studies were performed on selected ligands and FDA-approved drugs for DPP8 and DPP9 enzymes. Molecular dynamics simulation was run during 200 ns and the analysis of RMSD, RMSF, Rg, PCA, and hydrogen bonding were performed. The MD outputs showed stability of the ligand–protein complex compared to available drugs in the market. The total free binding energy obtained for the proposed DPP4 inhibitor was more negative than its co-crystal ligand (N7F). ZINC000003015356 confirmed the role of the five Lipinski rule and also, have low toxicity parameter according to properties. Finally, DFT calculations indicated that this compound is sufficiently soft.

Secretion of glucagon, GLP-1 and GIP may be affected by circadian rhythm in healthy males.

Glucagon is secreted from pancreatic alpha cells in response to low blood glucose and increases hepatic glucose production. Furthermore, glucagon enhances hepatic protein and lipid metabolism during a mixed meal. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted from gut endocrine cells during meals and control glucose homeostasis by potentiating insulin secretion and inhibiting food intake. Both glucose homeostasis and food intake have been reported to be affected by circadian rhythms and vice versa. In this study, we investigated whether the secretion of glucagon, GLP-1 and GIP was affected by circadian rhythms. A total of 24 healthy men with regular sleep schedules were examined for 24h at the hospital ward with 15h of wakefulness and 9h of sleep. Food intake was standardized, and blood samples were obtained every third hour. Plasma concentrations of glucagon, GLP-1 and GIP were measured, and data were analyzed by rhythmometric statistical methods. Available data on plasma glucose and plasma C-peptide were also included. Plasma concentrations of glucagon, GLP-1, GIP, C-peptide and glucose fluctuated with a diurnal 24-h rhythm, with the highest levels during the day and the lowest levels during the night: glucagon (p < 0.0001, peak time 18:26h), GLP-1 (p < 0.0001, peak time 17:28h), GIP (p < 0.0001, peak time 18:01h), C-peptide (p < 0.0001, peak time 17.59h), and glucose (p < 0.0001, peak time 23:26h). As expected, we found significant correlations between plasma concentrations of C-peptide and GLP-1 and GIP but did not find correlations between glucose concentrations and concentrations of glucagon, GLP-1 and GIP. Our results demonstrate that under meal conditions that are similar to that of many free-living individuals, plasma concentrations of glucagon, GLP-1 and GIP were observed to be higher during daytime and evening than overnight. These findings underpin disturbed circadian rhythm as a potential risk factor for diabetes and obesity. ClinicalTrials.gov Identifier: NCT06166368. Registered 12 December 2023.

Sympathetic NPY controls glucose homeostasis, cold tolerance, and cardiovascular functions in mice

Neuropeptide Y (NPY) is best known for its effects in the brain as an orexigenic and anxiolytic agent and in reducing energy expenditure. NPY is also co-expressed with norepinephrine (NE) in sympathetic neurons. Although NPY is generally considered to modulate noradrenergic responses, its specific roles in autonomic physiology remain under-appreciated. Here, we show that sympathetic-derived NPY is essential for metabolic and cardiovascular regulation in mice. NPY and NE are co-expressed in 90% of prevertebral sympathetic neurons and only 43% of paravertebral neurons. NPY-expressing neurons primarily innervate blood vessels in peripheral organs. Sympathetic-specific NPY deletion elicits pronounced metabolic and cardiovascular defects in mice, including reductions in insulin secretion, glucose tolerance, cold tolerance, and pupil size and elevated heart rate, while notably, however, basal blood pressure was unchanged. These findings provide insight into target tissue-specific functions of NPY derived from sympathetic neurons and imply its potential involvement in metabolic and cardiovascular diseases.

The adhesion GPCR GPR116/ADGRF5 has a dual function in pancreatic islets regulating somatostatin release and islet development

Glucose homeostasis is maintained by hormones secreted from different cell types of the pancreatic islets and controlled by manifold input including signals mediated through G protein-coupled receptors (GPCRs). RNA-seq analyses revealed expression of numerous GPCRs in mouse and human pancreatic islets, among them Gpr116/Adgrf5. GPR116 is an adhesion GPCR mainly found in lung and required for surfactant secretion. Here, we demonstrate that GPR116 is involved in the somatostatin release from pancreatic delta cells using a whole-body as well as a cell-specific knock-out mouse model. Interestingly, the whole-body GPR116 deficiency causes further changes such as decreased beta-cell mass, lower number of small islets, and reduced pancreatic insulin content. Glucose homeostasis in global GPR116-deficient mice is maintained by counter-acting mechanisms modulating insulin degradation. Our data highlight an important function of GPR116 in controlling glucose homeostasis.

Meta-analysis of randomized controlled trials of the effects of synbiotics, probiotics, or prebiotics in controlling glucose homeostasis in non-alcoholic fatty liver disease patients.

Background: Probiotics, prebiotics, and synbiotics have been suggested as a possible therapy for non-alcoholic fatty liver disease (NAFLD). However, their efficacy in improving blood glucose levels in NAFLD patients remains uncertain. Objective: The aim of this study was to assess the effects of supplementation with probiotics, prebiotics, or synbiotics on fasting blood glucose (FBG) levels in NAFLD patients. Methods: We searched PubMed, Web of Science, and Google Scholar for relevant trials published up to March 2024. Out of 3369 identified studies, 24 randomized controlled trials (RCTs) were included. Results: Probiotic, prebiotic, or synbiotic supplementation substantially reduced FBG (n = 23; standard mean difference (SMD) = -0.17; 95% confidence interval (CI): -0.30, -0.03; P = 0.02), fasting insulin levels (n = 12; SMD = -0.28; 95% CI: -0.49, -0.07; P = 0.01), and homeostatic model assessment for insulin resistance (HOMA-IR; n = 14; SMD = -0.28; 95% CI: -0.47, -0.09; P = 0.004). However, glycosylated hemoglobin (HbA1c; n = 3; SMD = -0.17; 95% CI: -0.48, 0.13; P = 0.27) was not significantly affected. The FBG-decreasing effect diminished as the body mass index (BMI) of volunteers increased in the baseline. Additionally, the number of probiotic strains and geographic region were shown to significantly affect FBG levels. Conclusion: This meta-analysis indicates that supplementation with probiotics, prebiotics, or synbiotics may aid in controlling glucose homeostasis in patients with NAFLD.

Investigation of the motif activity of transcription regulators in pancreatic β-like cell subpopulations differentiated from human induced pluripotent stem cells.

Pancreatic β-cells are composed of different subtypes that play a key role in the control of insulin secretion and thereby control glucose homeostasis. In vitro differentiation of human induced pluripotent stem cells (hiPSCs) into 3D spheroids leads to the generation of β-cell subtypes and thus to the development of islet-like structures. Using this cutting-edge cell model, the aim of the study was to decipher the signaling signature that underlines β-cell subtypes, with a focus on the search for the activity of motifs of important transcription regulators (TRs). The investigation was performed using data from previous single-cell sequencing analysis introduced into the integrated system for motif activity response analysis (ISMARA) of transcription regulators. We extracted the matrix of important TRs activated in the β-cell subpopulation and bi-hormonal-like β-cells. Based on these TRs and their targets, we built specific regulatory networks for main cell subpopulations. Our data confirmed the transcriptomic heterogeneity of the β-cell subtype lineage and suggested a mechanism that could account for the differentiation of β-cell subtypes during pancreas development. We do believe that our findings could be instrumental for understanding the mechanisms that affect the balance of β-cell subtypes, leading to impaired insulin secretion in type 2 diabetes.

Il diabete monogenico. Una condizione clinica frequentemente trascurata

Monogenic diabetes (MD) includes several forms of hyperglycemia caused by mutations in genes capable of controlling glucose homeostasis. Although MD explains 0.5-5.0% of non-autoimmune diabetes, it remains mostly overlooked. This is unfortunate, given that most of the genes involved in MD influence the monitoring and/or therapy of carrier patients, thus representing an excellent example of “precision medicine” implemented in real-life clinical practice. This review provides a practical update to help identify patients who merit genetic testing for MD and how to best clinically manage carrier patients.

High-intensity interval training attenuates impairment in regulatory protein machinery of mitochondrial quality control in skeletal muscle of diet-induced obese mice.

Mitochondrial quality control processes are essential in governing mitochondrial integrity and function. The purpose of the study was to examine the effects of 10 weeks of high-intensity interval training (HIIT) on the regulatory protein machinery of skeletal muscle mitochondrial quality control and whole-body glucose homeostasis in diet-induced obese mice. Male C57BL/6 mice were assigned to low-fat diet (LFD) or high-fat diet (HFD) group. After 10 weeks, HFD-fed mice were divided into sedentary and HIIT (HFD+HIIT) groups for another 10 weeks (n=9/group). Graded exercise test, glucose and insulin tolerance tests, mitochondrial respiration, and protein markers of mitochondrial quality control processes were determined. HFD-fed mice exhibited lower ADP-stimulated mitochondrial respiration (p<0.05). However, 10 weeks of HIIT prevented this impairment (p<0.05). Importantly, the ratio of Drp1(Ser616) over Drp1(Ser637) phosphorylation, an indicator of mitochondrial fission, was significantly higher in HFD-fed mice (p<0.05), but such increase was attenuated in HFD-HIIT compared to HFD (-35.7%, p<0.05). Regarding autophagy, skeletal muscle p62 content was lower in the HFD group than the LFD group (-35.1%, p<0.05); however, such reduction was disappeared in the HFD+HIIT group. In addition, LC3B II/I ratio was higher in the HFD group than the LFD group (15.5%, p<0.05) but was ameliorated in the HFD+HIIT group (-29.9%, p<0.05). Overall, our study demonstrated that 10 weeks of HIIT was effective in improving skeletal muscle mitochondrial respiration and the regulatory protein machinery of mitochondrial quality control in diet-induced obese mice through the alterations of mitochondrial fission protein Drp1 phosphorylations and p62/LC3B-mediated regulatory machinery of autophagy.

Daily rhythms of diabetogenic factors in men: role of type 2 diabetes and body weight.

Obesity is a major cause of type 2 diabetes. Transition from obesity to type 2 diabetes manifests in the dysregulation of hormones controlling glucose homeostasis and inflammation. As metabolism is a dynamic process that changes across 24 h, we assessed diurnal rhythmicity in a panel of 10 diabetes-related hormones. Plasma hormones were analysed every 2 h over 24 h in a controlled laboratory study with hourly isocaloric drinks during wake. To separate effects of body mass from type 2 diabetes, we recruited three groups of middle-aged men: an overweight (OW) group with type 2 diabetes and two control groups (lean and OW). Average daily concentrations of glucose, triacylglycerol and all the hormones except visfatin were significantly higher in the OW group compared to the lean group (P < 0.001). In type 2 diabetes, glucose, insulin, C-peptide, glucose-dependent insulinotropic peptide and glucagon-like peptide-1 increased further (P < 0.05), whereas triacylglycerol, ghrelin and plasminogen activator inhibitor-1 concentrations were significantly lower compared to the OW group (P < 0.001). Insulin, C-peptide, glucose-dependent insulinotropic peptide and leptin exhibited significant diurnal rhythms in all study groups (P < 0.05). Other hormones were only rhythmic in 1 or 2 groups. In every group, hormones associated with glucose regulation (insulin, C-peptide, glucose-dependent insulinotropic peptide, ghrelin and plasminogen activator inhibitor-1), triacylglycerol and glucose peaked in the afternoon, whereas glucagon and hormones associated with appetite and inflammation peaked at night. Thus being OW with or without type 2 diabetes significantly affected hormone concentrations but did not affect the timing of the hormonal rhythms.

TFEB and TFE3 control glucose homeostasis by regulating insulin gene expression.

To fulfill their function, pancreatic beta cells require precise nutrient-sensing mechanisms that control insulin production. Transcription factor EB (TFEB) and its homolog TFE3 have emerged as crucial regulators of the adaptive response of cell metabolism to environmental cues. Here, we show that TFEB and TFE3 regulate beta-cell function and insulin gene expression in response to variations in nutrient availability. We found that nutrient deprivation in beta cells promoted TFEB/TFE3 activation, which resulted in suppression of insulin gene expression. TFEB overexpression was sufficient to inhibit insulin transcription, whereas beta cells depleted of both TFEB and TFE3 failed to suppress insulin gene expression in response to amino acid deprivation. Interestingly, ChIP-seq analysis showed binding of TFEB to super-enhancer regions that regulate insulin transcription. Conditional, beta-cell-specific, Tfeb-overexpressing, and Tfeb/Tfe3 double-KO mice showed severe alteration of insulin transcription, secretion, and glucose tolerance, indicating that TFEB and TFE3 are important physiological mediators of pancreatic function. Our findings reveal a nutrient-controlled transcriptional mechanism that regulates insulin production, thus playing a key role in glucose homeostasis at both cellular and organismal levels.

Abstract 038: Adipocyte-specific BBSome Deficiency Impacts The Sympathetic Nervous System And Baroreceptor Reflex Sensitivity

The BBSome, a protein complex of 8 Bardet-Biedl syndrome (BBS) proteins including BBS1, has emerged as an important regulator of metabolic, cardiovascular, and autonomic functions. Patients with Bbs gene mutations display severe obesity, type II diabetes and hypertension. Previous studies demonstrated that neuronal BBSome contributes to metabolic homeostasis and blood pressure regulation, however the importance of adipocyte BBSome in controlling glucose homeostasis and blood pressure remains poorly understood. To address this, we generated mice lacking the BBSome specifically in adipocytes through selective deletion of the Bbs1 gene (Adipo Cre /Bbs1 fl/fl ) by crossing the adiponectin Cre (Adipo Cre ) male mice crossing with female Bbs1 floxed (Bbs1 fl/fl ) mice. Adipocyte-specific Cre recombinase was validated by further crossing the Adipo Cre mice with td-Tomato reporter mice. Bbs1 gene deletion in adipocytes was confirmed by measuring Bbs1 gene expression in adipose tissue using qRT-PCR. To induce obesity, mice were fed a high fat high sucrose diet (HFHSD) for 16 weeks starting at 4 weeks of age. Interestingly, the weight gain evoked by HFHSD was comparable between male and female Adipo Cre /Bbs1 fl/fl mice and littermate controls. Similarly, Adipo Cre /Bbs1 fl/fl mice displayed unaltered blood glucose as indicated by glucose and insulin tolerance tests. Using radiotelemetry, we found no significant difference in systolic, diastolic, and mean arterial pressure and heart rate between control and Adipo Cre /Bbs1 fl/fl mice fed HFHSD. Surprisingly, a significant increase in renal sympathetic nerve activity was observed in Adipo Cre /Bbs1 fl/fl mice (Control: 101.1 ± 16.23 spikes/sec, Adipo Cre /Bbs1 fl/fl : 133.2 ± 32.15 spikes/sec, p &lt; 0.05). Next, we measured baroreceptor reflex sensitivity by analyzing the responses to sodium nitroprusside (SNP) and phenylephrine (PE). The slope analysis showed that Adipo Cre /Bbs1 fl/fl mice were less sensitive to SNP (Control: -2.56 ± 0.82, Adipo Cre /Bbs1 fl/fl : -1.746± 0.29, p &lt; 0.05), demonstrating altered baroreflex. Taken together, our data implicate the adipocyte BBSome is a regulator of sympathetic nervous activation and baroreflex sensitivity.

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.