Impaired Glucose Uptake Research Articles

Impairment of Glucose Uptake Induced by Elevated Intracellular Ca2+ in Hippocampal Neurons of Malignant Hyperthermia-Susceptible Mice

Malignant hyperthermia (MH) is a genetic disorder triggered by depolarizing muscle relaxants or halogenated inhalational anesthetics in genetically predisposed individuals who have a chronic elevated intracellular Ca2+ concentration ([Ca2+]i) in their muscle cells. We have reported that the muscle dysregulation of [Ca2+]i impairs glucose uptake, leading to the development of insulin resistance in two rodent experimental models. In this study, we simultaneously measured the [Ca2+]i and glucose uptake in single enzymatically isolated hippocampal pyramidal neurons from wild-type (WT) and MH-R163C mice. The [Ca2+]i was recorded using a Ca2+-selective microelectrode, and the glucose uptake was assessed utilizing the fluorescent glucose analog 2-NBDG. The MH-R163C hippocampal neurons exhibited elevated [Ca2+]i and impaired insulin-dependent glucose uptake compared with the WT neurons. Additionally, exposure to isoflurane exacerbated these deficiencies in the MH-R163C neurons, while the WT neurons remained unaffected. Lowering [Ca2+]i using a Ca2+-free solution, SAR7334, or dantrolene increased the glucose uptake in the MH-R163C neurons without significantly affecting the WT neurons. However, further reduction of the [Ca2+]i below the physiological level using BAPTA decreased the insulin-dependent glucose uptake in both genotypes. Furthermore, the homogenates of the MH-R163C hippocampal neurons showed an altered protein expression of the PI3K/Akt signaling pathway and GLUT4 compared with the WT mice. Our study demonstrated that the chronic elevation of [Ca2+]i was sufficient to compromise the insulin-dependent glucose uptake in the MH-R163C hippocampal neurons. Moreover, reducing the [Ca2+]i within a specific range (100–130 nM) could reverse insulin resistance, a hallmark of type 2 diabetes mellitus (T2D).

Epileptiform activity in brain organoids derived from patient with Glucose Transporter 1 Deficiency Syndrome

IntroductionGlucose Transporter 1-Deficiency Syndrome (GLUT1-DS) is a rare genetic disorder caused by mutations in the gene encoding for GLUT1 and characterized by impaired glucose uptake in the brain. This leads to brain hypometabolism and the development of symptoms that include epilepsy, motor dysfunctions and cognitive impairment. The development of patient-specific in vitro models is a valuable tool for understanding the pathophysiology of rare genetic disorders and testing new therapeutic interventions.MethodsIn this study, we generated brain organoids from induced pluripotent stem cells (iPSCs) derived either from a GLUT1-DS patient or a healthy individual. The functional organoids were analyzed for cellular composition, maturity, and electrophysiological activity using a custom-made microelectrode array (MEA) platform, which allowed for the detection of spikes, burst patterns, and epileptiform discharges.ResultsImmunostaining revealed a similar distribution of neurons and astrocytes in both healthy and GLUT1-DS brain organoids, though GLUT1-DS brain organoids exhibited reduced cellular density and smaller overall size. Electrophysiological recordings demonstrated functional spike profiles in both organoid types. Notably, our study demonstrates that brain organoids derived from a GLUT1-DS patient exhibit distinct epileptiform activity and heightened sensitivity to glucose deprivation, reflecting key features of the disorder.DiscussionThese findings validate the use of brain organoids as a model for studying GLUT1-DS and highlight their potential for testing novel therapeutic strategies aimed at improving glucose metabolism and managing epilepsy in patients.

Impaired suppression of fatty acid release by insulin is a strong predictor of reduced whole-body insulin-mediated glucose uptake and skeletal muscle insulin receptor activation.

To examine factors underlying why most, but not all, adults with obesity exhibit impaired insulin-mediated glucose uptake, we compared: (1) adipose tissue fatty acid (FA) release, (2) skeletal muscle lipid droplet (LD) characteristics, and (3) insulin signalling events, in skeletal muscle of adults with obesity with relatively high versus low insulin-mediated glucose uptake. Seventeen adults with obesity (BMI: 36 ± 3 kg/m2) completed a 2 h hyperinsulinemic-euglycemic clamp with stable isotope tracer infusions to measure glucose rate of disappearance (glucose Rd) and FA rate of appearance (FA Ra). Skeletal muscle biopsies were collected at baseline and 30 min into the insulin infusion. Participants were stratified into HIGH (n = 7) and LOW (n = 10) insulin sensitivity cohorts by their glucose Rd during the hyperinsulinemic clamp (LOW< 400; HIGH >550 nmol/kgFFM/min/[μU/mL]). Insulin-mediated suppression of FA Ra was lower in LOW compared with HIGH (p < 0.01). In skeletal muscle, total intramyocellular lipid content did not differ between cohorts. However, the size of LDs in the subsarcolemmal region (SS) of type II muscle fibres was larger in LOW compared with HIGH (p = 0.01). Additionally, insulin receptor-β (IRβ) interactions with regulatory proteins CD36 and Fyn were lower in LOW versus HIGH (p < 0.01), which aligned with attenuated insulin-mediated Tyr phosphorylation of IRβ and downstream insulin-signalling proteins in LOW. Collectively, reduced ability for insulin to suppress FA mobilization, with accompanying modifications in intramyocellular LD size and distribution, and diminished IRβ interaction with key regulatory proteins may be key contributors to impaired insulin-mediated glucose uptake commonly found in adults with obesity.

Cellular and Molecular Pathophysiology of Gestational Diabetes.

Gestational diabetes (GD) is a metabolic disorder characterized by glucose intolerance during pregnancy, significantly impacting maternal and fetal health. Its global prevalence is approximately 14%, with risk factors including obesity, family history of diabetes, advanced maternal age, and ethnicity, which are linked to cellular and molecular disruptions in glucose regulation and insulin resistance. GD is associated with short- and long-term complications for both the mother and the newborn. For mothers, GD increases the risk of developing type 2 diabetes, cardiovascular diseases, and metabolic syndrome. In the offspring, exposure to GD in utero predisposes them to obesity, glucose intolerance, and metabolic disorders later in life. This review aims to elucidate the complex cellular and molecular mechanisms underlying GD to inform the development of effective therapeutic strategies. A systematic review was conducted using medical subject headings (MeSH) terms related to GD's cellular and molecular pathophysiology. Inclusion criteria encompassed original studies, systematic reviews, and meta-analyses focusing on GD's impact on maternal and fetal health, adhering to PRISMA guidelines. Data extraction captured study characteristics, maternal and fetal outcomes, key findings, and conclusions. GD disrupts insulin signaling pathways, leading to impaired glucose uptake and insulin resistance. Mitochondrial dysfunction reduces ATP production and increases reactive oxygen species, exacerbating oxidative stress. Hormonal influences, chronic inflammation, and dysregulation of the mammalian target of rapamycin (mTOR) pathway further impair insulin signaling. Gut microbiota alterations, gene expression, and epigenetic modifications play significant roles in GD. Ferroptosis and placental dysfunction primarily contribute to intrauterine growth restriction. Conversely, fetal macrosomia arises from maternal hyperglycemia and subsequent fetal hyperinsulinemia, resulting in excessive fetal growth. The chronic inflammatory state and oxidative stress associated with GD exacerbate these complications, creating a hostile intrauterine environment. GD's complex pathophysiology involves multiple disruptions in insulin signaling, mitochondrial function, inflammation, and oxidative stress. Effective management requires early detection, preventive strategies, and international collaboration to standardize care and improve outcomes for mothers and babies.

Endothelial Beta 1 Integrins are Necessary for Microvascular Function and Glucose Uptake.

Microvascular insulin delivery to myocytes is rate limiting for the onset of insulin-stimulated muscle glucose uptake. The structural integrity of capillaries of the microvasculature is regulated, in part, by a family of transmembrane adhesion receptors known as integrins, which are composed of an α and β subunit. The integrin β1 (itgb1) subunit is highly expressed in endothelial cells (EC). EC itgb1 is necessary for the formation of capillary networks during embryonic during development and its knockdown blunts the reactive hyperemia that manifests during ischemia reperfusion. We investigated the contribution of EC itgb1 in microcirculatory function and glucose uptake with emphasis in skeletal muscle. We hypothesized that loss of EC itgb1 would impair microvascular hemodynamics and glucose uptake during insulin stimulation, creating 'delivery'-mediated insulin resistance. An itgβ1 knockdown mouse model was developed to avoid lethality of embryonic gene knockout and the deteriorating health resulting from early post-natal inducible gene deletion. Mice with (itgb1fl/flSCLcre) and without (itgb1fl/fl) tamoxifen inducible stem cell leukemia cre recombinase (SLCcre) expression at 10 days post cre induction had comparable exercise tolerance and pulmonary and cardiac functions. Using robust in vivo experimental platforms (i.e., intravital microscopy and hyperinsulinemic-euglycemic clamp), we show that itgb1fl/flSCLcre mice compared to itgb1fl/fl littermates have, i) deficits in capillary flow rate, flow heterogeneity, and capillary density; ii) impaired insulin-stimulated glucose uptake despite sufficient transcapillary insulin efflux; and iii) reduced insulin-stimulated glucose uptake due to perfusion-limited glucose delivery. Thus, EC itgb1 is necessary for microcirculatory function and to meet the metabolic challenge of insulin stimulation.

In vivo mapping of postprandial hepatic glucose metabolism using dynamic magnetic resonance spectroscopy combined with stable isotope flux analysis in Roux-en-Y gastric bypass adults and non-operated controls: A case-control study.

Roux-en-Y gastric bypass (RYGB) surgery alters postprandial glucose profiles, causing post-bariatric hypoglycaemia (PBH) in some individuals. Due to the liver's central role in glucose homeostasis, hepatic glucose handling might differ in RYGB-operated patients with PBH compared to non-operated healthy controls (HC). We enrolled RYGB-operated adults with PBH and HCs (n = 10 each). Participants ingested 60 g of [6,6'-2H2]-glucose (d-glucose) after an overnight fast. Deuterium metabolic imaging (DMI) with interleaved 13C magnetic resonance spectroscopy was performed before and until 150 min post-d-glucose intake, with frequent blood sampling to quantify glucose enrichment and gluco-regulatory hormones until 180 min. Glucose fluxes were assessed by mathematical modelling. Outcome trajectories were described using generalized additive models. In RYGB subjects, the hepatic d-glucose signal increased early, followed by a decrease, whereas HCs exhibited a gradual increase and consecutive stabilization. Postprandial hepatic glycogen accumulation and the suppression of endogenous glucose production were lower in RYGB patients than in HCs, despite higher insulin exposure, indicating lower hepatic insulin sensitivity. The systemic rate of ingested d-glucose was faster in RYGB, leading to a higher, earlier plasma glucose peak and increased insulin secretion. Postprandial glucose disposal increased in RYGB patients, without between-group differences in peripheral insulin sensitivity. Exploiting DMI with stable isotope flux analysis, we observed distinct postprandial hepatic glucose trajectories and parameters of glucose-insulin homeostasis in RYGB patients with PBH versus HCs. Despite altered postprandial glucose kinetics and higher insulin exposure, there was no evidence of impaired hepatic glucose uptake or output predisposing to PBH in RYGB patients.

7449 A Genome-wide CRISPR Screen Identifies Drivers of Impaired Glucose Uptake in Human Insulin Resistance

Abstract Disclosure: N. Haider: None. Y. Lee: None. P. Yi: None. C.R. Kahn: None. Insulin resistance is a major risk factor in the development of type 2 diabetes (T2D), and metabolic syndrome. Although 25% of people within the general non-diabetic population are insulin resistant, the primary underlying cause of insulin resistance remains elusive. In this study, we have used induced pluripotent stem cells (iPSC) derived from non-diabetic humans at both ends of the insulin sensitivity spectrum, i.e., the top 20% of insulin resistance vs. the top 20% of insulin sensitive, as well as individuals with T2D to model human insulin resistance. We find that iPSCs differentiated into myoblasts (iMyos) from T2D and non-diabetic individuals in the highest quintile of insulin resistance (I-Res) show impaired insulin signaling and defective insulin-stimulated glucose uptake, as compared to iMyos from the insulin sensitive individuals (I-Sen), indicating that these cells in vitro mirror the alterations seen in vivo in a cell autonomous manner. To uncover the primary upstream drivers that contribute to the impaired glucose uptake associated with insulin resistance, we conducted a genome-wide loss-of-function screen using a CRISPR-based approach to identify genes that positively or negatively regulated glucose uptake in I-Res and T2D iMyos. Knockdown of ∼525 genes show effect to rescue the impaired glucose uptake in both I-Res and T2D iMyos, i.e., were negative regulators of glucose uptake. We hypothesized that important negative regulators of glucose uptake might be over-expressed at the protein level in I-Res and T2D iMyos and crossing the iMyos proteomics data with the CRISPR screen revealed 8 top candidates that are increased at the protein level and whose knockdown rescued glucose uptake in I-Res and T2D iMyos. These included candidates associated with cytoskeleton changes, protein kinases, transmembrane transport, mitochondrial and nuclear proteins. In summary, iPSC derived myoblasts from patients with insulin resistance and T2D mirror defects in glucose uptake observed in vivo. Combining CRISPR screening and global proteomics, we have identified important upstream regulators of insulin resistance in humans. Presentation: 6/2/2024

Hypoxia in Human Obesity: New Insights from Inflammation towards Insulin Resistance-A Narrative Review.

Insulin resistance (IR), marked by reduced cellular responsiveness to insulin, and obesity, defined by the excessive accumulation of adipose tissue, are two intertwined conditions that significantly contribute to the global burden of cardiometabolic diseases. Adipose tissue, beyond merely storing triglycerides, acts as an active producer of biomolecules. In obesity, as adipose tissue undergoes hypertrophy, it becomes dysfunctional, altering the release of adipocyte-derived factors, known as adipokines. This dysfunction promotes low-grade chronic inflammation, exacerbates IR, and creates a hyperglycemic, proatherogenic, and prothrombotic environment. However, the fundamental cause of these phenomena remains unclear. This narrative review points to hypoxia as a critical trigger for the molecular changes associated with fat accumulation, particularly within visceral adipose tissue (VAT). The activation of hypoxia-inducible factor-1 (HIF-1), a transcription factor that regulates homeostatic responses to low oxygen levels, initiates a series of molecular events in VAT, leading to the aberrant release of adipokines, many of which are still unexplored, and potentially affecting peripheral insulin sensitivity. Recent discoveries have highlighted the role of hypoxia and miRNA-128 in regulating the insulin receptor in visceral adipocytes, contributing to their dysfunctional behavior, including impaired glucose uptake. Understanding the complex interplay between adipose tissue hypoxia, dysfunction, inflammation, and IR in obesity is essential for developing innovative, targeted therapeutic strategies.

A Randomized Trial of the Efficacy of Three Weight Loss Diet Interventions in Overweight/Obese with Polycystic Ovary Syndrome.

Polycystic Ovary Syndrome (PCOS) is a highly prevalent, complex, heterogeneous, polygenic endocrine disorder characterized by metabolic and reproductive dysfunction that affects 8-13% of women of reproductive age worldwide. The pathogenesis of PCOS has not been fully clarified and includes genetics, obesity, and insulin resistance (IR). Oxidative stress (OS) of PCOS is independent of obesity. It can induce IR through post-insulin receptor defects, impair glucose uptake in muscle and adipose tissue, and exacerbate IR by reducing insulin secretion from pancreatic β-cells. To investigate the effects of Calorie Restricted Diet (CRD), High Protein Diet (HPD), and High Protein and High Dietary Fiber Diet (HPD+HDF) on body composition, insulin resistance, and oxidative stress in overweight/obese PCOS patients. A total of 90 overweight/obese patients with PCOS were selected to receive an 8- week medical nutrition weight loss intervention at our First Hospital of Peking University, and we randomly divided them into the CRD group (group A), the HPD group (group B), and the HPD+HDF group (group C), with 30 patients in each group. We measured their body composition, HOMA-IR index, and oxidative stress indicators. The t-test, Mann-Whitney U test, analysis of variance (ANOVA), and Kruskal-Wallis H test were used to compare the efficacy of the three methods. After eight weeks, the body weights of the three groups decreased by 6.32%, 5.70% and 7.24%, respectively, and the Visceral Fat Area (VFA) values decreased by 6.8 cm2, 13.4 cm2 and 23.45 cm2, respectively, especially in group C (p <0.05). The lean body mass (LBM), also known as the Fat-Free Mass (FFM) values of group B and group C after weight loss, were higher than that of group A (p <0.05). After weight loss, the homeostatic model assessment of insulin resistance (HOMA-IR) index and malondialdehyde (MDA) were decreased. Superoxide dismutase (SOD) was increased in all three groups (p <0.05), and the changes in SOD and MDA in group B and group C were more significant (p <0.05). HOMA-IR index positively correlated with body mass index (BMI) (r=0.195; p <0.05); MDA positively correlated with percent of body fat (PBF) (r=0.186; p <0.05) and HOMA-IR index (r=0.422; p <0.01); SOD positively correlated with LMI/FFMI (r=0.195; p <0.05), negatively correlated with HOMA-IR index (r=-0.433; p <0.01). All three diets were effective in reducing the body weight of overweight/obese patients with PCOS by more than 5% within 8 weeks and could improve both insulin resistance and oxidative stress damage. Compared with CRD, HPD and HPD+HDF diets could better retain lean body mass and significantly improve oxidative stress damage.

Endothelial β1 Integrins are Necessary for Microvascular Function and Glucose Uptake.

Microvascular insulin delivery to myocytes is rate limiting for the onset of insulin-stimulated muscle glucose uptake. The structural integrity of capillaries of the microvasculature is regulated, in part, by a family of transmembrane adhesion receptors known as integrins, which are composed of an α and β subunit. The integrin β1 (itgβ1) subunit is highly expressed in endothelial cells (EC). EC itgβ1 is necessary for the formation of capillary networks during embryonic during development and its knockdown in adult mice blunts the reactive hyperemia that manifests during ischemia reperfusion. In this study we investigated the contribution of skeletal muscle EC itgβ1 in microcirculatory function and glucose uptake. We hypothesized that loss of EC itgβ1 would impair microvascular hemodynamics and glucose uptake during insulin stimulation, creating 'delivery'-mediated insulin resistance. An itgβ1 knockdown mouse model was developed to avoid lethality of embryonic gene knockout and the deteriorating health resulting from early post-natal inducible gene deletion. We found that mice with (itgβ1fl/flSCLcre) and without (itgβ1fl/fl) inducible stem cell leukemia cre recombinase (SLCcre) expression at 10 days post cre induction have comparable exercise tolerance and pulmonary and cardiac functions. We quantified microcirculatory hemodynamics using intravital microscopy and the ability of mice to respond to the high metabolic demands of insulin-stimulated muscle using a hyperinsulinemic-euglycemia clamp. We show that itgβ1fl/flSCLcre mice compared to itgβ1fl/fl littermates have, i) deficits in capillary flow rate, flow heterogeneity, and capillary density; ii) impaired insulin-stimulated glucose uptake despite sufficient transcapillary insulin efflux; and iii) reduced insulin-stimulated glucose uptake due to perfusion-limited glucose delivery. Thus, EC itgβ1 is necessary for microcirculatory function and to meet the metabolic challenge of insulin stimulation.

Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells

Autophagy is central to the benefits of longevity signaling programs and to hematopoietic stem cell (HSC) response to nutrient stress. With age, a subset of HSCs increases autophagy flux and preserves regenerative capacity, but the signals triggering autophagy and maintaining the functionality of autophagy-activated old HSCs (oHSCs) remain unknown. Here, we demonstrate that autophagy is an adaptive cytoprotective response to chronic inflammation in the aging murine bone marrow (BM) niche. We find that inflammation impairs glucose uptake and suppresses glycolysis in oHSCs through Socs3-mediated inhibition of AKT/FoxO-dependent signaling, with inflammation-mediated autophagy engagement preserving functional quiescence by enabling metabolic adaptation to glycolytic impairment. Moreover, we show that transient autophagy induction via a short-term fasting/refeeding paradigm normalizes glycolytic flux and significantly boosts oHSC regenerative potential. Our results identify inflammation-driven glucose hypometabolism as a key driver of HSC dysfunction with age and establish autophagy as a targetable node to reset oHSC regenerative capacity.

Platycodin D Ameliorates Type 2 Diabetes-Induced Myocardial Injury by Activating the AMPK Signaling Pathway.

The current study aimed to assess the effectiveness of pharmacological intervention with Platycodin D (PD), a critically active compound isolated from the roots of Platycodon grandiflorum, in mitigating cardiotoxicity in a murine model of type 2 diabetes-induced cardiac injury and in H9c2 cells in vitro. Following oral administration for 4 weeks, PD (2.5 mg/kg) significantly suppressed the elevation of fasting blood glucose (FBG) levels, improved dyslipidemia, and effectively inhibited the rise of the cardiac injury markers creatine kinase isoenzyme MB (CK-MB) and cardiac troponin T (cTnT). PD treatment could ameliorate energy metabolism disorders induced by impaired glucose uptake by activating AMPK protein expression in the DCM mouse model, thereby promoting the GLUT4 transporter and further activating autophagy-related proteins. Furthermore, in vitro experiments demonstrated that PD exerted a concentration-dependent increase in cell viability while also inhibiting palmitic acid and glucose (HG-PA)-stimulated H9c2 cytotoxicity and activating AMPK protein expression. Notably, the AMPK activator AICAR (1 mM) was observed to upregulate the expression of AMPK in H9c2 cells after high-glucose and -fat exposure. Meanwhile, we used AMPK inhibitor Compound C (20 μM) to investigate the effect of PD activation of AMPK on cells. In addition, the molecular docking approach was employed to dock PD with AMPK, revealing a binding energy of -8.2 kcal/mol and indicating a tight interaction between the components and the target. PD could reduce the expression of autophagy-related protein p62, reduce the accumulation of autophagy products, promote the flow of autophagy, and improve myocardial cell injury. In conclusion, it has been demonstrated that PD effectively inhibits cardiac injury-induced type 2 diabetes in mice and enhances energy metabolism in HG-PA-stimulated H9c2 cells by activating the AMPK signaling pathway. These findings collectively unveil the potential cardioprotective effects of PD via modulation of the AMPK signaling pathway.

Unraveling the significance of PPP1R1A gene in pancreatic β-cell function: A study in INS-1 cells and human pancreatic islets

Background and aimsThe protein phosphatase 1 regulatory inhibitor subunit 1A (PPP1R1A) has been linked with insulin secretion and diabetes mellitus. Yet, its full significance in pancreatic β-cell function remains unclear. This study aims to elucidate the role of the PPP1R1A gene in β-cell biology using human pancreatic islets and rat INS-1 (832/13) cells. ResultsDisruption of Ppp1r1a in INS-1 cells was associated with reduced insulin secretion and impaired glucose uptake; however, cell viability, ROS, apoptosis or proliferation were intact. A significant downregulation of crucial β-cell function genes such as Ins1, Ins2, Pcsk1, Cpe, Pdx1, Mafa, Isl1, Glut2, Snap25, Vamp2, Syt5, Cacna1a, Cacna1d and Cacnb3, was observed upon Ppp1r1a disruption. Furthermore, silencing Pdx1 in INS-1 cells altered PPP1R1A expression, indicating that PPP1R1A is a target gene for PDX1. Treatment with rosiglitazone increased Ppp1r1a expression, while metformin and insulin showed no effect. RNA-seq analysis of human islets revealed high PPP1R1A expression, with α-cells showing the highest levels compared to other endocrine cells. Muscle tissues exhibited greater PPP1R1A expression than pancreatic islets, liver, or adipose tissues. Co-expression analysis revealed significant correlations between PPP1R1A and genes associated with insulin biosynthesis, exocytosis machinery, and intracellular calcium transport. Overexpression of PPP1R1A in human islets augmented insulin secretion and upregulated protein expression of Insulin, MAFA, PDX1, and GLUT1, while silencing of PPP1R1A reduced Insulin, MAFA, and GLUT1 protein levels. ConclusionThis study provides valuable insights into the role of PPP1R1A in regulating β-cell function and glucose homeostasis. PPP1R1A presents a promising opportunity for future therapeutic interventions.

Activation of GFRAL+ neurons induces hypothermia and glucoregulatory responses associated with nausea and torpor

GFRAL-expressing neurons actuate aversion and nausea, are targets for obesity treatment, and may mediate metformin effects by long-term GDF15-GFRAL agonism. Whether GFRAL+ neurons acutely regulate glucose and energy homeostasis is, however, underexplored. Here, we report that cell-specific activation of GFRAL+ neurons using a variety of techniques causes a torpor-like state, including hypothermia, the release of stress hormones, a shift from glucose to lipid oxidation, and impaired insulin sensitivity, glucose tolerance, and skeletal muscle glucose uptake but augmented glucose uptake in visceral fat. Metabolomic analysis of blood and transcriptomics of muscle and fat indicate alterations in ketogenesis, insulin signaling, adipose tissue differentiation and mitogenesis, and energy fluxes. Our findings indicate that acute GFRAL+ neuron activation induces endocrine and gluco- and thermoregulatory responses associated with nausea and torpor. While chronic activation of GFRAL signaling promotes weight loss in obesity, these results show that acute activation of GFRAL+ neurons causes hypothermia and hyperglycemia.

AMPK and Beyond: The Signaling Network Controlling RabGAPs and Contraction-Mediated Glucose Uptake in Skeletal Muscle.

Impaired skeletal muscle glucose uptake is a key feature in the development of insulin resistance and type 2 diabetes. Skeletal muscle glucose uptake can be enhanced by a variety of different stimuli, including insulin and contraction as the most prominent. In contrast to the clearance of glucose from the bloodstream in response to insulin stimulation, exercise-induced glucose uptake into skeletal muscle is unaffected during the progression of insulin resistance, placing physical activity at the center of prevention and treatment of metabolic diseases. The two Rab GTPase-activating proteins (RabGAPs), TBC1D1 and TBC1D4, represent critical nodes at the convergence of insulin- and exercise-stimulated signaling pathways, as phosphorylation of the two closely related signaling factors leads to enhanced translocation of glucose transporter 4 (GLUT4) to the plasma membrane, resulting in increased cellular glucose uptake. However, the full network of intracellular signaling pathways that control exercise-induced glucose uptake and that overlap with the insulin-stimulated pathway upstream of the RabGAPs is not fully understood. In this review, we discuss the current state of knowledge on exercise- and insulin-regulated kinases, hypoxia, nitric oxide (NO) and bioactive lipids that may be involved in the regulation of skeletal muscle glucose uptake.

Unravelling the Crosstalk between Estrogen Deficiency and Gut-biotaDysbiosis in the Development of Diabetes Mellitus.

Estrogens are classically considered essential hormonal signals, but they exert profound effects in a number of physiological and pathological states, including glucose homeostasis and insulin resistance. Estrogen deficiency after menopause in most women leads to increased androgenicity and changes in body composition, and it is recommended to manipulate the β-cell function of the pancreas, insulin-induced glucose transport, and hepatic glucose output, hence, the increasing incidence of type 2 diabetes mellitus. Recently, studies have reported that gut biota alteration due to estrogen deficiency contributes to altered energy metabolism and, hence, accentuates the pathology of diabetes mellitus. Emerging research suggests estrogen deficiency via genetic disposition or failure of ovaries to function in old age modulates the insulin resistance and glucose secretion workload on pancreatic beta cells by decreasing the levels of good bacteria such as Akkermansia muciniphila, Bifidobacterium spp., Lactobacillus spp., Faecalibacterium prausnitzii, Roseburia spp., and Prevotella spp., and increasing the levels of bad bacteria's such as Bacteroides spp., Clostridium difficile, Escherichia coli, and Enterococcus spp. Alteration in these bacteria's concentrations in the gut further leads to the development of impaired glucose uptake by the muscles, increased gluconeogenesis in the liver, and increased lipolysis and inflammation in the adipose tissues. Thus, the present review paper aims to clarify the intricate interactions between estrogen deficiency, gut microbiota regulation, and the development of diabetes mellitus.

Tryptophanylation of insulin receptor by WARS attenuates insulin signaling.

Increased circulating amino acid levels have been linked to insulin resistance and development of type 2 diabetes (T2D), but the underlying mechanism remains largely unknown. Herein, we show that tryptophan modifies insulin receptor (IR) to attenuate insulin signaling and impair glucose uptake. Mice fed with tryptophan-rich chow developed insulin resistance. Excessive tryptophan promoted tryptophanyl-tRNA synthetase (WARS) to tryptophanylate lysine 1209 of IR (W-K1209), which induced insulin resistance by inhibiting the insulin-stimulated phosphorylation of IR, AKT, and AS160. SIRT1, but not other sirtuins, detryptophanylated IRW-K1209 to increase the insulin sensitivity. Collectively, we unveiled the mechanisms of how tryptophan impaired insulin signaling, and our data suggested that WARS might be a target to attenuate insulin resistance in T2D patients.

Impact of lifestyle modification on nonalcoholic fatty liver with prediabetes and type 2 diabetes

Prediabetes is characterized by impaired glucose uptake and insulin sensitivity in the muscle, as well as a significant risk of developing diabetes, chronic renal disease, cardiovascular disease, and death. A definite bidirectional connection exists between pre-diabetes, diabetes, and NAFLD. The presence of NAFLD is associated with the subsequent development of new-onset type 2 diabetes (T2DM). There was a 6-fold rise in new-onset diabetes in people whose fatty liver severity progressed from mild to moderate or severe over 5 years, and a decrease in T2DM incidence comparable to that in those without steatosis. Insulin resistance is a common pathophysiological mechanism across metabolic illnesses, including prediabetes, diabetes, and NAFLD. As a result, better names for metabolically linked metabolic fatty liver disease have been considered. Lifestyle is the cornerstone of treatment for patients with prediabetes, T2DM, and NAFLD. Several significant randomized controlled trials show that a customized low-calorie meal plan and behavioral change are highly effective in preventing or delaying prediabetes, type 2 diabetes, and improving other cardiometabolic markers (such as blood pressure, lipids, and inflammation). Several drugs already approved for the treatment of prediabetes and diabetes are beneficial for NAFLD/NASH.

Brain insulin resistance and Alzheimer's disease: a systematic review.

The authors aimed to gather data from the current literature on brain insulin resistance (BIR) and its likely repercussions on neurodegenerative disorders, more specifically AD, through a systematic review. A comprehensive search was conducted in multiple medical databases, including the Cochrane Central Register of Controlled Trials, EMBASE, Medical Literature Analysis and Retrieval System Online (Medline), and PubMed®, employing the descriptors: "insulin resistance", "brain insulin resistance", "Alzheimer's disease", "neurodegeneration", and "cognition". The authors focused their search on English-language studies published between 2000 and 2023 that investigated the influence of BIR on neurodegenerative disorders or offered insights into BIR's underlying mechanisms. Seventeen studies that met the inclusion criteria were selected. The results indicate that BIR is a phenomenon observed in a variety of neurodegenerative disorders, including AD. Studies suggest that impaired glucose utilization and uptake, reduced adenosine triphosphate (ATP) production, and synaptic plasticity changes caused by BIR are linked to cognitive problems. However, conflicting results were observed regarding the association between AD and BIR, with some studies suggesting no association. Based on the evaluated studies, it can be concluded that the association between AD and BIR remains inconclusive, and additional research is needed to elucidate this relationship.

Deleting the ribosomal prolyl hydroxylase OGFOD1 protects mice against diet-induced obesity and insulin resistance.

Type 2 diabetes predisposes patients to heart disease, which is the primary cause of death across the globe. Type 2 diabetes often accompanies obesity and is defined by insulin resistance and abnormal glucose handling. Insulin resistance impairs glucose uptake and results in hyperglycemia, which damages tissues such as kidneys, liver, and heart. 2-oxoglutarate (2-OG)- and iron-dependent oxygenases (2-OGDOs), a family of enzymes regulating various aspects of cellular physiology, have been studied for their role in obesity and diet-induced insulin resistance. However, nothing is known of the 2-OGDO family member 2-oxoglutarate and iron-dependent prolyl hydroxylase domain containing protein 1 (OGFOD1) in this setting. OGFOD1 deletion leads to protection in cardiac ischemia-reperfusion injury and cardiac hypertrophy, which are two cardiac events that can lead to heart failure. Considering the remarkable correlation between heart disease and diabetes, the cardioprotection observed in OGFOD1-knockout mice led us to challenge these knockouts with high-fat diet. Wildtype mice fed a high-fat diet developed diet-induced obesity, insulin resistance, and glucose intolerance, but OGFOD1 knockout mice fed this same diet were resistant to diet-induced obesity and insulin resistance. These results support OGFOD1 down-regulation as a strategy for preventing obesity and insulin handling defects.