Disruption Of Glucose Homeostasis Research Articles

Olaparib-induced hyperglycemia in ovarian cancer patients - a case series analysis of a three-month therapy with a consideration of BMI.

Olaparib is a relatively new poly(ADP-ribose) polymerase inhibitor (PARPi) administered to ovarian cancer (OC) patients with a complete or partial response to first-line chemotherapy. One of the metabolic side effects of olaparib is the disruption of glucose homeostasis, often resulting in hyperglycemia The study was a retrospective analysis of olaparib-induced hyperglycemia in OC patients with initial normoglycemia following the first, second, and third month of olaparib treatment METHODS: The study involved 32 OC patients, classified into three groups according to their Body Mass Index (BMI): normal BMI (BMI 18.5-24.9kg/m2; n = 13), overweight (BMI 25-29.9kg/m2; n = 13), and obese (BMI ≥ 30kg/m2; n = 6). The fasting glucose (FG) concentration was evaluated after the first, second, and third cycle of olaparib treatment (a cycle is the equivalent of 28 days of treatment). The severity of the observed hyperglycemia was assessed using the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A significant increase in glycemia was observed after the first and second cycles of olaparib treatment in the group with normal BMI and after the third cycle in overweight and obese patients. There were no significant differences in glucose levels among the groups following the first, the second, and the third cycle. Grade 1 hyperglycemia with impaired fasting glucose levels (5.6-6.9mmol/l) was found in 15 patients (normal BMI: n = 4, overweight: n = 9, and obesity: n = 2), while glycemia typical of diabetes (≥ 7.0mmol/l) was observed in one obese patient. Regardless of the weight of OC patients, it is essential to control glycemia during olaparib treatment.

Interrupting T cell memory ameliorates exaggerated metabolic response to weight cycling.

People frequently experience cycles of weight gain and loss. This weight cycling has been demonstrated, in humans and animal models, to increase cardiometabolic disease and disrupt glucose homeostasis. Obesity itself - and to an even greater extent weight regain - causes adipose tissue inflammation, resulting in metabolic dysfunction. Studies show that even after weight loss, increased numbers of lipid associated macrophages and memory T cells persist in adipose tissue and become more inflammatory upon weight regain. These findings suggest that the immune system retains a "memory" of obesity, which may contribute to the elevated inflammation and metabolic dysfunction associated with weight cycling. Here, we show that blocking the CD70-CD27 axis, critical for formation of immunological memory, decreases the number of memory T cells and reduces T cell clonality within adipose tissue after weight loss and weight cycling. Furthermore, while mice with impaired ability to create obesogenic immune memory have similar metabolic responses as wildtype mice to stable obesity, they are protected from the worsened glucose tolerance associated with weight cycling. Our data are the first to target metabolic consequences of weight cycling through an immunomodulatory mechanism. Thus, we propose a new avenue of therapeutic intervention by which targeting memory T cells can be leveraged to minimize the adverse consequences of weight cycling. These findings are particularly timely given the increasing use of efficacious weight loss drugs, which will likely lead to more instances of human weight cycling.

Neuronal-ILC2 interactions regulate pancreatic glucagon and glucose homeostasis.

The immune system shapes body metabolism, while interactions between peripheral neurons and immune cells control tissue homeostasis and immunity. However, whether peripheral neuroimmune interactions orchestrate endocrine system functions remains unexplored. After fasting, mice lacking type 2 innate lymphoid cells (ILC2s) displayed disrupted glucose homeostasis, impaired pancreatic glucagon secretion, and inefficient hepatic gluconeogenesis. Additionally, intestinal ILC2s were found in the pancreas, which was dependent on their expression of the adrenergic beta 2 receptor. Targeted activation of catecholaminergic intestinal neurons promoted the accumulation of ILC2s in the pancreas. Our work provides evidence that immune cells can be regulated by neuronal signals in response to fasting, activating an inter-organ communication route that promotes pancreatic endocrine function and regulation of blood glucose levels.

Maternal Low-Protein Diet Leads to Mitochondrial Dysfunction and Impaired Energy Metabolism in the Skeletal Muscle of Male Rats.

A prenatal low-protein (LP) diet disrupts glucose homeostasis in adult offspring. Skeletal muscles are one of the main sites of glucose clearance, and mitochondria residing in the muscle fibers are central to glucose homeostasis. Our previous studies indicated that impaired mitochondrial health is central to dysregulated glucose metabolism in the gastrocnemius muscle of the LP-programmed female rats. In addition, dysfunctional mitochondria are often an indicator of underlying irregularities in energy metabolism and metabolic inflexibility. Therefore, this study examined the mitochondrial function and metabolic flexibility in the skeletal muscles of prenatal LP-programmed adult male rats. Pregnant Wistar rats were randomly allotted to a control diet (20% protein) or an isocaloric LP diet (6% protein). Standard laboratory rat chow was given to the dams and the pups after delivery and weaning. Gene and protein expressions, mtDNA copy number, and electron microscopy were assessed in gastrocnemius (GS) muscle, and the mitochondrial oxygen consumption rate was determined using isolated flexor digitorum brevis muscle fibers. The genes associated with mitochondrial outer membrane fusion, mitofusin1 and 2 (Mfn1 and Mfn2), fission (Fis1), and biogenesis (Pgc1B, Nrf1, and Esrra) were lower in the LP group. Further, our functional studies showed that the ATP-linked oxygen consumption rate (OCR), maximal, spare respiratory, and non-mitochondrial respiration-associated OCRs were lower in the LP rats. Further, the mRNA and protein expressions of Ndufb8, a key factor involved in the complex-I catalytic activity, were downregulated in the LP group. In addition, the expression of genes linked to mitochondrial pyruvate transport (Mpc1) and metabolism (Pdha1) was lower in the LP group. In contrast, the expression of mitochondrial fatty acid transporters (Cpt1a and Cpt2) was higher in the LP when compared to the control group. However, electron microscopic analysis exhibited no difference in the mitochondrial ultrastructure in the LP muscle compared to the control. Altogether, our results indicate that the LP diet affects the mitochondrial complex-I integrity and dynamics and leads to altered expression of genes associated with substrate oxidation and mitochondrial dysfunction in the skeletal muscle of the male LP offspring.

Zebrafish as a model to study PERK function in developmental diseases: implications for Wolcott-Rallison syndrome.

Developmental diseases are challenging to investigate due to their clinical heterogeneity and relatively low prevalence. The Wolcott-Rallison Syndrome (WRS) is a rare developmental disease characterized by skeletal dysplasia and permanent neonatal diabetes due to loss-of-function mutations in the endoplasmic reticulum stress kinase PERK (EIF2AK3). The lack of efficient and less invasive therapies for WRS highlights the need for new animal models that replicate the complex pathological phenotypes, while preserving scalability for drug screening. Zebrafish exhibits high fecundity and rapid development that facilitate efficient and scalable in vivo drug testing. Here, we aimed to assess the potential of zebrafish to study PERK function and its pharmacological modulation, and as model organism of developmental diseases such as the WRS. Using bioinformatic analyses, we showed high similarity between human and zebrafish PERK. We used the pharmacological PERK inhibitor GSK2606414, which was bioactive in zebrafish, to modulate PERK function. Using transgenic zebrafish expressing fluorescent pancreatic markers and a fluorescent glucose probe, we observed that PERK inhibition decreased β cell mass and disrupted glucose homeostasis. By combining behavioural and functional assays, we show that PERK-inhibited zebrafish present marked skeletal defects and defective growth, as well as neuromuscular and cardiac deficiencies, which are clinically relevant in WRS patients, while sparing parameters like otolith area and eye/body ratio which are not associated with WRS. These results show that zebrafish holds potential to study PERK function and its pharmacological modulation in developmental disorders like WRS, assisting research on their pathophysiology and experimental treatments.

Cholecystokinin-expressing neurons of the ventromedial hypothalamic nucleus control energy homeostasis.

The hypothalamus is the primary center of the brain that regulates energy homeostasis. The ventromedial hypothalamus (VMH) plays a central role in maintaining energy balance by regulating food intake, energy expenditure, and glucose levels. However, the cellular and molecular mechanisms underlying its functions are still poorly understood. Cholecystokinin (CCK) is one of many genes expressed in this hypothalamic nucleus. Peripheral CCK regulates food intake, body weight, and glucose homeostasis. However, current research does not explain the function of CCK neurons in specific nuclei of the hypothalamus and their likely roles in network dynamics related to energy balance and food intake. This study uses genetic and pharmacological methods to examine the role of CCK-expressing neurons in the VMH (CCKVMH). Namely, using a previously generated BAC transgenic line expressing Cre recombinase under the CCK promoter, we performed targeted manipulations of CCKVMH neurons. Histological and transcriptomic database analysis revealed extensive distribution of these neurons in the VMH, with significant heterogeneity in gene expression related to energy balance, including co-expression with PACAP and somatostatin. Pharmacogenetic acute inhibition via Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) resulted in increased food intake and altered meal patterns, characterized by higher meal frequency and shorter intermeal intervals. Furthermore, diphtheria toxin-mediated ablation of CCKVMH neurons led to significant weight gain and hyperphagia over time, increasing meal size and duration. These mice also exhibited impaired glucose tolerance, indicative of disrupted glucose homeostasis. Our findings underscore the integral role of CCKVMH neurons in modulating feeding behavior, energy homeostasis, and glucose regulation. This study enhances our understanding of the neurohormonal mechanisms underlying obesity and metabolic disorders, providing potential targets for therapeutic interventions.

Role of glucose in regulating menstrual cycle

Goal of the study: To find correlation between estrogen hormone and glucose intake. Introduction: The main estrogens: estradiol, estrone and their acyl-esters have been studied essentially related to their classical estrogenic functions. However their main effect in the body is probably the sustained control of core energy metabolism. With regard to energy, the estrogen molecular species act through control of glucose availability. Material and methods: There were analyzed articles from the PubMed database, from the last 5 years 2019-2024, mentioning such words as “estrogen”, “glucose”, “ menstrual cycle” [1]. Results: Estrogens play a paramount and continued regulatory role, to maintain energy (lipid / glucose) homeostasis. Estrogens have extensive and powerful control of energy homeostasis. Premenopausal women exhibit enhanced insulin sensitivity and reduced incidence of type 2 diabetes, compared with age matched men, but this advantage disappears after menopause with disrupted glucose homeostasis, in part owing to a reduction in circulating 17 β –estradiol (E2). Moreover a study shows the efficacy of a glucagon like peptide-1 and estrogen dual agonist (GLP1-E2) in pancreatic islet protection. The enzymes that are involved in the menstrual cycle are β-glucoronidase, thought to be involved in the final stages of mucopolysaccharide breakdown. Conclusion: So far there is limited information on the major role played by different forms of physiological estrogens in the control of energy metabolism at the whole body level. E2 protects the functionality of the pancreatic β cells, preventing apoptosis, adapting their function to insulin resistance and maintaining their insulin content. The lack of E2 availability also increases hepatic insulin clearance. Estrogen receptor α plays a crucial role in regulating glucose. However, the underlying mechanisms remain incompletely understood and therefore studies on the maintenance of (lipid / glucose) homeostasis are ongoing [2-10] in various neuro-endocrine and visceral multisystem biomedical areas, where the diagnostic role of markers is essential [11,12].

Fibroblast growth factor 1 (FGF1) improves glucose homeostasis, modulates gut microbial composition, and reduces inflammatory responses in rainbow trout (Oncorhynchus mykiss) fed a high-fat diet

High-fat diets (HFDs) are widely used in aquaculture due to their lipid and protein-conserving effects, thereby reducing feed costs. However, prolonged feeding of HFD often leads to metabolic disorders in fish, such as disruption of hepatic lipid homeostasis, liver injury, and disruption of glucose homeostasis. Fibroblast growth factor 1 (FGF1) plays an essential role in controlling glucose levels in the body and dampening immune reactions. However, its impact on teleosts remains poorly researched. The therapeutic potential of recombinant FGF1 (rFGF1) was examined in a 6-week culture experiment involving rainbow trout (Oncorhynchus mykiss) that were fed an HFD. The results revealed that rFGF1 significantly reduced serum glucose levels and hepatic PEPCK and G6PC activities, but improved hepatic glycogen (P < 0.05), compared to the HFD + PBS group. Further experiments indicated that the inhibitory effect of rFGF1 on hepatic gluconeogenesis was mediated by the cAMP signaling pathway and was dependent on the high expression of PDE4D. In addition, rFGF1 increased hepatic glycogen content, which involves the AKT-GSK3β axis. Despite this increase, rFGF1 did not lead to glycogen storage disease, as shown by reduced hepatic inflammation as a result of decreased GOT (glutamic oxaloacetic transaminase), GPT (glutamic pyruvic transaminase), and elevated SOD (superoxide dismutase) in the rFGF1-treated group, accompanied by decreased il-1β, il-6, and xbp-1, and elevated nrf2 and number of hepatocyte autophagosomes. Alterations in gut microbes and short-chain fatty acids (SCFAs) were noted, indicating that rFGF1 caused a notable rise in intestinal Lactobacillus, acetic acid, and butyric acid levels. This study investigated the molecular mechanisms of rFGF1 on glucose metabolism and inflammatory responses in an HFD-fed rainbow trout model, providing new insights to improve the regulation of glucose metabolism in carnivorous fish.

7725 Could COVID-19 Be the Trigger for Type 1 Diabetes?

Abstract Disclosure: E. Ahsan: None. F.F. Foo: None. A. Ravin: None. M. Akula: None. K. Hu: None. R. Ong: None. S. Holland: None. M. Hossain: None. J. Cheng: None. Introduction: COVID-19 disrupts glucose homeostasis, which may result in hyperglycemia and new-onset diabetes mellitus. It has been hypothesized to be caused by an increased inflammatory response, increased insulin resistance, and a degree of acute viral pancreatic damage. A meta-analysis showed that the incidence of new-onset diabetes was found to be as high as 14.4% (95% CI: [5.9%-25.8%]). Here, we report a case of COVID-19-induced diabetes to spread awareness among healthcare providers and encourage early detection to prevent long-term complications. Clinical Case: A 54-year-old African American female with a past medical history of hyperlipidemia, obesity, and hypothyroidism presented to our endocrinology office for evaluation and management of diabetes mellitus (DM). She presented with symptoms of 66-pound weight loss, polydipsia, polyphagia, and polyuria. Her labs on diagnosis were significant for blood glucose of 550 mg/dl (70-100 mg/dl), hemoglobin A1c &amp;gt;15.5% (&amp;lt;5.7%), and bicarbonate 23 mmol/L (20-31 mmol/L). She started on insulin and then switched to semaglutide after six months. Her fasting glucose on the follow-up visit was 103 mg/dl, the anti-glutamic acid decarboxylase 65 (GAD-65) antibody was 8,558.9 units/ml (&amp;lt;5 units/ml), C peptide was 1.9 ng/ml (0.5-2ng/ml), and Islet Antigen-2 (IA-2) autoantibody was &amp;lt;7.5 U/ml (0-7.49 U/ml). Despite positive antibodies, her C-peptide suggested enough beta-cell function, and she was switched from insulin to semaglutide. The patient was diagnosed with autoimmune diabetes, which may be from the COVID-19 infection, and was educated about regular follow-up and new medications like teplizumab that may help prevent the progression to needing insulin. Clinical Lesson: The exact mechanism of new-onset COVID-19-induced diabetes is still unknown. However, multiple risk factors are theorized to play a role in COVID-induced DM. These include defects in insulin production and glucose clearance, obesity, stress hyperglycemia, insulin resistance, and steroid therapy. Our patient had a history of obesity but no history of diabetes, steroid use, or any personal or family history of autoimmune processes. Compared to COVID-19 patients with normoglycemia or hyperglycemia, patients with preexisting diabetes and newly diagnosed diabetes experienced more severe complications, such as shock, ARDS, acute kidney injury, hypoalbuminemia, and severe COVID-19 complications. Additional research is required to investigate the various pathophysiologies and treatment options, including new medications that may prevent the disease's further progression. Diabetes caused by COVID-19 should be treated cautiously, and prompt diagnosis and care are essential to preventing further complications. Presentation: 6/3/2024

Impact of Microplastic Exposure on Blood Glucose Levels and Gut Microbiota: Differential Effects under Normal or High-Fat Diet Conditions.

Microplastics are emerging pollutants that have garnered significant attention, with evidence suggesting their association with the pathogenesis of type 2 diabetes mellitus. In order to assess the impact of polystyrene microplastic exposure on alterations in the gut microbiota and the subsequent implications for glucose dysregulation under different dietary conditions in mice, we investigated the effects and disparities in the blood glucose levels induced by polystyrene microplastic exposure in mice fed a high-fat diet versus those fed a normal diet. Using 16S rRNA sequencing and bioinformatics analyses, we explored the dynamic changes and discrepancies in the gut microbiota stability induced by polystyrene microplastic exposure under varied dietary conditions, and we screened for gut genera associated with the potential of polystyrene microplastics to disrupt glucose homeostasis. Our findings indicate that a high-fat diet resulted in abnormal mouse body weight, energy intake, blood glucose levels and related metabolic parameters. Additionally, polystyrene microplastic exposure exacerbated the glucose metabolism disorders induced by a high-fat diet. Furthermore, the composition and diversity of the mouse gut microbiota were significantly altered following microplastic exposure, with 11 gut genera exhibiting a differential presence between mice fed a high-fat diet combined with microplastic exposure compared to those fed a normal diet with microplastic exposure. Moreover, Ucg-009 played an intermediary role in the association between a high-fat diet and the fasting blood glucose. Hence, our study demonstrates that polystyrene microplastic exposure exacerbates high-fat diet-induced glucose metabolism disorders, whereas its impact on the blood glucose under normal dietary conditions is not significant, highlighting the differential influence attributable to distinct alterations in characteristic gut genera.

Advances in Understanding and Managing Gestational Diabetes Mellitus: A Comprehensive Review

Gestational Diabetes Mellitus (GDM) is a significant and growing concern in prenatal care, impacting maternal and neonatal health. This comprehensive review highlights recent advancements in the understanding and management of GDM. The pathophysiology of GDM involves complex interactions between genetic, environmental, and hormonal factors that disrupt glucose homeostasis during pregnancy. Improved screening techniques and diagnostic criteria have led to earlier and more accurate detection. Management strategies have evolved to include not only traditional lifestyle interventions such as diet and exercise but also novel pharmacological treatments and continuous glucose monitoring technologies. The role of multidisciplinary care teams in optimizing pregnancy outcomes is emphasized, ensuring tailored care that addresses the unique needs of each patient. Additionally, the review explores emerging research on the long-term implications of GDM for both mother and child, underscoring the importance of postpartum follow-up and preventive measures. These advancements collectively aim to enhance maternal and fetal outcomes, reduce complications, and provide a framework for future research and clinical practice in GDM.

Disruption of glucose homeostasis by bacterial infection orchestrates host innate immunity through NAD+/NADH balance

Metabolic reprogramming is crucial for activating innate immunity in macrophages, and the accumulation of immunometabolites is essential for effective defense against infection. The NAD+/NADH (ratio of nicotinamide adenine dinucleotide and its reduced counterpart) redox couple serves as a critical node that integrates metabolic pathways and signaling events, but how this metabolite couple engages macrophage activation remains unclear. Here, we show that the NAD+/NADH ratio serves as a molecular signal that regulates proinflammatory responses and type I interferon (IFN) responses divergently. Salmonella Typhimurium infection leads to a decreased NAD+/NADH ratio by inducing the accumulation of NADH. Further investigation shows that an increased NAD+/NADH ratio correlates with attenuated proinflammatory responses and enhanced type I IFN responses. Conversely, a decreased NAD+/NADH ratio is linked to intensified proinflammatory responses and restrained type I IFN responses. These results show that the NAD+/NADH ratio is an essential cell-intrinsic factor that orchestrates innate immunity, which enhances our understanding of how metabolites fine-tune innate immunity.

Genetic Deletion of Skeletal Muscle Inositol Polyphosphate Multikinase Disrupts Glucose Homeostasis and Impairs Exercise Tolerance.

Inositol phosphates are critical signaling messengers involved in a wide range of biological pathways in which inositol polyphosphate multikinase (IPMK) functions as a rate-limiting enzyme for inositol polyphosphate metabolism. IPMK has been implicated in cellular metabolism, but its function at the systemic level is still poorly understood. Since skeletal muscle is a major contributor to energy homeostasis, we have developed a mouse model in which skeletal muscle IPMK is specifically deleted and examined how a loss of IPMK affects whole-body metabolism. Here, we report that mice in which IPMK knockout is deleted, specifically in the skeletal muscle, displayed an increased body weight, disrupted glucose tolerance, and reduced exercise tolerance under the normal diet. Moreover, these changes were associated with an increased accumulation of triglyceride in skeletal muscle. Furthermore, we have confirmed that a loss of IPMK led to reduced beta-oxidation, increased triglyceride accumulation, and impaired insulin response in IPMK-deficient muscle cells. Thus, our results suggest that IPMK mediates the whole-body metabolism via regulating muscle metabolism and may be potentially targeted for the treatment of metabolic syndromes.

Hunting Metabolic Biomarkers for Exposure to Per- and Polyfluoroalkyl Substances: A Review.

Per- and polyfluoroalkyl substances (PFAS) represent a class of persistent synthetic chemicals extensively utilized across industrial and consumer sectors, raising substantial environmental and human health concerns. Epidemiological investigations have robustly linked PFAS exposure to a spectrum of adverse health outcomes. Altered metabolites stand as promising biomarkers, offering insights into the identification of specific environmental pollutants and their deleterious impacts on human health. However, elucidating metabolic alterations attributable to PFAS exposure and their ensuing health effects has remained challenging. In light of this, this review aims to elucidate potential biomarkers of PFAS exposure by presenting a comprehensive overview of recent metabolomics-based studies exploring PFAS toxicity. Details of PFAS types, sources, and human exposure patterns are provided. Furthermore, insights into PFAS-induced liver toxicity, reproductive and developmental toxicity, cardiovascular toxicity, glucose homeostasis disruption, kidney toxicity, and carcinogenesis are synthesized. Additionally, a thorough examination of studies utilizing metabolomics to delineate PFAS exposure and toxicity biomarkers across blood, liver, and urine specimens is presented. This review endeavors to advance our understanding of PFAS biomarkers regarding exposure and associated toxicological effects.

The impact of surgical intervention on statographic parameters of patients with diabetic foot syndrome

Taking into account that the prevalence of diabetes mellitus continues to increase worldwide, secondary complications associated with this endocrine disorder are becoming increasingly common. Disruption of glucose homeostasis and hyperglycemia lead to the activation of several pathological metabolic pathways, contributing to the development of vascular insufficiency and neurodegenerative processes in the lower limbs. These processes are the causes of a condition known as diabetic foot syndrome (DFS), which requires special attention and meticulous treatment. Complications in the form of trophic ulcers of the lower limbs are one of the serious consequences of diabetes mellitus (DM) since they often lead to severe medical and social problems, including high rates of limb amputations. The purpose of the research is to investigate the redistribution of plantar pressure depending on the volume of surgical intervention in patients with diabetic foot syndrome (DFS) by measuring individual statographic parameters. The analysis of a series of parameters from statographic studies in patients with diabetic foot syndrome undergoing various volumes of surgical interventions has allowed for a comprehensive understanding of the features of vertical standing of these patients. In the course of the research, it has been revealed that as the support area of the operated foot decreases, there is an increase in body oscillation in both the sagittal and frontal planes relative to the support area. It has been proven that in cases with a normal support area of the foot, the relative body oscillation decreases.

Common dietary emulsifiers promote metabolic disorders and intestinal microbiota dysbiosis in mice

Dietary emulsifiers are linked to various diseases. The recent discovery of the role of gut microbiota–host interactions on health and disease warrants the safety reassessment of dietary emulsifiers through the lens of gut microbiota. Lecithin, sucrose fatty acid esters, carboxymethylcellulose (CMC), and mono- and diglycerides (MDG) emulsifiers are common dietary emulsifiers with high exposure levels in the population. This study demonstrates that sucrose fatty acid esters and carboxymethylcellulose induce hyperglycemia and hyperinsulinemia in a mouse model. Lecithin, sucrose fatty acid esters, and CMC disrupt glucose homeostasis in the in vitro insulin-resistance model. MDG impairs circulating lipid and glucose metabolism. All emulsifiers change the intestinal microbiota diversity and induce gut microbiota dysbiosis. Lecithin, sucrose fatty acid esters, and CMC do not impact mucus–bacterial interactions, whereas MDG tends to cause bacterial encroachment into the inner mucus layer and enhance inflammation potential by raising circulating lipopolysaccharide. Our findings demonstrate the safety concerns associated with using dietary emulsifiers, suggesting that they could lead to metabolic syndromes.

PAR level mediates the link between ROS and inflammatory response in patients with type 2 diabetes mellitus

BackgroundType 2 diabetes mellitus (T2DM) is characterized by disrupted glucose homeostasis and metabolic abnormalities, with oxidative stress and inflammation playing pivotal roles in its pathophysiology. Poly(ADP-ribosyl)ation (PARylation) is a post-translational process involving the addition of ADP-ribose polymers (PAR) to target proteins. While preclinical studies have implicated PARylation in the interplay between oxidative stress and inflammation in T2DM, direct clinical evidence in humans remains limited. This study investigates the relationship between oxidative stress, PARylation, and inflammatory response in T2DM patients. MethodsThis cross-sectional investigation involved 61 T2DM patients and 48 controls. PAR levels were determined in peripheral blood cells (PBMC) by ELISA-based methodologies. Oxidative stress was assessed in plasma and PBMC. In plasma, we monitored reactive oxygen metabolites (d-ROMs) and ferric-reducing antioxidant power. In PBMC, we measured the expression of antioxidant enzymes SOD1, GPX1 and CAT by qPCR. Further, we evaluated the expression of inflammatory mediators such as IL6, TNF-α, CD68 and MCP1 by qPCR in PBMC. ResultsT2DM patients exhibited elevated PAR levels in PBMC and increased d-ROMs in plasma. Positive associations were found between PAR levels and d-ROMs, suggesting a link between oxidative stress and altered PAR metabolism. Mediation analysis revealed that d-ROMs mediate the association between HbA1c levels and PAR, indicating oxidative stress as a potential driver of increased PARylation in T2DM. Furthermore, elevated PAR levels were found to be associated with increased expression of pro-inflammatory cytokines IL6 and TNF-α in the PBMC of T2DM patients. ConclusionsThis study highlights that hyperactivation of PARylation is associated with poor glycemic control and the resultant oxidative stress in T2DM. The increase of PAR levels is correlated with the upregulation of key mediators of the inflammatory response. Further research is warranted to validate these findings and explore their clinical implications.

Gestational and Postpartum Exposure to PM2.5 Components and Glucose Metabolism in Chinese Women: A Prospective Cohort Study.

Pregnant women are physiologically prone to glucose intolerance, while the puerperium represents a critical phase for recovery. However, how air pollution disrupts glucose homeostasis during the gestational and early postpartum periods remains unclear. This prospective cohort study conducted an oral glucose tolerance test and measured the insulin levels of 834 pregnant women in Guangzhou, with a follow-up for 443 puerperae at 6-8 weeks postpartum. Residential PM2.5 and five chemical components were estimated by an established spatiotemporal model. The adjusted linear model showed that an IQR increase in gestational PM2.5 exposure was associated with an increase of 0.17 mmol/L (95% CI: 0.06, 0.28) in fasting plasma glucose (FPG) and 0.24 (95% CI: 0.05, 0.42) in the insulin resistance index. Postpartum PM2.5 exposure was linked to a 0.17 mmol/L (95% CI: 0.05, 0.28) elevation in FPG per IQR, with a strengthened association found in women with gestational diabetes (Pinteraction = 0.003). In the quantile-based g-computation model, NO3- consistently contributed to the combined effect of PM2.5 components on gestational and postpartum FPG. This study was the first to suggest that PM2.5 components were associated with exacerbated gestational insulin resistance and elevated postpartum FPG. Targeted interventions reducing the emissions of toxic PM2.5 components are essential to improving maternal glucose metabolism.

The MODY-associated KCNK16 L114P mutation increases islet glucagon secretion and limits insulin secretion resulting in transient neonatal diabetes and glucose dyshomeostasis in adults.

The gain-of-function mutation in the TALK-1 K+ channel (p.L114P) is associated with maturity-onset diabetes of the young (MODY). TALK-1 is a key regulator of β-cell electrical activity and glucose-stimulated insulin secretion. The KCNK16 gene encoding TALK-1 is the most abundant and β-cell-restricted K+ channel transcript. To investigate the impact of KCNK16 L114P on glucose homeostasis and confirm its association with MODY, a mouse model containing the Kcnk16 L114P mutation was generated. Heterozygous and homozygous Kcnk16 L114P mice exhibit increased neonatal lethality in the C57BL/6J and the CD-1 (ICR) genetic background, respectively. Lethality is likely a result of severe hyperglycemia observed in the homozygous Kcnk16 L114P neonates due to lack of glucose-stimulated insulin secretion and can be reduced with insulin treatment. Kcnk16 L114P increased whole-cell β-cell K+ currents resulting in blunted glucose-stimulated Ca2+ entry and loss of glucose-induced Ca2+ oscillations. Thus, adult Kcnk16 L114P mice have reduced glucose-stimulated insulin secretion and plasma insulin levels, which significantly impairs glucose homeostasis. Taken together, this study shows that the MODY-associated Kcnk16 L114P mutation disrupts glucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by inhibiting islet insulin secretion during development. These data suggest that TALK-1 is an islet-restricted target for the treatment for diabetes.

The MODY-associated KCNK16 L114P mutation increases islet glucagon secretion and limits insulin secretion resulting in transient neonatal diabetes and glucose dyshomeostasis in adults

The gain-of-function mutation in the TALK-1 K+ channel (p.L114P) is associated with maturity-onset diabetes of the young (MODY). TALK-1 is a key regulator of β-cell electrical activity and glucose-stimulated insulin secretion. The KCNK16 gene encoding TALK-1 is the most abundant and β-cell-restricted K+ channel transcript. To investigate the impact of KCNK16 L114P on glucose homeostasis and confirm its association with MODY, a mouse model containing the Kcnk16 L114P mutation was generated. Heterozygous and homozygous Kcnk16 L114P mice exhibit increased neonatal lethality in the C57BL/6J and the CD-1 (ICR) genetic background, respectively. Lethality is likely a result of severe hyperglycemia observed in the homozygous Kcnk16 L114P neonates due to lack of glucose-stimulated insulin secretion and can be reduced with insulin treatment. Kcnk16 L114P increased whole-cell β-cell K+ currents resulting in blunted glucose-stimulated Ca2+ entry and loss of glucose-induced Ca2+ oscillations. Thus, adult Kcnk16 L114P mice have reduced glucose-stimulated insulin secretion and plasma insulin levels, which significantly impairs glucose homeostasis. Taken together, this study shows that the MODY-associated Kcnk16 L114P mutation disrupts glucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by inhibiting islet insulin secretion during development. These data suggest that TALK-1 is an islet-restricted target for the treatment for diabetes.