Pathophysiology Of Type 2 Diabetes Research Articles

Ferroptosis-A Shared Mechanism for Parkinson's Disease and Type 2 Diabetes.

Type 2 diabetes (T2D) and Parkinson's disease (PD) are the two most frequent age-related chronic diseases. There are many similarities between the two diseases: both are chronic diseases; both are the result of a decrease in a specific substance-insulin in T2D and dopamine in PD; and both are caused by the destruction of specific cells-beta pancreatic cells in T2D and dopaminergic neurons in PD. Recent epidemiological and experimental studies have found that there are common underlying mechanisms in the pathophysiology of T2D and PD: chronic inflammation, mitochondrial dysfunction, impaired protein handling and ferroptosis. Epidemiological research has indicated that there is a higher risk of PD in individuals with T2D. Moreover, clinical studies have observed that the symptoms of Parkinson's disease worsen significantly after the onset of T2D. This article provides an up-to-date review on the intricate interplay between oxidative stress, reactive oxygen species (ROS) and ferroptosis in PD and T2D. By understanding the shared molecular pathways and how they can be modulated, we can develop more effective therapies, or we can repurpose existing drugs to improve patient outcomes in both disorders.

In-silico identification and functional characterization of common genes associated with type 2 diabetes and hypertension

Type 2 diabetes (T2D) and hypertension are global public health concerns and major metabolic disorders in humans. Experimental evidence indicates considerable hereditary influences on the etiology of T2D and hypertension, but the molecular basis of these diseases is still limited. Thus, the current study analyzed 185 (132 T2D and 53 hypertension) GWAS catalog datasets and identified 83 common genes linked to T2D and hypertension pathogenesis. These genes were further examined using various bioinformatics approaches to elucidate their molecular mechanisms underlying the pathophysiology of T2D and hypertension. Gene ontology (GO) analysis revealed the biological, cellular, and molecular functions of these genes, which were also linked to different T2D and hypertension pathways. Specifically, seven genes were found to be crucial for T2D, and nine were directly associated with hypertension. Protein-protein interaction (PPI) analysis identified 28 candidate genes and seven hub genes through 11 topological methods. Among 231 miRNAs, seven were significant in interacting with the hub genes, and nine transcription factors (TFs) out of 36 were linked to these hub genes. Additionally, two of the seven hub genes were downregulated by 43 FDA-approved drugs. These findings elucidate the molecular processes underlying T2D and hypertension, suggesting that targeting these genes could lead to future drug development and therapeutic strategies to treat T2D and hypertension.

Metabolomic Profiling of Adipose Tissue in Type 2 Diabetes: Associations with Obesity and Insulin Resistance.

The global prevalence of Type 2 Diabetes (T2D) poses significant public health challenges due to its associated severe complications. Insulin resistance is central to T2D pathophysiology, particularly affecting adipose tissue function. This cross-sectional observational study investigates metabolic alterations in subcutaneous adipose tissue (SAT) associated with T2D to identify potential therapeutic targets. We conducted a comprehensive metabolomic analysis of SAT from 40 participants (20 T2D, 20 ND-T2D), matched for sex, age, and BMI (Body Mass Index). Metabolite quantification was performed using GC/MS and LC/MS/MS platforms. Correlation analyses were conducted to explore associations between metabolites and clinical parameters. We identified 378 metabolites, including significant elevations in TCA cycle (tricarboxylic acid cycle) intermediates, branched-chain amino acids (BCAAs), and carbohydrates, and a significant reduction in the nucleotide-related metabolites in T2D subjects compared to those without T2D. Obesity exacerbated these alterations, particularly in amino acid metabolism. Adipocyte size negatively correlated with BCAAs, while adipocyte glucose uptake positively correlated with unsaturated fatty acids and glycerophospholipids. Our findings reveal distinct metabolic dysregulation in adipose tissue in T2D, particularly in energy metabolism, suggesting potential therapeutic targets for improving insulin sensitivity and metabolic health. Future studies should validate these findings in larger cohorts and explore underlying mechanisms to develop targeted interventions.

Differential effects of ganglioside lipids on the conformation and aggregation of islet amyloid polypeptide.

Despite causing over 1 million deaths annually, Type 2 Diabetes (T2D) currently has no curative treatments. Aggregation of the islet amyloid polypeptide (hIAPP) into amyloid plaques plays an important role in the pathophysiology of T2D and thus presents a target for therapeutic intervention. The mechanism by which hIAPP aggregates contribute to the development of T2D is unclear, but it is proposed to involve disruption of cellular membranes. However, nearly all research on hIAPP-lipid interactions has focused on anionic phospholipids, which are primarily present in the cytosolic face of plasma membranes. We seek here to characterize the effects of three gangliosides, the dominant anionic lipids in the outer leaflet of the plasma membrane, on the aggregation, structure, and toxicity of hIAPP. Our results show a dual behavior that depends on the molar ratio between the gangliosides and hIAPP. For each ganglioside, a low-lipid:peptide ratio enhances hIAPP aggregation and alters the morphology of hIAPP fibrils, while a high ratio eliminates aggregation and stabilizes an α-helix-rich hIAPP conformation. A more negative lipid charge more efficiently promotes aggregation, and a larger lipid headgroup improves inhibition of aggregation. hIAPP also alters the phase transitions of the lipids, favoring spherical micelles over larger tubular micelles. We discuss our results in the context of the available lipid surface area for hIAPP binding and speculate on a role for gangliosides in facilitating toxic hIAPP aggregation.

Sex differences in the plasma glucagon responses to a high carbohydrate meal and a glucose drink in type 2 diabetes

Elevated fasting glucagon concentrations and/or attenuated postprandial glucagon suppression are characteristics of type 2 diabetes (T2D) and contribute to hyperglycaemia. This study shows that hyperglucagonaemia is more prominent in males than females after a nutrient load in T2D, adding insights into sex differences in relation to the pathophysiology of T2D.

Joint B Vitamin Intake and Type 2 Diabetes Risk: The Mediating Role of Inflammation in a Prospective Shanghai Cohort.

Type 2 diabetes (T2D) is a global and complex public health challenge, and dietary management is acknowledged as critical in its prevention. Recent studies have highlighted the involvement of micronutrients in T2D pathophysiology; our study aims to assess the association between B vitamin intake and T2D risks and the mediating role of inflammation. In a prospective cohort design, data on B vitamins intake, including thiamine (B1), riboflavin (B2), niacin (B3), pyridoxine (B6), folate (B9), and cobalamin (B12), was obtained using a validated food frequency questionnaire (FFQ), and blood inflammatory biomarkers were analyzed according to standard protocol in the local hospitals at baseline from 44,960 adults in the Shanghai Suburban Adult Cohort and Biobank (SSACB). Incident T2D cases were identified according to a physician's diagnosis or medication records from the electronic medical information system. We employed logistic and weighted quantile sum regression models to explore the associations of single and combined levels of B vitamins with T2D and mediation analyses to investigate the effects of inflammation. Negative correlations between B vitamins and T2D were observed in the single-exposure models, except for B3. The analyses of joint exposure (B1, B2, B6, B9, and B12) also showed an inverse association (OR 0.80, 95% CI 0.71 to 0.88), with vitamin B6 accounting for 45.58% of the effects. Further mediation analysis indicated a mediating inflammatory impact, accounting for 6.72% of the relationship. Dietary intake of B vitamins (B1, B2, B6, B9, B12) was associated with a reduced T2D risk partially mediated by inflammation in Shanghai residents.

A secondary analysis of indices of hepatic and beta cell function following 12 weeks of carbohydrate and energy restriction vs. free-living control in adults with type 2 diabetes

BackgroundSubstantial weight loss in people living with type 2 diabetes (T2D) can reduce the need for glucose-lowering medications while concurrently lowering glycemia below the diagnostic threshold for the disease. Furthermore, weight-loss interventions have also been demonstrated to improve aspects of underlying T2D pathophysiology related to ectopic fat in the liver and pancreatic beta-cell function. As such, the purpose of this secondary analysis was to explore the extent to which a low-carbohydrate and energy-restricted (LCER) diet intervention improves markers of beta-cell stress/function, liver fat accumulation, and metabolic related liver function in people with type 2 diabetes.MethodsWe conducted secondary analyses of blood samples from a larger pragmatic community-based parallel-group randomized controlled trial involving a 12-week pharmacist implemented LCER diet (Pharm-TCR: <50 g carbohydrates; ~850–1100 kcal/day; n = 20) versus treatment-as-usual (TAU; n = 16). Participants were people with T2D, using ≥ 1 glucose-lowering medication, and a body mass index of ≥ 30 kg/m2. Main outcomes were C-peptide to proinsulin ratio, circulating microRNA 375 (miR375), homeostatic model assessment (HOMA) beta-cell function (B), fatty liver index (FLI), hepatic steatosis index (HSI), HOMA insulin resistance (IR), and circulating fetuin-A and fibroblast growth factor 21 (FGF21). Data were analysed using linear regression with baseline as a covariate.ResultsThere was no observed change in miR375 (p = 0.42), C-peptide to proinsulin ratio (p = 0.17) or HOMA B (p = 0.15). FLI and HSI were reduced by -25.1 (p < 0.0001) and − 4.9 (p < 0.0001), respectively. HOMA IR was reduced by -46.5% (p = 0.011). FGF21 was reduced by -161.2pg/mL (p = 0.035) with a similar tendency found for fetuin-A (mean difference: -16.7ng/mL; p = 0.11). These improvements in markers of hepatic function were accompanied by reductions in circulating metabolites linked to hepatic insulin resistance (e.g., diacylglycerols, ceramides) in the Pharm TCR group.ConclusionsThe Pharm-TCR intervention did not improve fasting indices of beta-cell stress; however, markers of liver fat accumulation and and liver function were improved, suggesting that a LCER diet can improve some aspects of the underlying pathophysiology of T2D.Trial registrationClinicaltrials.gov (NCT03181165).

Role for the Carotid Chemoreceptors in Glucose Tolerance in Human Type 2 Diabetes

Objectives: The carotid body (CB) chemoreceptors have been implicated in the development and progression of type 2 diabetes (T2D). CB denervation can prevent the development and worsening of T2D in pre-clinical models — although these data have yet to be translated to humans. We examined CB chemosensitivity in T2D, as well as the contribution of the CB to glucose tolerance. We hypothesized: 1) individuals with T2D would exhibit exaggerated CB sensitivity to hypoxia (hypoxic ventilatory response, HVR), 2) attenuation of CB chemoreceptor activity (i.e., hyperoxia) would improve glucose tolerance in T2D, and 3) the magnitude of the effect of hyperoxia on glucose tolerance would be related to the level of CB chemosensitivity. Methods: HVR was assessed in sixteen adults with T2D (6M/10F, 55±11 yrs, HbA1c 7.7±1.4%) and twenty-one healthy controls (9M/12F, 50±13 yrs, HbA1c 5.2±0.4%)(NCT05219994). A subset (n=9 per group) completed two additional visits randomized to normoxia (0.21 FiO2) and hyperoxia (1.0 FiO2). During each visit, blood glucose and plasma insulin were measured every 15 min for 2 hrs following consumption of a 75 g glucose drink and responses were calculated as area under the curve (AUC). Pearson correlations between HVR and the difference in AUC glucose and insulin between visits (ΔAUC = hyperoxia-normoxia) were conducted. Results: HVR was augmented in T2D compared to control (control, -0.47±0.39; T2D, -0.83±0.50 L/min/%; p=0.02). There was no effect of hyperoxia on AUCglucose (control, p=0.77; T2D, p=0.73) or AUCinsulin (control, p=0.70; T2D, p=0.41). Correlations were observed between HVR and ΔAUCglucose (R=0.67, p=0.047) and ΔAUCinsulin (R=-0.55, p=0.16)] in adults with T2D, but not in controls [ΔAUCglucose (R=-0.32, p=0.40), ΔAUCinsulin (R=-0.18, p=0.67)]. Conclusions: Individuals with T2D exhibit exaggerated CB sensitivity to hypoxia. Glucose tolerance was unaffected by attenuation of CB chemoreceptor activity; however, when examined in relation to CB sensitivity, glucose tolerance improved with hyperoxia in T2D adults with the highest HVR. Present data advance our understanding of the pathophysiology of T2D and support a potential role for the CB chemoreceptors in glucose tolerance in human T2D. MizzouForward Undergraduate Research Training Grant, University of Missouri Research Council, University of Missouri Alumni Association Richard Wallace Research Incentive Fund. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Unique features of β-cell metabolism are lost in type 2 diabetes.

Pancreatic β cells play an essential role in the control of systemic glucose homeostasis as they sense blood glucose levels and respond by secreting insulin. Upon stimulating glucose uptake in insulin-sensitive tissues post-prandially, this anabolic hormone restores blood glucose levels to pre-prandial levels. Maintaining physiological glucose levels thus relies on proper β-cell function. To fulfill this highly specialized nutrient sensor role, β cells have evolved a unique genetic program that shapes its distinct cellular metabolism. In this review, the unique genetic and metabolic features of β cells will be outlined, including their alterations in type 2 diabetes (T2D). β cells selectively express a set of genes in a cell type-specific manner; for instance, the glucose activating hexokinase IV enzyme or Glucokinase (GCK), whereas other genes are selectively "disallowed", including lactate dehydrogenase A (LDHA) and monocarboxylate transporter 1 (MCT1). This selective gene program equips β cells with a unique metabolic apparatus to ensure that nutrient metabolism is coupled to appropriate insulin secretion, thereby avoiding hyperglycemia, as well as life-threatening hypoglycemia. Unlike most cell types, β cells exhibit specialized bioenergetic features, including supply-driven rather than demand-driven metabolism and a high basal mitochondrial proton leak respiration. The understanding of these unique genetically programmed metabolic features and their alterations that lead to β-cell dysfunction is crucial for a comprehensive understanding of T2D pathophysiology and the development of innovative therapeutic approaches for T2D patients.

Investigating the Impact of IL6 on Insulin Secretion: Evidence from INS-1 Cells, Human Pancreatic Islets, and Serum Analysis

Interleukin-6 (IL6) is a pleiotropic cytokine implicated in metabolic disorders and inflammation, yet its precise influence on insulin secretion and glucose metabolism remains uncertain. This study examined IL6 expression in pancreatic islets from individuals with/without diabetes, alongside a series of functional experiments, including siRNA silencing; IL6 treatment; and assessments of glucose uptake, cell viability, apoptosis, and expression of key β-cell genes, which were conducted in both INS-1 cells and human islets to elucidate the effect of IL6 on insulin secretion. Serum levels of IL6 from Emirati patients with type 2 diabetes (T2D) were measured, and the effect of antidiabetic drugs on IL6 levels was studied. The results revealed that IL6 mRNA expression was higher in islets from diabetic and older donors compared to healthy or young donors. IL6 expression correlated negatively with PDX1, MAFB, and NEUROD1 and positively with SOX4, HES1, and FOXA1. Silencing IL6 in INS-1 cells reduced insulin secretion and glucose uptake independently of apoptosis or oxidative stress. Reduced expression of IL6 was associated with the downregulation of Ins, Pdx1, Neurod1, and Glut2 in INS-1 cells. In contrast, IL6 treatment enhanced insulin secretion in INS-1 cells and human islets and upregulated insulin expression. Serum IL6 levels were elevated in patients with T2D and associated with higher glucose, HbA1c, and triglycerides, regardless of glucose-lowering medications. This study provides a new understanding of the role of IL6 in β-cell function and the pathophysiology of T2D. Our data highlight differences in the response to IL6 between INS-1 cells and human islets, suggesting the presence of species-specific variations across different experimental models. Further research is warranted to unravel the precise mechanisms underlying the observed effects of IL-6 on insulin secretion.

Integration of omics technologies for the identification of predictive biomarkers in type 2 diabetes: a comprehensive analysis of recent literature

Background. Omics technologies, such as genomics, proteomics, metabolomics, and Transcriptomics are being used for identifying biomarkers. These biomarkers are unraveling the molecular mechanisms underlying type 2 diabetes mellitus (T2DM), which can help to promote more personalized treatment strategies and advance our understanding of disease pathogenesis. Omics approaches enable the examination of genetic, protein, metabolic, and gene expression profiles more comprehensively while offering insights into T2DM risk, progression, and potential therapeutic targets. Methods: This review follows a systematic methodology, aimed at evaluating omics technology’s role in diabetes research. Utilizing literature searches, we got an initial pool of 257 studies with a rigorous selection process and narrowed the selection to 10 high-quality studies. Our methodology approach ensured the inclusion of relevant, peer-reviewed articles that contribute significantly to understanding the application of omics technologies in predicting biomarkers for type 2 diabetes. Results: The systematic review identifies ten high-quality studies illuminating substantial omics technology’s role in advancing our understanding of type 2 diabetes (T2D). Collectively, these studies demonstrate how genomics, proteomics, metagenomics, metabolomics, and Transcriptomics have uncovered novel biomarkers and molecular pathways for T2D. Our findings underscore all the omics potentials specifically for developing predictive biomarkers, enhancing diagnostics, and tailoring personalized treatment strategies. Genetic variations, metabolic alterations, and protein and RNA expression profiles were highlighted as key areas where omics technologies offer insights into the pathophysiology and management of T2D.

Urolithin B protects mice from diet-induced obesity, insulin resistance, and intestinal inflammation by regulating gut microbiota composition.

The increasing prevalence of obesity and type 2 diabetes (T2D) signifies the failure of conventional treatments for these diseases. The gut microbiota has been proposed as a key player in the pathophysiology of diet-induced T2D. Urolithin B (Uro B), a gut microbiota-derived polyphenol metabolite, exerts several beneficial health effects. In this study, we investigated the metabolic effects of Uro B on high-fat/high-sucrose (HFHS)-fed mice and determined whether its antidiabetic effects are related to the modulation of the gut microbiota. C57BL/6J mice were fed either a chow or HFHS diet. HFHS-fed mice were administered daily with either a vehicle (water) or different doses of Uro B (100 or 200 mg kg-1) for eight weeks. The composition of the gut microbiota was assessed by 16S rRNA sequencing. The results showed that Uro B treatment reduced HFHS-induced weight gain and visceral obesity and decreased liver weight and triglyceride accumulation associated with blunted hepatic oxidative stress and inflammation. Furthermore, Uro B administration improved insulin sensitivity as revealed by improved insulin tolerance, a lower homeostasis model assessment of insulin resistance, and decreased glucose-induced hyperinsulinemia during the oral glucose tolerance test. Uro B treatment was found to lower the intestinal triglyceride content and alleviate intestinal inflammation and oxidative stress. Remarkably, Uro B treatment markedly increased the proportion of the mucin-degrading bacterium Akkermansia in metagenomic samples. In conclusion, Uro B exerts beneficial metabolic effects by alleviating HFHS diet-induced features of metabolic syndrome, which is associated with a proportional increase in the population of Akkermansia spp.

The first exome wide association study in Tunisia: identification of candidate loci and pathways with biological relevance for type 2 diabetes.

Type 2 diabetes (T2D) is a multifactorial disease involving genetic and environmental components. Several genome-wide association studies (GWAS) have been conducted to decipher potential genetic aberrations promoting the onset of this metabolic disorder. These GWAS have identified over 400 associated variants, mostly in the intronic or intergenic regions. Recently, a growing number of exome genotyping or exome sequencing experiments have identified coding variants associated with T2D. Such studies were mainly conducted in European populations, and the few candidate-gene replication studies in North African populations revealed inconsistent results. In the present study, we aimed to discover the coding genetic etiology of T2D in the Tunisian population. We carried out a pilot Exome Wide Association Study (EWAS) on 50 Tunisian individuals. Single variant analysis was performed as implemented in PLINK on potentially deleterious coding variants. Subsequently, we applied gene-based and gene-set analyses using MAGMA software to identify genes and pathways associated with T2D. Potential signals were further replicated in an existing large in-silico dataset, involving up to 177116 European individuals. Our analysis revealed, for the first time, promising associations between T2D and variations in MYORG gene, implicated in the skeletal muscle fiber development. Gene-set analysis identified two candidate pathways having nominal associations with T2D in our study samples, namely the positive regulation of neuron apoptotic process and the regulation of mucus secretion. These two pathways are implicated in the neurogenerative alterations and in the inflammatory mechanisms of metabolic diseases. In addition, replication analysis revealed nominal associations of the regulation of beta-cell development and the regulation of peptidase activity pathways with T2D, both in the Tunisian subjects and in the European in-silico dataset. The present study is the first EWAS to investigate the impact of single genetic variants and their aggregate effects on T2D risk in Africa. The promising disease markers, revealed by our pilot EWAS, will promote the understanding of the T2D pathophysiology in North Africa as well as the discovery of potential treatments.

An extended minimal model of OGTT: estimation of α- and β-cell dysfunction, insulin resistance, and the incretin effect.

Loss of insulin sensitivity, α- and β-cell dysfunction, and impairment in incretin effect have all been implicated in the pathophysiology of type 2 diabetes (T2D). Parsimonious mathematical models are useful in quantifying parameters related to the pathophysiology of T2D. Here, we extend the minimum model developed to describe the glucose-insulin-glucagon dynamics in the isoglycemic intravenous glucose infusion (IIGI) experiment to the oral glucose tolerance test (OGTT). The extended model describes glucose and hormone dynamics in OGTT including the contribution of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1), to insulin secretion. A new function describing glucose arrival from the gut is introduced. The model is fitted to OGTT data from eight individuals with T2D and eight weight-matched controls (CS) without diabetes to obtain parameters related to insulin sensitivity, β- and α-cell function. The parameters, i.e., measures of insulin sensitivity, a1, suppression of glucagon secretion, k1, magnitude of glucagon secretion, γ2, and incretin-dependent insulin secretion, γ3, were found to be different between CS and T2D with P values < 0.002, <0.017, <0.009, <0.004, respectively. A new rubric for estimating the incretin effect directly from modeling the OGTT is presented. The average incretin effect correlated well with the experimentally determined incretin effect with a Spearman rank test correlation coefficient of 0.67 (P < 0.012). The average incretin effect was found to be different between CS and T2D (P < 0.032). The developed model is shown to be effective in quantifying the factors relevant to T2D pathophysiology.NEW & NOTEWORTHY A new extended model of oral glucose tolerance test (OGTT) has been developed that includes glucagon dynamics and incretin contribution to insulin secretion. The model allows the estimation of parameters related to α- and β-cell dysfunction, insulin sensitivity, and incretin action. A new function describing the influx of glucose from the gut has been introduced. A new rubric for estimating the incretin effect directly from the OGTT experiment has been developed. The effect of glucose dose was also investigated.

Pathophysiological interactions between sarcopenia and type 2 diabetes: A two-way street influencing diagnosis and therapeutic options.

This review will try to elucidate the interconnected pathophysiology of sarcopenia and type 2 diabetes (T2D) and will try to identify a common pathway to explain their development. To this end, the PubMed and Scopus databases were searched for articles published about the underlying pathophysiology, diagnosis and treatment of both sarcopenia and T2D. The medical subject heading (MeSH) terms 'sarcopenia' AND 'diabetes mellitus' AND ('physiopathology' OR 'diagnosis' OR 'therapeutics' OR 'aetiology' OR 'causality') were used. After screening, 32 papers were included. It was evident that sarcopenia and T2D share multiple pathophysiological mechanisms. Common changes in muscle architecture consist of a shift in myocyte composition, increased myosteatosis and a decreased capacity for muscle regeneration. Further, both diseases are linked to an imbalance in myokine and sex hormone production. Chronic low-grade inflammation and increased levels of oxidative stress are also known pathophysiological contributors. In the future, research efforts should be directed towards discovering common checkpoints in the development of T2D and sarcopenia as possible shared therapeutic targets for both diseases. Current treatment for T2D with biguanides, incretins and insulin may already convey a protective effect on the development of sarcopenia. Furthermore, attention should be given to early diagnosis of sarcopenia within the population of people with T2D, given the sizeable physical and medical burden it encompasses. A combination of simple diagnostic techniques could be used at regular diabetes check-ups to identify sarcopenia at an early stage and start lifestyle modifications and treatment as soon as possible.

MTORC1 and SGLT2 Inhibitors-A Therapeutic Perspective for Diabetic Cardiomyopathy.

Diabetic cardiomyopathy is a critical diabetes-mediated co-morbidity characterized by cardiac dysfunction and heart failure, without predisposing hypertensive or atherosclerotic conditions. Metabolic insulin resistance, promoting hyperglycemia and hyperlipidemia, is the primary cause of diabetes-related disorders, but ambiguous tissue-specific insulin sensitivity has shed light on the importance of identifying a unified target paradigm for both the glycemic and non-glycemic context of type 2 diabetes (T2D). Several studies have indicated hyperactivation of the mammalian target of rapamycin (mTOR), specifically complex 1 (mTORC1), as a critical mediator of T2D pathophysiology by promoting insulin resistance, hyperlipidemia, inflammation, vasoconstriction, and stress. Moreover, mTORC1 inhibitors like rapamycin and their analogs have shown significant benefits in diabetes and related cardiac dysfunction. Recently, FDA-approved anti-hyperglycemic sodium-glucose co-transporter 2 inhibitors (SGLT2is) have gained therapeutic popularity for T2D and diabetic cardiomyopathy, even acknowledging the absence of SGLT2 channels in the heart. Recent studies have proposed SGLT2-independent drug mechanisms to ascertain their cardioprotective benefits by regulating sodium homeostasis and mimicking energy deprivation. In this review, we systematically discuss the role of mTORC1 as a unified, eminent target to treat T2D-mediated cardiac dysfunction and scrutinize whether SGLT2is can target mTORC1 signaling to benefit patients with diabetic cardiomyopathy. Further studies are warranted to establish the underlying cardioprotective mechanisms of SGLT2is under diabetic conditions, with selective inhibition of cardiac mTORC1 but the concomitant activation of mTORC2 (mTOR complex 2) signaling.

Blocking IL-6 signaling improves glucose tolerance via SLC39A5-mediated suppression of glucagon secretion.

Hyperinsulinemia, hyperglucagonemia, and low-grade inflammation are frequently presented in obesity and type 2 diabetes (T2D). The pathogenic regulation between hyperinsulinemia/insulin resistance (IR) and low-grade inflammation is well documented in the development of diabetes. However, the cross-talk of hyperglucagonemia with low-grade inflammation during diabetes progression is poorly understood. In this study, we investigated the regulatory role of proinflammatory cytokine interleukin-6 (IL-6) on glucagon secretion. The correlations between inflammatory cytokines and glucagon or insulin were analyzed in rhesus monkeys and humans. IL-6 signaling was blocked by IL-6 receptor-neutralizing antibody tocilizumab in obese or T2D rhesus monkeys, glucose tolerance was evaluated by intravenous glucose tolerance test (IVGTT). Glucagon and insulin secretion were measured in isolated islets from wild-type mouse, primary pancreatic α-cells and non-α-cells sorted from GluCre-ROSA26EYFP (GYY) mice, in which the enhanced yellow fluorescent protein (EYFP) was expressed under the proglucagon promoter, by fluorescence-activated cell sorting (FACS). Particularly, glucagon secretion in α-TC1 cells treated with IL-6 was measured, and RNA sequencing was used to screen the mediator underlying IL-6-induced glucagon secretion. SLC39A5 was knocking-down or overexpressed in α-TC1 cells to determine its impact in glucagon secretion and cytosolic zinc density. Dual luciferase and chromatin Immunoprecipitation were applied to analyze the signal transducer and activator of transcription 3 (STAT3) in the regulation of SLC39A5 transcription. Plasma IL-6 correlate positively with plasma glucagon levels, but not insulin, in rhesus monkeys and humans. Tocilizumab treatment reduced plasma glucagon, blood glucose and HbA1c in spontaneously obese or T2D rhesus monkeys. Tocilizumab treatment also decreased glucagon levels during IVGTT, and improved glucose tolerance. Moreover, IL-6 significantly increased glucagon secretion in isolated islets, primary pancreatic α-cells and α-TC1 cells. Mechanistically, we found that IL-6-activated STAT3 downregulated the zinc transporter SLC39A5, which in turn reduced cytosolic zinc concentration and ATP-sensitive potassium channel activity and augmented glucagon secretion. This study demonstrates that IL-6 increases glucagon secretion via the downregulation of zinc transporter SLC39A5. This result revealed the molecular mechanism underlying the pathogenesis of hyperglucagonemia and a previously unidentified function of IL-6 in the pathophysiology of T2D, providing a potential new therapeutic strategy of targeting IL-6/glucagon to preventing or treating T2D.

The role of miRNAs carried by extracellular vesicles in type 2 diabetes and its complications.

Diabetes poses severe global public health problems and places heavy burdens on the medical and economic systems of society. Type 2 diabetes (T2D) accounts for 90% of these cases. Diabetes also often accompanies serious complications that threaten multiple organs such as the brain, eyes, kidneys, and the cardiovascular system. MicroRNAs (miRNAs) carried by extracellular vesicles (EV-miRNAs) are considered to mediate cross-organ and cross-cellular communication and have a vital role in the pathophysiology of T2D. They also offer promising sources of diabetes-related biomarkers and serve as effective therapeutic targets. Here, we briefly reviewed studies of EV-miRNAs in T2D and related complications. Specially, we innovatively explore the targeting nature of miRNA action due to the target specificity of vesicle binding, aiding mechanism understanding as well as the detection and treatment of diseases.

Hidden chronic metabolic acidosis of diabetes type 2 (CMAD): Clues, causes and consequences.

Interpretation of existing data revealed that chronic metabolic acidosis is a pathognomic feature for type 2 diabetes (T2D), which is described here as "chronic metabolic acidosis of T2D (CMAD)" for the first time. The biochemical clues for the CMAD are summarised in the following; low blood bicarbonate (high anionic gap), low pH of interstitial fluid and urine, and response to acid neutralization, while the causes of extra protons are worked out to be; mitochondrial dysfunction, systemic inflammation, gut microbiota (GM), and diabetic lung. Although, the intracellular pH is largely preserved by the buffer system and ion transporters, a persistent systemic mild acidosis leaves molecular signature in cellular metabolism in diabetics. Reciprocally, there are evidences that CMAD contributes to the initiation and progression of T2D by; reducing insulin production, triggering insulin resistance directly or via altered GM, and inclined oxidative stress. The details about the above clues, causes and consequences of CMAD are obtained by searching literature spanning between 1955 and 2022. Finally, the molecular bases of CMAD are discussed in details by interpretation of an up-to-date data and aid of well constructed diagrams, with a conclusion unravelling that CMAD is a major player in T2D pathophysiology. To this end, the CMAD disclosure offers several therapeutic potentials for prevention, delay or attenuation of T2D and its complications.

1090-P: Association between Organ Fat and Type 2 Diabetes Risk Factors among High-Risk Latino Youth

Obesity is a well-established risk factor for type 2 diabetes (T2D) in youth. However, the contribution that organ fat plays to the pathophysiology of T2D among high-risk youth is sparsely documented. The purpose of this study was to determine the independent associations between hepatic and pancreatic fat fractions with insulin sensitivity and beta-cell function among Latino youth with obesity and prediabetes. This cross-sectional analysis involved 117 Latino adolescent boys (n=70) and girls (n=47), mean (±SD) age:14±1 years, fasting glucose: 102±8mg/dL, 2-hour glucose: 144±30mg/dL, and with obesity (BMI percentile: 98.52±1.13). Total body composition was assessed by DEXA, while hepatic and pancreatic fat contents were assessed using quantitative fat fraction magnetic resonance imaging at 3 Tesla. T2D risk factors included insulin sensitivity (Matsuda index) and beta-cell function (product of insulin sensitivity and insulinogenic index), estimated from a multi-sample 2-hour oral glucose tolerance test. Associations between organ fat and T2D risk factors were examined using Pearson correlation and multiple linear regression, adjusting for age, sex, and total body fat percentage (BF%). Insulin sensitivity significantly correlated with only BF% (r =-0.236, p=0.015), fat mass (r=-0.227, p=0.020), and hepatic fat fraction (r=-0.255, p=0.024), whereas beta-cell function significantly correlated with only BF% (r=-0.241, p=0.013). In multiple regression models, hepatic fat fraction (B= -0.045, p=0.041, Δr2=.034) but not pancreatic fat fraction (B= 0.058, p=0.179, Δr2= .015) was independently associated with insulin sensitivity, whereas neither measure of organ fat was associated with beta-cell function (each Δr2 &amp;lt;.01, each p&amp;gt;.38). Hepatic fat content was an independent predictor of insulin sensitivity among Latino youth with prediabetes. Further studies are needed to understand how adiposity contributes to beta-cell dysfunction among high-risk youth. Disclosure E.O.Owolabi: None. M.Olson: Advisory Panel; Rhythm Pharmaceuticals, Inc. H.H.Hu: None. A.Pena: None. K.A.Pituch: None. S.Bailey: None. W.C.Knowler: None. G.Q.Shaibi: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (R01DK107579, F31DK125037)