Pathophysiology Of Type 2 Diabetes Research Articles

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.

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)

1590-P: Post-Oral Glucose Load Hyperinsulinemia in Individuals with Metabolic Syndrome and Metabolic-Associated Fatty Liver Disease—First Steps toward the Development of Type 2 Diabetes?

Introduction: Metabolic associated fatty liver disease (MAFLD) increases the risk of incident type 2 diabetes (T2D), but mechanisms involved have not been clearly elucidated. Objective: To assess post-oral glucose tolerance test (OGTT) glucose metabolism, insulin resistance, secretion and clearance in individuals with metabolic alterations, with or without increased liver fat. Methods: Individuals with a BMI &amp;gt;25 kg/m2 and at least 1 criteria for metabolic syndrome were included in this analysis. Liver fat was quantified using MRI and participants were assigned to 2 groups according to &amp;gt; 5% liver fat (MAFLD group) or ≤ 5%. A 3h frequently-sampled OGTT was performed and oral minimal model was used to measure insulin sensitivity, secretion and disposition index. Results: Fifty participants were included in this analysis and 50% had a liver fat &amp;gt; 5%. Post-OGTT glucose concentrations and iAUC glucose were not different between groups (p -≥ 0.50), whereas post-OGTT insulin concentrations and iAUC were significantly higher in the MAFLD group (p &amp;lt; 0.03) and significantly associated with liver fat. The components of insulin secretion (dynamic, static and total) were not different between groups (p -≥ 0.27). Insulin sensitivity and dynamic disposition indices were lower in the MAFLD group and significantly associated with liver fat. but in a multivariable regression model including sex and BMI, liver fat was not statistically associated with these indices. Insulin clearance indices were significantly lower in the MAFLD group, and liver fat statistically explained most of the variance in the multivariate model (p&amp;lt; 0.02). Conclusion: Among individuals with metabolic alterations, the presence of MAFLD is associated with impaired insulin clearance and post-oral glucose load hyperinsulinemia. Insulin sensitivity and dynamic beta-cell function are also altered, features of the early pathophysiology of T2D. Disclosure G.Trépanier: None. T.Gignac: None. M.Pradeau: None. A.Morissette: None. A.Agrinier: None. C.Gagnon: Advisory Panel; Novo Nordisk, Other Relationship; Ascendis Pharma A/S, Research Support; Novo Nordisk. M.Vohl: None. A.Marette: Advisory Panel; Valbiotis, Amancia, Plexus, Acasti. A.Carreau: Advisory Panel; Novartis, Consultant; Valbiotis, Speaker's Bureau; Novo Nordisk Canada Inc.

Expression of Secretin and its Receptor Along the Intestinal Tract in Type 2 Diabetes Patients and Healthy Controls.

The hormone secretin (SCT) is released from intestinal S cells and acts via the SCT receptor (SCTR). Circulating SCT levels increase after Roux-en-Y gastric bypass surgery and have been associated with massive weight loss and high remission rates of type 2 diabetes (T2D) linked to these operations. Exogenous SCT was recently shown to reduce ad libitum food intake in healthy volunteers. To understand SCT biology and its potential role in T2D pathophysiology, we examined the intestinal mucosal expression profile of SCT and SCTR and evaluated the density of S cells along the intestinal tract of individuals with T2D and healthy controls. Using immunohistochemistry and messenger RNA (mRNA) sequencing, we analyzed intestinal mucosa biopsies sampled along the small intestine at 30-cm intervals and from 7 well-defined anatomical sites along the large intestine (during 2 sessions of double-balloon enteroscopy) in 12 individuals with T2D and 12 healthy controls. Both groups exhibited a progressive and similar decrease in SCT and SCTR mRNA expression and S-cell density along the small intestine, with reductions of 14, 100, and 50 times, respectively, in the ileum compared to the duodenum (used as reference). Negligible amounts of SCTR and SCT mRNA, as well as low S-cell density, were found in the large intestine. No significant differences were observed between the groups. SCT and SCTR mRNA expression and S-cell density were abundant in the duodenum and decreased along the small intestine. Very low SCT and SCTR mRNA levels and S-cell numbers were observed in the large intestine, without aberrations in individuals with T2D compared to healthy controls.

[Scientific evidence of the consequences of modernity].

The prevalence of type 2 diabetes (T2D) in Mexico is 14.4%. This disease is characterized by a state of hyperglycemia and chronic inflammation secondary to inadequate insulin secretion and its resistance. Among its risk factors for metabolic diseases development, the interaction between obesity, sedentary lifestyle, hypercaloric diets and genetic variants play an important role. For decades, different basic and applied research groups have worked in an interdisciplinary way to provide scientific evidence that has helped to understand the mechanisms involved in the pathophysiology of T2D in Mexicans. However, today the urgency of the advance and better proposals for prevention and management of patients with T2D makes it necessary to use translational medicine, which integrates scientific knowledge with the use of innovative technologies to provide comprehensive health care. In this sense, the present document concisely describes, with a translational approach, the implications of the interaction of environmental and genetic risk factors in the development of childhood obesity and T2D in Mexico.

Redox Balance in Type 2 Diabetes: Therapeutic Potential and the Challenge of Antioxidant-Based Therapy.

Oxidative stress is an important factor in the development of type 2 diabetes (T2D) and associated complications. Unfortunately, most clinical studies have failed to provide sufficient evidence regarding the benefits of antioxidants (AOXs) in treating this disease. Based on the known complexity of reactive oxygen species (ROS) functions in both the physiology and pathophysiology of glucose homeostasis, it is suggested that inappropriate dosing leads to the failure of AOXs in T2D treatment. To support this hypothesis, the role of oxidative stress in the pathophysiology of T2D is described, together with a summary of the evidence for the failure of AOXs in the management of diabetes. A comparison of preclinical and clinical studies indicates that suboptimal dosing of AOXs might explain the lack of benefits of AOXs. Conversely, the possibility that glycemic control might be adversely affected by excess AOXs is also considered, based on the role of ROS in insulin signaling. We suggest that AOX therapy should be given in a personalized manner according to the need, which is the presence and severity of oxidative stress. With the development of gold-standard biomarkers for oxidative stress, optimization of AOX therapy may be achieved to maximize the therapeutic potential of these agents.

Type 2 diabetes candidate genes, including PAX5, cause impaired insulin secretion in human pancreatic islets.

Type 2 diabetes (T2D) is caused by insufficient insulin secretion from pancreatic β cells. To identify candidate genes contributing to T2D pathophysiology, we studied human pancreatic islets from approximately 300 individuals. We found 395 differentially expressed genes (DEGs) in islets from individuals with T2D, including, to our knowledge, novel (OPRD1, PAX5, TET1) and previously identified (CHL1, GLRA1, IAPP) candidates. A third of the identified expression changes in islets may predispose to diabetes, as expression of these genes associated with HbA1c in individuals not previously diagnosed with T2D. Most DEGs were expressed in human β cells, based on single-cell RNA-Seq data. Additionally, DEGs displayed alterations in open chromatin and associated with T2D SNPs. Mouse KO strains demonstrated that the identified T2D-associated candidate genes regulate glucose homeostasis and body composition in vivo. Functional validation showed that mimicking T2D-associated changes for OPRD1, PAX5, and SLC2A2 impaired insulin secretion. Impairments in Pax5-overexpressing β cells were due to severe mitochondrial dysfunction. Finally, we discovered PAX5 as a potential transcriptional regulator of many T2D-associated DEGs in human islets. Overall, we have identified molecular alterations in human pancreatic islets that contribute to β cell dysfunction in T2D pathophysiology.

Human pancreatic islet microRNAs implicated in diabetes and related traits by large-scale genetic analysis

Genetic studies have identified≥240 loci associated with the risk of type 2 diabetes (T2D), yet most of these loci lie in non-coding regions, masking the underlying molecular mechanisms. Recent studies investigating mRNA expression in human pancreatic islets have yielded important insights into the molecular drivers of normal islet function and T2D pathophysiology. However, similar studies investigating microRNA (miRNA) expression remain limited. Here, we present data from 63 individuals, the largest sequencing-based analysis of miRNA expression in human islets to date. We characterized the genetic regulation of miRNA expression by decomposing the expression of highly heritable miRNAs into cis- and trans-acting genetic components and mapping cis-acting loci associated with miRNA expression [miRNA-expression quantitative trait loci (eQTLs)]. We found i) 84 heritable miRNAs, primarily regulated by trans-acting genetic effects, and ii) 5 miRNA-eQTLs. We also used several different strategies to identify T2D-associated miRNAs. First, we colocalized miRNA-eQTLs with genetic loci associated with T2D and multiple glycemic traits, identifying one miRNA, miR-1908, that shares genetic signals for blood glucose and glycated hemoglobin (HbA1c). Next, we intersected miRNA seed regions and predicted target sites with credible set SNPs associated with T2D and glycemic traits and found 32 miRNAs that may have altered binding and function due to disrupted seed regions. Finally, we performed differential expression analysis and identified 14 miRNAs associated with T2D status-including miR-187-3p, miR-21-5p, miR-668, and miR-199b-5p-and 4 miRNAs associated with a polygenic score for HbA1c levels-miR-216a, miR-25, miR-30a-3p, and miR-30a-5p.

Metabolic effects of L-citrulline in type 2 diabetes.

The prevalence of type 2 diabetes (T2D) is increasing worldwide. Decreased nitric oxide (NO) bioavailability is involved in the pathophysiology of T2D and its complications. L-citrulline (Cit), a precursor of NO production, has been suggested as a novel therapeutic agent for T2D. Available data from human and animal studies indicate that Cit supplementation in T2D increases circulating levels of Cit and L-arginine while decreasing circulating glucose and free fatty acids and improving dyslipidemia. The underlying mechanisms for these beneficial effects of Cit include increased insulin secretion from the pancreatic β cells, increased glucose uptake by the skeletal muscle, as well as increased lipolysis and β-oxidation, and decreased glyceroneogenesis in the adipose tissue. Thus, Cit has antihyperglycemic, antidyslipidemic, and antioxidant effects and has the potential to be used as a new therapeutic agent in the management of T2D. This review summarizes available literature from human and animal studies to explore the effects of Cit on metabolic parameters in T2D. It also discusses the possible mechanisms underlying Cit-induced improved metabolic parameters in T2D.

Basal Insulin/GLP-1 RA Fixed-Ratio Combinations as an Option for Advancement of Basal Insulin Therapy in Older Adults With Type 2 Diabetes.

The prevalence of type 2 diabetes (T2D) is increasing, and owing to the aging population, the number of older adults with T2D is growing rapidly. By virtue of their age, older adults are likely to have been living with the disease longer than their younger counterparts. This, coupled with differences in T2D pathophysiology between younger and older patients, means that older adults often require advancement of treatment from basal insulin. However, older adults with T2D represent a heterogeneous population, for whom the goals of treatment are complex, and overtreatment can increase the risk of complications. These factors highlight the need for individualized glycemic targets and therapeutic strategies. In this roundtable, the authors discuss the management of older adults with T2D--a large patient population who often require treatment simplification.

Once-Weekly Subcutaneous Semaglutide Improves Fatty Liver Disease in Patients with Type 2 Diabetes: A 52-Week Prospective Real-Life Study.

Nonalcoholic fatty liver disease (NAFLD) is commonly observed in patients with type 2 diabetes (T2D). Semaglutide, a glucagon-like peptide 1 receptor agonist, may have a therapeutic role by targeting common mechanisms involved in the pathophysiology of T2D and NAFLD. The study aimed to assess the effectiveness of Semaglutide on NAFLD in patients with T2D. Forty-eight patients were treated with subcutaneous Semaglutide in add-on to metformin for 52 weeks. After the baseline visit (T0), follow-up was scheduled quarterly (T3, and T6) and then at 12 months of therapy (T12). During each visit, body composition was analyzed by phase-sensitive bio-impedance, and NAFLD was diagnosed and staged by Ultrasound (US) imaging. Surrogate biomarkers of NAFLD were also calculated and followed over time. A significant decrease in anthropometric and glucometabolic parameters, insulin resistance, liver enzymes, and laboratory indices of hepatic steatosis was observed during treatment. Similarly, fat mass and visceral adipose tissue (VAT) decreased over time more than skeletal muscle and free-fat mass. US-assessed VAT thickness and the 12-point steatosis score also declined at T3 up to T12. Liver steatosis improved in most patients (70%), showing a reduction by at least one class in the semiquantitative US staging. Besides glucose control and body composition improvements, Semaglutide was effective in ameliorating the clinical appearance and severity of NAFLD in T2D patients.

A glucose-insulin-glucagon coupled model of the isoglycemic intravenous glucose infusion experiment

Type 2 diabetes (T2D) is a pathophysiology that is characterized by insulin resistance, beta- and alpha-cell dysfunction. Mathematical models of various glucose challenge experiments have been developed to quantify the contribution of insulin and beta-cell dysfunction to the pathophysiology of T2D. There is a need for effective extended models that also capture the impact of alpha-cell dysregulation on T2D. In this paper a delay differential equation-based model is developed to describe the coupled glucose-insulin-glucagon dynamics in the isoglycemic intravenous glucose infusion (IIGI) experiment. As the glucose profile in IIGI is tailored to match that of a corresponding oral glucose tolerance test (OGTT), it provides a perfect method for studying hormone responses that are in the normal physiological domain and without the confounding effect of incretins and other gut mediated factors. The model was fit to IIGI data from individuals with and without T2D. Parameters related to glucagon action, suppression, and secretion as well as measures of insulin sensitivity, and glucose stimulated response were determined simultaneously. Significant impairment in glucose dependent glucagon suppression was observed in patients with T2D (duration of T2D: 8 (6–36) months) relative to weight matched control subjects (CS) without diabetes (k1 (mM)−1: 0.16 ± 0.015 (T2D, n = 7); 0.26 ± 0.047 (CS, n = 7)). Insulin action was significantly lower in patients with T2D (a1 (10 pM min)−1: 0.000084 ± 0.0000075 (T2D); 0.00052 ± 0.00015 (CS)) and the Hill coefficient in the equation for glucose dependent insulin response was found to be significantly different in T2D patients relative to CS (h: 1.4 ± 0.15; 1.9 ± 0.14). Trends in parameters with respect to fasting plasma glucose, HbA1c and 2-h glucose values are also presented. Significantly, a negative linear relationship is observed between the glucagon suppression parameter, k1, and the three markers for diabetes and is thus indicative of the role of glucagon in exacerbating the pathophysiology of diabetes (Spearman Rank Correlation: (n = 12; (−0.79, 0.002), (−0.73,.007), (−0.86,.0003)) respectively).

اكتشاف جين جديد يساهم في الإصابة بمرض السكري ويؤثر في استقلاب الغلوكوز

الملخص المقدمة وهدف الدراسة: يعدّ مرض السكري من النوع الثاني مرضًا متعدد العوامل والجينات. وقد تم اكتشاف أكثر من 140 متغيرًا جينيًا وراثيًا مرتبطًا بسببية المرض، ولكنها تفسر فقط 10% من الأسباب الوراثية للسكري. لهذا، تسعى هذه الدراسة إلى استخدام نهج جديد تُحدَّد من خلاله جينات جديدة مشارِكة في فسيولوجية مرض السكري وإفراز الإنسولين. طريقة البحث: تم تحليل بيانات تسلسل الحمض النووي الريبوزي من جزر البنكرياس البشرية جُمعت من 89 متبرعًا. كما أُجريت سلسلة من التجارب الوظيفية في خلايا بيتا الحيوانية (INS-1) من الفئران للتحقق من الدور المحتمل للجين المرشح بما في ذلك تثبيط نشاطه، وإفراز الإنسولين، وحيوية الخلية، وموت الخلية المبرمج، والتعبير الجيني. النتائج: قد أظهر تحليل التعبير الجيني التفاضلي لبيانات تسلسل الحمض النووي الريبوزي أن 231 جينًا كان لها تعبير منخفض على نحو ملحوظ في جزر البنكرياس من المتبرعين المرضى بالسكري مقارنة بالأصحاء. وتم خفض عدد الجينات إلى 37 من جراء تطبيق قطع إحصائي أكثر صرامة. ومن بين تلك الجينات، تم اختيار (PPP1R1A) كجين مرشح بسبب ارتباطه القوي مع معدل السكري التراكمي، وتعبيره الجيني المرتفع في جزر البنكرياس البشرية مقارنة بباقي الجينات. وأيضًا، وُجد أن تعبير الجينات الوظيفية المهمة في خلايا بيتا مثل (INS) و(PDX1) و(GLUT2) و(INSR) انخفض على نحو كبير في الخلايا التي ثُبّط فيها نشاط (PPP1R1A). وخلصت الدراسة إلى أن (PPP1R1A) جين منظّم لوظيفة خلايا بيتا وإفراز الإنسولين، كما سلطت الضوء على قائمة من الجينات التي قد يكون لها دور وتأثير في مرض السكري. Background: Type 2 diabetes (T2D) is a multifactorial polygenic disease with an unclear causative mechanism. Close to 140 genetic variants are associated with T2D, but they only explain 10% of the heritability. Aim: In this study, we employed a novel approach to identify novel genes involved in the pathophysiology of T2D and insulin secretion. Methods: We analyzed RNA-sequencing data from human pancreatic islets at a global level. Furthermore, we performed a serial of functional experiments in rat pancreatic β-cells to validate the potential role of the candidate gene including siRNA silencing, insulin secretion, cell viability, apoptosis, QPCR, and western blot expression of the key molecule in β-cells. Results: Differential expression analysis reveals those 231 genes are significantly (P&lt;0.05) downregulated in diabetic islets compared to nondiabetics. However, the number of genes was restricted to 37 genes by applying a cutoff of (P&lt;0.01). Of these genes, PPP1R1A was selected as a candidate gene due to its strong correlation with HbA1c and high expression in human pancreatic islets. Silencing of PPP1R1A in INS-1 cells was markedly reduced, insulin secretion while cell viability and apoptosis were not affected. In addition, the expression of Insulin, PDX1, GLUT2, and INSR was significantly down-regulated in PPP1R1A-silenced cells. Expression of NEUROD1 and GCK was not affected. Conclusion: The study identifies PPP1R1A as a novel regulator of pancreatic β-cell function and insulin secretion. Moreover, it introduces a list of potential genes to be explored for their role in the pathogenesis of T2D.