scholarly journals Tissue-Specific Splicing and Dietary Interaction of a Mutant As160 Allele Determine Muscle Metabolic Fitness in Rodents

2021 ◽  
Author(s):  
Xinyu Yang ◽  
Qiaoli Chen ◽  
Qian Ouyang ◽  
Ping Rong ◽  
Weikuan Feng ◽  
...  
Keyword(s):  
Metabolic Disorders ◽  
Postprandial Hyperglycemia ◽  
Acid Oxidation ◽  
Metabolic Abnormalities ◽  
Glucose Utilisation ◽  
Dietary Interaction ◽  
Rat Myocytes ◽  
A Minor ◽  
Metabolic Fitness

<a>Ethnic groups are physiologically and genetically adapted to their diets. Inuit bear a frequent AS160<sup>R684X</sup> mutation that causes type 2 diabetes. Whether this</a> mutation evolutionarily confers adaptation in Inuit and how it causes metabolic disorders upon dietary changes are unknown due to limitations in human studies. Here, we develop a genetically-modified rat model bearing an orthologous AS160<sup>R693X</sup> mutation, which mimics human patients exhibiting postprandial hyperglycemia and hyperinsulinemia. Importantly, a sugar-rich diet aggravates metabolic abnormalities in AS160<sup>R693X</sup> rats. The AS160<sup>R693X</sup> mutation diminishes a dominant long-variant AS160 without affecting a minor short-variant AS160 in skeletal muscle, which suppresses muscle glucose utilisation but induces fatty acid oxidation. This fuel switch suggests a possible adaptation in Inuit who traditionally had lipid-rich hypoglycemic diets. Finally, induction of the short-variant AS160 restores glucose utilisation in rat myocytes and a mouse model. Our findings have implications for development of precision treatments for patients bearing the AS160<sup>R684X</sup> mutation.

scholarly journals Tissue-Specific Splicing and Dietary Interaction of a Mutant As160 Allele Determine Muscle Metabolic Fitness in Rodents

2021 ◽  
Author(s):  
Xinyu Yang ◽  
Qiaoli Chen ◽  
Qian Ouyang ◽  
Ping Rong ◽  
Weikuan Feng ◽  
...  
Keyword(s):  
Metabolic Disorders ◽  
Postprandial Hyperglycemia ◽  
Acid Oxidation ◽  
Metabolic Abnormalities ◽  
Glucose Utilisation ◽  
Dietary Interaction ◽  
Rat Myocytes ◽  
A Minor ◽  
Metabolic Fitness

<a>Ethnic groups are physiologically and genetically adapted to their diets. Inuit bear a frequent AS160<sup>R684X</sup> mutation that causes type 2 diabetes. Whether this</a> mutation evolutionarily confers adaptation in Inuit and how it causes metabolic disorders upon dietary changes are unknown due to limitations in human studies. Here, we develop a genetically-modified rat model bearing an orthologous AS160<sup>R693X</sup> mutation, which mimics human patients exhibiting postprandial hyperglycemia and hyperinsulinemia. Importantly, a sugar-rich diet aggravates metabolic abnormalities in AS160<sup>R693X</sup> rats. The AS160<sup>R693X</sup> mutation diminishes a dominant long-variant AS160 without affecting a minor short-variant AS160 in skeletal muscle, which suppresses muscle glucose utilisation but induces fatty acid oxidation. This fuel switch suggests a possible adaptation in Inuit who traditionally had lipid-rich hypoglycemic diets. Finally, induction of the short-variant AS160 restores glucose utilisation in rat myocytes and a mouse model. Our findings have implications for development of precision treatments for patients bearing the AS160<sup>R684X</sup> mutation.

scholarly journals Metformin enhances anti-mycobacterial responses by educating CD8+ T-cell immunometabolic circuits

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Julia Böhme ◽  
Nuria Martinez ◽  
Shamin Li ◽  
Andrea Lee ◽  
Mardiana Marzuki ◽  
...  
Keyword(s):  
T Cells ◽  
Protective Efficacy ◽  
Acid Oxidation ◽  
Protective Effects ◽  
Healthy Individuals ◽  
Mass Cytometry ◽  
Mitochondrial Mass ◽  
Survival Capacity ◽  
Metabolic Fitness

Abstract Patients with type 2 diabetes (T2D) have a lower risk of Mycobacterium tuberculosis infection, progression from infection to tuberculosis (TB) disease, TB morality and TB recurrence, when being treated with metformin. However, a detailed mechanistic understanding of these protective effects is lacking. Here, we use mass cytometry to show that metformin treatment expands a population of memory-like antigen-inexperienced CD8+CXCR3+ T cells in naive mice, and in healthy individuals and patients with T2D. Metformin-educated CD8+ T cells have increased (i) mitochondrial mass, oxidative phosphorylation, and fatty acid oxidation; (ii) survival capacity; and (iii) anti-mycobacterial properties. CD8+ T cells from Cxcr3−/− mice do not exhibit this metformin-mediated metabolic programming. In BCG-vaccinated mice and guinea pigs, metformin enhances immunogenicity and protective efficacy against M. tuberculosis challenge. Collectively, these results demonstrate an important function of CD8+ T cells in metformin-derived host metabolic-fitness towards M. tuberculosis infection.

scholarly journals Metabolic diseases affect male reproduction and induce signatures in gametes that may compromise the offspring health

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Sara C Pereira ◽  
Luís Crisóstomo ◽  
Mário Sousa ◽  
Pedro F Oliveira ◽  
Marco G Alves
Keyword(s):  
Type 2 Diabetes ◽  
Metabolic Disorders ◽  
Sperm Quality ◽  
Epigenetic Inheritance ◽  
Male Reproduction ◽  
Reproductive Age ◽  
Metabolic Abnormalities ◽  
Obesity And Diabetes ◽  
Harmful Effects

Abstract The most prevalent diseases worldwide are non-communicable such as obesity and type 2 diabetes. Noteworthy, the prevalence of obesity and type 2 diabetes is expected to steadily increase in the next decades, mostly fueled by bad feeding habits, stress, and sedentarism. The reproductive function of individuals is severely affected by abnormal metabolic environments, both at mechanical and biochemical levels. Along with mechanical dysfunctions, and decreased sperm quality (promoted both directly and indirectly by metabolic abnormalities), several studies have already reported the potentially harmful effects of metabolic disorders in the genetic and epigenetic cargo of spermatozoa, and the epigenetic inheritance of molecular signatures induced by metabolic profile (paternal diet, obesity, and diabetes). The inheritance of epigenetic factors towards the development of metabolic abnormalities means that more people in reproductive age can potentially suffer from these disorders and for longer periods. In its turn, these individuals can also transmit this (epi)genetic information to future generations, creating a vicious cycle. In this review, we collect the reported harmful effects related to acquired metabolic disorders and diet in sperm parameters and male reproductive potential. Besides, we will discuss the novel findings regarding paternal epigenetic inheritance, particularly the ones induced by paternal diet rich in fats, obesity, and type 2 diabetes. We analyze the data attained with in vitro and animal models as well as in long-term transgenerational population studies. Although the findings on this topic are very recent, epigenetic inheritance of metabolic disease has a huge societal impact, which may be crucial to tackle the ‘fat epidemic’ efficiently.

Recent Developments in Alpha-Glucosidase Inhibitors for Management of Type-2 Diabetes: An Update

2019 ◽  
Vol 25 (23) ◽  
pp. 2510-2525 ◽  
Author(s):  
Bashir Usman ◽  
Neha Sharma ◽  
Saurabh Satija ◽  
Meenu Mehta ◽  
Manish Vyas ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Patient Compliance ◽  
Postprandial Hyperglycemia ◽  
Diabetic Patients ◽  
Poor Patient ◽  
Glucosidase Inhibitors ◽  
Poor Patient Compliance ◽  
Recent Developments ◽  
Alpha Glucosidase

The incidence of diabetes has increased globally in recent years and figures of diabetic patients were estimated to rise up to 642 million by 2040. The disorder is accompanied with various complications if not managed at the early stages, and interlinked high mortality rate and morbidity with time. Different classes of drugs are available for the management of type 2 diabetes but were having certain limitations of their safety. Alphaglucosidase is a family of enzyme originated from the pancreas which plays a role in the anabolism of 80-90% of carbohydrate consumed into glucose. This glucose is absorbed into the blood and results in frank postprandial hyperglycemia and worsens the conditions of diabetic patients which precipitate complications. Inhibition of these enzymes helps to prevent postprandial hyperglycemia and the formation of glycated end products. Alphaglucosidase inhibitors are reported to be more important in adequate control of type 2, but marketed drugs have various side effects, such as poor patient compliance and also expensive. This proves the needs for other class of drugs with better efficacy, safety, patient compliance and economic. In this review, we have emphasized the recent advances in the field of new alpha-glucosidase inhibitors with improved safety and pharmacological profile.

Insulin Resistance and Glucose Homeostasis in Peritoneal Dialysis

2009 ◽  
Vol 29 (2_suppl) ◽  
pp. 145-148 ◽  
Author(s):  
Paulo Cezar Fortes ◽  
Thyago Proença de Moraes ◽  
Jamille Godoy Mendes ◽  
Andrea E. Stinghen ◽  
Silvia Carreira Ribeiro ◽  
...  
Keyword(s):  
Risk Factors ◽  
Insulin Resistance ◽  
Peritoneal Dialysis ◽  
Metabolic Disorders ◽  
Patient Survival ◽  
Metabolic Abnormalities ◽  
Dialysis Fluid ◽  
Altered Glucose ◽  
Insulin Homeostasis ◽  
Therapeutic Measures

Cardiovascular disease (CVD) is the main cause of death in peritoneal dialysis (PD) patients, a situation that can be explained by a combination of traditional and nontraditional risk factors for CVD in these patients. Glucose and insulin homeostasis are altered in chronic kidney disease (CKD) patients even in the early stages of CKD, leading to insulin resistance by various pathways. Several factors have been implicated in the pathogenesis of insulin resistance, including anemia, dyslipidemia, uremia, malnutrition, excess of parathyroid hormone, vitamin D deficiency, metabolic acidosis, and increase in plasma free fatty acids and proinflammatory cytokines. Insulin resistance and dyslipidemia are observed and increase with the progression of CKD, playing an important role in the pathogenesis of hypertension and atherosclerosis. Particularly in PD patients, exposure to glucose from dialysis fluid accentuates the foregoing metabolic abnormalities. In conclusion, insulin resistance and altered glucose metabolism are frequently observed in CKD, and although dialysis partly corrects those disturbances, the use of glucose PD solutions intensifies a series of harmful metabolic consequences. New therapeutic measures aimed at reducing metabolic disorders are urgently needed and perhaps will improve PD patient survival.

scholarly journals Potential of Beetroot and Blackcurrant Compounds to Improve Metabolic Syndrome Risk Factors

Metabolites ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 338
Author(s):  
Cameron Haswell ◽  
Ajmol Ali ◽  
Rachel Page ◽  
Roger Hurst ◽  
Kay Rutherfurd-Markwick
Keyword(s):  
Quality Of Life ◽  
Diabetes Mellitus ◽  
Risk Factors ◽  
Metabolic Syndrome ◽  
Metabolic Abnormalities ◽  
Dietary Nitrate ◽  
Increased Risk ◽  
High Concentrations

Metabolic syndrome (MetS) is a group of metabolic abnormalities, which together lead to increased risk of coronary heart disease (CHD) and type 2 diabetes mellitus (T2DM), as well as reduced quality of life. Dietary nitrate, betalains and anthocyanins may improve risk factors for MetS and reduce the risk of development of CHD and T2DM. Beetroot is a rich source of dietary nitrate, and anthocyanins are present in high concentrations in blackcurrants. This narrative review considers the efficacy of beetroot and blackcurrant compounds as potential agents to improve MetS risk factors, which could lead to decreased risk of CHD and T2DM. Further research is needed to establish the mechanisms through which these outcomes may occur, and chronic supplementation studies in humans may corroborate promising findings from animal models and acute human trials.

scholarly journals The Relationship between the Gut Microbiome and Metformin as a Key for Treating Type 2 Diabetes Mellitus

2021 ◽  
Vol 22 (7) ◽  
pp. 3566
Author(s):  
Chae Bin Lee ◽  
Soon Uk Chae ◽  
Seong Jun Jo ◽  
Ui Min Jerng ◽  
Soo Kyung Bae
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Glucose Metabolism ◽  
Gut Microbiome ◽  
Metabolic Disorders ◽  
Current Knowledge ◽  
Potential Target ◽  
The Relationship

Metformin is the first-line pharmacotherapy for treating type 2 diabetes mellitus (T2DM); however, its mechanism of modulating glucose metabolism is elusive. Recent advances have identified the gut as a potential target of metformin. As patients with metabolic disorders exhibit dysbiosis, the gut microbiome has garnered interest as a potential target for metabolic disease. Henceforth, studies have focused on unraveling the relationship of metabolic disorders with the human gut microbiome. According to various metagenome studies, gut dysbiosis is evident in T2DM patients. Besides this, alterations in the gut microbiome were also observed in the metformin-treated T2DM patients compared to the non-treated T2DM patients. Thus, several studies on rodents have suggested potential mechanisms interacting with the gut microbiome, including regulation of glucose metabolism, an increase in short-chain fatty acids, strengthening intestinal permeability against lipopolysaccharides, modulating the immune response, and interaction with bile acids. Furthermore, human studies have demonstrated evidence substantiating the hypotheses based on rodent studies. This review discusses the current knowledge of how metformin modulates T2DM with respect to the gut microbiome and discusses the prospect of harnessing this mechanism in treating T2DM.

scholarly journals The Landscape of microRNAs in βCell: Between Phenotype Maintenance and Protection

2021 ◽  
Vol 22 (2) ◽  
pp. 803
Author(s):  
Giuseppina Emanuela Grieco ◽  
Noemi Brusco ◽  
Giada Licata ◽  
Daniela Fignani ◽  
Caterina Formichi ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Metabolic Disorders ◽  
Molecular Mechanisms ◽  
Β Cell ◽  
Physiological Mechanisms ◽  
Effective Strategies ◽  
Chronic Hyperglycaemia ◽  
Shed Light

Diabetes mellitus is a group of heterogeneous metabolic disorders characterized by chronic hyperglycaemia mainly due to pancreatic β cell death and/or dysfunction, caused by several types of stress such as glucotoxicity, lipotoxicity and inflammation. Different patho-physiological mechanisms driving β cell response to these stresses are tightly regulated by microRNAs (miRNAs), a class of negative regulators of gene expression, involved in pathogenic mechanisms occurring in diabetes and in its complications. In this review, we aim to shed light on the most important miRNAs regulating the maintenance and the robustness of β cell identity, as well as on those miRNAs involved in the pathogenesis of the two main forms of diabetes mellitus, i.e., type 1 and type 2 diabetes. Additionally, we acknowledge that the understanding of miRNAs-regulated molecular mechanisms is fundamental in order to develop specific and effective strategies based on miRNAs as therapeutic targets, employing innovative molecules.

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