scholarly journals Loss of Stearoyl-CoA desaturase 1 leads to cardiac dysfunction and lipotoxicity

2021 ◽  
Vol 224 (18) ◽  
Author(s):  
Bryon F. Tuthill II ◽  
Christopher J. Quaglia ◽  
Eileen O'Hara ◽  
Laura Palanker Musselman
Keyword(s):  
Metabolic Disease ◽  
Type 2 Diabetes ◽  
Fat Body ◽  
Acyl Chain ◽  
Monounsaturated Fatty Acids ◽  
Protective Role ◽  
Gut Development ◽  
High Sugar ◽  
Stearoyl Coa Desaturase

ABSTRACT Diets high in carbohydrates are associated with type 2 diabetes and its co-morbidities, including hyperglycemia, hyperlipidemia, obesity, hepatic steatosis and cardiovascular disease. We used a high-sugar diet to study the pathophysiology of diet-induced metabolic disease in Drosophila melanogaster. High-sugar diets produce hyperglycemia, obesity, insulin resistance and cardiomyopathy in flies, along with ectopic accumulation of toxic lipids, or lipotoxicity. Stearoyl-CoA desaturase 1 is an enzyme that contributes to long-chain fatty acid metabolism by introducing a double bond into the acyl chain. Knockdown of stearoyl-CoA desaturase 1 in the fat body reduced lipogenesis and exacerbated pathophysiology in flies reared on high-sucrose diets. These flies exhibited dyslipidemia and growth deficiency in addition to defects in cardiac and gut function. We assessed the lipidome of these flies using tandem mass spectrometry to provide insight into the relationship between potentially lipotoxic species and type 2 diabetes-like pathophysiology. Oleic acid supplementation is able to rescue a variety of phenotypes produced by stearoyl-CoA desaturase 1 RNAi, including fly mass, triglyceride storage, gut development and cardiac failure. Taken together, these data suggest a protective role for monounsaturated fatty acids in diet-induced metabolic disease phenotypes.

scholarly journals Domeless receptor loss in fat body tissue reverts insulin resistance induced by a high-sugar diet in Drosophila melanogaster

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Fernanda Lourido ◽  
Daniela Quenti ◽  
Daniela Salgado-Canales ◽  
Nicolás Tobar
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Drosophila Melanogaster ◽  
Metabolic Response ◽  
Fat Body ◽  
High Sugar ◽  
Diabetes Model ◽  
Inflammatory Processes ◽  
Stat Pathway

AbstractInsulin resistance is a hallmark of type 2 diabetes resulting from the confluence of several factors, including genetic susceptibility, inflammation, and diet. Under this pathophysiological condition, the dysfunction of the adipose tissue triggered by the excess caloric supply promotes the loss of sensitivity to insulin at the local and peripheral level, a process in which different signaling pathways are involved that are part of the metabolic response to the diet. Besides, the dysregulation of insulin signaling is strongly associated with inflammatory processes in which the JAK/STAT pathway plays a central role. To better understand the role of JAK/STAT signaling in the development of insulin resistance, we used a simple organism, Drosophila melanogaster, as a type 2 diabetes model generated by the consumption of a high-sugar diet. In this model, we studied the effects of inhibiting the expression of the JAK/STAT pathway receptor Domeless, in fat body, on adipose metabolism and glycemic control. Our results show that the Domeless receptor loss in fat body cells reverses both hyperglycemia and the increase in the expression of the insulin resistance marker Nlaz, observed in larvae fed a high sugar diet. This effect is consistent with a significant reduction in Dilp2 mRNA expression and an increase in body weight compared to wild-type flies fed high sugar diets. Additionally, the loss of Domeless reduced the accumulation of triglycerides in the fat body cells of larvae fed HSD and also significantly increased the lifespan of adult flies. Taken together, our results show that the loss of Domeless in the fat body reverses at least in part the dysmetabolism induced by a high sugar diet in a Drosophila type 2 diabetes model.

scholarly journals Targeting the Incretin/Glucagon System With Triagonists to Treat Diabetes

2018 ◽  
Vol 39 (5) ◽  
pp. 719-738 ◽  
Author(s):  
Megan E Capozzi ◽  
Richard D DiMarchi ◽  
Matthias H Tschöp ◽  
Brian Finan ◽  
Jonathan E Campbell
Keyword(s):  
Metabolic Disease ◽  
Type 2 Diabetes ◽  
Bariatric Surgery ◽  
Drug Class ◽  
Clinical Findings ◽  
Metabolic Dysfunction ◽  
Multiple Receptors ◽  
Insulinotropic Peptide ◽  
The Brain

Abstract Glucagonlike peptide 1 (GLP-1) receptor agonists have been efficacious for the treatment of type 2 diabetes due to their ability to reduce weight and attenuate hyperglycemia. However, the activity of glucagonlike peptide 1 receptor–directed strategies is submaximal, and the only potent, sustainable treatment of metabolic dysfunction is bariatric surgery, necessitating the development of unique therapeutics. GLP-1 is structurally related to glucagon and glucose-dependent insulinotropic peptide (GIP), allowing for the development of intermixed, unimolecular peptides with activity at each of their respective receptors. In this review, we discuss the range of tissue targets and added benefits afforded by the inclusion of each of GIP and glucagon. We discuss considerations for the development of sequence-intermixed dual agonists and triagonists, highlighting the importance of evaluating balanced signaling at the targeted receptors. Several multireceptor agonist peptides have been developed and evaluated, and the key preclinical and clinical findings are reviewed in detail. The biological activity of these multireceptor agonists are founded in the success of GLP-1-directed strategies; by including GIP and glucagon components, these multireceptor agonists are thought to enhance GLP-1’s activities by broadening the tissue targets and synergizing at tissues that express multiple receptors, such at the brain and pancreatic isletβ cells. The development and utility of balanced, unimolecular multireceptor agonists provide both a useful tool for querying the actions of incretins and glucagon during metabolic disease and a unique drug class to treat type 2 diabetes with unprecedented efficacy.

Immunometabolism of obesity and diabetes: microbiota link compartmentalized immunity in the gut to metabolic tissue inflammation

2015 ◽  
Vol 129 (12) ◽  
pp. 1083-1096 ◽  
Author(s):  
Joseph B. McPhee ◽  
Jonathan D. Schertzer
Keyword(s):  
Metabolic Disease ◽  
Type 2 Diabetes ◽  
Immune Responses ◽  
Metabolic Diseases ◽  
The Body ◽  
Tissue Inflammation ◽  
Gut Barrier Function ◽  
Inflammatory Status ◽  
Obesity And Diabetes

The bacteria that inhabit us have emerged as factors linking immunity and metabolism. Changes in our microbiota can modify obesity and the immune underpinnings of metabolic diseases such as Type 2 diabetes. Obesity coincides with a low-level systemic inflammation, which also manifests within metabolic tissues such as adipose tissue and liver. This metabolic inflammation can promote insulin resistance and dysglycaemia. However, the obesity and metabolic disease-related immune responses that are compartmentalized in the intestinal environment do not necessarily parallel the inflammatory status of metabolic tissues that control blood glucose. In fact, a permissive immune environment in the gut can exacerbate metabolic tissue inflammation. Unravelling these discordant immune responses in different parts of the body and establishing a connection between nutrients, immunity and the microbiota in the gut is a complex challenge. Recent evidence positions the relationship between host gut barrier function, intestinal T cell responses and specific microbes at the crossroads of obesity and inflammation in metabolic disease. A key problem to be addressed is understanding how metabolite, immune or bacterial signals from the gut are relayed and transferred into systemic or metabolic tissue inflammation that can impair insulin action preceding Type 2 diabetes.

scholarly journals Advances in Acupuncture and its Associated Therapies for the Prevention and Treatment of Obesity Type 2 Diabetes Mellitus

2020 ◽  
Vol 4 (5) ◽  
Author(s):  
Kaiya Zhang ◽  
Yuanyuan Ren ◽  
Yanyan Zhou
Keyword(s):  
Diabetes Mellitus ◽  
Metabolic Disease ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Clinical Practice ◽  
Clinical Symptoms ◽  
Embedding Therapy ◽  
Prevention And Treatment ◽  
Treatment Of Obesity

Obesity type 2 diabetes mellitus is a common metabolic disease in clinical practice, and its prevalence is increasing rapidly with the aging of the population and changes in lifestyle. Acupuncture, as a distinctive therapy, has its unique advantages in the treatment of obesity type 2 diabetes and has an irreplaceable role in a variety of treatment methods. The author organized the literature on acupuncture and its related therapies to prevent and treat obesity type 2 diabetes in recent years and found that acupuncture and its associated therapies to prevent and treat obesity type 2 diabetes mainly include: simple acupuncture, electroacupuncture, acupoint catgut embedding therapy, auricular-plaster therapy and other treatments, all of which can safely and effectively improve clinical symptoms, acupuncture and its related therapies to treat obesity type 2 diabetes has a broad prospect, worthy of further clinical promotion.

Type 2 diabetes and aortic aneurysms: protective role of macrophages metabolism

2020 ◽  
Vol 68 ◽  
pp. 102-103
Author(s):  
Joseph Carboni ◽  
Nirvana Sadaghianloo ◽  
Brigitte Sibille ◽  
Claudine Moratal ◽  
Fabien Lareyre ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Protective Role ◽  
Aortic Aneurysms

scholarly journals Stearoyl CoA desaturase is a gatekeeper that protects human beta cells against lipotoxicity and maintains their identity

Diabetologia ◽  
2019 ◽  
Vol 63 (2) ◽  
pp. 395-409 ◽  
Author(s):  
Masaya Oshima ◽  
Séverine Pechberty ◽  
Lara Bellini ◽  
Sven O. Göpel ◽  
Mélanie Campana ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Beta Cell ◽  
Beta Cells ◽  
Cell Identity ◽  
Human Beta Cells ◽  
Human Beta Cell ◽  
Stearoyl Coa Desaturase

Abstract Aims/hypothesis During the onset of type 2 diabetes, excessive dietary intake of saturated NEFA and fructose lead to impaired insulin production and secretion by insulin-producing pancreatic beta cells. The majority of data on the deleterious effects of lipids on functional beta cell mass were obtained either in vivo in rodent models or in vitro using rodent islets and beta cell lines. Translating data from rodent to human beta cells remains challenging. Here, we used the human beta cell line EndoC-βH1 and analysed its sensitivity to a lipotoxic and glucolipotoxic (high palmitate with or without high glucose) insult, as a way to model human beta cells in a type 2 diabetes environment. Methods EndoC-βH1 cells were exposed to palmitate after knockdown of genes related to saturated NEFA metabolism. We analysed whether and how palmitate induces apoptosis, stress and inflammation and modulates beta cell identity. Results EndoC-βH1 cells were insensitive to the deleterious effects of saturated NEFA (palmitate and stearate) unless stearoyl CoA desaturase (SCD) was silenced. SCD was abundantly expressed in EndoC-βH1 cells, as well as in human islets and human induced pluripotent stem cell-derived beta cells. SCD silencing induced markers of inflammation and endoplasmic reticulum stress and also IAPP mRNA. Treatment with the SCD products oleate or palmitoleate reversed inflammation and endoplasmic reticulum stress. Upon SCD knockdown, palmitate induced expression of dedifferentiation markers such as SOX9, MYC and HES1. Interestingly, SCD knockdown by itself disrupted beta cell identity with a decrease in mature beta cell markers INS, MAFA and SLC30A8 and decreased insulin content and glucose-stimulated insulin secretion. Conclusions/interpretation The present study delineates an important role for SCD in the protection against lipotoxicity and in the maintenance of human beta cell identity. Data availability Microarray data and all experimental details that support the findings of this study have been deposited in in the GEO database with the GSE130208 accession code.

GLUT-1 or GLUT-4 transgenes in obese mice improve glucose tolerance but do not prevent insulin resistance

1999 ◽  
Vol 276 (2) ◽  
pp. E390-E400 ◽  
Author(s):  
Bess Adkins Marshall ◽  
Polly A. Hansen ◽  
Nancy J. Ensor ◽  
M. Allison Ogden ◽  
Mike Mueckler
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Transgenic Mice ◽  
Glucose Utilization ◽  
Wild Type ◽  
High Fat ◽  
Glut 1 ◽  
High Sugar ◽  
Glut 4

Insulin-stimulated glucose uptake is defective in patients with type 2 diabetes. To determine whether transgenic glucose transporter overexpression in muscle can prevent diabetes induced by a high-fat, high-sugar diet, singly (GLUT-1, GLUT-4) and doubly (GLUT-1 and -4) transgenic mice were placed on a high-fat, high-sugar diet or a standard chow diet. On the high-fat, high-sugar diet, wild-type but not transgenic mice developed fasting hyperglycemia and glucose intolerance (peak glucose of 337 ± 19 vs. 185–209 mg/dl in the same groups on the high-fat, high-sugar diet and 293 ± 13 vs. 166–194 mg/dl on standard chow). Hyperinsulinemic clamps showed that transporter overexpression elevated insulin-stimulated glucose utilization on standard chow (49 ± 4 mg ⋅ kg−1 ⋅ min−1in wild-type vs. 61 ± 4, 67 ± 5, and 63 ± 6 mg ⋅ kg−1 ⋅ min−1in GLUT-1, GLUT-4, and GLUT-1 and -4 transgenic mice given 20 mU ⋅ kg−1 ⋅ min−1insulin, and 54 ± 7, 85 ± 4, and 98 ± 11 in wild-type, GLUT-1, and GLUT-4 mice given 60–80 mU ⋅ kg−1 ⋅ min−1insulin). On the high-fat, high-sugar diet, wild-type and GLUT-1 mice developed marked insulin resistance, but GLUT-4 and GLUT-1 and -4 mice were somewhat protected (glucose utilization during hyperinsulinemic clamp of 28.5 ± 3.4 vs. 42.4 ± 5.9, 51.2 ± 8.1, and 55.9 ± 4.9 mg ⋅ kg−1 ⋅ min−1in wild type, GLUT-1, GLUT-4, GLUT-1 and -4 mice). These data demonstrate that overexpression of GLUT-1 and/or GLUT-4 enhances whole body glucose utilization and prevents the development of fasting hyperglycemia and glucose intolerance induced by a high-fat, high-sugar diet. GLUT-4 overexpression improves the insulin resistance induced by the diet. We conclude that upregulation of glucose transporters in skeletal muscle may be an effective therapeutic approach to the treatment of human type 2 diabetes.

Alpha-lipoic acid and its protective role in fructose induced endocrine-metabolic disturbances

2019 ◽  
Vol 10 (1) ◽  
pp. 16-25 ◽  
Author(s):  
María Cecilia Castro ◽  
Hernán Gonzalo Villagarcía ◽  
María Laura Massa ◽  
Flavio Francini
Keyword(s):  
Type 2 Diabetes ◽  
Lipoic Acid ◽  
Food Habits ◽  
Protective Role ◽  
Nutrient Composition ◽  
Alpha Lipoic Acid ◽  
Metabolic Disturbances ◽  
Refined Carbohydrates ◽  
High Calorie

In recent decades a worldwide increase has been reported in the consumption of unhealthy high calorie diets associated with marked changes in meal nutrient composition, such as a higher intake of refined carbohydrates, which leads to the speculation that changes in food habits have contributed to the current epidemic of obesity and type 2 diabetes.

Sign in / Sign up

Export Citation Format

Share Document