scholarly journals Activation of HIF1α Rescues the Hypoxic Response and Reverses Metabolic Dysfunction in the Diabetic Heart

Diabetes ◽  
2021 ◽  
pp. db210398
Author(s):  
Maria da Luz Sousa Fialho ◽  
Ujang Purnama ◽  
Kaitlyn MJH Dennis ◽  
Claudia N Montes Aparicio ◽  
Marcos Castro-Guarda ◽  
...  
Keyword(s):  
Diabetic Heart ◽  
Metabolic Dysfunction ◽  
Hypoxic Response

scholarly journals Activation of HIF1α Rescues the Hypoxic Response and Reverses Metabolic Dysfunction in the Diabetic Heart

2021 ◽  
Author(s):  
Maria da Luz Sousa Fialho ◽  
Ujang Purnama ◽  
Kaitlyn MJH Dennis ◽  
Claudia N Montes Aparicio ◽  
Marcos Castro-Guarda ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Metabolism ◽  
Target Genes ◽  
Metabolic Phenotype ◽  
Diabetic Heart ◽  
Acid Oxidation ◽  
Adaptation To Hypoxia ◽  
Metabolic Dysfunction ◽  
Hypoxic Response ◽  
Human Cardiomyocytes

Type 2 diabetes (T2D) impairs Hypoxia-Inducible Factor (HIF)1α activation, a master transcription factor that drives cellular adaptation to hypoxia. Reduced activation of HIF1α contributes to the impaired post-ischaemic remodelling observed following myocardial infarction in T2D. Molidustat is a HIF stabiliser currently undergoing clinical trials for the treatment of renal anaemia associated with chronic kidney disease, however, it may provide a route to pharmacologically activate HIF1α in the T2D heart. <br><p>In human cardiomyocytes, molidustat stabilised HIF1α and downstream HIF target genes, promoting anaerobic glucose metabolism. In hypoxia, insulin resistance blunted HIF1α activation and downstream signalling, but this was reversed by molidustat. In T2D rats, oral treatment with molidustat rescued the cardiac metabolic dysfunction caused by T2D, promoting glucose metabolism and mitochondrial function, whilst suppressing fatty acid oxidation and lipid accumulation. This resulted in beneficial effects on post-ischemic cardiac function, with the impaired contractile recovery in T2D heart reversed by molidustat treatment. <br>In conclusion, pharmacological HIF1α stabilisation can overcome the blunted hypoxic response induced by insulin resistance. In vivo this corrected the abnormal metabolic phenotype and impaired post-ischaemic recovery of the diabetic heart. Therefore, molidustat may be an effective compound to further explore the clinical translatability of HIF1α activation in the diabetic heart. </p> <p></p>

scholarly journals Activation of HIF1α Rescues the Hypoxic Response and Reverses Metabolic Dysfunction in the Diabetic Heart

2021 ◽  
Author(s):  
Maria da Luz Sousa Fialho ◽  
Ujang Purnama ◽  
Kaitlyn MJH Dennis ◽  
Claudia N Montes Aparicio ◽  
Marcos Castro-Guarda ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Metabolism ◽  
Target Genes ◽  
Metabolic Phenotype ◽  
Diabetic Heart ◽  
Acid Oxidation ◽  
Adaptation To Hypoxia ◽  
Metabolic Dysfunction ◽  
Hypoxic Response ◽  
Human Cardiomyocytes

Type 2 diabetes (T2D) impairs Hypoxia-Inducible Factor (HIF)1α activation, a master transcription factor that drives cellular adaptation to hypoxia. Reduced activation of HIF1α contributes to the impaired post-ischaemic remodelling observed following myocardial infarction in T2D. Molidustat is a HIF stabiliser currently undergoing clinical trials for the treatment of renal anaemia associated with chronic kidney disease, however, it may provide a route to pharmacologically activate HIF1α in the T2D heart. <br><p>In human cardiomyocytes, molidustat stabilised HIF1α and downstream HIF target genes, promoting anaerobic glucose metabolism. In hypoxia, insulin resistance blunted HIF1α activation and downstream signalling, but this was reversed by molidustat. In T2D rats, oral treatment with molidustat rescued the cardiac metabolic dysfunction caused by T2D, promoting glucose metabolism and mitochondrial function, whilst suppressing fatty acid oxidation and lipid accumulation. This resulted in beneficial effects on post-ischemic cardiac function, with the impaired contractile recovery in T2D heart reversed by molidustat treatment. <br>In conclusion, pharmacological HIF1α stabilisation can overcome the blunted hypoxic response induced by insulin resistance. In vivo this corrected the abnormal metabolic phenotype and impaired post-ischaemic recovery of the diabetic heart. Therefore, molidustat may be an effective compound to further explore the clinical translatability of HIF1α activation in the diabetic heart. </p> <p></p>

Abstract 14197: C14a Mutation Abolishes Mg53-Aggravated Glucose Metabolic Dysfunction and Exerts a Dominant Therapeutic Target for Ischemia and Reperfusion (i/r) Injury in Diabetic Heart

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Han Feng ◽  
Hao Shen ◽  
Matthew J Robeson ◽  
Hongkun Wu ◽  
Gengjia Chen ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Blood Glucose ◽  
Ischemia Reperfusion ◽  
Metabolic Phenotype ◽  
Diabetic Heart ◽  
Metabolic Dysfunction ◽  
Protective Function ◽  
Promising Target

Introduction: MG53, essential for cardiac ischemic protection, negatively regulates insulin receptor (IR) to trigger globular metabolic dysfunction, which makes up a big obstacle for its clinical use. In vitro evidence shows that C14A site of MG53 might be a promising target both to abolish MG53 regulation on IR and to keep as much protective function. However, in vivo effect on C14A mutation of MG53 is urgent to be explored. Results: Here, we found C14A knock-in mice exerted relieved insulin resistance, blood glucose, and metabolic phenotype in high fat diet-induced pre-diabetic model. C14A mutation did NOT lessen the protective effect of MG53 by either intracellular knock-in or extracellular addition of mutant protein against ischemia/reperfusion(I/R) injury in db/+ mice. Consistent with our previous study, we found that administration of MG53 on diabetic mice showed aggravated blood glucose, insulin resistance, and unstable cardiac function to induce a higher risk under I/R attack. C14A mutation reduced the affinity between IR ECD and MG53 to block recombinant human (rh) MG53-WT-triggered acute hyperglycemia, increased heart infarct area and death rate on db/db mice during I/R injury. Post-conditioning of rhMG53-C14A stabilized intra-operative blood glucose and showed stronger anti-I/R ability than MG53-WT protein on db/db mice. Conclusions: C14A mutation is a potential target for MG53 treatment on diabetic heart. This potential therapeutic approach for the treatment of patients within type 2 diabetes provides a strategy of gene engineering optimizing well-known target to draw on advantages and avoid pitfalls.

scholarly journals L-Carnitine Stimulates In Vivo Carbohydrate Metabolism in the Type 1 Diabetic Heart as Demonstrated by Hyperpolarized MRI

Metabolites ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 191
Author(s):  
Dragana Savic ◽  
Vicky Ball ◽  
M. Kate Curtis ◽  
Maria da Luz Sousa Fialho ◽  
Kerstin N. Timm ◽  
...  
Keyword(s):  
Diabetic Heart ◽  
Acid Oxidation ◽  
Metabolic Dysfunction ◽  
Carnitine Supplementation ◽  
Resonance Imaging ◽  
Male Wistar Rats ◽  
Hyperpolarized Mri ◽  
Magnetic Resonance Imaging Mri

The diabetic heart is energetically and metabolically abnormal, with increased fatty acid oxidation and decreased glucose oxidation. One factor contributing to the metabolic dysfunction in diabetes may be abnormal handling of acetyl and acyl groups by the mitochondria. L-carnitine is responsible for their transfer across the mitochondrial membrane, therefore, supplementation with L-carnitine may provide a route to improve the metabolic state of the diabetic heart. The primary aim of this study was to use hyperpolarized magnetic resonance imaging (MRI) to investigate the effects of L-carnitine supplementation on the in vivo metabolism of [1-13C]pyruvate in diabetes. Male Wistar rats were injected with either vehicle or streptozotocin (55 mg/kg) to induce type-1 diabetes. Three weeks of daily i.p. treatment with either saline or L-carnitine (3 g/kg/day) was subsequently undertaken. In vivo cardiac function and metabolism were assessed with CINE and hyperpolarized MRI, respectively. L-carnitine supplementation prevented the progression of hyperglycemia, which was observed in untreated streptozotocin injected animals and led to reductions in plasma triglyceride and ß-hydroxybutyrate concentrations. Hyperpolarized MRI revealed that L-carnitine treatment elevated pyruvate dehydrogenase flux by 3-fold in the diabetic animals, potentially through increased buffering of excess acetyl-CoA units in the mitochondria. Improved functional recovery following ischemia was also observed in the L-carnitine treated diabetic animals.

Postmenopausal Women with Endometrial Cancer Have Greater Metabolic Dysfunction and Higher BMI than Women with Benign Endometrium

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 302-LB
Author(s):  
KATHERINE M. COOKE ◽  
ERICA DUN ◽  
ANIKA K. ANAM ◽  
CLARE FLANNERY
Keyword(s):  
Endometrial Cancer ◽  
Postmenopausal Women ◽  
Metabolic Dysfunction

44-OR: PAR2-Regulated MIF Secretion from Non-Immune Cells in Adipose Tissue Is a Key Mechanism Involved in the Development of Metabolic Dysfunction

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 44-OR
Author(s):  
YIHENG HUANG ◽  
LIUJUN CHEN ◽  
YADAN QI ◽  
DAKE QI
Keyword(s):  
Adipose Tissue ◽  
Immune Cells ◽  
Metabolic Dysfunction

Dissociable hormonal responses to symptoms and stress in anorexia and bulimia nervosa

2019 ◽  
Author(s):  
Margaret L Westwater ◽  
Flavia Mancini ◽  
Jane Shapleske ◽  
Jaco Serfontein ◽  
Monique Ernst ◽  
...  
Keyword(s):  
Bulimia Nervosa ◽  
Acute Stress ◽  
Gut Hormones ◽  
Metabolic Dysfunction ◽  
Cortisol Reactivity ◽  
Psychological States ◽  
Study Session ◽  
Gut Hormone ◽  
Ad Libitum ◽  
Acyl Ghrelin

Background: Anorexia nervosa (AN) and bulimia nervosa (BN) are complex psychiatric conditions, in which both psychological and metabolic factors have been implicated. Critically, the experience of stress can precipitate loss-of-control eating in both conditions, suggesting an interplay between mental state and metabolic signaling. However, associations between psychological states, symptoms and metabolic processes in AN and BN have not been examined. Methods: Eighty-five women (n=22 AN binge/purge subtype, n=33 BN, n=30 controls) underwent remote salivary cortisol sampling and a two-day, inpatient study session to examine the effect of stress on cortisol, gut hormones (acyl-ghrelin, PYY, GLP-1) and food consumption. Participants were randomized to either an acute stress induction or control task on each day, and plasma hormones were serially measured before a naturalistic, ad libitum meal.Results: Cortisol awakening response (CAR) was augmented in AN but not BN relative to controls, with body mass index explaining the most variance in CAR (36%). Acute stress increased acyl-ghrelin and PYY in AN compared to controls; however, stress did not alter gut hormone profiles in BN. Instead, a group-by-stress interaction showed nominally reduced cortisol reactivity in BN, but not AN, compared to controls. Ad libitum consumption was lower in both patient groups and unaffected by stress.Conclusions: Findings extend previous reports of metabolic dysfunction in binge-eating disorders, identifying unique associations across disorders and under stress. Moreover, we observed disrupted homeostatic signaling in AN following psychological stress, which may explain, in part, the maintenance of dysregulated eating in this serious illness.

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