Phenotyping Type 2 Diabetes in Terms of Myocardial Insulin Resistance and Its Potential Cardiovascular Consequences: A New Strategy Based on 18F-FDG PET/CT

Background: Systemic insulin resistance is generally postulated as an independent risk factor of cardiovascular events in type 2 diabetes (T2D). However, the role of myocardial insulin resistance (mIR) remains to be clarified. Methods: Two 18F-FDG PET/CT scans were performed on forty-three T2D patients at baseline and after hyperinsulinemic–euglycemic clamp (HEC). Myocardial insulin sensitivity (mIS) was determined by measuring the increment in myocardial 18F-FDG uptake after HEC. Coronary artery calcium scoring (CACs) and myocardial radiodensity (mRD) were assessed by CT. Results: After HEC, seventeen patients exhibited a strikingly enhancement of myocardial 18F-FDG uptake and twenty-six a marginal increase, thus revealing mIS and mIR, respectively. Patients with mIR showed higher mRD (HU: 38.95 [33.81–44.06] vs. 30.82 [21.48–38.02]; p = 0.03) and CACs > 400 (AU: 52% vs. 29%; p = 0.002) than patients with mIS. In addition, HOMA-IR and mIS only showed a correlation in those patients with mIR. Conclusions: 18F-FDG PET combined with HEC is a reliable method for identifying patients with mIR. This subgroup of patients was found to be specifically at high risk of developing cardiovascular events and showed myocardial structural changes. Moreover, the gold-standard HOMA-IR index was only associated with mIR in this subgroup of patients. Our results open up a new avenue for stratifying patients with cardiovascular risk in T2D.

Review of Insulin Resistance in Dilated Cardiomyopathy and Implications for the Pediatric Patient Short Title: Insulin Resistance DCM and Pediatrics

Energy metabolism in the heart is affected during states of dysfunction. Understanding how the heart utilizes substrates in cardiomyopathy may be key to the development of alternative treatment modalities. Myocardial insulin resistance has been proposed as a possible barrier to effective glucose metabolism in the heart. Extensive literature on the topic in adult individuals exists; however, review in the pediatric population is sparse. The pathophysiology of disease in children and adolescents is unique. The aim of this paper is to review the current knowledge on insulin resistance in dilated cardiomyopathy while also filling the gap when considering care in the pediatric population.

Mitophagy in Diabetic Cardiomyopathy: Roles and Mechanisms

Cardiovascular disease is the leading complication of diabetes mellitus (DM), and diabetic cardiomyopathy (DCM) is a major cause of mortality in diabetic patients. Multiple pathophysiologic mechanisms, including myocardial insulin resistance, oxidative stress and inflammation, are involved in the development of DCM. Recent studies have shown that mitochondrial dysfunction makes a substantial contribution to the development of DCM. Mitophagy is a type of autophagy that takes place in dysfunctional mitochondria, and it plays a key role in mitochondrial quality control. Although the precise molecular mechanisms of mitophagy in DCM have yet to be fully clarified, recent findings imply that mitophagy improves cardiac function in the diabetic heart. However, excessive mitophagy may exacerbate myocardial damage in patients with DCM. In this review, we aim to provide a comprehensive overview of mitochondrial quality control and the dual roles of mitophagy in DCM. We also propose that a balance between mitochondrial biogenesis and mitophagy is essential for the maintenance of cellular metabolism in the diabetic heart.

Insulin Resistance in Skeletal Muscle Selectively Protects the Heart in Response to Metabolic Stress

<a>Obesity and type 2 diabetes mellitus (T2DM) are the leading causes of cardiovascular morbidity and mortality. Although insulin resistance is believed to underlie these disorders, </a><a>anecdotal evidence contradicts this common belief. Accordingly, obese patients with cardiovascular disease have better prognoses relative to leaner patients with the same diagnoses, whereas treatment of T2DM patients with thiazolidines, one of the popular insulin sensitizer drugs, significantly increases the risk of heart failure. </a>Using mice with skeletal muscle-specific <a>ablation of the insulin receptor </a>gene (MIRKO), we addressed this paradox by demonstrating that insulin signaling in skeletal muscles specifically mediated crosstalk with the heart, but not other metabolic tissues, to prevent cardiac dysfunction in response to metabolic stress. Despite severe hyperinsulinemia and aggregating obesity, MIRKO mice were protected from myocardial insulin resistance, mitochondrial dysfunction, and metabolic reprogramming in response to diet-induced obesity (DIO). Consequently, the MIRKO mice were also protected from myocardial inflammation, cardiomyopathy, and left ventricle dysfunction. Together, our findings suggest that insulin resistance in skeletal muscle functions as a double-edged sword in metabolic diseases.

Insulin Resistance in Skeletal Muscle Selectively Protects the Heart in Response to Metabolic Stress

<a>Obesity and type 2 diabetes mellitus (T2DM) are the leading causes of cardiovascular morbidity and mortality. Although insulin resistance is believed to underlie these disorders, </a><a>anecdotal evidence contradicts this common belief. Accordingly, obese patients with cardiovascular disease have better prognoses relative to leaner patients with the same diagnoses, whereas treatment of T2DM patients with thiazolidines, one of the popular insulin sensitizer drugs, significantly increases the risk of heart failure. </a>Using mice with skeletal muscle-specific <a>ablation of the insulin receptor </a>gene (MIRKO), we addressed this paradox by demonstrating that insulin signaling in skeletal muscles specifically mediated crosstalk with the heart, but not other metabolic tissues, to prevent cardiac dysfunction in response to metabolic stress. Despite severe hyperinsulinemia and aggregating obesity, MIRKO mice were protected from myocardial insulin resistance, mitochondrial dysfunction, and metabolic reprogramming in response to diet-induced obesity (DIO). Consequently, the MIRKO mice were also protected from myocardial inflammation, cardiomyopathy, and left ventricle dysfunction. Together, our findings suggest that insulin resistance in skeletal muscle functions as a double-edged sword in metabolic diseases.

miR-155-5p upregulation ameliorates myocardial insulin resistance via mTOR signaling in chronic alcohol drinking rats

Background Chronic alcohol intake is associated with an increased risk of alcoholic cardiomyopathy, which may present with pathological changes such as myocardial insulin resistance, leading to ventricular dilation and cardiac dysfunction. Although a correlation between microRNA-155 (miR-155) and insulin signaling has been identified, the underlying mechanism has not been elucidated to date. The purpose of the study was to determine whether overexpression of miR-155-5p in vivo could ameliorate chronic alcohol-induced myocardial insulin resistance and cardiac dysfunction. Material and Methods Wistar rats were fed with either alcohol or water for 20 weeks to establish chronic alcohol intakes model. Then the alcohol group were divided into three groups: model group, miRNA-155 group and AAV-NC group. Rats undergoing alcohol treatment were injected with AAV-miRNA-155 (adeno-associated virus 9) or its negative control AAV-NC, respectively. Gene expression was determined by real-time PCR, and protein expression was determined by western blot. Echocardiography was performed to assess terminal cardiac function. Insulin responsiveness was determined through the quantification of phosphorylated insulin receptor substrate 1 (ser 307) and phosphorylated insulin receptor (Tyr 1185) levels. Results We found that cardiac function was attenuated in chronic alcohol intake rats, with an activated mammalian target of rapamycin (mTOR) signaling pathway, accompanied by an increase in p-IRS1(ser 307) and a decrease in p-IR (Tyr 1185) level in myocardial tissue. Also, alcohol drinking significantly up-regulated miR-155-5p level and its overexpression decreased p-IRS1 (ser 307) and increased p-IR (Tyr 1185) levels, and meanwhile inhibited the mTOR signaling pathway. Conclusion miR-155-5p upregulation ameliorates myocardial insulin resistance via the mTOR signaling in chronic alcohol drinking rats. We propose that miR-155 may serve as a novel potential therapeutic target for alcoholic heart disease.