Growth differentiation factor 15 alleviates diastolic dysfunction in mice with experimental diabetic cardiomyopathy.

Growth differentiation factor 15 (GDF15) is a peptide with utility in obesity, as it decreases appetite and promotes weight loss. Because obesity increases the risk for type 2 diabetes (T2D) and cardiovascular disease, it is imperative to understand the cardiovascular actions of GDF15, especially since elevated GDF15 levels are an established biomarker for heart failure. As weight loss should be encouraged in the early stages of obesity-related prediabetes/T2D, where diabetic cardiomyopathy is often present, we assessed whether treatment with GDF15 influences its pathology. We observed that GDF15 treatment alleviates diastolic dysfunction in mice with T2D independent of weight loss. This cardioprotection was associated with a reduction in cardiac inflammation, which was likely mediated via indirect actions, as direct treatment of adult mouse cardiomyocytes and differentiated THP-1 human macrophages with GDF15 failed to alleviate lipopolysaccharide-induced inflammation. Therapeutic manipulation of GDF15 action may thus have utility for both obesity and diabetic cardiomyopathy.

Incretin-mediated control of cardiac energy metabolism.

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like-peptide-1 (GLP-1) are incretin hormones that stimulate insulin secretion and improve glycemic control in individuals with type 2 diabetes (T2D). Data from several cardiovascular outcome trials for GLP-1 receptor (GLP-1R) agonists have demonstrated significant reductions in the occurrence of major adverse cardiovascular events in individuals with T2D. Although the cardiovascular actions attributed to GLP-1R agonism have been extensively studied, little is known regarding the cardiovascular consequences attributed to GIP receptor (GIPR) agonism. As there is now an increasing focus on the development of incretin-based co-agonist therapies that activate both the GLP-1R and GIPR, it is imperative that we understand the mechanism(s) through which these incretins impact cardiovascular function. This is especially important considering that cardiovascular disease represents the leading cause of death in individuals with T2D. With increasing evidence that perturbations in cardiac energy metabolism are a major contributor to the pathology of diabetes-related cardiovascular disease, this may represent a key component through which GLP-1R and GIPR agonism influence cardiovascular outcomes. Not only do GIP and GLP-1 increase the secretion of insulin, they may also modify glucagon secretion, both of which have potent actions on cardiac substrate utilization. Herein we will discuss the potential direct and indirect actions through which GLP-1R and GIPR agonism impact cardiac energy metabolism while interrogating the evidence to support whether such actions may account for incretin-mediated cardioprotection in T2D.

Liraglutide alleviates experimental diabetic cardiomyopathy in a PDH-dependent manner.

Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist used for the treatment of T2D, has been shown to alleviate diabetic cardiomyopathy (DbCM) in experimental T2D, which was associated with increased myocardial glucose oxidation. To determine whether this increase in glucose oxidation is necessary for cardioprotection, we hypothesized that liraglutide's ability to alleviate DbCM would be abolished in mice with cardiomyocyte-specific deletion of pyruvate dehydrogenase (PDH; Pdha1CM-/- mice), the rate-limiting enzyme of glucose oxidation. Male Pdha1CM-/- mice and their α-myosin heavy chain Cre expressing littermates (αMHCCre mice) were subjected to experimental T2D via 10 weeks of high-fat diet supplementation, with a single low-dose injection of streptozotocin (75 mg/kg) provided at week 4. All mice were randomized to treatment with either vehicle control or liraglutide (30 µg/kg) twice daily during the final 2.5 weeks, with cardiac function assessed via ultrasound echocardiography. As expected, liraglutide treatment improved glucose homeostasis in both αMHCCre and Pdha1CM-/- mice with T2D, in the presence of mild weight loss. Parameters of systolic function were unaffected by liraglutide treatment in both αMHCCre and Pdha1CM-/- mice with T2D. However, liraglutide treatment alleviated diastolic dysfunction in αMHCCre mice, as indicated by an increase and decrease in the e'/a' and E/e' ratios, respectively. Conversely, liraglutide failed to rescue these indices of diastolic dysfunction in Pdha1CM-/- mice. Our findings suggest that increases in glucose oxidation are necessary for GLP-1R agonist mediated alleviation of DbCM. As such, strategies aimed at increasing PDH activity may represent a novel approach for the treatment of DbCM.

Ketone ester administration improves glycemia in obese mice.

During periods of prolonged fasting/starvation, the liver generates ketones [i.e., ß-hydroxybutyrate (ßOHB)] that primarily serve as alternative substrates for ATP production. Previous studies have demonstrated that elevations in skeletal muscle ketone oxidation contribute to obesity-related hyperglycemia, whereas inhibition of succinyl CoA:3-ketoacid CoA transferase (SCOT), the rate-limiting enzyme of ketone oxidation, can alleviate obesity-related hyperglycemia. As circulating ketone levels are a key determinant of ketone oxidation rates, we tested the hypothesis that increases in circulating ketone levels would worsen glucose homeostasis secondary to increases in muscle ketone oxidation. Accordingly, male C57BL/6J mice were subjected to high-fat diet-induced obesity, whereas their lean counterparts received a standard chow diet. Lean and obese mice were orally administered either a ketone ester (KE) or placebo, followed by a glucose tolerance test. In tandem, we conducted isolated islet perifusion experiments to quantify insulin secretion in response to ketones. We observed that exogenous KE administration robustly increases circulating ßOHB levels, which was associated with an improvement in glucose tolerance only in obese mice. These observations were independent of muscle ketone oxidation, as they were replicated in mice with a skeletal muscle-specific SCOT deficiency. Furthermore, the R-isomer of ßOHB produced greater increases in perifusion insulin levels versus the S-isomer in isolated islets from obese mice. Taken together, acute elevations in circulating ketones promote glucose-lowering in obesity. Given that only the R-isomer of ßOHB is oxidized, further studies are warranted to delineate the precise role of ß-cell ketone oxidation in regulating insulin secretion.NEW & NOTEWORTHY It has been demonstrated that increased skeletal muscle ketone metabolism contributes to obesity-related hyperglycemia. Since increases in ketone supply are key determinants of organ ketone oxidation rates, we determined whether acute elevations in circulating ketones following administration of an oral ketone ester may worsen glucose homeostasis in lean or obese mice. Our work demonstrates the opposite, as acute elevations in circulating ketones improved glucose tolerance in obese mice.

The antianginal ranolazine fails to improve glycaemia in obese liver-specific pyruvate dehydrogenase deficient male mice.

AIMS: Recent studies have demonstrated that stimulating pyruvate dehydrogenase (PDH, gene Pdha1), the rate-limiting enzyme of glucose oxidation, can reverse obesity-induced non-alcoholic fatty liver disease (NAFLD), which can be achieved via treatment with the antianginal ranolazine. Accordingly, our aim was to determine whether ranolazine's ability to mitigate obesity-induced NAFLD and hyperglycaemia requires increases in hepatic PDH activity. METHODS: We generated liver-specific PDH-deficient (Pdha1Liver-/- ) mice, which were provided a high-fat diet for 12 weeks to induce obesity. Pdha1Liver-/- mice and their albumin-Cre (AlbCre ) littermates were randomized to treatment with either vehicle control or ranolazine (50 mg/kg) once daily via oral gavage during the final 5 weeks, following which we assessed glucose and pyruvate tolerance. RESULTS: Pdha1Liver-/- mice exhibited no overt phenotypic differences (e.g. adiposity, glucose tolerance) when compared to their AlbCre littermates. Of interest, ranolazine treatment improved glucose tolerance and mildly reduced hepatic triacylglycerol content in obese AlbCre mice but not in obese Pdha1Liver-/- mice. The latter was independent of changes in hepatic mRNA expression of genes involved in regulating lipogenesis. CONCLUSIONS: Liver-specific PDH deficiency is insufficient to promote an NAFLD phenotype. Nonetheless, hepatic PDH activity partially contributes to how the antianginal ranolazine improves glucose tolerance and alleviates hepatic steatosis in obesity.

The Antipsychotic Dopamine 2 Receptor Antagonist Diphenylbutylpiperidines Improve Glycemia in Experimental Obesity by Inhibiting Succinyl-CoA:3-Ketoacid CoA Transferase.

Despite significant progress in understanding the pathogenesis of type 2 diabetes (T2D), the condition remains difficult to manage. Hence, new therapeutic options targeting unique mechanisms of action are required. We have previously observed that elevated skeletal muscle succinyl CoA:3-ketoacid CoA transferase (SCOT) activity, the rate-limiting enzyme of ketone oxidation, contributes to the hyperglycemia characterizing obesity and T2D. Moreover, we identified that the typical antipsychotic agent pimozide is a SCOT inhibitor that can alleviate obesity-induced hyperglycemia. We now extend those observations here, using computer-assisted in silico modeling and in vivo pharmacology studies that highlight SCOT as a noncanonical target shared among the diphenylbutylpiperidine (DPBP) drug class, which includes penfluridol and fluspirilene. All three DPBPs tested (pimozide, penfluridol, and fluspirilene) improved glycemia in obese mice. While the canonical target of the DPBPs is the dopamine 2 receptor, studies in obese mice demonstrated that acute or chronic treatment with a structurally unrelated antipsychotic dopamine 2 receptor antagonist, lurasidone, was devoid of glucose-lowering actions. We further observed that the DPBPs improved glycemia in a SCOT-dependent manner in skeletal muscle, suggesting that this older class of antipsychotic agents may have utility in being repurposed for the treatment of T2D.

Stimulating myocardial pyruvate dehydrogenase activity fails to alleviate cardiac abnormalities in a mouse model of human Barth syndrome.

Barth syndrome (BTHS) is a rare genetic disorder due to mutations in the TAFAZZIN gene, leading to impaired maturation of cardiolipin and thereby adversely affecting mitochondrial function and energy metabolism, often resulting in cardiomyopathy. In a murine model of BTHS involving short-hairpin RNA mediated knockdown of Tafazzin (TazKD mice), myocardial glucose oxidation rates were markedly reduced, likely secondary to an impairment in the activity of pyruvate dehydrogenase (PDH), the rate-limiting enzyme of glucose oxidation. Furthermore, TazKD mice exhibited cardiac hypertrophy with minimal cardiac dysfunction. Because the stimulation of myocardial glucose oxidation has been shown to alleviate diabetic cardiomyopathy and heart failure, we hypothesized that stimulating PDH activity would alleviate the cardiac hypertrophy present in TazKD mice. In order to address our hypothesis, 6-week-old male TazKD mice and their wild-type (WT) littermates were treated with dichloroacetate (DCA; 70 mM in the drinking water), which stimulates PDH activity via inhibiting PDH kinase to prevent inhibitory phosphorylation of PDH. We utilized ultrasound echocardiography to assess cardiac function and left ventricular wall structure in all mice prior to and following 6-weeks of treatment. Consistent with systemic activation of PDH and glucose oxidation, DCA treatment improved glycemia in both TazKD mice and their WT littermates, and decreased PDH phosphorylation equivalently at all 3 of its inhibitory sites (serine 293/300/232). However, DCA treatment had no impact on left ventricular structure, or systolic and diastolic function in TazKD mice. Therefore, it is unlikely that stimulating glucose oxidation is a viable target to improve BTHS-related cardiomyopathy.

New Therapeutic Options for Type 2 Diabetes Mellitus and Their Impact Against Ischemic Heart Disease.

Type 2 diabetes mellitus (T2DM) greatly increases risk for cardiovascular disease, including ischemic heart disease and myocardial infarction. With the completion of several cardiovascular outcomes trials (CVOTs) for new glucose-lowering therapies, including the sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor (GLP-1R) agonists, we now have strong evidence alluding to the cardioprotective nature of these agents in people with T2DM. These agents have frequently been observed to reduce rates for 3-point major adverse cardiovascular events, which encompass death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Herein we will provide an overview on whether reductions in nonfatal myocardial infarction and ischemic heart disease status are a key component of the improved cardiovascular outcomes in people with T2DM treated with either SGLT2 inhibitors or GLP-1R agonists. Observations from preclinical studies will be compared to their clinical counterparts, while being further interrogated to define potential mechanisms that may account for SGLT2 inhibitor or GLP-1R agonist-induced cardioprotection against ischemic heart disease. A better understanding of the role these agents have in impacting the progression of ischemic heart disease in individuals with T2DM will have a substantial impact in our management of this patient population.

An isoproteic cocoa butter-based ketogenic diet fails to improve glucose homeostasis and promote weight loss in obese mice.

High-fat and very low-carbohydrate based ketogenic diets have gained considerable popularity as a nonpharmacological strategy for obesity, due to their potential to enhance weight loss and improve glucose homeostasis. However, the effectiveness of a ketogenic diet toward metabolic health is equivocal. To better understand the impact of ketogenic diets in obesity, male and female mice were fed a 60% cocoa butter-based high-fat diet for 16-wk to induce obesity, following which mice were transitioned to either an 85% cocoa butter fat-based ketogenic diet, a 10% cocoa butter fat-based low-fat diet, or maintained on a high-fat diet for an additional 8-wk. All experimental diets were matched for sucrose and protein content and contained an identical micronutrient profile, with complex carbohydrates being the primary carbohydrate source in the low-fat diet. The transition to a ketogenic diet was ineffective at promoting significant body fat loss and improving glucose homeostasis in obese male and female mice. Alternatively, obese male and female mice transitioned to a low-fat and high-complex carbohydrate diet exhibited beneficial body composition changes and improved glucose tolerance that may, in part, be attributed to a mild decrease in food intake and a mild increase in energy expenditure. Our findings support the consumption of a diet low in saturated fat and rich in complex carbohydrates as a potential dietary intervention for the treatment of obesity and obesity-induced impairments in glycemia. Furthermore, our results suggest that careful consideration should be taken when considering a ketogenic diet as a nonpharmacological strategy for obesity.NEW & NOTEWORTHY It has been demonstrated that ketogenic diets may be a nutritional strategy for alleviating hyperglycemia and promoting weight loss in obesity. However, there are a number of inconsistencies with many of these studies, especially with regard to the macronutrient and micronutrient compositions of the diets being compared. Our work demonstrates that a ketogenic diet that is both micronutrient-matched and isoproteic with its comparator diets fails to improve glycemia or promote weight loss in obese mice.