Treatments for skeletal muscle abnormalities in heart failure: sodium-glucose transporter 2 and ketone bodies

Various skeletal muscle abnormalities are known to occur in heart failure (HF), and are closely associated with exercise intolerance. Particularly, abnormal energy metabolism caused by mitochondrial dysfunction in skeletal muscle is a cause of decreased endurance exercise capacity. However, to date, no specific drug treatment has been established for the skeletal muscle abnormalities and exercise intolerance occurring in HF patients. Sodium-glucose transporter 2 (SGLT2) inhibitors promote glucose excretion by suppressing glucose reabsorption in the renal tubules, which has a hypoglycemic effect independent of insulin secretion. Recently, large clinical trials have demonstrated that treatment with SGLT2 inhibitors suppresses cardiovascular events in patients who have HF with systolic dysfunction. Mechanisms of the therapeutic effects of SGLT2 inhibitors for HF have been suggested to be diuretic, suppression of neurohumoral factor activation, renal protection, and improvement of myocardial metabolism, but has not been clarified to date. SGLT2 inhibitors are known to increase blood ketone bodies. This suggests that they may improve the abnormal skeletal muscle metabolism in HF, i.e., improve fatty acid metabolism, suppress glycolysis, and utilize ketone bodies in mitochondrial energy production. Ultimately, they may improve aerobic metabolism in skeletal muscle, and suppress anaerobic metabolism and improve aerobic exercise capacity at the level of the anaerobic threshold. The potential actions of such SGLT2 inhibitors explain their effectiveness in HF, and may be candidates for new drug treatments aimed at improving exercise intolerance. In this review, we outlined the effects of SGLT2 inhibitors on skeletal muscle metabolism, with a particular focus on ketone metabolism.

Hypoglycemic and Hepatoprotective Effects of Dried and Rice-Fried Psidium guajava Leaves in Diabetic Rats

Psidium guajava leaves (PGL) have been long used as an adjuvant therapy for diabetics. The present study evaluated the in vivo hypoglycemic and hepatoprotective effects of dried and the rice-fried PGL decoctions (PGLD and RPGLD). Our results indicated that both PGLD and RPGLD could significantly decrease the contents of fasting blood glucose (FBG) and haemoglobin A1c (HbA1c) in diabetic rats. Compared with the HFD/STZ (high-fat diet with streptozotocin) group, the PGLD and RPGLD-treated diabetic rats showed different degrees of recovery against the liver pathological changes. The upregulated expressions of glucokinase (GK), glucose transporter 2 (GLUT2), insulin growth factor-1 (IGF-1), insulin receptor substrate-1 (IRS-1), and insulin receptor substrate-2 (IRS-2) in PGLD and RPGLD-treated groups were observed. In general, RPGLD exhibited a much better antidiabetic effect than PGLD, which was further verified by the comprehensive evaluation with the TOPSIS method. Besides, HPLC (high-performance liquid chromatography) and UPLC-MS/MS (ultra-performance liquid chromatography-tandem mass spectrometry) analyses revealed that the contents of the primary constituents (ellagic acid, hyperoside, isoquercitroside, reynoutrin, guaijaverin, auicularin, and quercetin) in RPGLD increased obviously compared with PGLD. These results shed new light on the antidiabetic potential and mechanism of PGL, as well as the “higher efficacy” of the rice-fried processing method in traditional Chinese medicine.

Model of Streptozotocin-Nicotinamide Induced Type 2 Diabetes: A Comparative Review

: The aim of the present study was to review the streptozotocin-nicotinamide (STZ-NA) diabetes model. Type 2 diabetes is more prevalent (90-95%) in adults than type 1. Experimentally-induced diabetes models may be established by chemicals, viral agents, insulin antibodies, surgery, etc. The most advisable and prompt method to induce diabetes is using chemicals, and STZ and alloxan are widely used chemicals. STZ has proven to be a better diabetogenic agent than alloxan because alloxan has many drawbacks, as it induces only type 1 diabetes, has a high mortality rate in rats, and causes ketosis in animals. Moreover, it has lesser selectivity towards β-cells, and the diabetes-induced is reversible. STZ can be used to induce both type 1 and type 2 diabetes. It is noted that the genotoxic behavior of STZ in animals is accomplished through a reduction of nicotinamide adenine dinucleotide (NAD+) in pancreatic β-cells via the GLUT2 (Glucose transporter 2), which can cause cellular damage by DNA (Deoxyribonucleic acid) strand breaks that lead to cell death. NA is a biochemical precursor of NAD+, and it is a poly-ADP-ribose-polymerase-1 (PARP-1) inhibitor. NAD+ is an important redox reaction co-enzyme for the production of adenosine triphosphate (ATP) and many other metabolic pathways. Extreme DNA damage contributes to the over-activation of PARP-1, loss of cellular resources, and necrotic cells death. Some studies have expressed that NA can protect pancreatic β-cells against the severe cytotoxicity of STZ. The review concluded that the STZ-NA model is dependent on the competency of NA to attain partial protection against the β-cytotoxic essence of STZ to induce type-2 diabetes.

Effect of Dapagliflozin and Magnesium Supplementation on Renal Magnesium Handling and Magnesium Homeostasis in Metabolic Syndrome

The prevalence of metabolic syndrome (MetS) is increasing, and patients with MetS are at an increased risk of cardiovascular disease and diabetes. There is a close link between hypomagnesemia and MetS. Administration of sodium-glucose transporter 2 (SGLT2) inhibitors has been reported to increase serum magnesium levels in patients with diabetes. We investigated the alterations in renal magnesium handling in an animal model of MetS and analyzed the effects of SGLT2 inhibitors. Adult rats were fed a fructose-rich diet to induce MetS in the first 3 months and were then treated with either dapagliflozin or magnesium sulfate-containing drinking water for another 3 months. Fructose-fed animals had increased insulin resistance, hypomagnesemia, and decreased urinary magnesium excretion. Dapagliflozin treatment improved insulin resistance by decreasing glucose and insulin levels, increased serum magnesium levels, and reduced urinary magnesium excretion. Serum vitamin D and parathyroid hormone levels were decreased in fructose-fed animals, and the levels remained low despite dapagliflozin and magnesium supplementation. In the kidney, claudin-16, TRPM6/7, and FXDY expression was increased in fructose-fed animals. Dapagliflozin increased intracellular magnesium concentration, and this effect was inhibited by TRPM6 blockade and the EGFR antagonist. We concluded that high fructose intake combined with a low-magnesium diet induced MetS and hypomagnesemia. Both dapagliflozin and magnesium sulfate supplementation improved the features of MetS and increased serum magnesium levels. Expression levels of magnesium transporters such as claudin-16, TRPM6/7, and FXYD2 were increased in fructose-fed animals and in those administered dapagliflozin and magnesium sulfate. Dapagliflozin enhances TRPM6-mediated trans-epithelial magnesium transport in renal tubule cells.

Effects of Sodium-Glucose Transporter 2 Inhibitors (SGLT2-I) in Patients With Ischemic Heart Disease (IHD) Treated by Coronary Artery Bypass Grafting via MiECC: Inflammatory Burden, and Clinical Outcomes at 5 Years of Follow-Up

Introduction: Minimally invasive extracorporeal circulation (MiECC) reduced inflammatory burden, leading to best clinical outcomes in patients treated with coronary artery bypass grafting (CABG). Despite this, the patients with type 2 diabetes mellitus (T2DM) vs those without T2DM (non-T2DM) have a worse prognosis, caused by over-inflammation and modulated by sodium-glucose transporter 2 receptors. However, we evaluated the inflammatory burden and clinical outcomes in non-T2DM vs T2DM patients under sodium-glucose transporter 2 inhibitors (SGLT2-I users) vs non-SGLT2-I users at 5 years of follow-up post-CABG via MiECC.Materials and methods: In a multicenter study, we screened consecutive patients with indications to receive CABG. The study endpoints were the inflammatory burden (circulating serum levels of tumor necrosis factor-alpha (TNF-α), interleukin 1 and 6 (IL-1 and IL-6), C-reactive protein (CRP), and leucocytes count) and the clinical outcomes at follow-up of 5 years in non-T2DM vs SGLT2-I users, in non-T2DM vs non-SGLT2-I users, and SGLT2-I users vs non-SGLT2-I users.Results: At baseline, and at one year and 5 years of follow-up, the non-T2DM vs SGLT2-I users, non-T2DM vs non-SGLT2-I users, and SGLT2-I users vs non-SGLT2-I users had the lowest values of IL-1, IL-6, and TNF-α (p < 0.05). At one year of follow-up, SGLT2-I users vs non-T2DM and non-SGLT2-I users vs non-T2DM users had a higher rate of all deaths, cardiac deaths, re-myocardial infarction, repeat revascularization, and stroke, and of the composite endpoint (p < 0.05). In a multivariate Cox regression analysis, the composite endpoint was predicted by IL-1 [2.068 (1.367–3.129)], TNF-α [1.989 (1.081–2.998)], and SGLT2-I [0.504 (0.078–0.861)].Conclusion: In T2DM patients, the SGLT2-I significantly reduced the inflammatory burden and ameliorated clinical outcomes at 5 years of follow-up post-CABG via MiECC.

The Roles of Liver Inflammation and the Insulin Signaling Pathway in PM2.5 Instillation-Induced Insulin Resistance in Wistar Rats

To elucidate the mechanism of how the liver participates in PM2.5-caused insulin resistance. A novel Wistar rat model was developed in this study by instilling a suspension of lyophilized PM2.5 sample (2.5 mg/kg, 5 mg/kg, or 10 mg/kg) collected from the atmosphere. Systemic insulin resistance indicators, including serum fasting blood glucose (FBG), fasting insulin (FINS), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and hemoglobin A1 (HbA1), were upregulated by the PM2.5 instillation. The area under the curve (AUCglu) calculated by intraperitoneal glucose tolerance testing (IPGTT) was also significantly greater in the PM2.5 instillation groups. Additionally, PM2.5 instillation was found to cause liver damage and inflammation. The serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBIL), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were significantly elevated by PM2.5 instillation. PM2.5 also triggered IL-6 and TNF-α transcription but inhibited mRNA synthesis and suppressed signaling activation of the insulin-phosphoinositide 3-kinase- (PI3K-) Akt-glucose transporter 2 (GLUT2) pathway in the rat liver by reducing the ratio of phosphorylated Akt to phosphorylated insulin receptor substrate 1 (IRS-1). Thus, PM2.5-induced inflammation activation and insulin signaling inhibition in the rat liver contribute to the development of systemic insulin resistance.

Effects of GLP-1RA and SGLT2i, Alone or in Combination, on Mouse Models of Type 2 Diabetes Representing Different Disease Stages

Glucagon-like peptide-1 receptor agonist (GLP-1RA) and sodium-dependent glucose transporter 2 inhibitor (SGLT2i), in addition to lowering glucose, have pleiotropic effects on the heart, kidneys, and liver. These drugs have thus come into widespread use for treating type 2 diabetes (T2DM). However, mechanistic comparisons and effects of combining these drugs have not been adequately studied. Employing diet-induced obese (DIO) mice and db/db mice as models of the early and advanced stages of T2DM, we evaluated effects of single or combined use of liraglutide (a GLP-1RA) and ipragliflozin (a SGLT2i). Treatments with liraglutide and/or ipragliflozin for 28 days improved glycemic control and reduced hepatic lipid accumulation similarly in DIO mice. In contrast, in db/db mice, despite similar favorable effects on fatty liver, liraglutide exerted no beneficial effects on glycemic control. Improved glycemic control in db/db mice treated with ipragliflozin was accompanied by increased pancreatic β-cell area and insulin content, both of which tended to rise further when ipragliflozin was combined with liraglutide. Our data suggest that liraglutide is more efficient at an earlier stage and ipragliflozin can be effective in both stages. In addition, their combined use is a potential option for treating advanced stage diabetes with fatty liver disease.

251 Dietary Tryptophan Supplementation Improves Fat and Glucose Metabolism in Low Birthweight Piglets

Low birthweight (LBW) is associated with complications such as insulin resistance, obesity and metabolic disturbances of glucose and fat metabolism in early life. Dietary tryptophan (Trp) has been shown to reduce liver fat and suppress hyperglycemia in different species. The objective of this study was to assess the effect of dietary Trp on growth and glucose and fat metabolism in LBW pigs. Piglets (7-days old) weighing < 2 kg were considered as LBW while those weighting > 2 kg were considered as normal birthweight (NBW) and randomly allocated to 4 milk-replacer based treatments (n = 7–8): 1) NBW-0% Trp (NBW-T0), 2) LBW-0% Trp (LBW-T0), 3) LBW-0.4% Trp (LBW-T0.4), and 4) LBW-0.8% Trp (LBW-T0.8) for 3 weeks. Growth parameters and body weight were measured biweekly. At week 3, blood and tissue samples were collected in overnight-fasted pigs after a meal test. The mRNA and protein abundance of key glucose and lipid metabolism markers were determined using qPCR and western blot, respectively. Univariate GLM with Dunnett’s post-hoc test (SPSS®) was used to analyze the data. Growth parameters did not change among groups. Plasma triglycerides concentration was lower in LBW-T0.4 and LBW-T0.8 compared to LBW-T0. Blood glucose was lower in LBW-T0.8 than LBW-T0 at 60 min following the meal test. LBW-T0.8 had a lower transcript and protein abundance of liver glucose transporter-2 relative to LBW-T0. Compared to LBW-T0, LBW-T0.8 had a higher mRNA abundance of glucokinase and tended to have a lower transcript of phosphoenolpyruvate carboxykinase in liver. Relative to LBW-T0, LBW-T0.4 tended to have a lower protein abundance of sodium-glucose co-transporter 1 in jejunum. Compared to LBW-T0, LBW-T0.4 and LBW-T0.8 had a lower transcript of liver acetyl-CoA carboxylase and LBW-T0.4 had a higher transcript of liver 3-hydroxyacyl-CoA dehydrogenase. In conclusion, Trp supplementation reduced the lipogenesis and gluconeogenesis, but increased the glycolysis in LBW piglets.