Tyrosine kinases inhibitors (TKIs) may alter glycaemia and may be cardiotoxic with importance in diabetic heart. We investigated the effect of multi-TKI crizotinib after short-term administration on metabolic modulators of the heart of diabetic rats. Experimental diabetes mellitus (DM) was induced by streptozotocin (STZ; 80 mg/kg, i.p.), controls received vehicle (CON). Three days after STZ, crizotinib (STZ+CRI; 25 mg/kg/day p.o.) or vehicle was administered for 7 days. Blood glucose, C-peptide and glucagon were assessed in plasma samples. Receptor tyrosine kinases (RTKs), cardiac glucose transporters and PPARs were determined in rat left ventricle by RT-qPCR method. Crizotinib moderately reduced blood glucose (by 25%, P<0.05) when compared to STZ rats. The drug did not affect levels of C-peptide, an indicator of insulin secretion, suggesting altered tissue glucose utilization. Crizotinib had no impact on cardiac RTKs. However, an mRNA downregulation of insulin-dependent glucose transporter Glut4 in hearts of STZ rats was attenuated after crizotinib treatment. Moreover, crizotinib normalized Ppard and reduced Pparg mRNA expression in diabetic hearts. Crizotinib decreased blood glucose independently of insulin and glucagon. This could be related to changes in regulators of cardiac metabolism such as GLUT4 and PPARs.

Background In spite of disrupted repolarization of diabetic heart, some studies report less tendency of diabetic heart to develop ventricular arrhythmias suggesting effective compensatory mechanism. We hypothesized that myocardial alterations in HCN2 and HCN4 channels occur under hyperglycaemia. Methods Diabetes was induced in rats using a single injection of streptozotocin (STZ; 55 mg/kg body weight, i.p.). Basal ECG was measured. Expression of mRNA for HCN channels, potassium channels and microRNA 1 and 133a were measured in ventricular tissues. Protein expression of HCN2 channel isoform was assessed in five different regions of the heart by western blotting. Differentiated H9c2 cell line was used to examine HCN channels expression under hyperglycaemia in vitro. Results Six weeks after STZ administration, heart rate was reduced, QRS complex duration, QT interval and T-wave were prolonged in diabetic rats compared to controls. mRNA and protein expressions of HCN2 decreased exclusively in the ventricles of diabetic rats. HCN2 expression levels in atria of STZ rats and H9c2 cells treated with excess of glucose were not changed. MicroRNA levels were stable in STZ rat hearts. We found significantly decreased mRNA levels of several potassium channels participating in repolarization, namely Kcnd2 (Ito1), Kcnh2 (IKr), Kcnq1 (IKs) and Kcnj11 (IKATP). Conclusions This result together with downregulated HCN2 channels suggest that HCN channels might be an integral part of ventricular electric remodelling and might play a role in cardiac repolarization projected in altered arrhythmogenic profile of diabetic heart.

Objectives Dapagliflozin (Dapa) could potentially be used to treat type 1 diabetes mellitus. We tested the hypothesis that it would influence blood lipid levels and visceral fat accumulation in a rodent diabetic model. Methods We used three groups of male Wistar rats: Controls, streptozotocin (STZ)-treated rats and STZ-treated orally with Dapa (STZ+Dapa), 10 mg/kg/day for six weeks. Blood glucose and serum lipids levels were determined. Plasma levels of lipases (hormone-sensitive lipase, HSL and lipoprotein lipase, LPL), adipokines (leptin and adiponectin) and proinflammatory cytokines [tumour necrosis factor-alpha (TNFα) and interleukin-6 (IL-6)] were determined by ELISA assays. mRNA levels in the perirenal fat were determined by real-time PCR. Key findings Dapa suppressed STZ-related hyperglycemia by 20% (P &lt; 0.05) and increased serum HDL when compared to the controls and the STZ-only treated rats (both P &lt; 0.05). STZ treatment caused elevations of other serum lipids that were resistant to Dapa treatment. Dapa treatment also increased both plasma and visceral fat mRNA levels of leptin, LPL and IL-6, while decreasing plasma and fat expressions of HSL and TNFα compared to the STZ-only treated rats (all P &lt; 0.05). Conclusions Our results suggest that Dapa, in addition to its antidiabetic effect, also influences the function of adipose tissue which could be beneficial in the treatment of diabetes.

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Objective: Patients with diabetes mellitus type1 (DM1) have a relative insulin deficiency with elevated triacylglycerides (TAG) production. Adipokines are important in fat distribution, inflammation, and endothelial function. Dapagliflozin (Dapa) and pioglitazone (Pio) are oral hypoglycemic drugs for the treatment of DM2. They have also pleiotropic effects on lipid profile and body weight. The effect of these drugs on lipoproteins and adipokines levels in DM1 is poorly understood. Design and method: DM1 in male Wistar rats was induced by a single dose of streptozotocin (STZ). Animals were then divided into five groups: Controls, diabetic animals (DM), DM treated with Dapa, DM treated with Pio, DM treated with combination DapaPio. Therapies were mixed in rat chow. Control and DM groups received standard chow. After 6 weeks of treatment serum glucose and lipid levels were determined. Visceral adipose tissue (VAT) gene expression of leptin (Lep), adiponectin (AdipoQ), hormone-sensitive lipase (HSL), lipoprotein lipase (LPL), tumor necrosis factor-alpha (TNFa) and interleukin 6 (IL6) were measured by RT qPCR and their levels in plasma were determined by ELISA method. Results: STZ injection led to a significant increase in both fasting and postprandial glucose levels and all levels of lipoproteins except high-density lipoproteins (HDL), which were decreased. We also found decreased levels of Lep, AdipoQ, LPL, and IL6, and increased HSL and TNFa in plasma in DM group. These results were supported by the same significant changes in gene expression in VAT. A combination of DapaPio resulted in a significant decrease in serum levels of both glucose levels. Pio and DapaPio administration decreased TAG and total cholesterol and increased HDL. Lep, AdipoQ, LPL and IL6 plasma levels were increased, and HSL, TNFa were decreased after administration of Dapa, Pio and their combination. Both monotherapy and combination significantly modulated Lep, TNFa and IL6 gene expression in VAT. Conclusions: DM1 in rats influenced not only glucose levels but also lipoproteins and adipokines in plasma, which could be affected by Dapa, Pio and DapaPio. Therapy can also change the gene expression of Lep, AdipoQ, TNFa, and IL6 in adipose tissue in rats with DM1.

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Overweight and obesity have been linked with increased intake of sugar-sweetened beverages. On the other hand, physical activity has been known to lead to weight loss. Therefore, we hypothesized that exercise might influence the Lactobacillus population in fecal microbiota as their changed abundance is often associated with shifts in the physical activity and diet. In our experiment, Wistar rats were allocated into groups with normal feed or added sugar-sweetened beverages with or without access to a running wheel. Interestingly, only a combination of physical activity and sweetened beverage intake was associated with a significant increase in fecal lactobacilli abundance, suggesting a connection between exercise and a rise in lactobacilli abundance. Moreover, physical activity has improved weight-related parameters and led to increased plasma and mRNA adiponectin levels. Ghrelin and leptin plasma levels were unaltered. Taken together, our results demonstrate that effect of physical activity on adiposity even during unhealthy feeding patterns is accompanied by increased lactobacilli abundance in the fecal microbiota population.

Objective: Crizotinib is a multitarget ALK/c-MET/ROS1/RON inhibitor that can potentially inhibit non-intended receptor tyrosine kinases (RTKs) which play a role in cardiac development, function and/or metabolism. Tyrosine kinase inhibitors (TKIs) studies in diabetic patients showed antidiabetic effects of some TKIs and several potential mechanisms were suggested including mechanisms via RTKs. We examined RTKs after short-term crizotinib treatment in diabetic heart. Design and method: To induce diabetes, male Wistar rats were injected with streptozotocin (STZ; 80 mg/kg, i.p.), controls received vehicle (CON). After 3 days, diabetic rats were treated with crizotinib in a dose 25 mg/kg/day p.o. (STZ+CRI) or vehicle p.o. for 7 days (STZ). mRNA expression of selected RTKs were assessed by RT-qPCR method in rat left ventricle samples. Blood glucose, c-peptide and glucagon in plasma samples and expression of cardiac glucose transporters Glut1 and Glut4 were assessed to determine impact on glucose homeostasis. Results: Intriguingly, crizotinib had a hypoglycaemic effect in diabetic animals (plasma glucose in STZ: 19.2 mmol/L vs. STZ+CRI: 14.5 mmol/L., P<0.05). STZ animals had lower c-peptide and unaltered glucagon plasma levels. However, plasma levels of c-peptide and glucagon were not changed after crizotinib treatment suggesting altered glucose utilization in tissues. In STZ rats, we detected downregulation of insulin dependent glucose transporter Glut4 (by 40% as compared to CON, P < 0.05). Interestingly, crizotinib prevented this downregulation. Insulin non-dependent Glut1 glucose transporter remained stable across all groups. Diabetes upregulated cardiac insulin receptor and Igf-1 receptor without significant crizotinib impact. Regarding RTKs, we observed unaltered c-Met, Flt1 and Erbb2 expressions in diabetic hearts without influence of crizotinib. Conclusions: Crizotinib had a hypoglycaemic effect in diabetic animals after short-term treatment. This was independent of insulin and glucagon levels. Crizotinib prevented cardiac insulin-dependent Glut4 decrease. Downregulation of cardiac insulin receptor family RTKs expression remains stable under crizotinib suggesting modulation of alternative pathways responsible for crizotinib action in diabetic rat heart.