Effect of canagliflozin and metformin on cortical neurotransmitters in a diabetic rat model.

BACKGROUND: The rapid economic development in the Arabian Gulf has resulted in lifestyle changes that have increased the prevalence of obesity and type 2 diabetes, with the greatest increases observed in Kuwait. Dyslipidemia and diabetes are risk factors for disruptions in cortical neurotransmitter homeostasis. This study investigated the effect of the antidiabetic medications canagliflozin (CAN) and metformin (MET) on the levels of cortical neurotransmitters in a diabetic rat model. MATERIALS AND METHODS: The rats were assigned to the control (C) group, the diabetic group that did not receive treatment (D) or the diabetic group treated with either CAN (10 mg/kg) or MET (100 mg/kg) for 2 or 4 weeks. Blood and urine glucose levels and cortical acetylcholinesterase (AChE) activity were assayed, and amino acid and monoamine levels were measured using HPLC. RESULTS: The diabetic group exhibited a significant increase in AChE activity and a decrease in monoamine and amino acid neurotransmitter levels. In the CAN group, AChE was significantly lower than that in the D and D + MET groups after 2 weeks of treatment. In addition, a significant increase in some cortical monoamines and amino acids was observed in the D + MET and D + CAN groups compared with the D group. Histopathological analysis revealed the presence of severe focal hemorrhage, neuronal degeneration, and cerebral blood vessel congestion, with gliosis in the cerebrum of rats in the D group. The CAN-treated group exhibited severe cerebral blood vessel congestion after 2 weeks of treatment and focal gliosis in the cerebrum after 4 weeks of treatment. Focal gliosis in the cerebrum of rats in the MET-treated group was observed after 2 and 4 weeks of treatment. CONCLUSIONS: We conclude that the effect of CAN and MET on neurotransmitters is potentially mediated by their antihyperglycemic and antihyperlipidemic effects. In addition, the effects of CAN on neurotransmitters might be associated with its receptor activity, and the effect of MET on neurotransmitters might be associated with cerebral metabolism.

Assessment of early diabetic renal changes with hyperpolarized [1-(13) C]pyruvate.

BACKGROUND: This experimental study explores a novel magnetic resonance imaging/spectroscopic (MRI/MRS) method that measures changes in renal metabolism in a diabetic rat model. This hyperpolarized metabolic MRI/MRS method allows monitoring of metabolic processes in seconds by >10 000-fold enhancement of the MR signal. The method has shown that the conversion of pyruvate to bicarbonate, i.e. pyruvate dehydrogenase (PDH) activity, is significantly altered in the myocardium already at the onset of diabetes, and the predominant Warburg effect is a valuable cancer maker via the lactate dehydrogenase (LDH) activity. We hypothesize that a similar change in PDH and LDH could be found in the early diabetic kidney. METHODS: In a streptozotocin rat model of type 1 diabetes, hyperpolarized (13) C-MRI and blood oxygenation level-dependent (1) H-MRI was employed to investigate the changes in renal metabolism in the diabetic and the control kidneys in vivo. RESULTS: The diabetic kidney showed a 149% increase in the lactate/pyruvate ratio compared with the control rat kidney, whereas the bicarbonate/pyruvate ratio was unchanged between the diabetic and the control rat kidneys, consistent with literature findings. These metabolic findings paralleled a reduced intrarenal oxygen availability as found by blood oxygenation level-dependent MRI. DISCUSSION: Hyperpolarized (13) C-MRI shows promise in the diagnosis and monitoring of early renal changes associated with diabetes, with the pyruvate/lactate ratio as an imaging biomarker for regional renal changes.

Differential regulation of the degradation of myofibrillar and total proteins in skeletal muscle of rats: effects of streptozotocin-induced diabetes, dietary protein and starvation.

In order to examine the effects of streptozotocin-induced diabetes, dietary protein, and starvation on protein degradation in skeletal muscle of perfused rat hindquarters, rates of myofibrillar and total protein degradation were estimated from the release of 3-methylhistidine (N tau-methylhistidine, 3-MH) and tyrosine, respectively. In rats fed a 20% protein diet (controls), the fractional degradation rate of myofibrillar protein was approximately 56% of the total muscle protein. In streptozotocin-induced diabetic rats, 3-MH release by perfused muscle increased significantly on d 1 of treatment and sustained a high level thereafter. By contrast, tyrosine release did not change. Feeding a 50% protein diet for 1 wk altered neither 3-MH nor tyrosine release. Protein-free feeding, though, suppressed tyrosine release to 49% of controls, but did not affect 3-MH release. Starvation for 3 d did not affect tyrosine release, but did increase 3-MH release to 203% of controls. These results indicate that in diabetic and starved rats myofibrillar protein is preferentially degraded, while in protein-deficient rats, non-myofibrillar protein degradation is selectively suppressed. From these observations, we conclude that the degradation of myofibrillar and non-myofibrillar proteins in skeletal muscle can be differentially regulated.