Linagliptin ameliorated cardiac fibrosis and restored cardiomyocyte structure in diabetic mice associated with the suppression of necroptosis.

AIMS/INTRODUCTION: Linagliptin is a selective dipeptidyl peptidase (DPP)-4 inhibitor capable of successfully regulating blood glucose levels. The cardiovascular protective effects of several DPP-4 inhibitors have been shown in preclinical studies; however, the detailed influence of DPP-4 inhibitors on diabetic pathological alterations in cardiac tissue has not yet been elucidated. MATERIALS AND METHODS: We combined laboratory-based experiments and bioinformatics techniques to identify suitable candidate targets with significant biological pathways. Mice with streptozotocin-induced insulin deficiency diabetic model were utilized for in vivo experiments. Mice were euthanized at 24 weeks after the induction of diabetes; linagliptin intervention was carried out for 4 weeks before euthanasia. Microarray analysis of heart samples was carried out. RESULTS: Mice with streptozotocin-induced diabetes, but not control mice, showed cardiac fibrosis with an endothelial-mesenchymal transition program, and myocardial fiber and sarcomere disruption; linagliptin alleviated these diabetes-associated pathological alterations without altering blood glucose levels. Bioinformatics analysis utilizing a microarray dataset identified 10 hub genes that were confirmed to have human disease relevance by Gene Expression Omnibus analysis. Among these hub genes, we focused on the Sox9-necroptosis axis as a therapeutic target in diabetic hearts. Indeed, diabetic mice showed the induction of necroptosis-associated genes and the phosphorylation of RIP3 and mixed lineage kinase domain-like protein. CONCLUSIONS: Linagliptin showed excellent heart protection in mice with streptozotocin-induced diabetes associated with alterations in human disease-relevant hub genes. Further investigation is required to determine why DPP-4 inhibitors do not show similar superior organ-protective effects in the clinical setting.

Adenosine/adenosine type 1 receptor signaling pathway did not play dominant roles on the influence of sodium-glucose cotransporter 2 inhibitor in the kidney of bovine serum albumin-overloaded streptozotocin-induced diabetic mice.

AIMS/INTRODUCTION: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to display excellent renoprotective effects in diabetic kidney disease with macroalbuminuria/proteinuria. Regarding the renoprotective mechanism of SGLT2i, a sophisticated hypothesis was made by explaining the suppression of glomerular hypertension/hyperfiltration through the adenosine/adenosine type 1 receptor (A1R) signaling-mediated restoration of the tubuloglomerular feedback mechanism; however, how such A1R signaling is relevant for renoprotection by SGLT2i in diabetic kidney disease with proteinuria has not been elucidated. MATERIALS AND METHODS: Streptozotocin-induced diabetic CD-1 mice were injected with bovine serum albumin (BSA) and treated with SGLT2i in the presence/absence of A1R inhibitor administration. RESULTS: We found that the influences of SGLT2i are essentially independent of the activation of A1R signaling in the kidney of BSA-overloaded streptozotocin-induced diabetic mice. BSA-overloaded diabetic mice showed the trend of kidney damage with higher glomerular filtration rate (GFR) and the significant induction of fibrogenic genes, such as transforming growth factor-ß2 and collagen type III. SGLT2i TA-1887 suppressed diabetes-induced GFR in BSA-overloaded diabetic mice was associated with the significant suppression of transforming growth factor-ß2 and collagen type III; A1R-specific inhibitor 8-cyclopentyl-1,3-dipropylxanthine did not cancel the effects of TA-1887 on either GFR or associated gene levels. Both TA-1887 and 8-cyclopentyl-1,3-dipropylxanthine-treated BSA-overloaded diabetic mice showed suppressed glycated hemoglobin levels associated with the increased food intake. When analyzing the association among histological evaluation, GFR and potential fibrogenic gene levels, each group of mice showed distinct correlation patterns. CONCLUSIONS: A1R signaling activation was not the dominant mechanism on the influence of SGLT2i in the kidney of BSA-overloaded diabetic mice.

Sodium-glucose cotransporter 2 inhibitors in type 2 diabetes patients with renal function impairment slow the annual renal function decline, in a real clinical practice.

AIMS/INTRODUCTION: The aim of this study was to elucidate whether sodium-glucose cotransporter 2 inhibitors (SGLT2is) treatment has any renoprotective effect for type 2 diabetes mellitus patients with an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2 in clinical practice. MATERIALS AND METHODS: We evaluated the annual eGFR slope in 85 type 2 diabetes mellitus patients with renal impairment, treated with SGLT2is ≥2 years. Each patient's eGFR was <60 mL/min/1.73 m2 at the start of SGLT2is therapy. The calculation of the annual change in eGFR for each patient was obtained by acquired eGFR data before and after 2 years of the initial SGLT2is administration, followed by analysis of the changes in the mean eGFR slope. RESULTS: The participants' mean age was 72.0 ± 9.4 years, and the mean eGFR was 47.1 ± 9.7 mL/min/1.73 m2 at the start of additional treatment with SGLT2is. The mean annual eGFR slope after SGLT2is administration (-0.11 ± 0.20 mL/min/1.73 m2 /year) was significantly slower than before SGLT2is administration (-2.93 ± 0.59 mL/min/1.73 m2 /year; P < 0.0001). Additionally, SGLT2is treatment slowed the annual decline of eGFR, independent of the levels of both the initial eGFR and albuminuria levels before SGLT2is therapy was started. In the patient groups who showed an annual eGFR decline of ≥3 and 1-3 mL/min/1.73 m2 , there was a significant slowing of the decline after SGLT2is therapy, compared with before the treatment (P < 0.001, respectively). CONCLUSIONS: SGLT2is administration slows the decline observed in the annual renal function in type 2 diabetes mellitus patients with eGFR of <60 mL/min/1.73 m2 in clinical practice.

Effects of SGLT2 Inhibitors on Atherosclerosis: Lessons from Cardiovascular Clinical Outcomes in Type 2 Diabetic Patients and Basic Researches.

Atherosclerosis-caused cardiovascular diseases (CVD) are the leading cause of mortality in type 2 diabetes mellitus (T2DM). Sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective oral drugs for the treatment of T2DM patients. Multiple pre-clinical and clinical studies have indicated that SGLT2 inhibitors not only reduce blood glucose but also confer benefits with regard to body weight, insulin resistance, lipid profiles and blood pressure. Recently, some cardiovascular outcome trials have demonstrated the safety and cardiovascular benefits of SGLT2 inhibitors beyond glycemic control. The SGLT2 inhibitors empagliflozin, canagliflozin, dapagliflozin and ertugliflozin reduce the rates of major adverse cardiovascular events and of hospitalization for heart failure in T2DM patients regardless of CVD. The potential mechanisms of SGLT2 inhibitors on cardioprotection may be involved in improving the function of vascular endothelial cells, suppressing oxidative stress, inhibiting inflammation and regulating autophagy, which further protect from the progression of atherosclerosis. Here, we summarized the pre-clinical and clinical evidence of SGLT2 inhibitors on cardioprotection and discussed the potential molecular mechanisms of SGLT2 inhibitors in preventing the pathogenesis of atherosclerosis and CVD.

Significance of SGLT2 inhibitors: lessons from renal clinical outcomes in patients with type 2 diabetes and basic researches.

Diabetic kidney disease (DKD), a microvascular complication of diabetes, has been the leading cause of end-stage kidney disease (ESKD). Accordingly, patients with type 2 diabetes mellitus (T2DM) develop renal damage due to multiple metabolic and cardiorenal disease-related risk factors, including hyperglycemia, hypertension, dyslipidemia, hyperuricemia, and overnutrition/obesity. Despite multifactorial management including the administration of renin-angiotensin system inhibitors, patients often do not experience sufficient suppression of DKD progression and, thus, remain at risk for ESKD. Recent studies on cardiovascular outcomes among patients with T2DM have clearly shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors, such as empagliflozin, canagliflozin, and dapagliflozin, have cardiorenal protective effects apart from their glucose-lowering effects. In particular, SGLT2 inhibitors have been found to improve renal outcomes, including ESKD, by slowing renal function decline and reducing urinary albumin excretion through their class effect. The proposed mechanisms for the renoprotective effects of SGLT2 inhibitors include the action of tubulo-glomerular feedback system and attenuation of hypoxia and metabolic stress in proximal tubular cells mediated through the inhibition of excessive glucose and sodium reabsorption, increased erythropoiesis, or increased ketone body production.

Case report of superior mesenteric artery syndrome that developed in a lean type 2 diabetes patient and was associated with rapid body weight loss after sodium-glucose cotransporter 2 inhibitor administration.

A 58-year-old women who was diagnosed with type 2 diabetes 20 years earlier had been treated with antidiabetic medicines since she was aged 40 years. After sodium-glucose cotransporter 2 inhibitors administration, her bodyweight rapidly decreased from 40 to 30 kg over a period of 3 weeks. She had abdominal symptoms, including nausea, especially after a meal. On admission, physical examinations and laboratory data showed euglycemic ketoacidosis, dehydration and low insulin secretion levels. Additionally, abdominal contrast computed tomography showed the finding of superior mesenteric artery syndrome. This case urges caution, including rapid excessive bodyweight loss and euglycemic ketoacidosis, on the use of sodium-glucose cotransporter 2 for lean diabetes patients.

Severe electrolytes disorders with the interstitial kidney alterations in the patient with the history of total thyroidectomy and parathyroidectomy: possible role of vitamin D deficiency.

Vitamin D plays vital role for the health, and its deficiency has been implicated in the diverse pathological conditions such as hypomagnesemia and abnormal immune system. Here, we present a case of severe electrolytes disorders (hypokalemia and hypomagnesemia etc.) and kidney damages associated with vitamin D deficiency.