Dapagliflozin suppresses glucagon signaling in rodent models of diabetes (original) (raw)
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Nature medicine, 2015
Type 2 diabetes (T2D) is characterized by chronic hyperglycemia resulting from a deficiency in insulin signaling, because of insulin resistance and/or defects in insulin secretion; it is also associated with increases in glucagon and endogenous glucose production (EGP). Gliflozins, including dapagliflozin, are a new class of approved oral antidiabetic agents that specifically inhibit sodium-glucose co-transporter 2 (SGLT2) function in the kidney, thus preventing renal glucose reabsorption and increasing glycosuria in diabetic individuals while reducing hyperglycemia. However, gliflozin treatment in subjects with T2D increases both plasma glucagon and EGP by unknown mechanisms. In spite of the rise in EGP, T2D patients treated with gliflozin have lower blood glucose levels than those receiving placebo, possibly because of increased glycosuria; however, the resulting increase in plasma glucagon levels represents a possible concerning side effect, especially in a patient population alr...
Effect of dapagliflozin alone and in combination with insulin in a rat model of type 1 diabetes
Journal of Veterinary Medical Science, 2020
Dapagliflozin is a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor; it reduces glucose reabsorption via the kidney and increases the glucose excretion in urine. This inhibitor functions through a unique insulin-independent mechanism, and is therefore a potential new approach for the treatment of hyperglycemia in patients with diabetes. In this study, we evaluated the effectiveness of the SGLT2 inhibitor, dapagliflozin, by using a rat model of type 1 diabetes. Type 1 diabetes was induced by a single intraperitoneal injection of 60 mg/kg streptozotocin (STZ). The STZ-induced rats showed marked hyperglycemia and other metabolic abnormalities. We clarified the hypoglycemic effect of the combination treatment of dapagliflozin with a low dose of insulin compared with dapagliflozin alone and insulin alone in 3-week and 8-week studies. Our results showed that dapagliflozin in combination with a low dose of insulin significantly lowered hyperglycemia, hypercholesterolemia, and hypertriglyceridemia. Furthermore, the antioxidant status and body weight were improved. In contrast, treatment with dapagliflozin alone did not improve the blood glucose levels, lipid profile, antioxidant status, or body weight. These findings suggested that in type 1 diabetes, dapagliflozin was effective in combination with a low dose of insulin; however, the administration of dapagliflozin alone did not achieve a significant effect.
The Journal of pharmacology and experimental therapeutics, 2014
Type 2 diabetes is characterized by impaired β-cell function associated with progressive reduction of insulin secretion and β-cell mass. Evidently, there is an unmet need for treatments with greater sustainability in β-cell protection and antidiabetic efficacy. Through an insulin and β cell-independent mechanism, empagliflozin, a specific sodium glucose cotransporter type 2 (SGLT-2) inhibitor, may potentially provide longer efficacy. This study compared the antidiabetic durability of empagliflozin treatment (10 mg/kg p.o.) against glibenclamide (3 mg/kg p.o.) and liraglutide (0.2 mg/kg s.c.) on deficient glucose homeostasis and β-cell function in Zucker diabetic fatty (ZDF) rats. Empagliflozin and liraglutide led to marked improvements in fed glucose and hemoglobin A1c levels, as well as impeding a progressive decline in insulin levels. In contrast, glibenclamide was ineffective. Whereas the effects of liraglutide were less pronounced at week 8 of treatment compared with week 4, tho...
Dapagliflozin: a sodium glucose cotransporter 2 inhibitor in development for type 2 diabetes
2010
Type 2 diabetes mellitus (T2DM) is a growing worldwide epidemic. Patients face lifelong therapy to control hyperglycemia and prevent the associated complications. There are many medications, with varying mechanisms, available for the treatment of T2DM, but almost all target the declining insulin sensitivity and secretion that are associated with disease progression. Medications with such insulin-dependent mechanisms of action often lose efficacy over time, and there is increasing interest in the development of new antidiabetes medications that are not dependent upon insulin. One such approach is through the inhibition of renal glucose reuptake. Dapagliflozin, the first of a class of selective sodium glucose cotransporter 2 inhibitors, reduces renal glucose reabsorption and is currently under development for the treatment of T2DM. Here, we review the literature relating to the preclinical and clinical development of dapagliflozin.
Dapagliflozin Ameliorates Glycemic State, Lipid Profile and Renal Functions in Type 2 Diabetic Rats
Benha Medical Journal, 2020
Background: Diabetic kidney disease is the leading cause of chronic kidney disease worldwide. Sodium glucose cotransporter-2 inhibitors may provide a recent solution with better control. Aim: to study the effect of dapagliflozin on glycemic state, lipid profile, renal functions, renal histopathology and some underlying possible mechanisms in type 2 diabetic rats. Methods: Fifty adult male albino rats were divided into five groups: Non-diabetic, diabetic non-treated, diabetic metformintreated, diabetic dapagliflozin-treated and diabetic combined metformin & dapagliflozin-treated. Type 2 diabetes was induced by high fat dietlow dose streptozotocin. Metformin or dapagliflozin were given. RBF and RVR were measured. Fasting serum glucose, HbA1c, serum insulin, lipid profile, renal function tests, TAC, MDA and TNF-α were measured then HOMA-IR, LDL-C & creatinine clearance were calculated. Histopathological examination of kidney sections was performed. Results: Hyperglycemia, hyperinsulinemia, insulin resistance, dyslipidemia, impairment of renal functions, altered oxidative and inflammatory modulators status, and changes in renal morphology were observed in diabetic rats. Individual treatment with metformin or dapagliflozin significantly improved those parameters however, better improvement in renal functions was observed in dapagliflozin as compared to metformin-treated groups. Diabetic combined metformin & dapagliflozin-treated group revealed significant improvement in glycemic state, renal function, TNF-α and oxidative stress as compared to dapagliflozin-treated group. Conclusion: Although metformin is better than dapagliflozin in glycemic control, dapagliflozin is more renoprotective than metformin. Combined dapagliflozin and metformin treatment resulted in significant improvement in glycemic state and renal functions in diabetic rats which is better than individual treatment. dapagliflozin had a complementary effect to metformin treatment in T2DM.
Glucagon as a Critical Factor in the Pathology of Diabetes
Diabetes, 2011
tudies from the laboratory of Roger Unger presented in the current issue of Diabetes highlight the potential benefit of reducing glucagon action by examining the effects of glucagon receptor knockout (Gcgr 2/2) on the phenotype of type 1 diabetes in the mouse (1). The aim of the study was to determine if glucagon action, by itself, causes the lethal consequences of insulin deficiency. Because treatment of Gcgr 2/2 mice with the b-cell toxin streptozotocin (STZ) previously had no effect on circulating insulin levels or pancreatic islet architecture (2), Lee et al. (1) administered a double dose of STZ to maximize b-cell destruction. Unlike STZ treated wild-type Gcgr +/+ mice, which became severely hyperglycemic, STZ-treated mice lacking glucagon signaling appeared to be in a normal state of health and were completely protected from the manifestations of diabetes (1), as shown previously by the same group in alloxan treated Gcgr 2/2 mice (3) and by Hancock et al. (4) in STZtreated mice lacking glucagon because of a-cell deletion. Fasting hyperglycemia did not occur in STZ-treated Gcgr 2/2 mice, and astonishingly, the animals demonstrated normal or even improved glucose disposal in response to a glucose tolerance test, despite the absence of a rise in plasma insulin. These results led the authors to speculate that insulin action during glucose absorption is largely directed toward overcoming the hepatic actions of glucagon. They theorized that insulin would have little or no role in a liver not exposed to the action of glucagon because it would be in a permanent glucose storage mode. Glucagon antagonistic peptides, neutralizing antibodies, receptor antisense oligonucleotides, and/or receptor nonpeptidyl antagonists have previously been shown to lower plasma glucose in several rodent models of diabetes (5,6). Likewise, reversal of diabetes by leptin therapy in the rodent has been attributed to a reduction in plasma glucagon (3,7), although other actions of leptin could not be ruled out. Reduction of glucagon in pancreatectomized canines caused a marked decrease in hepatic glucose production (8) and suppression of glucagon in diabetic humans improved glucose tolerance (9,10). Thus, there is strong evidence supporting a role for glucagon in contributing to diabetic hyperglycemia.
Sodium–glucose cotransporter 2 inhibitor Dapagliflozin attenuates diabetic cardiomyopathy
Cardiovascular Diabetology
Background: Diabetes mellitus type 2 (DM2) is a risk factor for developing heart failure but there is no specific therapy for diabetic heart disease. Sodium glucose transporter 2 inhibitors (SGLT2I) are recently developed diabetic drugs that primarily work on the kidney. Clinical data describing the cardiovascular benefits of SGLT2Is highlight the potential therapeutic benefit of these drugs in the prevention of cardiovascular events and heart failure. However, the underlying mechanism of protection remains unclear. We investigated the effect of Dapagliflozin-SGLT2I, on diabetic cardiomyopathy in a mouse model of DM2. Methods: Cardiomyopathy was induced in diabetic mice (db/db) by subcutaneous infusion of angiotensin II (ATII) for 30 days using an osmotic pump. Dapagliflozin (1.5 mg/kg/day) was administered concomitantly in drinking water. Male homozygous, 12-14 weeks old WT or db/db mice (n = 4-8/group), were used for the experiments. Isolated cardiomyocytes were exposed to glucose (17.5-33 mM) and treated with Dapagliflozin in vitro. Intracellular calcium transients were measured using a fluorescent indicator indo-1. Results: Angiotensin II infusion induced cardiomyopathy in db/db mice, manifested by cardiac hypertrophy, myocardial fibrosis and inflammation (TNFα, TLR4). Dapagliflozin decreased blood glucose (874 ± 111 to 556 ± 57 mg/dl, p < 0.05). In addition it attenuated fibrosis and inflammation and increased the left ventricular fractional shortening in ATII treated db/db mice. In isolated cardiomyocytes Dapagliflozin decreased intracellular calcium transients, inflammation and ROS production. Finally, voltage-dependent L-type calcium channel (CACNA1C), the sodium-calcium exchanger (NCX) and the sodium-hydrogen exchanger 1 (NHE) membrane transporters expression was reduced following Dapagliflozin treatment. Conclusion: Dapagliflozin was cardioprotective in ATII-stressed diabetic mice. It reduced oxygen radicals, as well the activity of membrane channels related to calcium transport. The cardioprotective effect manifested by decreased fibrosis, reduced inflammation and improved systolic function. The clinical implication of our results suggest a novel pharmacologic approach for the treatment of diabetic cardiomyopathy through modulation of ion homeostasis.
Dapagliflozin Does Not Directly Affect Human α or β Cells
Endocrinology, 2020
Selective inhibitors of sodium glucose cotransporter-2 (SGLT2) are widely used for the treatment of type 2 diabetes and act primarily to lower blood glucose by preventing glucose reabsorption in the kidney. However, it is controversial whether these agents also act on the pancreatic islet, specifically the α cell, to increase glucagon secretion. To determine the effects of SGLT2 on human islets, we analyzed SGLT2 expression and hormone secretion by human islets treated with the SGLT2 inhibitor dapagliflozin (DAPA) in vitro and in vivo. Compared to the human kidney, SLC5A2 transcript expression was 1600-fold lower in human islets and SGLT2 protein was not detected. In vitro, DAPA treatment had no effect on glucagon or insulin secretion by human islets at either high or low glucose concentrations. In mice bearing transplanted human islets, 1 and 4 weeks of DAPA treatment did not alter fasting blood glucose, human insulin, and total glucagon levels. Upon glucose stimulation, DAPA treat...