- Effects of phosphate binders on the gastrointestinal absorption of arsenate and of an SGLT2 inhibitor drug on the urinary excretion of arsenite in mice. [Journal Article]
- ETEnviron Toxicol Pharmacol 2017 Jan 03; 49:179-187
- Arsenate (As(V)) and arsenite (As(III)) are typical sources of acute and chronic arsenic poisoning. Therefore, reducing inner exposure to these arsenicals is a rational objective. Because As(V) mimic...
Arsenate (As(V)) and arsenite (As(III)) are typical sources of acute and chronic arsenic poisoning. Therefore, reducing inner exposure to these arsenicals is a rational objective. Because As(V) mimics phosphate, phosphate binder drugs may decrease the intestinal As(V) absorption. Indeed, lanthanum and aluminium salts and sevelamer removed As(V) from solution in vitro, especially at acidic pH. In mice gavaged with As(V), lanthanum chloride, lanthanum carbonate and aluminium hydroxide given orally also lowered the urinary excretion and tissue levels of As(V) and its metabolites, indicating that they decreased the gastrointestinal As(V) absorption. As some glucose transporters may carry As(III), the effect of the SGLT2 inhibitor dapagliflozin was investigated in As(III)-injected mice. While producing extreme glucosuria, dapagliflozin barely affected the urinary excretion and tissue concentrations of As(III) and its metabolites. Thus, phosphate binders (especially lanthanum compounds) can reduce the gastrointestinal absorption of As(V); however, SGLT2 inhibition cannot diminish the renal reabsorption of As(III).
- Emerging roles of sodium-glucose cotransporter 2 inhibitors in cardiology. [Review]
- JCJ Cardiol 2016 Dec 30
- The ultimate goal of treatment in people with diabetes mellitus is to prevent development of cardiovascular (CV) disease, resulting in prolongation of healthy life expectancy. Although impaired glyce...
The ultimate goal of treatment in people with diabetes mellitus is to prevent development of cardiovascular (CV) disease, resulting in prolongation of healthy life expectancy. Although impaired glycemic metabolism has a central role in its pathology, a number of studies have demonstrated that remedy for its imbalance cannot necessarily be accomplished as a therapeutic goal. A comprehensive medical approach against multi-factorial pathologies in diabetes, such as insulin resistance, obesity, hypertension, and dyslipidemia, in addition to diet and exercise therapy should be rather performed in the routine clinical setting. Along with such conceptual transition, what is required in anti-diabetes agents has also changed, and several anti-diabetes agents have been newly placed on the market in this decade. Such agents are required to undergo global pre- or post-marketing clinical trials assessing CV safety. A growing body of clinical evidence from those trials is now accumulating, and empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has first demonstrated significant risk reduction, relative to placebo, in CV death, overall mortality, and hospitalization for worsened heart failure in high-risk patients with diabetes mellitus. An SGLT2 inhibitor is a unique glucose-lowering agent and at the same time has multifaceted effects on hemodynamic and metabolic parameters beyond glycemic control. A major mode of action of SGLT2 inhibitors appears to be 'glycosuria' and 'natriuresis,' leading to amelioration of systemic glycemic homeostasis and potential cardio-renal protection. However, the precise mechanisms by which SGLT2 inhibitors affect benefits on the CV systems are yet to be fully elucidated. Thus, although we are now facing several unanswered concerns lurking behind the successful trial, SGLT2 inhibitors surely play several important roles in high-quality management of not only diabetes, but also CV medicine. This review summarizes our current understandings and future perspectives of SGLT2 inhibitors in CV medicine.
- SGLT-2 inhibitors: Their pleiotropic properties. [Review]
- DMDiabetes Metab Syndr 2016 Dec 09
- Type 2 diabetes mellitus has become a global pandemic. Nowadays, it is estimated that approximately 415 million people all over the world have diabetes. The sodium glucose co-transporters 2 inhibitor...
Type 2 diabetes mellitus has become a global pandemic. Nowadays, it is estimated that approximately 415 million people all over the world have diabetes. The sodium glucose co-transporters 2 inhibitors are a new class of glucose-lowering agents, which act through a novel mechanism by producing a decline in glucose re-absorption in the kidney, thereby increasing glycosuria and decreasing serum glucose levels. Data suggest that apart from lowering HbA1c, they produce a small but significant weight loss and a small decrease in blood pressure. Also, they possess nephro-protective potential. These drugs are demonstrated to restore intra-glomerular pressure by increasing angiotensin (1-7), which exerts vasodilatory and anti-inflammatory effects. Their profile on cardiovascular events is still under investigation. In this review, the pleiotropic potential of this novel class of glucose-lowering levels will be discussed. Further research is warranted to determine their safety in the long term.
- Glycosuria and Renal Outcomes in Patients with Nondiabetic Advanced Chronic Kidney Disease. [Journal Article]
- SRSci Rep 2016 Dec 23; 6:39372
- Sodium glucose cotransporter 2 inhibitors have shown a potential for renoprotection beyond blood glucose lowering. Glycosuria in nondiabetic patients with chronic kidney disease (CKD) is sometimes no...
Sodium glucose cotransporter 2 inhibitors have shown a potential for renoprotection beyond blood glucose lowering. Glycosuria in nondiabetic patients with chronic kidney disease (CKD) is sometimes noted. Whether glycosuria in CKD implies a channelopathy or proximal tubulopathy is not known. The consequence of glycosuria in CKD is also not studied. We performed a cross-sectional study for the association between glycosuria and urine electrolyte excretion in 208 nondiabetic patients. Fractional excretion (FE) of glucose >4% was 3.4%, 6.3% and 62.5% in CKD stage 3, 4 and 5, respectively. These patients with glycosuria had higher FE sodium, FE potassium, FE uric acid, UPCR, and urine NGAL-creatinine ratio. We conducted a longitudinal study for the consequence of glycosuria, defined by dipstick, in 769 nondiabetic patients with stage 4-5 CKD. Glycosuria was associated with a decreased risk for end-stage renal disease (adjusted hazard ratio: 0.77; CI = 0.62-0.97; p = 0.024) and for rapid renal function decline (adjusted odds ratio: 0.63; CI = 0.43-0.95; p = 0.032); but glycosuria was not associated with all-cause mortality or cardiovascular events. The results were consistent in the propensity-score matched cohort. Glycosuria is associated with increased fractional excretion of electrolytes and is related to favorable renal outcomes in nondiabetic patients with stage 5 CKD.
- The impact of SGLT2 inhibitors, compared with insulin, on diabetic bone disease in a mouse model of type 1 diabetes. [Journal Article]
- BONEBone 2016 Oct 28
- Skeletal co-morbidities in type 1 diabetes include an increased risk for fracture and delayed fracture healing, which are intertwined with disease duration and the presence of other diabetic complica...
Skeletal co-morbidities in type 1 diabetes include an increased risk for fracture and delayed fracture healing, which are intertwined with disease duration and the presence of other diabetic complications. As such, chronic hyperglycemia is undoubtedly a major contributor to these outcomes, despite standard insulin-replacement therapy. Therefore, using the streptozotocin (STZ)-induced model of hypoinsulinemic hyperglycemia in DBA/2J male mice, we compared the effects of two glucose lowering therapies on the fracture resistance of bone and markers of bone turnover. Twelve week-old diabetic (DM) mice were treated for 9weeks with: 1) oral canagliflozin (CANA, dose range ~10-16mg/kg/day), an inhibitor of the renal sodium-dependent glucose co-transporter type 2 (SGLT2); 2) subcutaneous insulin, via minipump (INS, 0.125units/day); 3) co-therapy (CANA+INS); or 4) no treatment (STZ, without therapy). These groups were also compared to non-diabetic control groups. Untreated diabetic mice experienced increased bone resorption and significant deficits in cortical and trabecular bone that contributed to structural weakness of the femur mid-shaft and the lumbar vertebra, as determined by three-point bending and compression tests, respectively. Treatment with either canagliflozin or insulin alone only partially rectified hyperglycemia and the diabetic bone phenotype. However, when used in combination, normalization of glycemic control was achieved, and a prevention of the DM-related deterioration in bone microarchitecture and bone strength occurred, due to additive effects of canagliflozin and insulin. Nevertheless, CANA-treated mice, whether diabetic or non-diabetic, demonstrated an increase in urinary calcium loss; FGF23 was also increased in CANA-treated DM mice. These findings could herald ongoing bone mineral losses following CANA exposure, suggesting that certain CANA-induced skeletal consequences might detract from therapeutic improvements in glycemic control, as they relate to diabetic bone disease.
- Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. [Review]
- NRNat Rev Nephrol 2017; 13(1):11-26
- The kidney has a pivotal role in maintaining glucose homeostasis by using glucose as a metabolic fuel, by producing glucose through gluconeogenesis, and by reabsorbing all filtered glucose through th...
The kidney has a pivotal role in maintaining glucose homeostasis by using glucose as a metabolic fuel, by producing glucose through gluconeogenesis, and by reabsorbing all filtered glucose through the sodium-glucose cotransporters SGLT1 and SGLT2 located in the proximal tubule. In patients with diabetes, the maximum glucose reabsorptive capacity (TmG) of the kidney, as well as the threshold for glucose spillage into the urine, are elevated, contributing to the pathogenesis of hyperglycaemia. By reducing the TmG and, more importantly, the threshold of glucosuria, SGLT2 inhibitors enhance glucose excretion, leading to a reduction in fasting and postprandial plasma glucose levels and improvements in both insulin secretion and insulin sensitivity. The beneficial effects of SGLT2 inhibition extend beyond glycaemic control, however, with new studies demonstrating that inhibition of renal glucose reabsorption reduces blood pressure, ameliorates glucotoxicity and induces haemodynamic effects that lead to improved cardiovascular and renal outcomes in patients with type 2 diabetes mellitus. In this Review we examine the role of SGLT2 and SGLT1 in the regulation of renal glucose reabsorption in health and disease and the effect of SGLT2 inhibition on renal function, glucose homeostasis, and cardiovascular disease.
- GeneReviews(®) [BOOK]
- BOOKUniversity of Washington, Seattle: Seattle (WA)
- Berardinelli-Seip congenital lipodystrophy (BSCL) is usually diagnosed at birth or soon thereafter. Because of the absence of functional adipocytes, lipid is stored in other tissues, including muscle...
Berardinelli-Seip congenital lipodystrophy (BSCL) is usually diagnosed at birth or soon thereafter. Because of the absence of functional adipocytes, lipid is stored in other tissues, including muscle and liver. Affected individuals develop insulin resistance and approximately 25%-35% develop diabetes mellitus between ages 15 and 20 years. Hepatomegaly secondary to hepatic steatosis and skeletal muscle hypertrophy occur in all affected individuals. Hypertrophic cardiomyopathy is reported in 20%-25% of affected individuals and is a significant cause of morbidity from cardiac failure and early mortality.
- Inversion of excreted intravenous contrast-fluid levels in the urinary bladder on computed tomography. [Journal Article]
- RCRadiol Case Rep 2016; 11(4):318-322
- Fluid-fluid levels occur on computed tomography due to differences in density between the 2 fluids. For example, intravenous (IV) contrast excreted into the urinary bladder layers posterior with grav...
Fluid-fluid levels occur on computed tomography due to differences in density between the 2 fluids. For example, intravenous (IV) contrast excreted into the urinary bladder layers posterior with gravity in the supine patient with normal, unopacified urine layering anterior, due to their differing densities. The rare presence of inverted fluid-contrast levels in the bladder calls attention to the existence of pathology such as microscopic hematuria, infectious debris, glycosuria, and purulent fluid. In such instances, the hypodense, nonopacified urine is the abnormality and is often only recognized due to the excreted IV contrast "floating" on top of it within the bladder. Here, we describe a case in which the development of inverted fluid-contrast levels in the urinary bladder on computed tomography during a patient's hospital stay heralded further investigation with urinalysis and urinary culture, with the known, worrisome causes able to be excluded.
- 6q24 Transient Neonatal Diabetes - How to Manage while Waiting for Genetic Results. [Journal Article]
- FPFront Pediatr 2016; 4:124
- Diabetes, rare in the neonatal period, should be evoked in every newborn presenting with unexplained intrauterine and early postnatal growth retardation. This case report illustrates the clinical cou...
Diabetes, rare in the neonatal period, should be evoked in every newborn presenting with unexplained intrauterine and early postnatal growth retardation. This case report illustrates the clinical course and therapeutic approach of a newborn diagnosed with transient diabetes. The baby was born at 37 weeks of gestation with a severe intrauterine growth restriction. Except a mild macroglossia and signs of growth restriction, physical examination was normal. On the fifth day of life, hyperglycemia (180 mg/dl) was noted, and the next day, the diagnosis of diabetes was confirmed (high blood sugar, glucosuria, undetectable levels of insulin and C-peptide). Insulin infusion, initially intravenously and then subcutaneously, was started, tailored to assure the growth catch-up and normalize the blood sugar levels. At the age of 4 weeks, the baby returned at home under pump. At 8 weeks, the clinical impression of evolution to a transient diabetes (decreasing needs of insulin with very satisfactory weight gain) was genetically confirmed (paternal uniparental disomy of chromosome 6). There is no screening for neonatal diabetes, but the clinical suspicion avoids the metabolic decompensation and allows early initiation of insulin therapy. The genetic approach (for disease itself and its associated features) relies on timely clinical updates.
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- Fanconi Syndrome Associated with Hyponatremia in Two Patients with Legionella Pneumonia. [Journal Article]
- IMIntern Med 2016; 55(23):3479-3484
- Legionella pneumophila is a cause of community-acquired pneumonia that is reported to induce electrolyte disorders, including hyponatremia, hypokalemia, and hypophosphatemia. We herein report two Jap...
Legionella pneumophila is a cause of community-acquired pneumonia that is reported to induce electrolyte disorders, including hyponatremia, hypokalemia, and hypophosphatemia. We herein report two Japanese men with Legionella pneumonia and hyponatremia and hypophosphatemia. These findings were associated with an elevation of urinary low-molecular-weight tubular protein, including urinary β2-microglobulin, N-acetyl-β-D-glucosaminidase, the fractional excretion of phosphate and uric acid, and the presence of glycosuria and panaminoaciduria, suggesting that their electrolyte disorders had been caused by Fanconi syndrome. In these two cases, hyponatremia was probably due to salt wasting. Electrolyte disorders caused by Legionella pneumonia are corrected by treatment of the primary disease and fluid administration.