(Glucosuria) articles in PubMed
- A recurrent deletion in the SLC5A2 gene including the intron 7 branch site responsible for familial renal glucosuria. [Journal Article]
- Sci Rep 2016; 6:33920SR
- Familial renal glycosuria (FRG) is caused by mutations in the SLC5A2 gene, which codes for Na(+)-glucose co-transporters 2 (SGLT2). The aim of this study was to analyze and identify the mutations in ...
Familial renal glycosuria (FRG) is caused by mutations in the SLC5A2 gene, which codes for Na(+)-glucose co-transporters 2 (SGLT2). The aim of this study was to analyze and identify the mutations in 16 patients from 8 families with FRG. All coding regions, including intron-exon boundaries, were analyzed using PCR followed by direct sequence analysis. Six mutations in SLC5A2 gene were identified, including five missense mutations (c.393G > C, p.K131N; c.1003A > G, p.S335G; c.1343A > G, p.Q448R; c.1420G > C, p.A474P; c.1739G > A, p.G580D) and a 22-bp deletion in intron 7 (c.886(-10_-31)del) removing the putative branch point sequence. By the minigene studies using the pSPL3 plasmids, we confirmed that the deletion c.886(-10_-31)del acts as a splicing mutation. Furthermore, we found that this deletion causes exclusion of exon 8 in the SCL5A2 transcript in patients. The mutation c.886(-10_-31)del was present in 5 (62.5%) of 8 families, and accounts for about 37.5% of the total alleles (6/16). In conclusion, six mutations resulting in FRG were found, and the c.886(-10_-31)del may be the high frequency mutation that can be screened in FRG patients with uniallelic or negative SLC5A2 mutations.
- Osteomalacia induced by long-term low-dose adefovir dipivoxil: Clinical characteristics and genetic predictors. [Journal Article]
- Bone 2016 Sep 21BONE
- CONCLUSIONS: ADV can be nephrotoxic at a conventional dosage. The G/A genotype at c.2934 of the ABCC2 gene may be a predictor of patients at greater risk for developing ADV-associated tubulopathy. Larger case-control studies are needed to further verify this finding.
- Thyroid hormone treatment decreases hepatic glucose production and renal reabsorption of glucose in alloxan-induced diabetic Wistar rats. [Journal Article]
- Physiol Rep 2016; 4(18)PR
- The thyroid hormone (TH) plays an important role in glucose metabolism. Recently, we showed that the TH improves glycemia control by decreasing cytokines expression in the adipose tissue and skeletal...
The thyroid hormone (TH) plays an important role in glucose metabolism. Recently, we showed that the TH improves glycemia control by decreasing cytokines expression in the adipose tissue and skeletal muscle of alloxan-induced diabetic rats, which were also shown to present primary hypothyroidism. In this context, this study aims to investigate whether the chronic treatment of diabetic rats with T3 could affect other tissues that are involved in the control of glucose homeostasis, as the liver and kidney. Adult Male Wistar rats were divided into nondiabetic, diabetic, and diabetic treated with T3 (1.5 μg/100 g BW for 4 weeks). Diabetes was induced by alloxan monohydrate (150 mg/kg, BW, i.p.). Animals showing fasting blood glucose levels greater than 250 mg/dL were selected for the study. After treatment, we measured the blood glucose, serum T3, T4, TSH, and insulin concentration, hepatic glucose production by liver perfusion, liver PEPCK, GAPDH, and pAKT expression, as well as urine glucose concentration and renal expression of SGLT2 and GLUT2. T3 reduced blood glucose, hepatic glucose production, liver PEPCK, GAPDH, and pAKT content and the renal expression of SGLT2 and increased glycosuria. Results suggest that the decreased hepatic glucose output and increased glucose excretion induced by T3 treatment are important mechanisms that contribute to reduce serum concentration of glucose, accounting for the improvement of glucose homeostasis control in diabetic rats.
- OS 05-04 EMPAGLIFLOZIN EXERTS CARDIO- AND NEPHRO-PROTECTIVE EFFECTS IN COHEN-ROSENTHAL DIABETIC HYPERTENSIVE RATS. [Journal Article]
- J Hypertens 2016; 34 Suppl 1:e58-9JH
- CONCLUSIONS: Empa has additive beneficial effects by preventing diabetic/hypertensive induced adverse cardiac remodeling, as well as impairment of kidney function. Our findings provide mechanistic insight into the protective effect of Empa on type 2 diabetes associated with risk for cardiovascular events.
- BR 08-1 HIGH SODIUM INTAKE REDUCTION IN DIABETES WITH HYPERTENSION. [Journal Article]
- J Hypertens 2016; 34 Suppl 1:e544JH
- Management of hypertension in diabetes is critical for reducing cardiovascular mortality and morbidity. Dietary approaches for controlling high blood pressure have historically focused on sodium. Thu...
Management of hypertension in diabetes is critical for reducing cardiovascular mortality and morbidity. Dietary approaches for controlling high blood pressure have historically focused on sodium. Thus, many guidelines recommend that patients with type 2 diabetes reduce high sodium intake. Nonetheless, the potential benefits of sodium reduction are debatable. The kidney has a crucial role in glucose filtration and reabsorption in addition to its regulation of fluid and electrolyte homeostasis. A key factor linking sodium uptake and glucose transport is the sodium-glucose cotransporter 2 (SGLT2) in renal proximal tubular cells. In hyperglycemic states, the renal proximal tubule raises its capacity to reabsorb glucose and sodium from the proximal tubule in response to hyperglycemia because of increased SGLT2 activity. Selective SGLT2 inhibitors improve glycemic control and slightly lower blood pressure in diabetic patients.In the past decade, activation of peroxisome proliferator-activated receptors (PPARs) has become a novel effective treatment for cardiometabolic diseases. The kidney differentially expresses all three PPAR subtypes, PPARα, PPARγ and PPARδ. Although PPARγ agonists are widely used to treat type 2 diabetes, sodium and water retention still poses a significant limitation to its clinical application. PPARδ is expressed ubiquitously, including in adipose tissues and the kidney. The activation of PPARδ alleviates dyslipidemia, hyperglycemia, and insulin resistance in rodents of obesity and diabetes. Importantly, PPARδ activation by its agonists exerts renal protective effects in diabetic mice. Furthermore, the PPARδ agonists increased adipose adiponectin expression, which are shown to exert multiple beneficial effects against cardiometabolic disorders. However, it is unknown whether PPARδ can regulate renal sodium handing and glucose transport. We hypothesized that PPARδ participates in sodium transport and glucose reabsorption in the kidney, resulting in improved sodium and glucose homeostasis. Here, we present ample evidence to reveal that adipose PPARδ activation promotes natriuresis and glycosuria in mice on high salt diet, which is associated with SGLT2 inhibition in the renal proximal tubule. Our evidence confirms that adipose PPARδ-mediated adiponectin plays a crucial role in the inhibition of renal SGLT2. We also revealed that under physiological circumstances, high sodium intake-induced natriuresis is impaired in diabetic mice because of increased SGLT2 activity. We further observe that type 2 diabetic patients with uncontrolled hyperglycemia have reduced natriuresis, and plasma adiponectin level is closely related to natriuresis in diabetic patients. Overall, the PPARδ-mediated adiponectin maintains equilibrium between urinary glucose transport and sodium reabsorption through regulation of SGLT2 in the kidney, however, this mechanism is impaired in diabetes.Diabetes and hypertension are often comorbid in patients. Both clinical trials and experimental studies imply that the excess sodium intake raises cardiometabolic risk. Type 2 diabetic patients are more susceptible to hypertension because of their increased exchangeable sodium and salt sensitivity compared with non-diabetic individuals. High sodium intake leads to insulin resistance and greater glomerular pressure, resulting in high blood pressure and albuminuria in type 2 diabetic patients. Our study shows that high sodium intake reduced body weight and fasting blood glucose level while it increased natriuresis in wild type mice. However, this effect was blunted in adipose-specific PPARδ knockout mice and also in diabetic db/db mice. Furthermore, we demonstrate that long-term high sodium intake specifically stimulates adipose PPARδ expression which is associated with elevating tissue sodium content in mice. These findings suggest that PPARδ participates in the regulation of sodium homeostasis. This effect is strikingly different from that of PPARγ agonists, thiazolidinediones that cause sodium and fluid retention.Adiponectin is a secreted protein in adipose tissue and its production is stimulated by PPARδ activation. Our study shows that high sodium intake also increased plasma adiponectin level, and its expression in both the perirenal fat and renal cortex. We also showed that adiponectin suppresses SGLT2 expression at the transcriptional level. Reducing sodium retention is a critical issue in the management of diabetic patients. Although diuretics are commonly used to reduce sodium retention, long-term diuretic treatment is associated with higher mortality in diabetic patients with hypertension. We show that renal SGLT2 dysfunction was found in diabetic db/db mice and inhibition of SGLT2 by dapagliflozin lowered natriuresis and glycosuria in these mice. Diabetic patients with uncontrolled hyperglycemia reduced natriuresis compared with well-treated patients. Furthermore, natriuresis was largely influenced by blood glucose level in diabetic patients. This finding suggests that well-controlled hyperglycemia may be more effective to alleviate sodium retention in diabetes regardless of their hypoglycemia drugs used. In addition, we reported before that telmisartan, an angiotensin II receptor blocker (ARB), reduced adipogenesis through activation of adipose PPARδ and improved insulin resistance through stimulation of PPARδ in skeletal muscle of mice (He et al., Hypertension, 2010; Li et al., Diabetes, 2013). ARB is also reported to increase plasma adiponectin level and inhibit renal SGLT2 expression in diabetic rats. Therefore, the potential benefit of ARB in the regulation of sodium and glucose homeostasis warrants further investigation.In summary, we reveal a previously unrecognized role of adipose PPARδ activation-induced natriuresis in mice. Our mechanistic study suggests that this renal benefit is associated with adiponectin-mediated inhibition of renal SGLT2. However, this pathway for maintaining appropriate sodium metabolism in response to high sodium intake is impaired in diabetes, and this defect might result in hyperglycemia-induced sodium retention. We also show that maintaining euglycemia status is a critical factor influencing natriuresis. Our findings provide insights into the physiological role of the PPARδ/adiponectin/SGLT2 pathway in the regulation of sodium and glucose homeostasis. Activation of PPARδ through promotion of adiponectin may represent a promising tool in the management of hypertensive diabetic patients who are exposed to high sodium intake.
- SY 10-3 SGLT2 INHIBITORS AS POTENTIAL ANTIHYPERTENSIVE AND RENOPROTECTIVE AGENTS. [Journal Article]
- J Hypertens 2016; 34 Suppl 1:e186JH
- Remarkable progress has been achieved in the field of diabetes with the development of incretin analogues, dipeptidyl peptidase IV inhibitors and novel insulin analogues; nevertheless, there is an un...
Remarkable progress has been achieved in the field of diabetes with the development of incretin analogues, dipeptidyl peptidase IV inhibitors and novel insulin analogues; nevertheless, there is an unmet need for additional therapeutic options. The new generation of drugs, denoted gliflozines, that specifically interfere with sodium-glucose cotransporters (SGLT)-2 and exhibit a favourable impact on glucose metabolism in patients with type 2 diabetes are emerging as hopeful avenues. The resultant negative energy balance caused by glucosuria results in long-term weight losses, significantly reduced HbA1c levels approximating 0.5-1.0% and may in addition exert beneficial effects on blood pressure, reactive oxygen products and inflammatory mediators. Studies indicate improvement in β-cell glucose sensitivity and insulin sensitivity in patients treated with gliflozines, a decrease in tissue glucose disposal and interestingly an increase in endogenous glucose production.Recent evidence link SGLT2 inhibition with reduction of cardiovascular events in type 2 diabetes (EMPA-REG OUTCOME study) and markers of kidney damage (that is micro- and macroalbuminuria). Notably the rate of side effects observed under SGLT2 inhibition was low and discerned by some trials, however markedly higher in earlier trials. Main questions towards the safety profile are still unanswered given that long-term clinical outcome data with SGLT2 inhibition are lacking and the cardiovascular safety profile is under scrutiny in large trials. Hemodynamic effects by SGLT2 inhibition are the most likely the reason for cardio- and renoprotective effects. Thus, selective SGLT2 inhibitors have a huge potential to meet patients' needs which will be covered in the lecture.
- SY 10-1 RENAL GLUCOSE HANDLING AND SGLT2. [Journal Article]
- J Hypertens 2016; 34 Suppl 1:e186JH
- The kidneys maintain glucose homeostasis through its utilization, gluconeogenesis, and reabsorption. Glucose is freely filtered and reabsorbed in order to retain energy essential between meals. The a...
The kidneys maintain glucose homeostasis through its utilization, gluconeogenesis, and reabsorption. Glucose is freely filtered and reabsorbed in order to retain energy essential between meals. The amount of glucose reabsorbed by the kidneys is equivalent to the amount entering the filtration system. With a daily glomerular filtration rate of 180 L, approximately 180 g (180 L/day × 100 mg/dL) of glucose must be reabsorbed each day to maintain an average fasting plasma glucose concentration of 5.6 mmol/L (100 mg/dL). The reabsorption increases with increase in plasma glucose concentration up to approximately 11 mmol/L (198 mg/dL). At this threshold level, the system becomes saturated and the maximal resabsorption rate-the glucose transport maximum (Tm G ) is reached. No more glucose can be absorbed, and the kidneys begin excreting it in the urine-the beginning of glycosuria. Reabsorption of glucose occurs mainly in the proximal tubule and is mediated by 2 different transport proteins, Sodium Glucose Cotransporter (SGLT)1 and SGLT2. SGLT1, which are found in the straight section of the proximal tubule (S3), are responsible for approximately 10% of glucose reabsorption. The other 90% of filtered glucose is reabsorbed through by SGLT2, which are located in the convoluted section on the proximal tubule (S1). The SGLT2 are located on the luminal side of the early proximal tubule S1 segment. Absorption of sodium across the cell membrane creates an energy gradient that in turn allows glucose to be absorbed. On the other side of the cell, sodium is reabsorbed through sodium-potassium ATPase pump into the bloodstream. The concentration gradient within the cell, resulting from this exchange drives glucose reabsorption into the bloodstream via the Glucose transporter (GLUT) 2. The role of kidneys in glucose regulation has been well recognized in the recent years, and inhibition of glucose reabsorption by SGLT2 inhibitors has evolved as a promising target for therapeutic intervention in diabetes mellitus and an added benefit in hypertension.(Figure is included in full-text article.).
- Renal effects of SGLT2 inhibition with a novel antisense oligonucleotide. [Journal Article]
- J Pharmacol Exp Ther 2016 Sep 7JP
- ISIS 388626 is an antisense SGLT2 inhibitor, designed to treat type 2 diabetes mellitus by induction of glycosuria. ISIS 388626 was demonstrated to be safe and effective in preclinical trails in seve...
ISIS 388626 is an antisense SGLT2 inhibitor, designed to treat type 2 diabetes mellitus by induction of glycosuria. ISIS 388626 was demonstrated to be safe and effective in preclinical trails in several species. We undertook the present study to evaluate the safety and efficacy of 13 weekly doses of 50, 100 and 200 mg ISIS 388626 in humans. ISIS 388626 increased 24 hour urinary glucose excretion dose-dependently with 508.9 ± 781.45 mg/day in the 100 mg and 1299.8 ± 1833.4 mg/day in the 200 mg cohort, versus 88.7 ± 259.29 mg/day in the placebo group. ISIS 388626 induced a reversible increase in serum creatinine, with the largest effect after 8 doses of ISIS 388626 (200 mg), (0.38 ± 0.089 mg/dL; 44% increase over baseline). Three subjects were discontinued due to creatinine increases. The renal clearance test revealed no indications for impairment of glomerular filtration or renal perfusion. The creatinine increases were accompanied by a rise in the levels of urinary renal damage markers (B2M, total protein, KIM1, aGST, NAG). Other treatment related AE's included mild ISRs, occurring in 8-19% of the subjects. In conclusion, ISIS 388626 treatment induced glucosuria at a dose level of 200 mg/week. This intended pharmacological effect was small, amounting approximately 1% of total amount of filtered glucose. Changes in serum and urinary markers were indicative of transient renal dysfunction, most likely of tubular origin. Whether the glycosuria is caused by specific SGLT2 inhibition or general tubular dysfunction or a combination remains uncertain.
- Sodium-glucose cotransporter 2 inhibition: cardioprotection by treating diabetes-a translational viewpoint explaining its potential salutary effects. [Review]
- Eur Heart J Cardiovasc Pharmacother 2016; 2(4):244-55EH
- Diabetes is a growing epidemic worldwide characterized by an elevated concentration of blood glucose, associated with a high incidence of cardiovascular disease and mortality. Although in general red...
Diabetes is a growing epidemic worldwide characterized by an elevated concentration of blood glucose, associated with a high incidence of cardiovascular disease and mortality. Although in general reduction of hyperglycaemia is considered a therapeutic goal, hypoglycaemic therapies do not necessarily reduce cardiovascular mortality and may even aggravate cardiovascular risk factors, such as body weight. A new class of antidiabetic drugs acts by inhibition of the sodium-glucose cotransporter 2 (SGLT2), which (partially) prevents reabsorption of glucose from the renal filtrate. The induction of glucose excretion via the urine (glycosuria) was turned into an effective strategy to reduce blood glucose. Ancillary advantages are the caloric and volumetric loss and thereby the reduction of body weight and blood pressure. Additionally, SGLT2 inhibition has been suggested to exert direct cardioprotective effects by the reduction of cardiac fibrosis, inflammation, and oxidative stress. This article summarizes the functional consequences of SGLT2 inhibition on the diabetic and hyperglycaemic organism. We especially focused on the effects on the kidney and the cardiovascular system as described in experimental studies. The interesting observations in experimental studies may extend to clinical medicine, as a recent trial reported a decrease in heart failure outcomes in patients at high cardiovascular risk. In conclusion, SGLT2 inhibition represents a novel treatment, which might be a promising target not only to (further) reduce blood glucose but also to target other cardiovascular risk factors. More research and long-term follow-ups will reveal the specific influence of SGLT2 inhibition on the circulatory system and cardiovascular outcomes.
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- Genitourinary infections in diabetic patients in the new era of diabetes therapy with sodium-glucose cotransporter-2 inhibitors. [Review]
- Nutr Metab Cardiovasc Dis 2016 Jul 12NM
- CONCLUSIONS: Diabetic patients are at high risk of UTIs and of GI. Only GI are associated with poor glycemic control. Although patients treated with SGLT-2 inhibitors have an increased 3-5 fold risk of GI, proper medical education can reduce this risk.