- Zinc supplementation alleviates hyperglycemia and associated metabolic abnormalities in streptozotocin-induced diabetic rats. [Journal Article]
- CJCan J Physiol Pharmacol 2016 Aug 7; :1-10
- The cause and effect relationship between diabetes and zinc is complex and unclear. This animal study has examined the potential of zinc supplementation in beneficial modulating hyperglycemia, insuli...
The cause and effect relationship between diabetes and zinc is complex and unclear. This animal study has examined the potential of zinc supplementation in beneficial modulating hyperglycemia, insulin secretion, and metabolic abnormalities associated with diabetes. The study was conducted in streptozotocin-induced diabetic rats. Groups of hyperglycemic rats were subjected to dietary interventions for 6 weeks with zinc supplementation (5 times and 10 times the normal level). Supplemental-zinc-fed diabetic groups showed significant control on hyperglycemia and hypoinsulinemia. There was a significant reduction in protein glycosylation, glucosuria, and urinary excretion of proteins and urea in diabetic animals maintained on a zinc-supplemented diet. Diabetic rats showed significantly higher plasma albumin and lower plasma urea and creatinine levels upon zinc supplementation. Significant alterations in insulin sensitivity indices HOMA-IR, HOMA-B, and QUICKI were also indicated by zinc supplementation. The pathological abnormalities in pancreatic islets of diabetic animals were significantly alleviated by dietary zinc intervention. This study provides the first evidence that zinc supplementation can partially ameliorate the severity of diabetic hyperglycemia and associated metabolic abnormalities, hypoinsulinemia, insulin resistance, and altered pancreatic morphology. Thus, zinc supplementation may offer a significant potential for clinical application in managing diabetic hyperglycemia and related metabolic complications.
- Genitourinary infections in diabetic patients in the new era of diabetes therapy with sodium-glucose cotransporter-2 inhibitors. [Review]
- NMNutr Metab Cardiovasc Dis 2016; 26(11):963-970
- 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.
- Osteomalacia induced by long-term low-dose adefovir dipivoxil: Clinical characteristics and genetic predictors. [Journal Article]
- BONEBone 2016; 93:97-103
- 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.
- BR 08-1 HIGH SODIUM INTAKE REDUCTION IN DIABETES WITH HYPERTENSION. [Journal Article]
- JHJ Hypertens 2016; 34 Suppl 1 - ISH 2016 Abstract Book:e544
- 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]
- JHJ Hypertens 2016; 34 Suppl 1 - ISH 2016 Abstract Book:e186
- 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]
- JHJ Hypertens 2016; 34 Suppl 1 - ISH 2016 Abstract Book:e186
- 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.).
- OS 05-04 EMPAGLIFLOZIN EXERTS CARDIO- AND NEPHRO-PROTECTIVE EFFECTS IN COHEN-ROSENTHAL DIABETIC HYPERTENSIVE RATS. [Journal Article]
- JHJ Hypertens 2016; 34 Suppl 1 - ISH 2016 Abstract Book:e58-e59
- 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.
- Prevalence of proteinuria in school children (aged 12-14 years) in Kashmir valley, India, using dipstick method. [Journal Article]
- SJSaudi J Kidney Dis Transpl 2016 Sep-Oct; 27(5):1006-1010
- Screening for kidney diseases by urinalysis in school children is being conducted in many parts of the world with inexpensive tools such as urinary dipsticks. We conducted this study to know the prev...
Screening for kidney diseases by urinalysis in school children is being conducted in many parts of the world with inexpensive tools such as urinary dipsticks. We conducted this study to know the prevalence of asymptomatic proteinuria in school children (age group 12-14 years) in Kashmir valley as no previous study is available. After applying exclusion criteria, 2068 children were screened for proteinuria by dipstick method. Another test was performed in the children with abnormal findings in the first sample with dipstick of the same brand, after a period of one-month. These children were also assessed by timed urine collection (i.e., 24 h urinary protein). In the first dipstick test, the prevalence of proteinuria in the studied population was 6.2% which persisted in 2.17% after second dipstick examination. No child in the studied group was found to have glycosuria. In our study, no statistically significant association was found between proteinuria and gender, body mass index, or hypertension. In our study, the prevalence of persistent proteinuria in school children (age group 12-14 years) in Kashmir valley was almost similar to the studies conducted in different parts of the world.
- Detection of 'Candidatus Neoehrlichia mikurensis' and other Anaplasmataceae and Rickettsiaceae in Canidae in Switzerland and Mediterranean countries. [Journal Article]
- SASchweiz Arch Tierheilkd 2016; 158(10):691-700
- 'Candidatus Neoehrlichia mikurensis' is an emerging tick-borne zoonotic agent that primarily affects immunocompromised human patients. Dogs and foxes are frequently exposed to ticks, and both species...
'Candidatus Neoehrlichia mikurensis' is an emerging tick-borne zoonotic agent that primarily affects immunocompromised human patients. Dogs and foxes are frequently exposed to ticks, and both species are in close proximity to humans. This is the first study to systematically investigate the occurrence of 'Candidatus Neoehrlichia mikurensis' in Canidae in Europa. We analyzed 1'739 blood samples from dogs in Switzerland, Italy, Spain and Portugal and 162 blood samples from free-ranging red foxes (Vulpes vulpes) in Switzerland. All samples were tested using a previously described multiplex real-time PCR for the Anaplasmataceae family, the 'Candidatus Neoehrlichia' genus and the 'Candidatus Neoehrlichia mikurensis' species. All Anaplasmataceae positive samples were subsequently tested using specific real-time PCRs for Anaplasma phagocytophilum, Anaplasma platys, Ehrlichia canis and Rickettsia helvetica. Among the tested animals, one dog from Zurich tested positive for 'Candidatus Neoehrlichia mikurensis'. The 12-year old West Highland white terrier had been splenectomized 3 months prior to the blood collection and presented with polyuria/polydipsia. Fanconi syndrome was diagnosed based on glucosuria with normoglycemia and hyperaminoaciduria. A. platys and E. canis were detected in 14/249 dogs from Sicily and Portugal; two of the dogs were coinfected with both agents. Four Swiss foxes tested positive for A. phagocytophilium. R. helvetica was detected for the first time in a red fox. In conclusion, 'Candidatus Neoehrlichia mikurensis' infection should be considered in sick dogs, particularly when immunocompromised. The pathogen seems not to be widespread in Canidae in the investigated countries. Conversely, other Anaplasmataceae were more readily detected in dogs and foxes.
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- TREATMENT OF DIABETES MELLITUS IN A GOLDEN LION TAMARIN (LEONTOPITHECUS ROSALIA) WITH THE GLUCAGON-LIKE PEPTIDE-1 MIMETIC EXENATIDE. [Journal Article]
- JZJ Zoo Wildl Med 2016; 47(3):903-906
- An 8-yr-old male golden lion tamarin ( Leontopithecus rosalia ) was diagnosed with diabetes mellitus based on hyperglycemia and persistent glycosuria. Initial treatment consisted of the oral antihype...
An 8-yr-old male golden lion tamarin ( Leontopithecus rosalia ) was diagnosed with diabetes mellitus based on hyperglycemia and persistent glycosuria. Initial treatment consisted of the oral antihyperglycemic medications glipizide and metformin that resulted in decreased blood glucose concentrations; however, marked glycosuria persisted. Insufficient improvement on oral antihyperglycemic therapy and poor feasibility of daily subcutaneous insulin therapy led to an investigation into an alternative therapy with extended-release exenatide, a glucagon-like peptide-1 (GLP-1) mimetic, at a dosage of 0.13 mg/kg subcutaneously once per month. Following treatment with exenatide, the persistent glycosuria resolved, the animal maintained normal blood glucose concentrations, and had lower serum fructosamine concentrations compared to pretreatment levels. Based on these findings, extended-release exenatide could be considered as a therapeutic option in nonhuman primates with diabetes mellitus that do not respond to oral antihyperglycemics and in which daily subcutaneous insulin is not feasible.