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- Analysis of the Effect of Canagliflozin on Renal Glucose Reabsorption and Progression of Hyperglycemia in Zucker Diabetic Fatty Rats. [JOURNAL ARTICLE]
- J Pharmacol Exp Ther 2014 Sep 12.
Sodium-glucose cotransporter 2 (SGLT2) plays a major role in renal glucose reabsorption. To analyze the potential of insulin-independent blood glucose control, the effects of the novel SGLT2 inhibitor canagliflozin on renal glucose absorption and the progression of hyperglycemia were analyzed in Zucker diabetic fatty (ZDF) rats. The transporter activity of recombinant human and rat SGLT2 was inhibited by canagliflozin, with 150-12,000-fold selectivity over other glucose transporters. Moreover, in vivo treatment with canagliflozin induced glucosuria in mice, rats, and dogs in a dose-dependent manner. It inhibited apparent glucose reabsorption by 55% in normoglycemic rats and by 94% in hyperglycemic rats. The inhibition of glucose reabsorption markedly reduced hyperglycemia in ZDF rats but did not induce hypoglycemia in normoglycemic animals. The change in urinary glucose excretion should not be used as a marker to predict the glycemic effects of this SGLT2 inhibitor. In ZDF rats, plasma glucose and HbA1c levels progressively increased with age, and pancreatic β-cell failure developed at 13 weeks of age. Treatment with canagliflozin for 8 weeks from the prediabetic stage suppressed the progression of hyperglycemia, prevented the decrease in plasma insulin levels, increased pancreatic insulin contents, and minimized the deterioration of islet structure. These results indicate that selective inhibition of SGLT2 with canagliflozin controls the progression of hyperglycemia by inhibiting renal glucose reabsorption in ZDF rats. In addition, the preservation of β-cell function suggests that canagliflozin treatment reduces glucose toxicity via an insulin-independent mechanism.
- Greater Dose-Ranging Effects on A1C Levels Than on Glucosuria With LX4211, a Dual Inhibitor of Sodium Glucose Transporters SGLT1 and SGLT2, in Type 2 Diabetes on Metformin Monotherapy. [JOURNAL ARTICLE]
- Diabetes Care 2014 Sep 11.
To assess the dose-ranging efficacy and safety of LX4211, a dual inhibitor of sodium glucose cotransporter 1 (SGLT1) and SGLT2, in type 2 diabetes.Type 2 diabetic patients inadequately controlled on metformin were randomly assigned to 75 mg once a day, 200 mg once daily, 200 mg twice daily, or 400 mg once daily of LX4211 or placebo. Primary end point was A1C change from baseline to week 12. Secondary end points included changes in blood pressure (BP) and body weight.Baseline characteristics in 299 patients randomly assigned to LX4211 or placebo in this 12-week dose-ranging study were similar: mean age 55.9 years, A1C 8.1% (65 mmol/mol), BMI 33.1 kg/m(2), and BP 124/79 mmHg. LX4211 significantly reduced A1C to week 12 in a dose-dependent manner by 0.42% (4.6 mmol/mol), 0.52% (5.7 mmol/mol), 0.80% (8.7 mmol/mol), and 0.92% (10.0 mmol/mol), respectively (P < 0.001 each), compared with 0.09% (1.0 mmol/mol) for placebo. Greater A1C reductions were produced by 400 mg once a day than 200 mg once a day LX4211 without higher urinary glucose excretion, suggesting a contribution of SGLT1 inhibition. Significant reductions were seen in body weight (-1.85 kg; P < 0.001) and systolic BP (-5.7 mmHg; P < 0.001), but diastolic BP was unchanged (-1.6; P = 0.164). Adverse events with LX4211 were mild to moderate and similar to placebo, including urinary tract infections and gastrointestinal-related events; genital infections were limited to LX4211 groups (0-5.0%). No hypoglycemia occurred.Dual inhibition of SGLT1/SGLT2 with LX4211 produced significant dose-ranging improvements in glucose control without dose-increasing glucosuria and was associated with reductions in weight and systolic BP in metformin-treated type 2 diabetes.
- A Novel Therapeutic Agent for Type 2 Diabetes Mellitus: SGLT2 Inhibitor. [Journal Article, Review]
- Diabetes Metab J 2014 Aug; 38(4):261-73.
Type 2 diabetes mellitus (T2DM) is a complex endocrine and metabolic disorder, and a major public health problem that is rapidly increasing in prevalence. Although a wide range of pharmacotherapies for glycemic control is now available, management of T2DM remains complex and challenging. The kidneys contribute immensely to glucose homeostasis by reabsorbing glucose from the glomerular filtrate. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a new class of antidiabetic agents that inhibit glucose absorption from the kidney independent of insulin, offer a unique opportunity to improve the outcomes of patients with T2DM. In this review, we provide an overview of two globally-approved SGLT2 inhibitors, dapagliflozin and canagliflozin, and discuss their effects and safety. This information will help clinicians to decide whether these drugs will benefit their patients.
- Diabetes Insipidus: Celebrating a Century of Vasopressin Therapy. [JOURNAL ARTICLE]
- Endocrinology 2014 Sep 11.:en20141385.
Diabetes mellitus, widely known to the ancients for polyuria and glycosuria, budded off diabetes insipidus (DI) about 200 years ago, based on the glucose-free polyuria that characterized a subset of patients. In the late 19th century, clinicians identified the posterior pituitary as the site of pathology, and pharmacologists found multiple bioactivities there. Early in the 20th century, the amelioration of the polyuria with extracts of the posterior pituitary inaugurated a new era in therapy and advanced the hypothesis that DI was due to a hormone deficiency. Decades later, a subset of patients with polyuria unresponsive to therapy were recognized, leading to the distinction between central DI and nephrogenic DI, an early example of a hormone-resistant condition. Recognition that the posterior pituitary had 2 hormones was followed by du Vigneaud's Nobel Prize winning isolation, sequencing, and chemical synthesis of oxytocin and vasopressin. The pure hormones accelerated the development of bioassays and immunoassays that confirmed the hormone deficiency in vasopressin-sensitive DI and abundant levels of hormone in patients with the nephrogenic disorder. With both forms of the disease, acquired and inborn defects were recognized. Emerging concepts of receptors and of genetic analysis led to the recognition of patients with mutations in the genes for 1) arginine vasopressin (AVP), 2) the AVP receptor 2 (AVPR2), and 3) the aquaporin 2 water channel (AQP2). We recount here the multiple skeins of clinical and laboratory research that intersected frequently over the centuries since the first recognition of DI.
- Osteomalacia complicating renal tubular acidosis in association with Sjogren's syndrome. [JOURNAL ARTICLE]
- Saudi J Kidney Dis Transpl 2014 September-October; 25(5):1072-1077.
Renal involvement in Sjogren's syndrome (SS) is not uncommon and may precede other complaints. Tubulointerstitial nephritis is the most common renal disease in SS and may lead to renal tubular acidosis (RTA), which in turn may cause osteomalacia. Nevertheless, osteomalacia rarely occurs as the first manifestation of a renal tubule disorder due to SS. We herewith describe a 43-year-old woman who was admitted to our hospital for weakness, lumbago and inability to walk. X-ray of the long bones showed extensive demineralization of the bones. Laboratory investigations revealed chronic kidney disease with serum creatinine of 2.3 mg/dL and creatinine clearance of 40 mL/min, hypokalemia (3.2 mmol/L), hypophosphatemia (0.4 mmol/L), hypocalcemia (2.14 mmol/L) and hyperchloremic metabolic acidosis (chlorine: 114 mmol/L; alkaline reserve: 14 mmol/L). The serum alkaline phosphatase levels were elevated. The serum levels of 25-hydroxyvitamin D and 1,25-dihydroxy vitamin D were low and borderline low, respectively, and the parathyroid hormone level was 70 pg/L. Urinalysis showed inappropriate alkaline urine (urinary PH: 7), glycosuria with normal blood glucose, phosphaturia and uricosuria. These values indicated the presence of both distal and proximal RTA. Our patient reported dryness of the mouth and eyes and Schirmer's test showed xerophthalmia. An accessory salivary gland biopsy showed changes corresponding to stage IV of Chisholm and Masson score. Kidney biopsy showed diffuse and severe tubulo-interstitial nephritis with dense lymphoplasmocyte infiltrates. Sicca syndrome and renal interstitial infiltrates indicated SS as the underlying cause of the RTA and osteomalacia. The patient received alkalinization, vitamin D (Sterogyl ®), calcium supplements and steroids in an initial dose of 1 mg/kg/day, tapered to 10 mg daily. The prognosis was favorable and the serum creatinine level was 1.7 mg/dL, calcium was 2.2 mmol/L and serum phosphate was 0.9 mmol/L.
- An alternative to the use of animals to teach diabetes mellitus. [Journal Article]
- Adv Physiol Educ 2014 Sep; 38(3):235-8.
We developed an alternative approach to teach diabetes mellitus in our practical classes, replacing laboratory animals. We used custom rats made of cloth, which have a ventral zipper that allows stuffing with glass marbles to reach different weights. Three mock rats per group were placed into metabolic cages with real food and water and with test tubes containing artificial urine, simulating a sample collection of 24 h. For each cage, we also provided other test tubes with artificial blood and urine, simulating different levels of hyperglycemia. The artificial "diabetic" urine contained different amounts of anhydrous glucose and acetone to simulate two different levels of glycosuria and ketonuria. The simulated urine of a nondiabetic rat was prepared without the addition of glucose or acetone. An Accu-Chek system is used to analyze glycemia, and glycosuria and ketonuria intensity were analyzed by means of a Urocolor bioassay. In the laboratory classroom, students were told that they would receive three rats to find out which one has type 1 or type 2 diabetes mellitus. To do so, they had to weigh the animals, quantify the water and food ingestion, and analyze the artificial blood and urine for glycemia, glycosuria, and ketonuria. Only at the end of class did we reveal that the urine and blood were artificial. Students were instructed to plot the data in a table, discuss the results within their group, and write an individual report. We have already used this practical class with 300 students, without a single student refusing to participate.
- Early effect of NTBC on renal tubular dysfunction in hereditary tyrosinemia type 1. [JOURNAL ARTICLE]
- Mol Genet Metab 2014 Aug 1.
Hereditary tyrosinemia type 1 (HT1) is characterized by severe progressive liver disease and renal tubular dysfunction. NTBC therapy has revolutionized the management of HT1 but its effect on renal tubular function has so far been poorly investigated. The aim of this study was to describe the early effect of NTBC on renal tubular disease in patients with HT1.Five HT1 patients (age between 5 and 53months) with different types of presentation were evaluated before and during the first 2weeks of therapy with NTBC in a retrospective case analysis for phosphate metabolism and renal tubular function.Before starting NTBC therapy, all children manifested signs of renal dysfunction which included hypophosphatemia, acidosis, reduced phosphate reabsorption, aminoaciduria, glycosuria (Fanconi syndrome), and variable degree of proteinuria. Some patients also presented increased urinary calcium/creatinine ratio and raised fractional excretion of sodium. Starting of NTBC therapy resulted in the rapid normalization of plasma phosphate within one week from its initiation in majority of patients and in all patients during the second week of therapy. TmP/GFR normalized in 48h, while the other markers of renal dysfunction showed an improving trend over 2weeks.NTBC is an efficient treatment for renal tubular dysfunction in HT1, allowing the return to normal function within a few weeks. Its early effect on renal tubular cells appeared to be very rapid, particularly in normalizing plasma phosphate and TmP/GFR. In our series of patients, the TmP/GFR resulted as the most reliable index of tubular function.
- Serum uric acid and disorders of glucose metabolism: the role of glycosuria. [JOURNAL ARTICLE]
- Braz J Med Biol Res 2014 Aug 22.:0.
Hyperuricemia has been associated with hypertension, diabetes mellitus, and metabolic syndrome. We studied the association between hyperuricemia and glycemic status in a nonrandomized sample of primary care patients. This was a cross-sectional study of adults ≥20 years old who were members of a community-based health care program. Hyperuricemia was defined as a value >7.0 mg/dL for men and >6.0 mg/dL for women. The sample comprised 720 participants including controls (n=257) and patients who were hypertensive and euglycemic (n=118), prediabetic (n=222), or diabetic (n=123). The mean age was 42.4±12.5 years, 45% were male, and 30% were white. The prevalence of hyperuricemia increased from controls (3.9%) to euglycemic hypertension (7.6%) and prediabetic state (14.0%), with values in prediabetic patients being statistically different from controls. Overall, diabetic patients had an 11.4% prevalence of hyperuricemia, which was also statistically different from controls. Of note, diabetic subjects with glycosuria, who represented 24% of the diabetic participants, had a null prevalence of hyperuricemia, and statistically higher values for fractional excretion of uric acid, Na excretion index, and prevalence of microalbuminuria than those without glycosuria. Participants who were prediabetic or diabetic but without glycosuria had a similarly elevated prevalence of hyperuricemia. In contrast, diabetic patients with glycosuria had a null prevalence of hyperuricemia and excreted more uric acid and Na than diabetic subjects without glycosuria. The findings can be explained by enhanced proximal tubule reabsorption early in the course of dysglycemia that decreases with the ensuing glycosuria at the late stage of the disorder.
- Lower urinary tract symptoms in women with diabetes mellitus: a current review. [Journal Article]
- Curr Urol Rep 2014 Oct; 15(10):440.
A literature review of the most current publications studying lower urinary tract symptoms (LUTS) and findings in diabetic women was conducted including articles from January 2013 to April 2014. Current reports consistently note that aging and obesity are significantly associated with worsened LUTS in diabetic women. Glucosuria has variable effects on urodynamic parameters and LUTS, but has a significant association with urinary tract infection (UTI) and incontinence at clinically relevant numbers, such as HbA1C values. The presence of severe nocturia in diabetic patients warrants careful surveillance for cardiovascular risks given the significant association with mortality. Diabetics appear to be at higher risk for colonization with the virulent, extended-spectrum, β-lactamase-producing Escherichia coli and Klebsiella species in UTI. Novel therapies in glycemic control and for diabetic bladder dysfunction are undergoing animal model trials with encouraging results. The most promising of these includes stem cell therapy, although a need exists for human studies.
- An uncommon presentation of Sjögren's syndrome and brucellosis. [JOURNAL ARTICLE]
- Transfus Apher Sci 2014 Jul 23.
We describe herein a case of hypokalemia due to proximal renal tubular acidosis (RTA) and Fanconi's syndrome (FS) and nephrogenic diabetes insipidus with DIC - a rare complication of Sjögren's syndrome (SS) and brucellosis. The interesting feature of this case was the presentation with severe hypokalemia, causing acute flaccid quadriparesis with cardiac arrest which is extremely rare. The patient was a 48-year-old woman who suffered cardiopulmonary arrest an hour after hospitalization. Analysis of a blood sample obtained before her cardiopulmonary arrest yielded surprising results: laboratory investigations showed profound hypokalemia (1.1 mEq/L) with renal K wasting, hyperchloremic metabolic acidosis with normal anion gap, hypophosphatemia with hypouricemia, glucosuria, and proteinuria. A diagnosis of RTA and FS were made. On the seventh day, she looked acutely ill, temperature 38.8 °C and pale, and her physical examination revealed purpuric skin lesions on both legs. The serum antibrucella titration agglutination test was found to be 1 of 160 positive with a nosocomial infection. The clinical and laboratory findings were consistent with disseminated intravascular coagulation (DIC). She was unable to concentrate her urine and so a diagnosis of nephrogenic diabetes insipidus (NDI) was reached. A thorough survey for the cause of FS, RTA and NDI revealed that she had xerophthalmia and xerostomia accompanied by high anti-Ro antibody, positive Schirmer test, confirming the diagnosis of SS.