Hypothalamic MC4R regulates glucose homeostasis through adrenaline-mediated control of glucose reabsorption via renal GLUT2 in mice.

AIMS/HYPOTHESIS: Melanocortin 4 receptor (MC4R) mutation is the most common cause of known monogenic obesity in humans. Unexpectedly, humans and rodents with MC4R deficiency do not develop hyperglycaemia despite chronic obesity and insulin resistance. To explain the underlying mechanisms for this phenotype, we determined the role of MC4R in glucose homeostasis in the presence and absence of obesity in mice. METHODS: We used global and hypothalamus-specific MC4R-deficient mice to investigate the brain regions that contribute to glucose homeostasis via MC4R. We performed oral, intraperitoneal and intravenous glucose tolerance tests in MC4R-deficient mice that were either obese or weight-matched to their littermate controls to define the role of MC4R in glucose regulation independently of changes in body weight. To identify the integrative pathways through which MC4R regulates glucose homeostasis, we measured renal and adrenal sympathetic nerve activity. We also evaluated glucose homeostasis in adrenaline (epinephrine)-deficient mice to investigate the role of adrenaline in mediating the effects of MC4R in glucose homeostasis. We employed a graded [13C6]glucose infusion procedure to quantify renal glucose reabsorption in MC4R-deficient mice. Finally, we measured the levels of renal glucose transporters in hypothalamus-specific MC4R-deficient mice and adrenaline-deficient mice using western blotting to ascertain the molecular mechanisms underlying MC4R control of glucose homeostasis. RESULTS: We found that obese and weight-matched MC4R-deficient mice exhibited improved glucose tolerance due to elevated glucosuria, not enhanced beta cell function. Moreover, MC4R deficiency selectively in the paraventricular nucleus of the hypothalamus (PVH) is responsible for reducing the renal threshold for glucose as measured by graded [13C6]glucose infusion technique. The MC4R deficiency suppressed renal sympathetic nerve activity by 50% in addition to decreasing circulating adrenaline and renal GLUT2 levels in mice, which contributed to the elevated glucosuria. We further report that adrenaline-deficient mice recapitulated the increased excretion of glucose in urine observed in the MC4R-deficient mice. Restoration of circulating adrenaline in both the MC4R- and adrenaline-deficient mice reversed their phenotype of improved glucose tolerance and elevated glucosuria, demonstrating the role of adrenaline in mediating the effects of MC4R on glucose reabsorption. CONCLUSIONS/INTERPRETATION: These findings define a previously unrecognised function of hypothalamic MC4R in glucose reabsorption mediated by adrenaline and renal GLUT2. Taken together, our findings indicate that elevated glucosuria due to low sympathetic tone explains why MC4R deficiency does not cause hyperglycaemia despite inducing obesity and insulin resistance. Graphical abstract.

A role for tubular Na+/H+ exchanger NHE3 in the natriuretic effect of the SGLT2 inhibitor empagliflozin.

Inhibitors of proximal tubular Na+-glucose cotransporter 2 (SGLT2) are natriuretic, and they lower blood pressure. There are reports that the activities of SGLT2 and Na+-H+ exchanger 3 (NHE3) are coordinated. If so, then part of the natriuretic response to an SGLT2 inhibitor is mediated by suppressing NHE3. To examine this further, we compared the effects of an SGLT2 inhibitor, empagliflozin, on urine composition and systolic blood pressure (SBP) in nondiabetic mice with tubule-specific NHE3 knockdown (NHE3-ko) and wild-type (WT) littermates. A single dose of empagliflozin, titrated to cause minimal glucosuria, increased urinary excretion of Na+ and bicarbonate and raised urine pH in WT mice but not in NHE3-ko mice. Chronic empagliflozin treatment tended to lower SBP despite higher renal renin mRNA expression and lowered the ratio of SBP to renin mRNA, indicating volume loss. This effect of empagliflozin depended on tubular NHE3. In diabetic Akita mice, chronic empagliflozin enhanced phosphorylation of NHE3 (S552/S605), changes previously linked to lesser NHE3-mediated reabsorption. Chronic empagliflozin also increased expression of genes involved with renal gluconeogenesis, bicarbonate regeneration, and ammonium formation. While this could reflect compensatory responses to acidification of proximal tubular cells resulting from reduced NHE3 activity, these effects were at least in part independent of tubular NHE3 and potentially indicated metabolic adaptations to urinary glucose loss. Moreover, empagliflozin increased luminal α-ketoglutarate, which may serve to stimulate compensatory distal NaCl reabsorption, while cogenerated and excreted ammonium balances urine losses of this "potential bicarbonate." The data implicate NHE3 as a determinant of the natriuretic effect of empagliflozin.

Acute canagliflozin treatment protects against in vivo myocardial ischemia-reperfusion injury in non-diabetic male rats and enhances endothelium-dependent vasorelaxation.

BACKGROUND: The sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin has been shown to reduce major cardiovascular events in type 2 diabetic patients, with a pronounced decrease in hospitalization for heart failure (HF) especially in those with HF at baseline. These might indicate a potent direct cardioprotective effect, which is currently incompletely understood. We sought to characterize the cardiovascular effects of acute canagliflozin treatment in healthy and infarcted rat hearts. METHODS: Non-diabetic male rats were subjected to sham operation or coronary artery occlusion for 30 min, followed by 120 min reperfusion in vivo. Vehicle or canagliflozin (3 µg/kg bodyweight) was administered as an intravenous bolus 5 min after the onset of ischemia. Rats underwent either infarct size determination with serum troponin-T measurement, or functional assessment using left ventricular (LV) pressure-volume analysis. Protein, mRNA expressions, and 4-hydroxynonenal (HNE) content of myocardial samples from sham-operated and infarcted rats were investigated. In vitro organ bath experiments with aortic rings from healthy rats were performed to characterize a possible effect of canagliflozin on vascular function. RESULTS: Acute treatment with canagliflozin significantly reduced myocardial infarct size compared to vehicle (42.5 ± 2.9% vs. 59.3 ± 4.2%, P = 0.006), as well as serum troponin-T levels. Canagliflozin therapy alleviated LV systolic and diastolic dysfunction following myocardial ischemia-reperfusion injury (IRI), and preserved LV mechanoenergetics. Western blot analysis revealed an increased phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and endothelial nitric-oxide synthase (eNOS), which were not disease-specific effects. Canagliflozin elevated the phosphorylation of Akt only in infarcted hearts. Furthermore, canagliflozin reduced the expression of apoptotic markers (Bax/Bcl-2 ratio) and that of genes related to myocardial nitro-oxidative stress. In addition, treated hearts showed significantly lower HNE positivity. Organ bath experiments with aortic rings revealed that preincubation with canagliflozin significantly enhanced endothelium-dependent vasodilation in vitro, which might explain the slight LV afterload reducing effect of canagliflozin in healthy rats in vivo. CONCLUSIONS: Acute intravenous administration of canagliflozin after the onset of ischemia protects against myocardial IRI. The medication enhances endothelium dependent vasodilation independently of antidiabetic action. These findings might further contribute to our understanding of the cardiovascular protective effects of canagliflozin reported in clinical trials.

Diuretic Effects of Sodium Glucose Cotransporter 2 Inhibitors and Their Influence on the Renin-Angiotensin System.

The renin-angiotensin system (RAS) plays an important role in regulating body fluids and blood pressure. However, inappropriate activation of the RAS contributes to the pathogenesis of cardiovascular and renal diseases. Recently, sodium glucose cotransporter 2 (SGLT2) inhibitors have been used as anti-diabetic agents. SGLT2 inhibitors induce glycosuria and improve hyperglycemia by inhibiting urinary reabsorption of glucose. However, in the early stages of treatment, these inhibitors frequently cause polyuria and natriuresis, which potentially activate the RAS. Nevertheless, the effects of SGLT2 inhibitors on RAS activity are not straightforward. Available data indicate that treatment with SGLT2 inhibitors transiently activates the systemic RAS in type 2 diabetic patients, but not the intrarenal RAS. In this review article, we summarize current evidence of the diuretic effects of SGLT2 inhibitors and their influence on RAS activity.

Reduced renal sympathetic nerve activity contributes to elevated glycosuria and improved glucose tolerance in hypothalamus-specific Pomc knockout mice.

OBJECTIVE: Hypothalamic arcuate nucleus-specific pro-opiomelanocortin deficient (ArcPomc-/-) mice exhibit improved glucose tolerance despite massive obesity and insulin resistance. We demonstrated previously that their improved glucose tolerance is due to elevated glycosuria. However, the underlying mechanisms that link glucose reabsorption in the kidney with ArcPomc remain unclear. Given the function of the hypothalamic melanocortin system in controlling sympathetic outflow, we hypothesized that reduced renal sympathetic nerve activity (RSNA) in ArcPomc-/- mice could explain their elevated glycosuria and consequent enhanced glucose tolerance. METHODS: We measured RSNA by multifiber recording directly from the nerves innervating the kidneys in ArcPomc-/- mice. To further validate the function of RSNA in glucose reabsorption, we denervated the kidneys of WT and diabetic db/db mice before measuring their glucose tolerance and urine glucose levels. Moreover, we performed western blot and immunohistochemistry to determine kidney GLUT2 and SGLT2 levels in either ArcPomc-/- mice or the renal-denervated mice. RESULTS: Consistent with our hypothesis, we found that basal RSNA was decreased in ArcPomc-/- mice relative to their wild type (WT) littermates. Remarkably, both WT and db/db mice exhibited elevated glycosuria and improved glucose tolerance after renal denervation. The elevated glycosuria in obese ArcPomc-/-, WT and db/db mice was due to reduced renal GLUT2 levels in the proximal tubules. Overall, we show that renal-denervated WT and diabetic mice recapitulate the phenotype of improved glucose tolerance and elevated glycosuria associated with reduced renal GLUT2 levels observed in obese ArcPomc-/- mice. CONCLUSION: Hence, we conclude that ArcPomc is essential in maintaining basal RSNA and that elevated glycosuria is a possible mechanism to explain improved glucose tolerance after renal denervation in drug resistant hypertensive patients.

Mathematical rationalization for the renal tubular transport: revised concepts.

The current emphasis on kinetics and in situ control of molecular exchanges, across the tubular membrane, has not been paralleled by corresponding improvements in our understanding of tubular behaviour at the macroscopic level of classical physiology. In this paper, we propose a mathematical rationalization of macroscopic tubular transport by means of a principal transport equation, originating from the law of mass action between substrate and carrier. The other equations, derived from the main one, demonstrate the possibility of distinguishing between transporters with low affinity and high capacity and transporters with high affinity and low capacity. Moreover, our model formalizes both tubular reabsorption and tubular secretion. Regarding the renal calcium handling, our model confirms the two-compartment system proposed by Mioni in 1971, with some important variants, which are in agreement with the fractional reabsorptions of this cation along the tubule, as verified by micro-puncture technique. To obtain the frequency distribution of saturated tubules, we have utilized the infinitesimal analysis method, starting from the equations proposed by Smith in 1943, concluding that all titration curves result from the combined effect of enzymatic approach and anatomical heterogeneity of the nephrons. The theoretical equations included in our manuscript reflect substantial and palpable physiological mechanisms able to suggest diagnosis and therapy of some electrolyte and hormonal disorders. At the end of this paper, we highlight advantages and disadvantages detectable by comparing our mathematical approach with Marshall's and Bijvoet's methods, proposed, respectively, in 1976 and 1984.

Bone marrow transplantation improves proximal tubule dysfunction in a mouse model of Dent disease.

Dent disease is a rare X-linked tubulopathy caused by mutations in the endosomal chloride-proton exchanger (ClC-5) resulting in defective receptor-mediated endocytosis and severe proximal tubule dysfunction. Bone marrow transplantation has recently been shown to preserve kidney function in cystinosis, a lysosomal storage disease causing proximal tubule dysfunction. Here we test the effects of bone marrow transplantation in Clcn5Y/- mice, a faithful model for Dent disease. Transplantation of wild-type bone marrow in Clcn5Y/- mice significantly improved proximal tubule dysfunction, with decreased low-molecular-weight proteinuria, glycosuria, calciuria, and polyuria four months after transplantation, compared to Clcn5Y/- mice transplanted with ClC-5 knockout bone marrow. Bone marrow-derived cells engrafted in the interstitium, surrounding proximal tubule cells, which showed a rescue of the apical expression of ClC-5 and megalin receptors. The improvement of proximal tubule dysfunction correlated with Clcn5 gene expression in kidneys of mice transplanted with wild-type bone marrow cells. Coculture of Clcn5Y/- proximal tubule cells with bone marrow-derived cells confirmed rescue of ClC-5 and megalin, resulting in improved endocytosis. Nanotubular extensions between the engrafted bone marrow-derived cells and proximal tubule cells were observed in vivo and in vitro. No rescue was found when the formation of the tunneling nanotubes was prevented by actin depolymerization or when cells were physically separated by transwell inserts. Thus, bone marrow transplantation may rescue the epithelial phenotype due to an inherited endosomal defect. Direct contacts between bone marrow-derived cells and diseased tubular cells play a key role in the rescue mechanism.

Hyperosmolar hyperglycemic state: a historic review of the clinical presentation, diagnosis, and treatment.

The hyperosmolar hyperglycemic state (HHS) is the most serious acute hyperglycemic emergency in patients with type 2 diabetes. von Frerichs and Dreschfeld described the first cases of HHS in the 1880s in patients with an "unusual diabetic coma" characterized by severe hyperglycemia and glycosuria in the absence of Kussmaul breathing, with a fruity breath odor or positive acetone test in the urine. Current diagnostic HHS criteria include a plasma glucose level >600 mg/dL and increased effective plasma osmolality >320 mOsm/kg in the absence of ketoacidosis. The incidence of HHS is estimated to be <1% of hospital admissions of patients with diabetes. The reported mortality is between 10 and 20%, which is about 10 times higher than the mortality rate in patients with diabetic ketoacidosis (DKA). Despite the severity of this condition, no prospective, randomized studies have determined best treatment strategies in patients with HHS, and its management has largely been extrapolated from studies of patients with DKA. There are many unresolved questions that need to be addressed in prospective clinical trials regarding the pathogenesis and treatment of pediatric and adult patients with HHS.

Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks' treatment with empagliflozin once daily in patients with type 2 diabetes.

AIM: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of empagliflozin in patients with type 2 diabetes following oral administration of 10, 25 or 100 mg doses once daily over 28 days. METHODS: A total of 78 patients were assigned to empagliflozin 10 mg (n = 16), 25 mg (n = 16) or 100 mg (n = 30) or placebo (n = 16) for 28 days. Assessments included adverse events (AEs) and pharmacokinetic and pharmacodynamic endpoints. RESULTS: Empagliflozin exposure increased dose-proportionally over the dose range 10-100 mg and showed linear pharmacokinetics with respect to time. Urinary glucose excretion (UGE) increased from baseline to day 1 by 74, 90 and 81 g with empagliflozin 10, 25 and 100 mg, respectively. The increases in UGE were maintained over 28 days with multiple dosing. Virtually no change in UGE was observed in the placebo group. Significant reductions from baseline in mean daily plasma glucose and fasting plasma glucose were observed with empagliflozin compared with placebo. The incidence of AEs was similar in the empagliflozin and placebo groups (50.0, 56.3 and 66.7% with empagliflozin rising doses and 62.5% with placebo). The most frequently reported AEs were pollakiuria (10.3%), nasopharyngitis (9.0%), constipation (9.0%) and headache (7.7%). CONCLUSIONS: Oral administration of empagliflozin at doses of 10, 25 or 100 mg once daily over 28 days resulted in significant increases in UGE and reductions in blood glucose compared with placebo, and were well tolerated in patients with type 2 diabetes.

Diabetes mellitus: formas de presentación clínica y diagnóstico diferencial de la hiperglucemia en la infancia y adolescencia / Diabetes mellitus: clinical presentation and differential diagnosis of hyperglycemia in childhood and adolescence

La diabetes mellitus es una de las enfermedades crónicas más frecuentes en la infancia. Constituye un conjunto de enfermedades clínica y etiopatogénicamente heterogéneo, aunque más del 95% de los casos en nuestro entorno corresponden a diabetes tipo 1 autoinmune. Los avances ocurridos durante los últimos años han permitido la adscripción de un número cada vez mayor de pacientes a subtipos distintos. En esos casos, el diagnóstico correcto se ve facilitado por el hecho de que muchas de estas causas raras de diabetes se asocian con síndromes clínicos específicos o se manifiestan a una edad determinada. Muchas de ellas son, además, subsidiarias de diagnóstico molecular. El objetivo de esta revisión es poner al día los conocimientos actuales en este campo con objeto de facilitar la consecución de un diagnóstico preciso y entender las implicaciones del mismo sobre el tratamiento y el pronóstico de dichos pacientes(AU)

Diabetes mellitus is one of the most common chronic diseases in childhood. Despite being a clinical and etiopathogenically heterogeneous disorder, type 1 autoimmune diabetes accounts for more than 95% of cases in children. Recent advances have meant that a growing number of patients have been assigned to other subtypes of diabetes. In such cases, the correct diagnosis is facilitated by the fact that many of these rare causes of diabetes are associated with specific clinical syndromes or may present at a certain age. Many of them are also subsidiaries of molecular diagnosis. The aim of this review is to update the current knowledge in this field of pediatric diabetes, in an attempt to determine the most accurate diagnosis and its implications on appropriate treatment and prognosis(AU)

[Glycosuria with SGLT-2 inhibitors--a new treatment approach for type 2 diabetes mellitus]. / Glukosurie mittels SGLT-2-Inhibitoren. Ein neuesTherapieprinzip bei Diabetes mellitusTyp 2.

BACKGROUND: A new mechanism of action in the form of sodium-glucose co-transporter-(SGLT-)2 inhibitors will be available shortly for the treatment of type 2 diabetic patients. METHOD: Overview. RESULTS AND CONCLUSIONS: Fasting and postprandial blood glucose and HbA(1c) concentrations are indirectly reduced by the inhibition of glucose reabsorption and increased glycosuria. SGLT-2 inhibitors also have a positive impact on body weight and blood pressure of type 2 diabetics. In the available registration trials conducted to date, the SGLT-2 inhibitors appeared overall as a safe class of drugs. The clinical importance of an increased incidence of genital infections--in particular in special patientpopulations--requires further clarification. Long-term trials are currently underway to verify safety and in particular cardiovascular effects of this drug class.

Short communication: effect of temporary glycosuria on molasses consumption in Holstein calves.

This study was conducted to determine the effect of experimentally increased glucose demand on voluntary consumption of molasses by dairy calves. Three-week-old calves received 0.365 g of phlorizin by s.c. injection. Urinary output and molasses consumption were measured hourly, and urinary glucose concentration was screened. Molasses consumption for the 24 h after treatment was (mean +/- SE) 72.0 g (+/-7) for the control group and 142 g (+/-1) for the phlorizin-treated group. Urinary output for the 8-h test period was 1.13 kg for the control group and 1.67 kg for the phlorizin-treated calves. Mean urinary glucose peaked at 10 g/L by 4 h after treatment for calves given phlorizin, whereas the concentration for the control group remained close to 0 g/L. Phlorizin treatment increased voluntary consumption of molasses in 3-wk-old Holstein calves.

Renal phenotype in Lowe Syndrome: a selective proximal tubular dysfunction.

BACKGROUND AND OBJECTIVES: Lowe syndrome is defined by congenital cataracts, mental retardation, and proximal tubulopathy and is due to mutations in OCRL. Recently, mutations in OCRL were found to underlie some patients with Dent disease, characterized by low molecular weight proteinuria, hypercalciuria, and nephrocalcinosis. This phenotypic heterogeneity is poorly understood. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The renal phenotype of 16 patients with Lowe syndrome (10.9 +/- 7.0 yr) under care of the authors was characterized to define overlap of symptoms with Dent disease and infer clues about OCRL function. Medical charts of patients were reviewed for data regarding glomerular filtration rate and markers of proximal tubular function. RESULTS: All patients had low molecular weight proteinuria and albuminuria. Lysosomal enzymuria was elevated in all 11 patients assessed. Fifteen patients had hypercalciuria, and 14 aminoaciduria. Seven patients required bicarbonate and three required phosphate replacement; all others maintained normal serum values without supplementation. None of the patients had detectable glycosuria, and none had clinically overt rickets. GFR was mildly to moderately impaired and highly variable, with a trend of deterioration with age. CONCLUSIONS: Patients with Lowe syndrome do not have renal Fanconi syndrome but a selective proximal tubulopathy, variable in extent and dominated by low molecular weight proteinuria and hypercalciuria, the classical features of Dent disease. These findings suggest that OCRL and ClC-5, the chloride channel mutated in Dent disease, are involved in similar reabsorption pathways in the proximal tubule.

Renal hyaluronan content during experimental uncontrolled diabetes in rats.

With diabetes mellitus, the ability of the kidneys to maintain fluid balance is affected. Hyperglycaemia increases production of hyaluronan in cultured kidney cells implying that diabetes promotes induction of hyaluronan in the kidney. The aim of the present study was to determine if the interstitial matrix component hyaluronan is differently distributed within the kidney in diabetic rats compared to non-diabetic rats. Furthermore, to test if diabetic rats are able to respond with diuresis upon a hypotonic fluid load. The normal heterogeneous intrarenal distribution of hyaluronan was confirmed in non-diabetic control rats, with 60-fold more in the papilla than in the cortex. In diabetic animals, the cortical hyaluronan was unaffected but the papillary hyaluronan content was 3-fold higher than in non-diabetic rats. This increase correlated with a more than three-fold induction of the papillary hyaluronan-synthase 2 mRNA expression. In non-diabetic animals, 2 h water loading increased papillary hyaluronan (+93%) and diuresis (17-fold). In diabetic animals, baseline diuresis was 8-fold higher than in non-diabetic animals, which correlated with hyperglycaemia, glucosuria and proteinuria. Water loading in diabetic animals did not further increase papillary hyaluronan or diuresis: the urine flow rate decreased. To conclude, papillary hyaluronan is elevated in diabetic rats, which coincides with induction of hyaluronan-synthase 2 mRNA, hyperglycaemia, glucosuria, proteinuria and overt diuresis. The inability to respond to a water load with further diuresis may be related to the already elevated papillary hyaluronan and the inability to change hyaluronan during water loading.

[Evaluation of the 7-day immersion effect on the renal excretory function].

In an experiment with 7-d immersion of 8 male test-subjects (21-26 y.o.) we investigated excretion with urine of total protein, creatinine, urea, uric acid, glucose, K, Na, Ca, P, Mg, 12 groups of proteins and 5 enzymes. Results of the investigation bring to the conclusion that 7-d immersion does not impact the kidney functioning. Analysis of uroproteinogram failed to detect shifts in glomerular filtration or tubular reabsorption which correlates with the absence of significant changes in uroenzymogram. Even profuse diuresis was unable to provoke abnormally high protein and glucose excretion, whereas electrolyte excretion normalized fairly soon. Increased excretion of creatinine, urea, Ca, Mg and P appears to reflect activation of catabolism in skeletal muscles.

Glucose intolerance during hormonal therapy for prostate cancer.

The aim of this study was to examine the influence of hormonal therapy (HT) on glucose metabolism in prostate cancer (PCa) patients. Fifty-two PCa patients receiving HT with gonadotropin-releasing hormone (GnRH) analogues and/or antiandrogen drugs were enrolled in this study. Both blood and urine samples were taken a few hours after breakfast before and after HT, and glucose levels in the blood and urine were measured. Elevations of blood glucose levels of 30-50, 50-100 and over 100 mg/dl after HT as compared with the levels before HT were observed in two, eight and five patients, respectively. Urine examination revealed deterioration of glucosuria in seven patients. The mean blood glucose level after HT was significantly higher than that measured before HT. The elevation of blood glucose level significantly correlated with concurrence of diabetes mellitus (DM) and higher body mass index (BMI) before HT. Deterioration of glucosuria significantly correlated with the concurrence of DM. HT for PCa patients, especially with concurrent DM or obesity, induces elevation of the blood glucose level and deterioration of glucosuria. Therefore, glucose intolerance should be considered during HT for PCa.

Glucocorticoid-induced diabetes mellitus: prevalence and risk factors in primary renal diseases.

BACKGROUND/AIMS: In patients with primary renal diseases the current knowledge of hyperglycemia associated with corticosteroid therapy is limited. We therefore examined the prevalence and risk factors of glucocorticoid-induced diabetes mellitus (DM) in primary renal diseases. METHODS: Patients were recruited with primary renal diseases who were started on corticosteroids between April 2002 and June 2005. In patients with DM, an impaired fasting glucose level and/or positive urinary glucose analyses before corticosteroids therapy were excluded. RESULTS: During corticosteroid therapy (initial dose: prednisolone 0.75 +/- 0.10 mg/kg/day), DM was newly diagnosed in 17 (40.5%) of 42 patients. All of the 17 patients were diagnosed as having DM by postprandial hyperglycemia at 2 h after lunch, although they had normal fasting blood glucose levels. Age (OR 1.40, 95% CI 1.06-1.84) and body mass index (OR 1.87, 95% CI 1.03-3.38) were determined as independent risk factors for glucocorticoid-induced DM. CONCLUSION: Over 40% of patients with primary renal disease developed DM during treatment with corticosteroids. A high age and high body mass index are the independent risk factors for glucocorticoid-induced DM. 24-hour urinary glucose analyses and postprandial plasma glucose are useful for detecting glucocorticoid-induced DM.

Potential causes of weight gain in type 1 diabetes mellitus.

AIM: To investigate the potential causes of weight gain with insulin therapy and improved diabetic control in type 1 diabetes mellitus. METHODS: This was an open-label prospective study of insulin therapy of 6 months duration in an academic medical centre. Twenty-one subjects with type 1 diabetes were enrolled. The goal was to achieve an haemoglobin A1c (HbA1c) in the range of individuals without diabetes (<5.6%). At baseline, 3 and 6 months, weight, resting energy expenditure, appetite assessment, food intake, activity level, HbA1c and 24-h glycosuria and urea nitrogen were measured. Plasma leptin, ghrelin and adiponectin levels and body fat were measured at baseline and 6 months. RESULTS: At baseline, average weight was 73.7 +/- 17.4 kg and HbA1c was 10.0 +/- 2.2%. Weight increased by 2.15 kg (2.69% of baseline) by 6 months whereas the HbA1c dropped by 1.71% (16.3%) to 7.9%. Energy intake differences between 3 and 6 months had a negative correlation with weight gain, but the changes in glycosuria, appetite scores and the frequency of hypoglycaemia did not correlate with weight gain. Glycaemic control did not correlate with weight change but tended to correlate with fat mass increase (p = 0.064; r = -0.51). An increase in the activity levels between 3 and 6 months correlated with decreasing fat mass (p = 0.037; r = -0.74). The changes in the appetite scores had a negative correlation with fat mass gain (p = 0.035; r = -0.61). The changes in lean body mass correlated with protein and total energy intake (p = 0.007, r = 0.85 and p = 0.003, r = 0.73 respectively). The changes in leptin levels correlated with weight gain. CONCLUSIONS: The lipogenic effect of insulin with subsequent increase in fat mass may be the primary cause of this weight gain that can be attenuated by the increases in the activity levels. The negative correlation of energy intake and appetite scores with fat mass gain suggests that they do not play a significant role in fat mass gain whereas energy intake did correlate with lean body mass gain.

Kidney toxicity of ingested uranium from drinking water.

BACKGROUND: In experimental settings, uranium is toxic to kidneys, but effects on humans are unclear. Ingestion of water from drilled wells is a source of high uranium exposure in some populations. METHODS: Uranium exposure was measured in 95 men and 98 women aged 18 to 81 years who had used drinking water from drilled wells for an average of 16 years. Urinary N-acetyl-gamma-d-glucosaminidase, alkaline phosphatase, lactate dehydrogenase, gamma-glutamyltransferase, and glutathione-S-transferase; serum cystatin C; and urinary and serum calcium, phosphate, glucose, and creatinine were measured to evaluate possible toxic effects of uranium on kidney cells and renal function. In addition, supine blood pressure was measured. Associations between uranium exposure and the outcome variables were modeled by using linear regression with adjustment for age, sex, body mass index, smoking, and analgesic use. RESULTS: Median uranium concentration in drinking water was 25 microg/L (interquartile range, 5 to 148 microg/L; maximum, 1,500 microg/L). Indicators of cytotoxicity and kidney function did not show evidence of renal damage. No statistically significant associations with uranium in urine, water, hair, or toenails was found for 10 kidney toxicity indicators. Uranium exposure was associated with greater diastolic and systolic blood pressures, and cumulative uranium intake was associated with increased glucose excretion in urine. CONCLUSION: Continuous uranium intake from drinking water, even at relatively high exposures, was not found to have cytotoxic effects on kidneys in humans.