Osmoregulation in children with cystic fibrosis.

Hyponatremia is not rare in cystic fibrosis and might be due to several mechanisms. An endocrine and renal imbalance in water and salt homeostasis was suggested. To address this hypothesis, we assessed the urinary concentrating and diluting ability in 12 cystic fibrosis patients (6 females, 6 males) and in two control groups: 14 children with pneumonia (9 females, 5 males) and in 13 healthy children (9 females, 4 males). Renal concentrating ability was evaluated following overnight water deprivation. Urine osmolality was not significantly different between groups. Renal diluting ability was assessed by means of a water-load test. This provoked a decrease in urine osmolality, as well as an increase in diuresis and solute-free water excretion. These changes were comparable among groups.Conclusion: Children with cystic fibrosis show a preserved renal concentrating and diluting capacity. A generalized endocrine and renal imbalance in water and salt homeostasis therefore appears unlikely.What is Known:•Hyponatremia sometimes occurs in cystic fibrosis.What is New:•Osmoregulation is normal in cystic fibrosis.

A high-fat, high-saturated fat diet decreases insulin sensitivity without changing intra-abdominal fat in weight-stable overweight and obese adults.

PURPOSE: We sought to determine the effects of dietary fat on insulin sensitivity and whether changes in insulin sensitivity were explained by changes in abdominal fat distribution or very low-density lipoprotein (VLDL) fatty acid composition. METHODS: Overweight/obese adults with normal glucose tolerance consumed a control diet (35 % fat/12 % saturated fat/47 % carbohydrate) for 10 days, followed by a 4-week low-fat diet (LFD, n = 10: 20 % fat/8 % saturated fat/62 % carbohydrate) or high-fat diet (HFD, n = 10: 55 % fat/25 % saturated fat/27 % carbohydrate). All foods and their eucaloric energy content were provided. Insulin sensitivity was measured by labeled hyperinsulinemic-euglycemic clamps, abdominal fat distribution by MRI, and fasting VLDL fatty acids by gas chromatography. RESULTS: The rate of glucose disposal (Rd) during low- and high-dose insulin decreased on the HFD but remained unchanged on the LFD (Rd-low: LFD: 0.12 ± 0.11 vs. HFD: -0.37 ± 0.15 mmol/min, mean ± SE, p < 0.01; Rd-high: LFD: 0.11 ± 0.37 vs. HFD: -0.71 ± 0.26 mmol/min, p = 0.08). Hepatic insulin sensitivity did not change. Changes in subcutaneous fat were positively associated with changes in insulin sensitivity on the LFD (r = 0.78, p < 0.01) with a trend on the HFD (r = 0.60, p = 0.07), whereas there was no association with intra-abdominal fat. The LFD led to an increase in VLDL palmitic (16:0), stearic (18:0), and palmitoleic (16:1n7c) acids, while no changes were observed on the HFD. Changes in VLDL n-6 docosapentaenoic acid (22:5n6) were strongly associated with changes in insulin sensitivity on both diets (LFD: r = -0.77; p < 0.01; HFD: r = -0.71; p = 0.02). CONCLUSIONS: A diet very high in fat and saturated fat adversely affects insulin sensitivity and thereby might contribute to the development of type 2 diabetes. CLINICALTRIALS. GOV IDENTIFIER: NCT00930371.

Effects of dietary fat and saturated fat content on liver fat and markers of oxidative stress in overweight/obese men and women under weight-stable conditions.

Dietary fat and oxidative stress are hypothesized to contribute to non-alcoholic fatty liver disease and progression to steatohepatitis. To determine the effects of dietary fat content on hepatic triglyceride, body fat distribution and markers of inflammation and oxidative stress, overweight/obese subjects with normal glucose tolerance consumed a control diet (CONT: 35% fat/12% saturated fat/47% carbohydrate) for ten days, followed by four weeks on a low fat (LFD (n = 10): 20% fat/8% saturated fat/62% carbohydrate) or high fat diet (HFD (n = 10): 55% fat/25% saturated fat/27% carbohydrate). Hepatic triglyceride content was quantified by MRS and abdominal fat distribution by MRI. Fasting biomarkers of inflammation (plasma hsCRP, IL-6, IL-12, TNFα, IFN-γ) and oxidative stress (urinary F2-α isoprostanes) were measured. Body weight remained stable. Compared to the CONT, hepatic triglyceride decreased on the LFD (mean (95% CI): change -2.13% (-3.74%, -0.52%)), but did not change on the HFD and there was no significant difference between the LFD and HFD. Intra-abdominal fat did not change significantly on either diet, but subcutaneous abdominal fat increased on the HFD. There were no significant changes in fasting metabolic markers, inflammatory markers and urinary F2-α isoprostanes. We conclude that in otherwise healthy overweight/obese adults under weight-neutral conditions, a diet low in fat and saturated fat has modest effects to decrease liver fat and may be beneficial. On the other hand, a diet very high in fat and saturated fat had no effect on hepatic triglyceride or markers of metabolism, inflammation and oxidative stress.

Vasotocin analogues with selective natriuretic, kaliuretic and antidiuretic effects in rats.

The aim of the present study was an investigation of mechanisms mediating selective effect of vasotocin analogues on water, sodium, and potassium excretion. We tested vasotocin analogues: Mpa(1)-vasotocin (dAVT), Mpa(1)-Arg(4)-vasotocin (dAAVT) and Mpa(1)-DArg(8)-vasotocin (dDAVT). The effects on water, sodium, and potassium transport were evaluated in experiments using normal and water-loaded Wistar rats. It was shown that all tested peptides exerted antidiuretic activity. Vasotocin and dAVT induced natriuresis and kaliuresis in rats. V1a agonist (Phe(2)-Ile(3)-Orn(8)-vasopressin) reproduced the renal effects of dAVT on sodium and potassium excretion but not on water reabsorption. dAAVT, dDAVT and V2 agonist (desmopressin) induced kaliuresis without any effect on sodium excretion. Natriuresis was associated with increase in cGMP excretion, whereas kaliuresis was correlated with rise of cAMP excretion. V1a antagonist (Pmp(1)-Tyr(Me)(2)-vasopressin) significantly reduced the dAVT-stimulated natriuresis and did not influence on urinary potassium excretion. V2 antagonist (Pmp(1)-DIle(2)-Ile(4)-vasopressin) significantly reduced the dAVT- and dAAVT-induced kaliuresis. It is assumed that effects of the nonapeptides on sodium and potassium transport are independent of their antidiuretic activity and mediated by different subtypes of V receptors (the V1a or V1a-like receptor for natriuretic effect and V2 or V2-like one for kaliuretic). In accordance to the data obtained, there is a possibility of selective regulation of renal water reabsorption and urinary sodium and potassium excretion with involvement of neurohypophysial hormones.

Physiological mechanisms for the increase in renal solute-free water clearance by a glucagon-like peptide-1 mimetic.

The aim of the present study was to clarify the mechanisms mediating the effect of a glucagon-like peptide-1 (GLP-1) mimetic on solute-free water excretion in rats. The GLP-1 mimetic exenatide (0.05-5.0 nmol/kg, i.m.), alone and in combination with either a vasopressin V2 receptor antagonist (15 nmol/kg, i.p.) or vasopressin (0.01 nmol/kg, i.m.), was injected into control and water-loaded (water 10-50 mL/kg, p.o., or 50 mL/kg of 0.6% NaCl, i.p.) rats to evaluate the role of collecting duct water permeability in the hydrouretic effect. Urinary prostaglandin (PG) E2 excretion and the effects of diclofenac (5 mg/kg, i.m.) and GLP-1 receptor antagonist (0.15 µmol/kg, i.p.) on exenatide action were assessed. The hydrouretic effect of exenatide was equivalent following oral or intraperitoneal water loading, and was proportional to the volume of water administered. Injection of exenatide, under conditions of a maximal decrease in collecting duct water permeability (V2 receptor antagonist administration in water-loaded rats), additionally stimulated solute-free water formation. The GLP-1 receptor antagonist weakened the hydrouretic action of exenatide. Urinary PGE2 excretion increased following water loading (47 ± 6 vs 24 ± 4 ng/kg over a 30 min period) and was enhanced as a result of additional exenatide injection (69 ± 10 ng/kg). Diclofenac and vasopressin delayed the hydrouretic effect of exenatide. The effect of exenatide on solute-free water clearance in water-loaded rats is presumably mediated by stimulation of PGE2 secretion and reinforcement of tubular fluid influx from the proximal tubule to the distal segment of the nephron and collecting duct.

Synthesis of new vasotocin analogues: effects on renal water and ion excretion in rats.

Vasopressin and nonmammalian hormone vasotocin are known to increase the water permeability of mammalian collecting ducts, frog skin and the urinary bladder. Neurohypophysial nonapeptides have also been shown to interfere with the regulation of renal ion transport. The subject of this study was a search for vasopressin and vasotocin analogues with selective effects on renal water, sodium and potassium excretion. During this study, we synthesised the following peptides: 13 vasotocin analogues modified at positions 4 (Thr or Arg), 7 (Gly or Leu) and 8 (D-Arg, Lys or Glu); 4 vasopressin analogues modified at positions 4 and 8; and 9 peptides shortened or extended at the C-terminal or with substitutions for Gly-NH2. Most of these peptides had mercaptopropionic acid (Mpa) instead of Cys in position 1. The effects of these nonapeptides on renal water, sodium and potassium transport were evaluated in in vivo experiments using Wistar rats. Some nonapeptides possessed antidiuretic, natriuretic and kaliuretic activities ([Mpa(1)]-arginine vasotocin, [Mpa(1), homoArg(8)]-vasotocin, [Mpa(1), Thr(4)]-arginine vasotocin and [Mpa(1), Arg(4)]-arginine vasopressin). Substitutions at positions 4 and 8 increased the selectivity of peptide actions. The antidiuretic [D-Arg(8)]-vasotocin analogues had no effects on sodium excretion. [Mpa(1), Arg(4)]-arginine vasotocin was antidiuretic and kaliuretic but not natriuretic. [Mpa(1), Glu(8)]-oxytocin had weak natriuretic activity without any effects on water and potassium transport. In accordance with the data obtained, synthesised vasotocin analogues could be good candidates for pharmaceuticals selectively regulating renal sodium and potassium transport, which is of clinical importance.

Colesevelam improves oral but not intravenous glucose tolerance by a mechanism independent of insulin sensitivity and ß-cell function.

OBJECTIVE: To determine the mechanism by which the bile acid sequestrant colesevelam improves glycemic control. RESEARCH DESIGN AND METHODS: We performed a frequently sampled intravenous glucose tolerance test (FSIGT) with minimal model analysis and a meal tolerance test (MTT) in 20 subjects with impaired fasting glucose (11 men, 9 women; mean age 60.7 ± 1.9 years, BMI 29.4 ± 0.9 kg/m(2)) in a single-blind study after 2 weeks of placebo treatment and 8 weeks of colesevelam 3.75 g daily. From these tests, insulin sensitivity, ß-cell function, and glucose tolerance were determined, along with gastrointestinal peptide levels during the MTT. RESULTS: Fasting plasma glucose and HbA(1c) decreased with colesevelam (from 5.9 ± 0.1 to 5.7 ± 0.1 mmol/L, P < 0.05, and from 5.86 ± 0.06 to 5.76 ± 0.06%, P = 0.01, respectively), but fasting insulin did not change. Colesevelam had no effect on any FSIGT measures. In contrast, the MTT incremental area under the curve (iAUC) for both glucose (from 249.3 ± 28.5 to 198.8 ± 23.6 mmol/L · min, P < 0.01) and insulin (from 20,130 [13,542-35,292] to 13,086 [9,804-21,138] pmol/L · min, P < 0.05) decreased with colesevelam. However, the ratio of iAUC insulin to iAUC glucose was not changed. iAUC for cholecystokinin (CCK) increased (from 43.2 [0-130.1] to 127.1 [47.2-295.2] pmol/L · min, P < 0.01), while iAUC for fibroblast growth factor 19 decreased (from 11,185 [1,346-17,661] to 2,093 [673-6,707] pg/mL · min, P < 0.01) with colesevelam. However, iAUC for glucagon, glucose-dependent insulinotropic peptide, and glucagon-like peptide 1 did not change. CONCLUSIONS: Colesevelam improves oral but not intravenous glucose tolerance without changing insulin sensitivity, ß-cell function, or incretins. This effect may be at least partially explained by the colesevelam-induced increase in CCK.