Epinephrine and potassium homeostasis

Epinephrine and potassium homeostasis. The effect of epinephrine on potassium metabolism was examined in six subjects. Each subject participated in four studies as follows: (1) potassium chloride infusion (0.75 mEq/kg, i.v.) given over 2 hours, (2) epinephrine (0.05 µg/kg·min) plus potassium chloride, (3) propranolol (1.43 µg/kg·min) plus epinephrine plus potassium chloride, and (4) propranolol plus potassium chloride. The epinephrine infusion with potassium chloride led to a marked improvement in potassium tolerance, which was due to a greater than twofold increase in the extrarenal disposal of potassium (P < 0.001). The enhancing effect of epinephrine on extrarenal potassium uptake was completely reversed with the beta-blocking agent propranolol. When propranolol alone was infused with potassium chloride, a significant decrease in the extrarenal disposal of potassium was observed. When potassium chloride was infused alone, 47% of the administered potassium load was excreted in the urine. Epinephrine infusion with potassium chloride markedly inhibited the urinary excretion of potassium (UKV) to rates that were actually below the basal potassium excretion rate (P <0.001). Propranolol almost completely reversed this effect of epinephrine on UKV, and when propranolol was infused alone, an enhancement in UKV (P < 0.005) was observed. Insulin adds only a minor contribution to the enhancing effect of epinephrine on extrarenal potassium disposal and does not contribute at all to the inhibitory effect of epinephrine on renal potassium excretion. These results demonstrate that epinephrine ameliorates the rise in plasma potassium concentration following potassium chloride infusion. Because none of the infused potassium was excreted during the 4-hour study period, the improvement in potassium tolerance must result from an enhancement in extrarenal potassium disposal. The ability of propranolol to reverse both the extrarenal and renal effects indicates that the action of epinephrine is mediated via stimulation of the beta receptor.Epinéphrine et homéostasie du potassium. L'effet de l'épinéphrine sur le métabolisme du potassium a été étudié chez six sujets. Chaque sujet a participé à quatre études de la façon suivante: (1) perfusion de chlorure de potassium (0,75 mEq/kg, i.v.) administré en 2 heures, (2) épinéphrine (0,05 µg/kg·min) plus chlorure de potassium, (3) propranolol (1,43 µg/kg·min) plus épinéphrine plus chlorure de potassium, et (4) propranolol plus chlorure de potassium. La perfusion d'épinéphrine avec du chlorure de potassium détermine une augmentation importante de la tolérance au potassium, laquelle est due à une augmentation de plus du double de la disposition extra-rénale du potassium (P < 0,001). L'effet d'augmentation par l'épinéphrine de la captation extra-rénale du potassium a été complètement aboli par le bêta bloquant propranolol. Quand le propsranolol seul a été perfusé avec du chlorure de potassium, une diminution significative de la disposition extra-rénale de potassium a été observée. Quand le chlorure de potassium est perfusé seul, 47% de la charge administrée sont excrétés dans les urines. La perfusion d'épinéphrine avec le chlorure de potassium a abaissé de façon importante UKV à des débits inférieurs aux valeurs basales (P < 0,001). Le propranolol abolit presque complètement cet effet de l'épinéphrine sur UKV et quand le propranolol est perfusé seul une augmentation de UKV (P < 0,005) apparaît. L'insuline n'apporte qu'une faible contribution à l'effet d'augmentation par l'épinéphrine de la disposition extra-rénale du potassium et ne contribue pas du tout à l'effet inhibiteur de l'épinéphrine sur l'excrétion rénale de potassium. Ces résultats démontrent que l'épinéphrine minimise l'élévation de la concentration plasmatique de potassium consécutive à une perfusion de chlorure de potassium. Du fait que le potassium perfusé n'est pas excrété pendant les 4 heures de l'étude il est prouvé que l'amélioration de la tolérance au potassium est la conséquence d'une augmentation de sa disposition extra-rénale. La capacité qu'a le propranolol d'abolir à la fois l'effet rénal et l'effet extra-rénal indique que cette action de l'épinéphrine a pour médiateur la stimulation des récepteurs bêta

Pathogenesis of Insulin Resistance in Skeletal Muscle

Insulin resistance in skeletal muscle is manifested by decreased insulin-stimulated glucose uptake and results from impaired insulin signaling and multiple post-receptor intracellular defects including impaired glucose transport, glucose phosphorylation, and reduced glucose oxidation and glycogen synthesis. Insulin resistance is a core defect in type 2 diabetes, it is also associated with obesity and the metabolic syndrome. Dysregulation of fatty acid metabolism plays a pivotal role in the pathogenesis of insulin resistance in skeletal muscle. Recent studies have reported a mitochondrial defect in oxidative phosphorylation in skeletal muscle in variety of insulin resistant states. In this review, we summarize the cellular and molecular defects that contribute to the development of insulin resistance in skeletal muscle

Adrenergic modulation of potassium metabolism in uremia

Adrenergic modulation of potassium metabolism in uremia. The effect of chronic beta adrenergic blockade on potassium homeostasis during moderate intensity exercise (40% of VO2 max) was examined in seven end-stage renal patients who were being maintained on chronic dialysis treatment. Subjects participated in three study protocols: 1) exercise alone, 2) exercise plus propranolol (a nonselective beta-1, beta-2 antagonist), and 3) exercise plus metoprolol (a specific beta-1 antagonist). The basal potassium concentration was similar in all three studies and averaged 4.95 ± 0.12 mEq/liter. During Study 1 (exercise alone), plasma potassium rose by 0.26 ± 0.09 mEq/liter. During exercise with propranolol, plasma K concentration rose significantly higher (Δ plasma K = 0.44 ± 0.26 mEq/liter; P < 0.05 vs. exercise alone). In contrast, the rise in plasma K during exercise with metoprolol (Δ plasma K = 0.20 ± 0.08 mEq/liter) was similar to that observed with exercise alone. Differences in potassium homeostasis between metoprolol and propranolol could not be explained by differences in hemodynamic parameters, levels of potassium regulatory hormones, or acid base status. Thus, the higher rise in potassium concentration during exercise with propranolol could only be explained by adrenergic blockade at the beta-2 receptor site. These results support the concept that adrenergic control of extrarenal potassium homeostasis in dialysis patients is mediated at the beta-2 receptor. Since a deterioration in potassium homeostasis during exercise is observed with beta-2, but not beta-1 blockade, selective beta-1 adrenergic blocking agents may be safer in dialysis patients

Role of plasma arginine vasopressin in the impaired water diuresis of isolated glucocorticoid deficiency in the rat

Role of plasma arginine vasopressin in the impaired water diuresis of isolated glucocorticoid deficiency in the rat. The role of antidiuretic hormone in the impaired water excretion of isolated glucocorticoid deficiency was investigated in the thyroxin-re-placed, anterior hypophysectomized rat. Hypophysectomized rats demonstrated marked impairment in the excretion of an oral water load (32 ± 4% vs. 94 ± 4%), plasma hypoosmolality (281 ± 2 vs. 289 ± 2 mOsm/kg), and hyponatremia (129 ± 1 vs. 140 ± 1 mEq/liter) compared to controls (all P < 0.001). These defects were associated with increased levels of plasma arginine vasopressin (3.05 ± 0.45 vs. 1.38 ± 0.11 pg/ml; P < 0.001). Following physiologic corticosterone replacement in hypophysectomized rats, the percentage of the water load excreted, free water clearance, plasma sodium, plasma osmolality, and circulating levels of plasma arginine vasopressin were all restored to control values. This correction of water diuresis occurred in the absence of changes in GFR or solute excretion. The defect in water excretion and the elevation of plasma arginine vasopressin could not be corrected by chronic extracellular volume expansion in the absence of glucocorticoid replacement. It is concluded that (a) increased secretion of vasopressin plays an important role in the impaired water diuresis of isolated glucorticoid deficiency; (b) physiologic corticosterone replacement corrects both the impaired water excretion and the increased secretion of vasopressin associated with glucocorticoid deficiency; and (c) a volume-independent nonosmotic stimulus to vasopressin secretion may be activated by the chronic absence of glucocorticoid hormones.Rôle de l'rginine vasopressine du plasma dans l'ncapacite de diluer l'urine au cours du déficit isolé en glucocorticoïdes chez le rat. Le rôle de l'hormone antidiurétique dans l'incapacité à diluer l'urine au cours du déficit isolé en glucocorticoïdes a été étudié chez des rats ayant subi une hypophysectomie antérieure et compensés par de la thyroxine. Les rats hypohysectomisés ont un déficit important de l'excrétion d'une charge en eau (32 ± 4% contre 94 ± 4%), une hypoosmolalité plasmatique (281 ± 2 contre 289 ± 2 mOsm/kg), et une hyponatrémie (129 ± 1 contre 140 ± 1 mEq/liter), par comparaison aux contrôles (P < 0,001). Ces modifications sont associées à des concentrations plasmatiques élevées d'arginine vasopressine (3,05 ± 0,45 contre 1,38 ± 0,11 pg/ml; P < 0,001). L'administration de corticostérone aux rats hypophysectomisés ramène aux valeurs contrôles le pourcentage de la charge d'eau excrétée, la clearance de l'eau libre, la natrémie, l'osmolalité plasmatique et la concentration circulante d'arginine vasopressine. Cette restauration de la diurèse aqueuse est observée en l'absence de modifications du débit de filtration glomérulaire ou du débit urinaire de substances dissoutes. Le déficit d'excrétion de l'eau et l'augmentation de l'arginine vasopressine du plasma ne peuvent pas être corrigés par une expansion chronique du volume extra-cellulaire en l'absence de traitement substitutif par les glucocorticoïdes. I1 est conclu que: (a) l'augmentation de la sécrétion de vasopressine joue un rôle important dans l'incapacité de diluer les urines observée au cours du déficit en glucocorticoïdes; (b) un traitement substitutif par des doses physiologiques de corticostérone corrige à la fois le déficit d'excrétion de l'eau et la sécrétion excessive de vasopressine associés au déficit en glucocorticoïdes; et (c) un stimulus, non osmotique et indépendant du volume extracellulaire, de la sécrétion de vasopressine peut être activé par l'absence chronique d'hormones glucocorticoïdes

Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials

AIMS/HYPOTHESIS: Delayed-release metformin (Metformin DR) was developed to maximise gut-based mechanisms of metformin action by targeting the drug to the ileum. Metformin DR was evaluated in two studies. Study 1 compared the bioavailability and effects on circulating glucose and gut hormones (glucagon-like peptide-1, peptide YY) of Metformin DR dosed twice-daily to twice-daily immediate-release metformin (Metformin IR). Study 2 compared the bioavailability and glycaemic effects of Metformin DR dosages of 1,000 mg once-daily in the morning, 1,000 mg once-daily in the evening, and 500 mg twice-daily. METHODS: Study 1 was a blinded, randomised, crossover study (three × 5 day treatment periods) of twice-daily 500 mg or 1,000 mg Metformin DR vs twice-daily 1,000 mg Metformin IR in 24 participants with type 2 diabetes conducted at two study sites (Celerion Inc.; Tempe, AZ, and Lincoln, NE, USA). Plasma glucose and gut hormones were assessed over 10.25 h at the start and end of each treatment period; plasma metformin was measured over 11 h at the end of each treatment period. Study 2 was a non-blinded, randomised, crossover study (three × 7 day treatment periods) of 1,000 mg Metformin DR once-daily in the morning, 1,000 mg Metformin DR once-daily in the evening, or 500 mg Metformin DR twice-daily in 26 participants with type 2 diabetes performed at a single study site (Celerion, Tempe, AZ). Plasma glucose was assessed over 24 h at the start and end of each treatment period, and plasma metformin was measured over 30 h at the end of each treatment period. Both studies implemented centrally generated computer-based randomisation using a 1:1:1 allocation ratio. RESULTS: A total of 24 randomised participants were included in study 1; of these, 19 completed the study and were included in the evaluable population. In the evaluable population, all treatments produced similar significant reductions in fasting glucose (median reduction range, -0.67 to -0.81 mmol/l across treatments) and postprandial glucose (Day 5 to baseline AUC0-t ratio = 0.9 for all three treatments) and increases in gut hormones (Day 5 to baseline AUC0-t ratio range: 1.6-1.9 for GLP-1 and 1.4-1.5 for PYY) despite an almost 60% reduction in systemic metformin exposure for 500 mg Metformin DR compared with Metformin IR. A total of 26 randomised participants were included in study 2: 24 had at least one dose of study medication and at least one post-dose pharmacokinetic/pharmacodynamic assessment and were included in the pharmacokinetic/pharmacodynamic intent-to-treat analysis; and 12 completed all treatment periods and were included in the evaluable population. In the evaluable population, Metformin DR administered once-daily in the morning had 28% (90% CI -16%, -39%) lower bioavailability (least squares mean ratio of metformin AUC0-24) compared with either once-daily in the evening or twice-daily, although the glucose-lowering effects were maintained. In both studies, adverse events were primarily gastrointestinal in nature, and indicated similar or improved tolerability for Metformin DR vs Metformin IR; there were no clinically meaningful differences in vital signs, physical examinations or laboratory values. CONCLUSIONS/INTERPRETATION: Dissociation of gut hormone release and glucose lowering from plasma metformin exposure provides strong supportive evidence for a distal small intestine-mediated mechanism of action. Directly targeting the ileum with Metformin DR once-daily in the morning may provide maximal metformin efficacy with lower doses and substantially reduce plasma exposure. Metformin DR may minimise the risk of lactic acidosis in those at increased risk from metformin therapy, such as individuals with renal impairment. TRIAL REGISTRATION: Clinicaltrials.gov NCT01677299, NCT01804842 FUNDING: : This study was funded by Elcelyx Therapeutics Inc

Determinants of the Increase in Fasting Plasma Ketone Concentration during SGLT2 Inhibition in NGT, IFG and T2DM Patients

To examine metabolic factors that influence ketone production after sodium-glucose cotransport inhibitor (SGLT2) administration RESEARCH DESIGN AND METHODS: Fasting plasma glucose, insulin, glucagon, free fatty acid and ketone concentrations were measured in 15 type 2 diabetes mellitus (T2DM) and 16 non-diabetic subjects before and at 1 and 14 days after treatment with empagliflozin

Dapagliflozin enhances fat oxidation and ketone production in patients with type 2 diabetes

OBJECTIVE Insulin resistance is associatedwithmitochondrial dysfunction and decreased ATP synthesis. Treatment of individuals with type 2 diabetes mellitus (T2DM) with sodium-glucose transporter 2 inhibitors (SGLT2i) improves insulin sensitivity. However, recent reports have demonstrated development of ketoacidosis in subjects with T2DM treated with SGLT2i. The current study examined the effect of improved insulin sensitivity with dapagliflozin on 1) mitochondrial ATP synthesis and 2) substrate oxidation rates and ketone production. RESEARCH DESIGN AND METHODS The study randomized 18 individuals with T2DMto dapagliflozin (n = 9) or placebo (n = 9). Before and after 2 weeks, subjects received an insulin clamp with tritiated glucose, indirect calorimetry, and muscle biopsies. RESULTS Dapagliflozin reduced fasting plasma glucose (167 ± 13 to 128 ± 6 mg/dL) and increased insulin-stimulated glucose disposal by 36% (P < 0.01). Glucose oxidation decreased (1.06 to 0.80 mg/kg · min, P < 0.05), whereas nonoxidative glucose disposal (glycogen synthesis) increased (2.74 to 4.74 mg/kg · min, P = 0.03). Dapagliflozin decreased basal glucose oxidation and increased lipid oxidation and plasma ketone concentration (0.05 to 0.19 mmol/L, P < 0.01) in association with an increase in fasting plasma glucagon (77 ± 8 to 94 ± 13, P < 0.01). Dapagliflozin reduced the ATP synthesis rate, which correlated with an increase in plasma ketone concentration. CONCLUSIONS Dapagliflozin improved insulin sensitivity and caused a shift from glucose to lipid oxidation, which, together with an increase in glucagon-to-insulin ratio, provide the metabolic basis for increased ketone production

Effect of exenatide on splanchnic and peripheral glucose metabolism in type 2 diabetic subjects

OBJECTIVE: Our objective was to examine the mechanisms via which exenatide attenuates postprandial hyperglycemia in type 2 diabetes mellitus (T2DM). STUDY DESIGN: Seventeen T2DM patients (44 yr; seven females, 10 males; body mass index = 33.6 kg/m(2); glycosylated hemoglobin = 7.9%) received a mixed meal followed for 6 h with double-tracer technique ([1-(14)C]glucose orally; [3-(3)H]glucose i.v.) before and after 2 wk of exenatide. In protocol II (n = 5), but not in protocol I (n = 12), exenatide was given in the morning of the repeat meal. Total and oral glucose appearance rates (RaT and RaO, respectively), endogenous glucose production (EGP), splanchnic glucose uptake (75 g - RaO), and hepatic insulin resistance (basal EGP x fasting plasma insulin) were determined. RESULTS: After 2 wk of exenatide (protocol I), fasting plasma glucose decreased (from 10.2 to 7.6 mm) and mean postmeal plasma glucose decreased (from 13.2 to 11.3 mm) (P < 0.05); fasting and meal-stimulated plasma insulin and glucagon did not change significantly. After exenatide, basal EGP decreased (from 13.9 to 10.8 mumol/kg . min, P < 0.05), and hepatic insulin resistance declined (both P < 0.05). RaO, gastric emptying (acetaminophen area under the curve), and splanchnic glucose uptake did not change. In protocol II (exenatide given before repeat meal), fasting plasma glucose decreased (from 11.1 to 8.9 mm) and mean postmeal plasma glucose decreased (from 14.2 to 10.1 mm) (P < 0.05); fasting and meal-stimulated plasma insulin and glucagon did not change significantly. After exenatide, basal EGP decreased (from 13.4 to 10.7 mumol/kg . min, P = 0.05). RaT and RaO decreased markedly from 0-180 min after meal ingestion, consistent with exenatide\u27s action to delay gastric emptying. CONCLUSIONS: Exenatide improves 1) fasting hyperglycemia by reducing basal EGP and 2) postmeal hyperglycemia by reducing the appearance of oral glucose in the systemic circulation

Metabolic effects of muraglitazar in type 2 diabetic subjects

AIM: To assess the effect of muraglitazar, a dual peroxisome proliferator-activated receptor (PPAR)gamma-alpha agonist, versus placebo on metabolic parameters and body composition in subjects with type 2 diabetes mellitus (T2DM). METHODS: Twenty-seven T2DM subjects received oral glucose tolerance test (OGTT), euglycaemic insulin clamp with deuterated glucose, measurement of total body fat (DEXA), quantitation of muscle/liver (MRS) and abdominal subcutaneous and visceral (MRI) fat, and then were randomized to receive, in addition to diet, muraglitazar (MURA), 5 mg/day, or placebo (PLAC) for 4 months. RESULTS: HbA1c(c) decreased similarly (2.1%) during both MURA and PLAC treatments despite significant weight gain with MURA (+2.5 kg) and weight loss with PLAC (-0.7 kg). Plasma triglyceride, LDL cholesterol, free fatty acid (FFA), hsCRP levels all decreased with MURA while plasma adiponectin and HDL cholesterol increased (p < 0.05-0.001). Total body (muscle), hepatic and adipose tissue sensitivity to insulin and beta cell function all improved with MURA (p < 0.05-0.01). Intramyocellular, hepatic and abdominal visceral fat content decreased, while total body and subcutaneous abdominal fat increased with MURA (p < 0.05-0.01). CONCLUSIONS: Muraglitazar (i) improves glycaemic control by enhancing insulin sensitivity and beta cell function in T2DM subjects, (ii) improves multiple cardiovascular risk factors, (iii) reduces muscle, visceral and hepatic fat content in T2DM subjects. Despite similar reduction in A1c with PLAC/diet, insulin sensitivity and beta cell function did not improve significantly

Using the Schmahmann Syndrome Scale to Assess Cognitive Impairment in Young Adults with Metabolic Syndrome: A Hypothesis-Generating Report

The posterior cerebellum is the most significantly compromised brain structure in individuals with metabolic syndrome (MetS) (Kotkowski et al., 2019). In light of this, we hypothesized that cognitive decline reported in patients with MetS is likely related to posterior cerebellar atrophy. In this study, we performed a post-hoc analyses using T1-weighted magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) in the form of voxel-wise tract-based spatial statistics (TBSS), biometric, and psychometric data from young participants with (n = 52, aged 18–35 years) and without MetS (n = 52, aged 18–35 years). To test the predictive value of components of the Schmahmann Syndrome scale (SSS), also known as the cerebellar cognitive affective syndrome scale, we used structural equation modeling to adapt available psychometric scores in our participant sample to the SSS and compare them to the composite score of all psychometric data available. Our key findings point to a statistically significant correlation between TBSS fractional anisotropy (FA) values from DTI and adapted SSS psychometric scores in individuals with MetS (r2 = .139, 95% CI = 0.009, .345). This suggests that the SSS could be applied to assess cognitive and likely neuroanatomical effects associated with MetS. We strongly suggest that future work aimed at investigating the neurocognitive effects of MetS and related comorbidities (i.e. dyslipidemia, diabetes, obesity) would benefit from implementing and further exploring the validity of the SSS scale in this patient population