Heritability of variation in glycaemic response to metformin:a genome-wide complex trait analysis

BACKGROUND: Metformin is a first-line oral agent used in the treatment of type 2 diabetes, but glycaemic response to this drug is highly variable. Understanding the genetic contribution to metformin response might increase the possibility of personalising metformin treatment. We aimed to establish the heritability of glycaemic response to metformin using the genome-wide complex trait analysis (GCTA) method. METHODS: In this GCTA study, we obtained data about HbA1c concentrations before and during metformin treatment from patients in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) study, which includes a cohort of patients with type 2 diabetes and is linked to comprehensive clinical databases and genome-wide association study data. We applied the GCTA method to estimate heritability for four definitions of glycaemic response to metformin: absolute reduction in HbA1c; proportional reduction in HbA1c; adjusted reduction in HbA1c; and whether or not the target on-treatment HbA1c of less than 7% (53 mmol/mol) was achieved, with adjustment for baseline HbA1c and known clinical covariates. Chromosome-wise heritability estimation was used to obtain further information about the genetic architecture. FINDINGS: 5386 individuals were included in the final dataset, of whom 2085 had enough clinical data to define glycaemic response to metformin. The heritability of glycaemic response to metformin varied by response phenotype, with a heritability of 34% (95% CI 1-68; p=0·022) for the absolute reduction in HbA1c, adjusted for pretreatment HbA1c. Chromosome-wise heritability estimates suggest that the genetic contribution is probably from individual variants scattered across the genome, which each have a small to moderate effect, rather than from a few loci that each have a large effect. INTERPRETATION: Glycaemic response to metformin is heritable, thus glycaemic response to metformin is, in part, intrinsic to individual biological variation. Further genetic analysis might enable us to make better predictions for stratified medicine and to unravel new mechanisms of metformin action. FUNDING: Wellcome Trust

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

Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes

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European Medicines Agency: approval of new glucose-lowering medicines for type 2 diabetes

Since 2005 all new glucose‐lowering medicines to be used in Europe have required approval by the European Medicines Agency (EMA) through a centralised procedure [1]. This involves assessment of a detailed file of data generated during the preclinical studies and phase 1‐3 clinical trials, along with the proposed product label. The file is subject to internal review and some aspects may also receive external review, giving rise to questions that are referred back to the sponsor and may lead to additional studies. The assessment is considered by the Committee for Medicinal Products for Human Use (CHMP) and if approval is recommended then a marketing authorisation is usually granted by the European Commission

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

Meta‐analysis of the association between sodium‐glucose co‐transporter‐2 inhibitors and risk of skin cancer among patients with type 2 diabetes

A slight increase in melanoma risk was observed among sodium‐glucose co‐transporter‐2 (SGLT‐2) inhibitor users in the regular reports. However, the association remains uncertain. To address this issue, we performed a systematic search of electronic databases up to May 2, 2018 and a meta‐analysis of 21 randomized controlled trials (RCTs) involving 20 308 patients. We did not find a significant increase in risk of melanoma among SGLT‐2 inhibitor users (Peto odds ratio [OR], 2.17; 95% confidence interval [CI], 0.80‐5.89; I2, 0%). Similar results were observed in the subgroup analyses according to the type of SGLT‐2 inhibitor, type of control, ages of patients, race/ethnicity, and trial durations. For non‐melanoma skin cancer risk, no significant difference was observed when all trials were combined (Peto OR, 0.70; 95% CI, 0.47‐1.07; I2, 0%), while a significantly decreased risk was observed among trials with duration <52 weeks (Peto OR, 0.12; 95% CI, 0.02‐0.59; I2, 0%). No evidence of publication bias was detected in the analyses. Current evidence from RCTs did not support a significantly increased risk of skin cancer associated with SGLT‐2 inhibitors

Fasting Versus Postload Plasma Glucose Concentration and the Risk for Future Type 2 Diabetes: Results from the Botnia Study

OBJECTIVE—The purpose of this study was to assess the efficacy of the postload plasma glucose concentration in predicting future risk of type 2 diabetes, compared with prediction models based on measurement of the fasting plasma glucose (FPG) concentration