Metyrapone is effective therapy for short- and long-term control of hypercortisolemia in CS.

Inhibition of glucose transport in the kidney, to produce glucosuria and thus directly lower blood glucose seems a remarkably simple way to treat diabetes (type 1 or type 2). The development of sodium-glucose co-transporter-2 (SGLT2) inhibitors and their subsequent clinical development has on one hand shown this to be true, but at another level has helped reveal a complex web of interacting effects starting in the kidney and modulating multiple metabolic pathways in a variety of other organs. These underlie the now clear benefits of this class of drugs in the management of type 2 diabetes from glucose lowering, weight loss and blood pressure reduction through to the reductions in cardiovascular and renal complications observed in long-term outcomes trials. They also explain some of the adverse effects that have emerged, including the risk of diabetic ketoacidosis. This review describes the effects of SGLT2 inhibition in relation to this complex physiology, and shows how this can favourably alter the pathophysiology of type 2 diabetes.anti-diabetic drug, clinical physiology, type 2 diabetes, SGLT2 inhibitor 1 | INTRODUCTION Sodium glucose transporter 2 inhibitors (SGLT2i) are one of the newest classes of drugs available to lower glucose in people with type 2 diabetes, but their origins go back to the 19th century, when phlorizin, extracted from the bark of apple trees was shown to induce glucosuria. Phlorizin was later used experimentally as a tool to help understand renal glucose transport and the effects of glucose toxicity, as it could be used to lower blood glucose without directly affecting insulin secretion or sensitivity. 1 However its therapeutic potential was limited, due to poor oral bioavailability, and effects on gut glucose absorption that resulted in diarrhoea; phlorizin also has an active metabolite (phloretin) that inhibits the GLUT1 glucose transporter that is important for normal glucose transport in many tissues. 2 Research conducted in the last 20 years has now identified the specific mechanisms by which phlorizin is able to induce glucosuria and lower blood glucose, and led to the development of drugs that are highly selective inhibitors of renal (and/or gut) glucose transport. These drugs work by inhibiting the facilitative sodium glucose co-transporters (SGLTs) that are responsible for renal glucose reabsorption (predominantly SGLT2 with some contribution from SGLT1, which also has a major role in gut glucose absorption). 3 Despite early concerns about some adverse effects that occur as a result of glucosuria, the development of SGLTi (and potentially dual inhibitors of SGLT1 and SGLT2) has led to greater understanding of the fundamental physiological processes involved in glucose transport in the kidney and gastrointestinal (GI) tract. These medications have both predictable and surprising effects that underpin some of their observed therapeutic benefits and adverse effects. This review will focus on the underlying physiology and show how this is modified by pharmacological inhibition of SG...

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are the latest addition to the class of oral glucose-lowering drugs. They have been rapidly adopted into clinical practice because of therapeutic advantages, including weight loss and reduction in blood pressure, in addition to glycaemic benefits and a low intrinsic risk of hypoglycaemia. Although there are extensive data on the clinical effects of SGLT2 inhibition, the metabolic effects of inhibiting renal glucose reabsorption have not been fully described. Recent studies have identified compensatory metabolic effects, such as an increase in endogenous glucose production, and have also shown an increase in glucagon secretion during SGLT2 inhibition. In addition, there is a discrepancy between the expected and observed weight loss found in clinical studies on SGLT2 inhibitors, probably as a result of changes in energy balance with this treatment approach. SGLT2 inhibition is likely to have intriguing effects on whole body metabolism which have not been fully elucidated, and which, if explained, might help optimize the use of this new class of medicines.

S154Diabetes Care Volume 39, Supplement 2, August 2016 SGLT2 THERAPYsensitizer (6,7). GLP-1 is part of the physiological system signaling satiety (8,9), reduces food intake and promotes weight loss in humans (10), and delays gastric emptying (11). Early studies showed that continuous subcutaneous GLP-1 infusion effectively lowered fasting and postprandial glucose levels and promoted weight loss in patients with T2DM (12). However, endogenous human GLP-1 has a short half-life (2-3 min) due to breakdown in the circulation by protease enzymes, notably, dipeptidyl peptidase (DPP)-4, which cleaves the molecule to leave the inactive GLP-1 (9-36). Hence, native GLP-1 has limited therapeutic efficacy. Pharmaceutical development took two routes: inhibition of the DPP-4-degrading enzyme and prolongation of the biological half-life by developing DPP-4-resistant GLP-1 receptor agonists (GLP-1 RAs). DPP-4 InhibitorsFour oral DPP-4 inhibitors (DPP-4i) are approved for use in both the U.S. and the European Union (sitagliptin, saxagliptin, alogliptin, and linagliptin) ( Table 1). Vildagliptin is approved in the European Union but not the U.S. Several other agents of this class are marketed worldwide (for example, omaragliptin and trelagliptin are available only in Japan). All five DPP-4i appear to have similar efficacy in terms of glucose lowering. An 18-week, phase 3b, multicenter, double-blind trial of saxagliptin versus sitagliptin has demonstrated noninferiority as add-on therapy to metformin (13). Trelagliptin, a once-weekly DPP-4i, was studied against alogliptin once daily and has demonstrated noninferiority in the Japanese population studied (14). Meta-analysis of DPP-4i has shown an average HbA 1c reduction (20.74%) (15) that is slightly less efficacious than sulfonylureas when used as monotherapy and similar to metformin and pioglitazone (16) but inferior to GLP-1 RAs. DPP-4i can be used in combination with other oral agents or with basal insulin (17), although the reduction of HbA 1c with insulin is modest (18,19). The DPP-4i are weight neutral and have a low risk of hypoglycemia. DPP-4i: Adverse EffectsIn general, the adverse effect profile of the DPP-4i is quite favorable. With the exception of linagliptin, the DPP-4i require dose reduction in patients with renal impairment. Some concern has been raised about the risk of pancreatitis and pancreatic cancer, based on preclinical studies and reports from postmarketing surveillance studies. However, the current data do not support a likely association (20). The U.S. Food and Drug Administration (FDA) has recently issued a warning about the possibility of joint pain developing during DPP-4i treatment after review of 33 cases reported over the past 8 years. However, the potential mechanism(s) are uncertain and a causal link is unproven, although symptoms appear to resolve after treatment withdrawal (21). Several large cardiovascular (CV) outcome trials have been completed, comparing these agents with placebo on the background of standard diabetes care (Table 2), and have ...

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IntroductionSodium glucose cotransporter 2 (SGLT2) inhibitors are effective blood-glucose-lowering medications with beneficial effects on body weight in patients with type 2 diabetes mellitus (T2DM). However, observed weight loss is less than that predicted from quantified glycosuria, suggesting a compensatory increase in energy intake or a decrease in energy expenditure. Studies using dual-energy X-ray absorptiometry (DEXA) have suggested most body weight change is due to loss of adipose tissue, but organ-specific changes in fat content (eg, liver, skeletal muscle) have not been determined. In this randomised, double-blind, placebo-controlled crossover study, we aim to study the compensatory changes in energy intake, eating behaviour and energy expenditure accompanying use of the SGLT2 inhibitor, dapagliflozin. Additionally, we aim to quantify changes in fat distribution using MRI, in liver fat using proton magnetic resonance spectroscopy (1H-MRS) and in central nervous system (CNS) responses to food images using blood oxygen level dependent (BOLD) functional MRI (fMRI).Methods and analysisThis outpatient study will evaluate the effect of dapagliflozin (10 mg), compared with placebo, on food intake and energy expenditure at 7 days and 12 weeks. 52 patients with T2DM will be randomised to dapagliflozin or placebo for short-term and long-term trial interventions in a within participants, crossover design. The primary outcome is the difference in energy intake during a test meal between dapagliflozin and placebo. Intake data are collected automatically using a customised programme operating a universal eating monitor (UEM). Secondary outcomes include (1) measures of appetite regulation including rate of eating, satiety quotient, appetite ratings (between and within meals), changes in CNS responses to food images measured using BOLD-fMRI, (2) measures of energy expenditure and (3) changes in body composition including changes in liver fat and abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT).Ethical approvalThis study has been approved by the North West Liverpool Central Research Ethics Committee (14/NW/0340) and is conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice (GCP).Trial registration numberISRCTN14818531. EUDRACT number 2013-004264-60.

SGLT2 inhibitors represent a novel class of oral glucoselowering treatment that addresses some important unmet clinical needs in the treatment of type 2 diabetes, specifically weight reduction and a low propensity to cause hypoglycaemia. SGLT2 inhibition lowers the renal threshold for glucose excretion, resulting in renal glycosuria, a shift in substrate utilisation from carbohydrate to fat oxidation and hyperglucagonaemia; this poses a theoretical risk for ketoacidosis (including euglycaemic ketoacidosis) in the presence of other precipitating factors, especially reduction in insulin doses or low carbohydrate intake. There have been reports of several cases of ketoacidosis, mostly euglycaemic, and in people with type 1 or type 2 diabetes. Subsequent to this there were warnings from regulatory bodies (FDA and EMEA). In this article, we examine the reports of ketoacidosis associated with SGLT2 inhibition and try to explain the intrinsic pathophysiological mechanisms associated with this class of drugs which might contribute to ketoacidosis. The implications of these for clinical practice are summarised with key messages to health care providers. Br J Diabetes Vasc Dis 2015;15:155-158

ObjectiveTo identify clinical and biochemical characteristics associated with 7- & 30-day mortality and intensive care admission amongst diabetes patients admitted with COVID-19.Research Design and MethodsWe conducted a cohort study collecting data from medical notes of hospitalised people with diabetes and COVID-19 in 7 hospitals within the Mersey-Cheshire region from 1 January to 30 June 2020. We also explored the impact on inpatient diabetes team resources. Univariate and multivariate logistic regression analyses were performed and optimised by splitting the dataset into a training, test, and validation sets, developing a robust predictive model for the primary outcome.ResultsWe analyzed data from 1004 diabetes patients (mean age 74.1 (± 12.6) years, predominantly men 60.7%). 45% belonged to the most deprived population quintile in the UK. Median BMI was 27.6 (IQR 23.9-32.4) kg/m2. The primary outcome (7-day mortality) occurred in 24%, increasing to 33% by day 30. Approximately one in ten patients required insulin infusion (9.8%). In univariate analyses, patients with type 2 diabetes had a higher risk of 7-day mortality [p < 0.05, OR 2.52 (1.06, 5.98)]. Patients requiring insulin infusion had a lower risk of death [p = 0.02, OR 0.5 (0.28, 0.9)]. CKD in younger patients (<70 years) had a greater risk of death [OR 2.74 (1.31-5.76)]. BMI, microvascular and macrovascular complications, HbA1c, and random non-fasting blood glucose on admission were not associated with mortality. On multivariate analysis, CRP and age remained associated with the primary outcome [OR 3.44 (2.17, 5.44)] allowing for a validated predictive model for death by day 7.ConclusionsHigher CRP and advanced age were associated with and predictive of death by day 7. However, BMI, presence of diabetes complications, and glycaemic control were not. A high proportion of these patients required insulin infusion warranting increased input from the inpatient diabetes teams.