BACKGROUND The effects of empagliflozin, an inhibitor of sodium–glucose cotransporter 2, in addition to standard care, on cardiovascular morbidity and mortality in patients with type 2 diabetes at high cardiovascular risk are not known. METHODS We randomly assigned patients to receive 10 mg or 25 mg of empagliflozin or placebo once daily. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, as analyzed in the pooled empagliflozin group versus the placebo group. The key secondary composite outcome was the primary outcome plus hospitalization for unstable angina. RESULTS A total of 7020 patients were treated (median observation time, 3.1 years). The primary outcome occurred in 490 of 4687 patients (10.5%) in the pooled empagliflozin group and in 282 of 2333 patients (12.1%) in the placebo group (hazard ratio in the empagliflozin group, 0.86; 95.02% confidence interval, 0.74 to 0.99; P = 0.04 for superiority). There were no significant between-group differences in the rates of myocardial infarction or stroke, but in the empagliflozin group there were significantly lower rates of death from cardiovascular causes (3.7%, vs. 5.9% in the placebo group; 38% relative risk reduction), hospitalization for heart failure (2.7% and 4.1%, respectively; 35% relative risk reduction), and death from any cause (5.7% and 8.3%, respectively; 32% relative risk reduction). There was no significant between-group difference in the key secondary outcome (P = 0.08 for superiority). Among patients receiving empagliflozin, there was an increased rate of genital infection but no increase in other adverse events. CONCLUSIONS Patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care. (Funded by Boehringer Ingelheim and Eli Lilly; EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676.)

/pdf/empagliflozin-cardiovascular-outcomes-and-mortality-in-type-48se5zm30q.pdf

Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes.

Metal ions are essential cofactors for a wealth of biological processes, including oxidative phosphorylation, gene regulation and free-radical homeostasis. Failure to maintain appropriate levels of metal ions in humans is a feature of hereditary haemochromatosis, disorders of metal-ion deficiency, and certain neurodegenerative diseases. Despite their pivotal physiological roles, however, there is no molecular information on how metal ions are actively absorbed by mammalian cells. We have now identified a new metal-ion transporter in the rat, DCT1, which has an unusually broad substrate range that includes Fe2+, Zn2+, Mn2+, Co2+, Cd2+, Cu2+, Ni2+ and Pb2+. DCT1 mediates active transport that is proton-coupled and depends on the cell membrane potential. It is a 561-amino-acid protein with 12 putative membrane-spanning domains and is ubiquitously expressed, most notably in the proximal duodenum. DCT1 is upregulated by dietary iron deficiency, and may represent a key mediator of intestinal iron absorption. DCT1 is a member of the 'natural-resistance-associated macrophage protein' (Nramp) family and thus its properties provide insight into how these proteins confer resistance to pathogens.

Cloning and characterization of a mammalian proton-coupled metal-ion transporter

BackgroundDiabetes confers an increased risk of adverse cardiovascular and renal events. In the EMPA-REG OUTCOME trial, empagliflozin, a sodium–glucose cotransporter 2 inhibitor, reduced the risk of major adverse cardiovascular events in patients with type 2 diabetes at high risk for cardiovascular events. We wanted to determine the long-term renal effects of empagliflozin, an analysis that was a prespecified component of the secondary microvascular outcome of that trial. MethodsWe randomly assigned patients with type 2 diabetes and an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m2 of body-surface area to receive either empagliflozin (at a dose of 10 mg or 25 mg) or placebo once daily. Prespecified renal outcomes included incident or worsening nephropathy (progression to macroalbuminuria, doubling of the serum creatinine level, initiation of renal-replacement therapy, or death from renal disease) and incident albuminuria. ResultsIncident or worsening nephropathy occurred in ...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1515920

Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes

In 2012, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) published a position statement on the management of hyperglycemia in patients with type 2 diabetes (1,2). This was needed because of an increasing array of antihyperglycemic drugs and growing uncertainty regarding their proper selection and sequence. Because of a paucity of comparative effectiveness research on long-term treatment outcomes with many of these medications, the 2012 publication was less prescriptive than prior consensus reports. We previously described the need to individualize both treatment targets and treatment strategies, with an emphasis on patient-centered care and shared decision making, and this continues to be our position, although there are now more head-to-head trials that show slight variance between agents with regard to glucose-lowering effects. Nevertheless, these differences are often small and would be unlikely to reflect any definite differential effect in an individual patient.

The ADA and EASD have requested an update to the position statement incorporating new data from recent clinical trials. Between June and September of 2014, the Writing Group reconvened, including one face-to-face meeting, to discuss the changes. An entirely new statement was felt to be unnecessary. Instead, the group focused on those areas where revisions were suggested by a changing evidence base. This briefer article should therefore be read as an addendum to the previous full account (1,2).

Glucose control remains a major focus in the management of patients with type 2 diabetes. However, this should always be in the context of a comprehensive cardiovascular risk factor reduction program, to include smoking cessation and the adoption of other healthy lifestyle habits, blood pressure control, lipid management with priority to statin medications, and, in some circumstances, antiplatelet therapy. Studies have conclusively determined that reducing hyperglycemia decreases the onset and progression of …

/pdf/management-of-hyperglycemia-in-type-2-diabetes-2015-a-4q16ecnrp1.pdf

Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach: Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes

/pdf/management-of-hyperglycemia-in-type-2-diabetes-2015-a-231ibsb3i5.pdf

Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient- Centered Approach

There are two classes of glucose transporters involved in glucose homeostasis in the body, the facilitated transporters or uniporters (GLUTs) and the active transporters or symporters (SGLTs). The ...

Biology of Human Sodium Glucose Transporters

Organic substrates (sugars, amino acids, carboxylic acids and neutrotransmitters) are actively transported into eukaryotic cells by Na+ co-transport. Some of the transport proteins have been identified—for example, intestinal brush border Na+/glucose and Na+/proline transporters1,2 and the brain Na+/Cl–/GABA transporter3—and progress has been made in locating their active sites and probing their conformational states1,2,4–7. The archetypical Na+-driven transporter is the intestinal brush border Na+/glucose co-transporter (see ref. 8), and a defect in the co-transporter is the origin of the congenital glucose–galactose malabsorption syndrome9. Here we describe cloning of this co-transporter by a method new to membrane proteins. We have sequenced the cloned DNA and have found no homology between the Na+/glucose co-transporter and either the mammalian facilitated glucose carrier or the bacterial sugar transport proteins. This suggests that the mammalian Na+-driven transporter has no evolutionary relationship to the other sugar transporters.

Expression cloning and cDNA sequencing of the Na+/glucose co-transporter

INTRODUCTION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......... 582 ALKALI-CATION SELECTIVITY IN NONLIVING SySTEMS..... . . . . . . . . . . . . . . .. 583 ALKALI-CATION SELECTIVITY IN BIOLOGICAL SYSTEMS. . . . . . . . . . . . . . . . . . .. 587 THE ORIGIN OF ALKALI-CATION EQUILIBRIUM SELECTIVITY .. .. . .. . .... . \" 589 ANION SELECTIVITY. . . • . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 595 DIVALENT-CATION SELECTIVITY. . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . .. 599 OTHER IONS. . . . . .. . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 603 N ON-COULOMB FORCES, AND THE MEANING OF THE TRANSITION SEQUENCES 60S \"UNCHARGED\" MEMBRANES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . • . . . . . . . . . . . . 607 DEGREE OF HYDRATION. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 608 EFFECT OF SITE SPACING OR ION COORDINATION NUMBER. • . . . . . . . . . . . . .. 609 ENTROPY EFFECTS.... . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . .. 609 N ONEQUILIBRIUM SELECTIVITY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 609 PORE RADIUS AND ALKALI-CATION SELECTIVITY.. . . . . . . . . . . . . . . . . . . .. ... 612 SUMMARY OF ION SELECTIVITY. • . . . • . . . . . . . . . . . . . . . . . . . . . . . . . . . . 614

http://jareddiamond.org/Jared_Diamond/Further_Reading_files/Diamond%201969.pdf

Biological membranes: the physical basis of ion and nonelectrolyte selectivity.

Secondary active glucose transport occurs by at least four members of the SLC5 gene family. This review considers the structure and function of two premier members, SGLT1 and SGLT2, and their role in intestinal glucose absorption and renal glucose reabsorption. Genetics disorders of SGLTs include Glucose-Galactose Malabsorption, and Familial Renal Glucosuria. SGLT1 plays a central role in Oral Rehydration Therapy used so effectively to treat secretory diarrhoea such as cholera. Increasing attention is being focused on SGLTs as drug targets for the therapy of diabetes.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2796.2006.01746.x

Active sugar transport in health and disease

In humans, the kidneys filter approximately 180 g of D-glucose from plasma each day, and this is normally reabsorbed in the proximal tubules. Although the mechanism of reabsorption is well understood, Na(+)-glucose cotransport across the brush-border membrane and facilitated diffusion across the basolateral membrane, questions remain about the identity of the genes responsible for cotransport across the brush border. Genetic studies suggest that two different genes regulate Na(+)-glucose cotransport, and there is evidence from animal studies to suggest that the major bulk of sugar is reabsorbed in the convoluted proximal tubule by a low-affinity, high-capacity transporter and that the remainder is absorbed in the straight proximal tubule by a high-affinity, low-capacity transporter. There are at least three different candidates for these human renal Na(+)-glucose cotransporters. This review will focus on the structure-function relationships of these three transporters, SGLT1, SGLT2, and SGLT3.

https://www.physiology.org/doi/pdf/10.1152/ajprenal.2001.280.1.F10

Ernest M. Wright

Papers

Biology of Human Sodium Glucose Transporters

Expression cloning and cDNA sequencing of the Na+/glucose co-transporter

Biological membranes: the physical basis of ion and nonelectrolyte selectivity.

Active sugar transport in health and disease

Renal Na(+)-glucose cotransporters.