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

Considerable evidence has accumulated indicating that the multidrug transporter or P-glycoprotein plays a role in the development of simultaneous resistance to multiple cytotoxic drugs in cancer cells. In recent years, various approaches such as mutational analyses and biochemical and pharmacological characterization have yielded significant information about the relationship of structure and function of P-glycoprotein. However, there is still considerable controversy about the mechanism of action of this efflux pump and its function in normal cells. This review summarizes current research on the structure-function analysis of P-glycoprotein, its mechanism of action, and facts and speculations about its normal physiological role.

Biochemical, cellular, and pharmacological aspects of the multidrug transporter

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Biochemical, cellular, and pharmacological aspects of the multidrug

Type 2 diabetes mellitus (T2DM) is an expanding global health problem, closely linked to the epidemic of obesity. Individuals with T2DM are at high risk for both microvascular complications (including retinopathy, nephropathy and neuropathy) and macrovascular complications (such as cardiovascular comorbidities), owing to hyperglycaemia and individual components of the insulin resistance (metabolic) syndrome. Environmental factors (for example, obesity, an unhealthy diet and physical inactivity) and genetic factors contribute to the multiple pathophysiological disturbances that are responsible for impaired glucose homeostasis in T2DM. Insulin resistance and impaired insulin secretion remain the core defects in T2DM, but at least six other pathophysiological abnormalities contribute to the dysregulation of glucose metabolism. The multiple pathogenetic disturbances present in T2DM dictate that multiple antidiabetic agents, used in combination, will be required to maintain normoglycaemia. The treatment must not only be effective and safe but also improve the quality of life. Several novel medications are in development, but the greatest need is for agents that enhance insulin sensitivity, halt the progressive pancreatic β-cell failure that is characteristic of T2DM and prevent or reverse the microvascular complications. For an illustrated summary of this Primer, visit: http://go.nature.com/V2eGfN.

Type 2 diabetes mellitus.

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

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

Thyroid Na+/I- symporter. Mechanism, stoichiometry, and specificity.

Water is transported across epithelial membranes in the absence of
 any hydrostatic or osmotic gradients. A prime example is the small
 intestine, where 10 liters of water are absorbed each day. Although
 water absorption is secondary to active solute transport, the coupling
 mechanism between solute and water flow is not understood. We have
 tested the hypothesis that water transport is directly linked to solute
 transport by cotransport proteins such as the brush border
 Na+/glucose cotransporter. The Na+/glucose
 cotransporter was expressed in Xenopus oocytes, and the
 changes in cell volume were measured under sugar-transporting and
 nontransporting conditions. We demonstrate that 260 water molecules are
 directly coupled to each sugar molecule transported and estimate that
 in the human intestine this accounts for 5 liters of water absorption
 per day. Other animal and plant cotransporters such as the
 Na+/Cl−/γ-aminobutyric acid,
 Na+/iodide and H+/amino acid transporters
 are also able to transport water and this suggests that cotransporters
 play an important role in water homeostasis.

https://www.pnas.org/content/pnas/93/23/13367.full.pdf

Cotransport of Water by the Na + /glucose Cotransporter

The human Na+/d-glucose cotransporter 2 (hSGLT2) is believed to be responsible for the bulk of glucose reabsorption in the kidney proximal convoluted tubule. Since blocking reabsorption increases u...

Donald D. F. Loo

Papers

Biology of Human Sodium Glucose Transporters

Active sugar transport in health and disease

Thyroid Na+/I- symporter. Mechanism, stoichiometry, and specificity.

Cotransport of Water by the Na + /glucose Cotransporter

Glucose transport by human renal Na+/d-glucose cotransporters SGLT1 and SGLT2