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      Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications

      Diabetic Medicine

      Blackwell Publishing Ltd

      gluconeogenesis, kidney, sodium glucose co-transporter 2, Type 2 diabetes mellitus

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          Abstract

          Abstract

          Considerable data have accumulated over the past 20 years, indicating that the human kidney is involved in the regulation of glucose via gluconeogenesis, taking up glucose from the circulation, and by reabsorbing glucose from the glomerular filtrate. In light of the development of glucose-lowering drugs involving inhibition of renal glucose reabsorption, this review summarizes these data. Medline was searched from 1989 to present using the terms ‘renal gluconeogenesis’, ‘renal glucose utilization’, ‘diabetes mellitus’ and ‘glucose transporters’. The human liver and kidneys release approximately equal amounts of glucose via gluconeogenesis in the post-absorptive state. In the postprandial state, although overall endogenous glucose release decreases substantially, renal gluconeogenesis increases by approximately twofold. Glucose utilization by the kidneys after an overnight fast accounts for ∼10% of glucose utilized by the body. Following a meal, glucose utilization by the kidney increases. Normally each day, ∼180 g of glucose is filtered by the kidneys; almost all of this is reabsorbed by means of sodium–glucose co-transporter 2 (SGLT2), expressed in the proximal tubules. However, the capacity of SGLT2 to reabsorb glucose from the renal tubules is finite and, when plasma glucose concentrations exceed a threshold, glucose appears in the urine. Handling of glucose by the kidney is altered in Type 2 diabetes mellitus (T2DM): renal gluconeogenesis and renal glucose uptake are increased in both the post-absorptive and postprandial states, and renal glucose reabsorption is increased. Specific SGLT2 inhibitors are being developed as a novel means of controlling hyperglycaemia in T2DM.

          Diabet. Med. 27, 136–142 (2010)

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          Most cited references 52

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          Sodium-Glucose Cotransport Inhibition With Dapagliflozin in Type 2 Diabetes

          OBJECTIVE Dapagliflozin, a novel inhibitor of renal sodium-glucose cotransporter 2, allows an insulin-independent approach to improve type 2 diabetes hyperglycemia. In this multiple-dose study we evaluated the safety and efficacy of dapagliflozin in type 2 diabetic patients. RESEARCH DESIGN AND METHODS Type 2 diabetic patients were randomly assigned to one of five dapagliflozin doses, metformin XR, or placebo for 12 weeks. The primary objective was to compare mean change from baseline in A1C. Other objectives included comparison of changes in fasting plasma glucose (FPG), weight, adverse events, and laboratory measurements. RESULTS After 12 weeks, dapagliflozin induced moderate glucosuria (52–85 g urinary glucose/day) and demonstrated significant glycemic improvements versus placebo (ΔA1C −0.55 to −0.90% and ΔFPG −16 to −31 mg/dl). Weight loss change versus placebo was −1.3 to −2.0 kg. There was no change in renal function. Serum uric acid decreased, serum magnesium increased, serum phosphate increased at higher doses, and dose-related 24-h urine volume and hematocrit increased, all of small magnitude. Treatment-emergent adverse events were similar across all groups. CONCLUSIONS Dapagliflozin improved hyperglycemia and facilitates weight loss in type 2 diabetic patients by inducing controlled glucosuria with urinary loss of ∼200–300 kcal/day. Dapagliflozin treatment demonstrated no persistent, clinically significant osmolarity, volume, or renal status changes.
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            Phlorizin: a review.

            The dihydrochalcone phlorizin is a natural product and dietary constituent found in a number of fruit trees. It has been used as a pharmaceutical and tool for physiology research for over 150 years. Phlorizin's principal pharmacological action is to produce renal glycosuria and block intestinal glucose absorption through inhibition of the sodium-glucose symporters located in the proximal renal tubule and mucosa of the small intestine. This review covers the role phlorizin has played in the history of diabetes mellitus and its use as an agent to understand fundamental concepts in renal physiology as well as summarizes the physiology of cellular glucose transport and the pathophysiology of renal glycosuria. It reviews the biology and pathobiology of glucose transporters and discusses the medical botany of phlorizin and the potential effects of plant flavonoids, such as phlorizin, on human metabolism. Lastly, it describes the clinical pharmacology and toxicology of phlorizin, including investigational uses of phlorizin and phlorizin analogs in the treatment of diabetes, obesity, and stress hyperglycemia. Copyright (c) 2004 John Wiley & Sons, Ltd.
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              Long-term follow-up after tight control of blood pressure in type 2 diabetes.

              Post-trial monitoring of patients in the United Kingdom Prospective Diabetes Study (UKPDS) examined whether risk reductions for microvascular and macrovascular disease, achieved with the use of improved blood-pressure control during the trial, would be sustained. Among 5102 UKPDS patients with newly diagnosed type 2 diabetes mellitus, we randomly assigned, over a 4-year period beginning in 1987, 1148 patients with hypertension to tight or less-tight blood-pressure control regimens. The 884 patients who underwent post-trial monitoring were asked to attend annual UKPDS clinics for the first 5 years, but no attempt was made to maintain their previously assigned therapies. Annual questionnaires completed by patients and general practitioners were used to follow patients who were unable to attend the clinic in years 1 through 5, and questionnaires were used for all patients in years 6 to 10. Seven prespecified aggregate clinical end points were examined on an intention-to-treat basis, according to the previous randomization categories. Differences in blood pressure between the two groups during the trial disappeared within 2 years after termination of the trial. Significant relative risk reductions found during the trial for any diabetes-related end point, diabetes-related death, microvascular disease, and stroke in the group receiving tight, as compared with less tight, blood-pressure control were not sustained during the post-trial follow-up. No risk reductions were seen during or after the trial for myocardial infarction or death from any cause, but a risk reduction for peripheral vascular disease associated with tight blood-pressure control became significant (P=0.02). The benefits of previously improved blood-pressure control were not sustained when between-group differences in blood pressure were lost. Early improvement in blood-pressure control in patients with both type 2 diabetes and hypertension was associated with a reduced risk of complications, but it appears that good blood-pressure control must be continued if the benefits are to be maintained. (UKPDS 81; Current Controlled Trials number, ISRCTN75451837.) 2008 Massachusetts Medical Society
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                Author and article information

                Journal
                Diabet Med
                Diabet. Med
                dme
                Diabetic Medicine
                Blackwell Publishing Ltd (Oxford, UK )
                0742-3071
                1464-5491
                February 2010
                : 27
                : 2
                : 136-142
                Affiliations
                University of Rochester School of Medicine Rochester, NY, USA
                Author notes
                John E. Gerich, MD, University of Rochester School of Medicine, 601 Elmwood Ave, Box MED/CRC, Rochester, NY 14642, USA. E-mail: JOHNGERICH@ 123456compuserve.com
                Article
                10.1111/j.1464-5491.2009.02894.x
                4232006
                20546255
                © 2010 The Author. Journal compilation © 2010 Diabetes UK
                Categories
                Review Article

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