Diabetes aktuell 2013; 11(2): 68-76
DOI: 10.1055/s-0033-1347026
Schwerpunkt
© Georg Thieme Verlag Stuttgart · New York

Glukoseregulation der Niere und SGLT2-Inhibition – Neue therapeutische Optionen bei Diabetes mellitus

Regulation of Glucose in the Kidney an SGLT2-Inhibition
Stephan Martin
1   Westdeutsches Diabetes- und Gesundheitszentrum, Düsseldorf
› Author Affiliations
Further Information

Publication History

Publication Date:
13 May 2013 (online)

Die Niere ist ganz wesentlich an der Glukosehomöostase durch Glukoneogenese, Clearance und Degradation des zirkulierenden Insulins sowie die Rückresorption von Glukose aus dem Glomerulumfiltrat beteiligt. Diese Erkenntnisse haben dazu beigetragen, ein innovatives Therapiekonzept zur Reduktion der Blutglukose zu entwickeln. Dieses basiert auf der Inhibition der durch Natrium-abhängige Glukose-Co-Transporter-2 (SGLT-2 / sodium dependent glucose co-transporter-2) mediierten Glukoserückresorption in der Niere. Die umfangreichste publizierte Studienlage liegt für den SGLT2-Inhibitor Dapagliflozin vor, der seit kurzem auf dem deutschen Markt verfügbar ist. Mit Canagliflozin steht eine weitere Substanz kurz vor der Markteinführung, Empagliflozin wird im kommenden Jahr folgen. Die Substanzgruppe zeigt in den bisherigen Studien bei Typ-2-Diabetes eine HbA1c-Senkung bei Gewichtsabnahme und geringer Hypoglykämiegefahr. In der klinischen Routine wird sich zeigen, ob die erhöhte Rate an Harnwegs- bzw. Genitalinfektionen ein generelles Problem darstellt. Die Glukoseausscheidung über den Harn bewirkt eine leichte osmotische Diurese. Ist ein Patient nicht Hypotonie- oder Hypovolämie-gefährdet, kann er durch die blutdrucksenkende Wirkung der SGLT2-Inhibition zusätzlich profitieren. Aufgrund der zum Teil unzureichenden Blutdruckeinstellung bei Personen mit Typ-2-Diabetes kann die blutdrucksenkende Wirkung der SGLT2-Inhibition, die sich in einigen Studien zeigte, zusätzlichen therapeutischen Nutzen bieten.

The kidney is involved in the glucose homoeostasis by regulating gluconeogenesis, clearance and degradation of circulating insulin, as well as reabsorption of glucose from the glomerular filtrate. Recent research findings have contributed to the development of an innovative therapeutic concept to reduce blood glucose levels based on the inhibition of SGLT-2 mediated glucose reabsorption in the kidney. The largest number of clinical studies is published for the SGLT-2 inhibitor dapagliflozin, that was introduced into the German market recently. Canagliflozin is the next product that will be launched, Empagliflozin will follow later. The SGLT-2 inhibitors show in the published trials a reduction of HbA1c together with weight loss and a low risk of hypoglycaemia. The agent's use in the clinical routine will show whether the increased incidence of urinary tract infections and genital infections is a general problem. The elimination of glucose via the urine produces a slight degree of os-motic diuresis. Patients not at risk of hypotension or volume depletion may also draw an additional benefit from the antihypertensive effect produced by SGLT-2 inhibition. In persons with type 2 diabetes with inadequate blood-pressure control, the antihypertensive effect of SGLT2 inhibition shown in several studies may hence be an additional therapeutic benefit.

 
  • Literatur

  • 1 Gerich JE, Meyer C, Woerle HJ, Stumvoll M. Renal gluconeogenesis: its importance in human glucose homeostasis. Diabetes Care 2001; 24: 382-391
  • 2 Nurjhan N, Bucci A, Perriello G et al. Glutamine: a major gluconeogenic precursor and vehicle for interorgan carbon transport in man. J Clin Invest 1995; 95: 272-277
  • 3 Krebs HA. Renal gluconeogenesis. Adv Enzyme Regul 1963; 1: 385-400
  • 4 Biava C, Grossman A, West M. Ultrastructural observations on renal glycogen in normal and pathologic human kidneys. Lab Invest 1966; 15: 330-356
  • 5 Meyer C, Dostou J, Nadkarni V, Gerich J. Effects of physiological hyperinsulinemia on systemic, renal, and hepatic substrate metabolism. Am J Physiol 1998; 275: 915-921
  • 6 Stumvoll M, Chintalapudi U, Perriello G et al. Uptake and release of glucose by the human kidney. Postabsorptive rates and responses to epinephrine. J Clin Invest 1995; 96: 2528-2533
  • 7 Bowman RH. Gluconeogenesis in the isolated perfused rat kidney. J Biol Chem 1970; 245: 1604-1612
  • 8 Cersosimo E, Garlick P, Ferretti J. Renal substrate metabolism and gluconeogenesis during hypoglycemia in humans. Diabetes 2000; 49: 1186-1193
  • 9 Cersosimo E, Garlick P, Ferretti J. Renal glucose production during insulin-induced hypoglycemia in humans. Diabetes 1999; 48: 261-266
  • 10 Meyer C, Dostou JM, Gerich JE. Role of the human kidney in glucose counterregulation. Diabetes 1999; 48: 943-948
  • 11 Valera Mora ME, Scarfone A, Calvani M, Greco AV, Mingrone G. Insulin clearance in obesity. J Am Coll Nutr 2003; 22: 487-493
  • 12 Sato H, Terasaki T, Mizuguchi H, Okumura K, Tsuji A. Receptor-recycling model of clearance and distribution of insulin in the perfused mouse liver. Diabetologia 1991; 34: 613-621
  • 13 Rabkin R, Ryan MP, Duckworth WC. The renal metabolism of insulin. Diabetologia 1984; 27: 351-357
  • 14 Fischer KF, Lees JA, Newman JH. Hypoglycemia in hospitalized patients. Causes and outcomes. N Engl J Med 1986; 13: 1245-1250
  • 15 Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern Med 2007; 261: 32-43
  • 16 Lee WS, Kanai Y, Wells RG, Hediger MA. The high affinity Na+/glucose cotransporter. Re-evaluation of function and distribution of expression. J Biol Chem 1994; 22: 12032-12039
  • 17 Persson P, Hansell P, Palm F. Tubular reabsorption and diabetes-induced glomerular hyperfiltration. Acta Physiol 2010; 200: 3-10
  • 18 Hediger MA, Coady MJ, Ikeda TS, Wright EM. Expression cloning and cDNA sequencing of the Na+/glucose co-transporter. Nature 1987; 330: 379-381
  • 19 van den Heuvel LP, Assink K, Willemsen M, Monnens L. Autosomal recessive renal glucosuria attributable to a mutation in the sodium glucose cotransporter (SGLT2). Hum Genet 2002; 111: 544-547
  • 20 Calado J, Sznajer Y, Metzger D et al. Twenty-one additional cases of familial renal glucosuria: absence of genetic heterogeneity, high prevalence of private mutations and further evidence of volume depletion. Nephrol Dial Transplant 2008; 23: 3874-3879
  • 21 DeFronzo RA, Simonson D, Ferrannini E. Hepatic and peripheral insulin resistance: a common feature of type 2 (non-insulin-dependent) and type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1982; 23: 313-319
  • 22 Meyer C, Woerle HJ, Dostou JM, Welle SL, Gerich JE. Abnormal renal, hepatic, and muscle glucose metabolism following glucose ingestion in type 2 diabetes. Am J Physiol Endocrinol Metab 2004; 287: 1049-10456
  • 23 Stumvoll M, Meyer C, Perriello G et al. Human kidney and liver gluconeogenesis: evidence for organ substrate selectivity. Am J Physiol 1998; 274: 817-826
  • 24 Bakris GL, Fonseca VA, Sharma K, Wright EM. Renal sodium-glucose transport: role in diabetes mellitus and potential clinical implications. Kidney Int 2009; 75: 1272-1277
  • 25 Mogensen CE. Maximum tubular reabsorption capacity for glucose and renal hemodynamcis during rapid hypertonic glucose infusion in normal and diabetic subjects. Scand J Clin Lab Invest 1971; 28: 101-109
  • 26 Derlacz RA, Hyc K, Usarek M et al. PPAR-gamma-independent inhibitory effect of rosiglitazone on glucose synthesis in primary cultured rabbit kidney-cortex tubules. Biochem Cell Biol 2008; 86: 396-404
  • 27 Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010; 375: 2223-2233
  • 28 Bailey CJ, Gross JL, Hennicken D et al. Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102-week trial. BMC Med DOI: 10.1186/1741-7015-11-43. 2013; 11
  • 29 Nauck MA, Del Prato S, Meier JJ et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care 2011; 34: 2015-2022
  • 30 Strojek K, Yoon KH, Hruba V et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial. Diabetes Obes Metab 2011; 13: 928-938
  • 31 Wilding JPH, Woo V, Soler NG et al. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin. Ann Intern Med 2012; 156: 405-415
  • 32 Rosenstock J, Vico M, Wei L, Salsali A, List JF. Effects of Dapagliflozin, a Sodium-Glucose Cotransporter-2 Inhibitor, on Hemoglobin A1c, Body Weight, and Hypoglycemia Risk in Patients With Type 2 Diabetes Inadequately Controlled on Pioglitazone Monotherapy. Diabetes Care 2012; 35: 1473-1478
  • 33 Bolinder J, Ljunggren Ö, Kullberg J et al. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab Epub 2012 Jan 11 2012; 97
  • 34 Rosenstock J, Aggarwal N, Polidori D et al. Canagliflozin DIA 2001 Study Group. Dose-Ranging Effects of Canagliflozin, a Sodium-Glucose Cotransporter 2 Inhibitor, as Add-On to Metformin in Subjects With Type 2 Diabetes. Diabetes Care Epub 2012 Apr 9 2012; 35
  • 35 Ferrannini E, Seman L, Seewaldt-Becker E et al. A Phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes. Diabetes Obes Metab DOI: 10.1111/dom.12081. [Epub ahead of print] 08.02.2013;
  • 36 Musso G, Gambino R, Cassader M, Pagano G. A novel approach to control hyperglycemia in type 2 diabetes: Sodium glucose co-transport (SGLT) inhibitors. Systematic review and meta-analysis of randomized trials. Ann Med 2012; 44: 375-393
  • 37 Bailey CJ, Iqbal N, T'joen C, List JF. Dapagliflozin monotherapy in drug-naïve patients with diabetes: a randomized-controlled trial of low-dose range. Diabetes Obes Metab 2012; 14: 951-959
  • 38 Stenlöf K, Cefalu WT, Kim KA et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab (online 26.12.2012) 2012;