SGLT 2 and renal absorption of glucose in the kidney

The importance of the kidney's role in glucose homeostasis has gained wider understanding:

• the development of a pharmacological class of anti-diabetes agents targeting the kidney has provided additional treatment options for the management of type 2 diabetes mellitus (T2DM)
  • sodium glucose co-transporter type 2 (SGLT2) inhibitors decrease renal glucose reabsorption, which results in enhanced urinary glucose excretion and subsequent reductions in plasma glucose and glycosylated haemoglobin concentrations

Filtration and the reabsorption of glucose in the kidney

• healthy individuals are able to maintain tight glucose homeostasis by closely regulating glucose production, reabsorption, and utilization
  
  
• in people without diabetes, about 180 g of glucose is filtered daily by the renal glomeruli, and is then reabsorbed in the proximal convoluted tubule (PCT)
  • this is achieved by passive transporters - facilitated glucose transporters (GLUTs), and active co-transporters - sodium-glucose co-transporters (SGLTs). There are six identified SGLTs, of which two (SGLT1 and SGLT2) are considered most important
  • glycosuria (i.e., the excretion of glucose through the kidneys) only occurs if the maximal capacity of various glucose transporter proteins (350 mg glucose/min) is exceeded. This used to be considered a marker of pathology, but another explanation is that by preventing excessive rises in blood glucose levels, glucuresis mitigates the adverse effects associated with hyperglycaemia
    
    
• sodium-glucose co-transporter-2 inhibitors work by inhibiting SGLT2 in the PCT, to prevent reabsorption of glucose and facilitate its excretion in urine
  
  
• as glucose is excreted, its plasma levels fall leading to an improvement in all glycemic parameters
  • this mechanism of action is dependent on blood glucose levels, and is independent of the actions of insulin. Therefore, there is minimal potential for hypoglycaemia and no risk of overstimulation or fatigue of beta cells. Because their mode of action relies upon normal renal glomerular-tubular function, SGLT2i efficacy is reduced in people with renal impairment.[1]
  • glucose is filtered through the tubule and then transported via the tubular epithelial cells through the basolateral membrane into the peritubular capillary. Under optimal conditions, when tubular glucose load is approximately 120mg/min or less, there is no glucose loss in urine
    • however, when the glucose load exceeds approximately 220mg/min (glucose threshold), glucose starts to appear in the urine
      
      
• glycosuria associated with SGLT2 inhibitor use is associated with a net calorie loss of approximately 200-300kcla/day,[2] which in turn leads to a reduction in body weight, ranging from 1 to 5kg, partly through volume depletion but also through loss of fat mass.[1]
  
  
• SGLT2 inhibitors also induce a mild osmotic diuresis (voiding of an additional 400ml/day), which is thought to explain decreases in systolic blood pressure of 2-5mmHg associated with SGLT2i therapy.[3]

Notes:

• the maximum renal capacity for tubular reabsorption (Tm) of glucose is greater in animal models with type 1 and type 2 diabetes
  • in people with type 1 diabetes, Mogensen et al. showed that the glucose Tm is increased. Conflicting results have been reported in patients with type 2 diabetes
  • clinically, the most common cause of glycosuria is diabetes
    • patients do not excrete glucose in the urine until the concentration of blood glucose is over 180mg/dl, which does not normally occur in people without diabetes
• transepithelial glucose transport involves the two classes of glucose transporters, SGLTs and facilitative diffusion glucose transporters (GLUTs)
  • renal glucose reabsorption occurs mainly in the S1 segment of the proximal tubule by the coordinated action of the SGLT2 and GLUT2 located in the luminal and basolateral membranes, respectively
  • only a small and residual amount of glucose is reabsorbed in the S3 segment, where SGLT1 is present in the luminal membrane, co-expressed with GLUT1 in the basolateral membrane
  • intestinal glucose absorption occurs mostly in the duodenum and in the initial portion of the jejunum, and involves the co-expression of SGLT1 and GLUT2
    • in all these processes, SGLTs present in the luminal membrane transport glucose from the lumen into the intracellular medium, where glucose accumulates generating a gradient that favors its transport through the GLUTs in the basolateral membrane, from the cytoplasm to the interstitium

Reference:

• 1. Kalra S. Sodium Glucose Co-Transporter-2 (SGLT2) inhibitors: A review of their basic and clinical pharmacology. Diabetes Ther 2014;5(2):355-366
• 2. MacEwen A, McKay GA, Fisher M. Drugs for diabetes: paart 8 SCGLT2 inhibitors. Br J Cardiol 2012;19:26-9
• 3. Bailey AV, Day C. The role of SGLT2 inhibitors in type 2 diabetes. Br J Fam Med 2014;2(4). https://www.bjfm.co.uk/media/6893/bjfm_july_29-30_32-33_diabetes.pdf
• 4. Mogensen CE. Maximum tubular reabsorpiton capacity for glucose and renal hemodynamics during rapid hypertonic glucose infusion in normal and diabetic subjects. Scan J Clin Lab Invest 1971;28:101-9.