Tuesday, November 13, 2012

GLUCOSE TRANSPORTERS

Glucose uptake is mediated by energy independent process of facilitated diffusion down its concentration gradient involving glucose transporters (GLUTs) and against the concentration gradient involving sodium-glucose cotransporters (SGLTs). GLUTs composed of 12 membrane spanning helices with intracellular loop connecting the 6th and 7th helices. The facilitative transport of glucose is saturable, stereoselective and bidirectional.

GLUT-1:


  1. Ubiquitous: e.g. RBC, placenta, colon, kidneys. It is the major GLUT in fetus and tissue culture cells.
  2. Low Km (35-90 mg/dl)
  3. Facilitated diffusion.
  4. Liver, adipose tissue, muscle cell also expresses GLUT1 & 3 during starvation.
  5. Dysfunction can cause hypoglycorrachia (low CSF glucose), but normal blood glucose.

 GLUT-2:


  1.  Liver, intestine kidneys, beta cells.
  2.  High Km (about 450 mg/dl) and high Vmax
  3.  Facilitated diffusion and bidirectional.
  4.  Major glucose sensor.
  5.  In humans, an inactivating mutation of GLUT2 is present in Fanconi-Bickel syndrome, a rare autosomal recessive disorder of carbohydrate metabolism, characterized by fasting hypoglycemia, hepatorenal glycogen accumulation, glucose and galactose intolerance, and a characteristic proximal tubular nephropathy.

 GLUT-3:


  1.  Ubiquitous: E.g. brain, placenta, kidneys.
  2.  Lowest Km 
  3.  Facilitated diffusion of glucose in brain
§              Liver, adipose tissue, muscle cell also expresses GLUT-1 & 3 during starvation.

 GLUT-4:


  1. Skeletal muscle, adipocytes, heart
  2. Low Km (36-90 mg/dl)
§            Facilitated diffusion and insulin stimulated glucose transport.

 GLUT-5:


  1.  Jejunum
  2.  Facilitated diffusion of fructose not glucose
Fig. How Glucose is transported in intestine ?

Na+-GLUCOSE COTRANSPORTERS (SGLT family)


  • 14 Tm alpha helices. Two isoforms described SGLT1 and 2.
  • Intestine (SGLT1) responsible of dietary uptake of glucose and galactose. Renal tubules (SGLT2) responsible of glucose uptake from proximal tubule.
  •  Move glucose against concentration gradient
  •  Actively transports glucose using Na+ gradient.
Class-I GLUTs consists of high affinity GLUT 1, 3 and 4 and low affinity GLUT2. GLUT 5, 9, 11, 17 are class-II having high affinity for fructose and other transporter whose function is unknown (GLUT6-14).

GLUT1 and 3 are always present in cell surface whereas GLUT4 are present in cytoplasm when insulin is absent. But when insulin is present they are expressed out and increase in number 6-10 folds. When insulin level decline these are sequestered by phagocytosis ready for recycling.

In T2DM there is Insulin resistance syndrome and glucose resistance. Insulin resistance is caused by unresponsiveness of GLUT4 to insulin, also mutation of GLUT1 and 2 are also associated. The insulin sensitizing agents’ metformin and thiazolidinediones increases expression of GLUT4 as does physical exercise.

Uptake of glucose by these transporters is along concentration gradient as intracellular glucose is actively metabolized by hexokinase and glucokinase. In resting post absorptive state about 70% glucose is metabolized by insulin independent manner. This insulin dependent and mostly independent mechanism is impaired in Type 2 DM and in normoglycaemic subjects with family history of diabetes (glucose resistance).

Na+ glucose cotransporters are responsible for active glucose transport in renal tubules and intestinal epithelia by at least 3 known sodium-glucose cotransporters (SGLT1-3). SGLT1 mutation is associated with glucose-galactose malabsorption syndrome that cause fatal infantile diarrhea. Mutation in SGLT2 is associated with renal glycosuria.

Insulin mediated glucose transport is the rate limiting step for glucose metabolism. This uptake defect is the cause of reduced insulin sensitivity seen in T-2 diabetes. Either GLUT4 are unresponsive to insulin or are not expressed. The insulin sensitizing agents like metformin and thiazolidinedione and exercise increases expression of GLUT1, 4.  
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