Tuesday, November 13, 2012

FATE OF INTRACELLULAR GLUCOSE

(Source: Clinical Biochemistry, Marshall 4th Edition)

Hexokinase and glucokinase reaction traps glucose as G 6-phosphate inside cell since GLUTs are bidirectional.

Hexokinase types I-III (isozymes, named according to their electrophoretic mobility) are widely distributed and have low Km 10-6 to 10-1 but hexokinase IV (glucokinase, predominantly expressed in liver and beta cells) has high Km (upto 280 mg/dL) so it sense glucose when it reaches beyond physiological range and this determines rate of insulin secretion from β-cells.
These hexokinases I, II, III undergo allosteric feedback inhibition by their product G 6-phosphate but not IV.

Hexokinase I - highest amount in brain and kidney and significantly associated with mitochondria.

Hexokinase II - predominant in insulin responsive skeletal muscle and adipose tissue and is mostly cytosolic. Exercise, insulin and catecholamines all induce hexokinase II mRNA.

Hexokinase III - predominant in spleen and lymphocytes

Hexokinase IV - stimulated by insulin and glucose in beta cells and inhibited by cAMP in liver. In liver glucokinase is sequestered in nucleus by glucokinase regulatory protein when extracellular glucose is low but when glucose is high and insulin is released this comes to cytosol.

This glucose uptake/utilization and hexokinase activity is found to be diminished or defective in diabetics or those with familial history of diabetes. The condition of hyperglycemia is more severe in case of defect in beta cell hexokinase IV. Hexokinases might be a potential candidate gene in T-2 DM

Loss of function mutation of glucokinase is responsible for maturity onset diabetes of young (MODY).

Note: G 6-phosphatase mainly found in liver and kidney can dephosphorylate and release glucose. This is necessary for release of glucose by gluconeogenesis by liver and renal cells during hypoglycemia or during hypo-insulinemic condition, starvation. This is absent in muscle so muscle do not contribute to blood glucose. Its activity inhibited by insulin and glucose and this inhibit the endogenous glucose production during fed state. This enzyme is induced by glucagon and glucocorticoid. The enzyme G 6-phosphatase tanslocase transport G 6-phosphate from cytoplasm to lumen of ER where G 6-phosphatase is located. Deficiency of this enzyme or its translocase causes Type 1 glycogen storage disease (von Gierke’s disease). In T-2 diabetes, due to relative insulin-insensitivity, it is overactive and there is increased hepatic glucose production. Metformin and thiazolidinediones reduces the activity of G 6-phosphatase. 

After entering the cell and being phosphorylated glucose undergoes various pathways.

1.      Undergo glycolysis and TCA cycle
2.      Undergo pentose phosphate pathway
3.      Metabolized anaerobically to produce lactate
4.  Used to synthesize glycerol, carbon skeleton of non-essential amino acids, glycoproteins, glycolipids, acetyl CoA formed is used to synthesize fatty acids)
5.      Stored as glycogen.

PDH (which is required for oxidation of pyruvate) in muscle is stimulated by exercise and in most tissues by insulin, but this stimulation is reduced in diabetes. PDH inactivation by PDK kinase activity is enhanced in insulin resistance and T-2 diabetes because insulin activates PDH kinase and here there is insulin insensitivity, so glucose cannot enter TCA. Mitochondrial diseases have been reported to cause insulin resistance or diabetes as fuel oxidation occurs here. E.g. DIDMOAD syndrome (Diabetes insipidus, Diabetes mellitus, optic atrophy and deafness). Mutation in mitochondrial DNA is suggested to account for 1% diabetes.

Note: Glyceraldehyde 3 phosphate dehydrogenase apart from glycolysis, in membrane it is involved in endocytosis, in cytoplasm participates in control of gene expression, and in nucleus it is involved in DNA replication and repair. Its blockage or defect is also found to cause protein glycation.

It is postulated that increased availability of substrates like FFA or ketone bodies, entering the TCA via acetyl-CoA may lead to excess generation of citrate, with consequent inhibition of PFK, thus shunting glucose down alternative non-oxidative pathways (the glucose-FFA or Randle cycle). This leads to diminished glucose oxidation as seen in diabetes.
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