Hypoglycaemia accumulation

Exercise is an essential yet neglected aspect of treatment for type 2 diabetes especially in its early stages where insulin resistance may predominate. Accumulation of at least 30 0 minutes of moderate physical activity on most days of the week is recommended. For type 1 diabetes the emphasis must be on adjusting the therapeutic regimen to allow safe sports participation to prevent precipitation of ketoacidosis or hypoglycaemia. Extra care is required in cases with known complications like proliferative retinopathy, nephropathy, foot ulcers and cardiac or peripheral vascular disease. 

Glycogen synthase Enlarged liver, accumulation of fat (fatty liver) fasting hypoglycaemia occasional muscle cramping... 

Primary carnitine deficiency is caused by a deficiency in the plasma-membrane carnitine transporter. Intracellular carnitine deficiency impairs the entry of long-chain fatty acids into the mitochondrial matrix. Consequently, long-chain fatty acids are not available for p oxidation and energy production, and the production of ketone bodies (which are used by the brain) is also impaired. Regulation of intramitochondrial free CoA is also affected, with accumulation of acyl-CoA esters in the mitochondria. This in turn affects the pathways of intermediary metabolism that require CoA, for example the TCA cycle, pyruvate oxidation, amino acid metabolism, and mitochondrial and peroxisomal -oxidation. Cardiac muscle is affected by progressive cardiomyopathy (the most common form of presentation), the CNS is affected by encephalopathy caused by hypoketotic hypoglycaemia, and skeletal muscle is affected by myopathy. 

Hereditary fructose intolerance is caused by an autosomal recessive hereditary defect of the enzyme fructose-l-phosphate aldolase. Whenever fructose is supplied, severe hypoglycaemia and functional disorders occur in the liver, kidneys and CNS. The prevalence is estimated at 1 20,000 births. As with galactose intolerance, the gene which codes aldolase B is also localized on chromosome 9. This enzyme defect causes fructose-l-phosphate to accumulate in the liver and tissue. The cleavage of fructose-1,6-biphosphate is only slightly compromised since the enzymes aldolase A and C are available for this process. The consumption of phosphate and ATP in the tissue results in various functional disorders (i.) inhibition of gluconeogenesis in the liver and kidneys, (2.) increase in lactate in the serum with metabolic acidosis, (3.) decrease in protein synthesis in the liver, and (4.) functional disorders of the proximal tubular cells with development of Fanconi s syndrome, (s. pp 593, 594) (193, 194, 196, 198)... 

In the elderly patient, the elimination half-life is significantly increased for most sulphonylureas, although this effect is compensated by reduced absorption and volume of distribution. Owing to the mainly hepatic elimination of the sulphonylureas, their accumulation and therefore hypoglycaemia may be expected. Nevertheless, the clinical significance of this accumulation is questionable, since the metabolic function of the liver is maintained even in severe liver diseases, and elimination of the metabolites... 

A 58-year-old woman with longstanding type 2 diabetes taking metformin 500 mg twiee daily developed serious acute renal failure and lactic acidosis one month after starting rofecoxib. She made a full recovery. Rofecoxib could have precipitated acute renal failure, which would lead to the accumulation of metformin, and metformin-associated lactic acidosis. For a case of hypoglycaemia attributed to ramipril and naproxen-induced renal failure in a patient taking metformin and glibenclamide, see Glibenclamide, below. 

Naproxen. A case of severe hypoglycaemia in a diabetic patient was attributed to the accumulation of glibenclamide and metformin due to deterioration in renal function caused by the concurrent use of ramipril and naproxen. ... 

Chloramphenicol inhibits the liver enzymes concerned with the metabolism of tolbutamide, and probably chlorpropamide as well, leading to their accumulation in the body. This is reflected in prolonged half-lives, reduced blood glucose levels and occasionally acute hypoglycaemia. " ... 

Figure 26.4 GSD III, Cori s disease. This is named after husband and wife, Carl and Gerty Cori (so note the apostrophe if you prefer Coris s disease). GSD III is caused by a deficiency of debranching enzyme so liinit dextrin accumulates, which is an abnormal form of glycogen where the branches are reduced to a-(l —>6) stumps. GSD III presents with hypoglycaemia and hepatomegaly.

Figure 26.6 GSD I, von Gierke s disease. GSD I (autosomal recessive) is caused by hepatic glucose 6-phosphatase deficiency so the liver loses its ability to prevent hypoglycaemia. Neonatal hypoglycaemia can be severe and glycogen is stored in excess in the liver and kidney. Other features that are a consequence of accumulation of glucose 6-phosphate are hyperlactataemia, hyperlipidaemia, hyperuricaemia and gout.

Biotin. Biotin deficiency blocks pyruvate carboxylase resulting in an accumulation of pyruvate and lactate. It suppresses gluconeogenesis and causes fasting hypoglycaemia. 

Two less frequent types of brain oedema merit mentioning in cases of severe hypoglycaemia, due to insulin shock, oedema associated with pallor of white matter in corresponding myelin stains has been demonstrated [19]. This may find its explanation in the decrease of cerebral phospholipids demonstrated in rats subjected to experimental hypoglycaemia [20]. Brain oedema has also been observed in children afflicted with galactosaemia. In these cases, it is ascribed to osmotic action of the accumulated galactitol (dulcitol) [21,22]. 

For example, the NADH excess produced by the actions of alcohol and aldehyde dehydrogenases depletes NAD" " levels and thus inhibits ghicnneogenesis by the tricarboxylic add (TCA) cyde by blocking conversion of ladate to pymvate. In fact, the reverse reaction can be favoured, leading to accumulation of lactate. The overall effed of this is a lowering of blocxl pH and hypoglycaemia. This becomes more pronounced in individuals with low levels of stored glycogen. 

Propionyl-CoA is the key intermediate in the formation of the majority of the abnormal urinary metabolites observed in propionic acidaemia and is also responsible for the accumulation of odd-carbon-number fatty acids and abnormal triglycerides and lipids in the disease by competition with acetyl-CoA in fatty acid biosynthesis. The metabolite may also inhibit other enzyme systems, particularly in mitochondria, giving rise to other symptoms. Inhibition of A -acetylglutamate synthetase has been used to explain the hyper-ammonaemia that is frequently observed in patients with propionic acidaemia (Coude et al., 1979), sometimes occurring as the major presenting biochemical abnormality (Harris et ai, 1980). Inhibition of other enzyme systems and of mitochondrial function by propionyl-CoA may well also be responsible for the occasional occurrence of hypoglycaemia in the diseases. Propionyl-CoA accumulation is also Important in the biochemical and clinical presentation of patients with methylmalonic aciduria, the disease described in the next section (11.2). 

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