Disorders of carbohydrate metabolism

Many disorders of carbohydrate metabolism are characterized by hypoglycaemia and attacks of neuroglycopenia. Hypoglycaemia can also be caused by disorders affecting the use of other fuels, such as those producing fatty acids and ketone bodies which are important alternative sources of energy. Thus when investigating a patient with hypoglycaemia it is necessary to investigate not only pathways that provide glucose directly, but also those which spare glucose utilization and thus provide defence mechanisms when carbohydrate energy sources become depleted. The defence mechanisms that are activated during fasting to preserve blood glucose are: ◆ glycogenolysis—glucose liberation from glycogen degradation ◆ gluconeogenesis—glucose production from pyruvate/lactate and from noncarbohydrate sources such as glucogenic amino acids and glycerol ◆ fatty acid β‎-oxidation—catabolism of triglycerides to acetyl-CoA and ketone bodies The interrelation between these glucose generating pathways is shown in Fig. 12.3.1.1. Although there is much overlap, the activation of these defence mechanisms during fasting is sequential. The first defence mechanism, glycogenolysis, is exhausted within 8–12 h of fasting. The second and third defence mechanisms provide glucose once glycogen stores have been depleted. In a patient with glycogen storage disease (GSD) where glycogenolysis is blocked, gluconeogenesis and fatty acid oxidation are activated immediately on fasting and can only maintain normoglycaemia for a few hours. In patients with defects affecting gluconeogenesis or fatty acid oxidation, hypoglycaemia does not occur until glycogen stores have been depleted. When more than one pathway is affected, as in GSD I, where neither glycogenolysis nor gluconeogenesis can release glucose into the circulation, patients can be entirely dependent on oral carbohydrate intake to maintain normoglycaemia. These pathways are also susceptible to hormonal influences. Insulin in particular inhibits all three pathways and stimulates some enzymes of the reverse pathways: glycogen synthesis, glycolysis, and fatty acid synthesis. Therefore hyperinsulinaemia of whatever cause leads to severe hypoglycaemia which is resistant to treatment. Other hormones, such as glucagon, adrenaline, and growth hormone, also activate some enzymes of glucose homoeostasis, though less markedly. This is discussed elsewhere. The metabolism of the other monosaccharides, galactose and fructose, is connected with that of glucose. As well as causing hypoglycaemia, inherited defects that affect the metabolism of these sugars lead to the accumulation of toxic metabolites which also contribute to pathology (see below).