Hypoglycaemia in Clinical Diabetes

NORMAL GLUCOSE HOMEOSTASIS 3Box 1.2Actions of glucagonLiver↑ Glycogenolysis↑ Gluconeogenesis↑ Extraction of alanine↑ KetogenesisNo significant peripheral actionThe metabolic effects of insulin and glucagon and their relationship to glucose homeostasisare best considered in relationship to fasting and the postprandial state (Siegal and Kreisberg,1975). In both these situations it is the relative and not absolute concentrations of thesehormones that are important.Fasting (Figure 1.1a)During fasting, insulin concentrations are reduced and glucagon increased, which maintainsblood glucose concentrations in accordance with rule 1 above. The net effect is toreduce peripheral glucose utilisation, to increase hepatic glucose production and to providenon-glucose fuels for tissues not entirely dependent on glucose. After a short (for exampleovernight) fast, glucose production needs to be 5–6 g/h to maintain blood glucose concentrations,with the brain using 80% of this. Glycogenolysis provides 60–80% and gluconeogenesis20–40% of the required glucose. In prolonged fasts, glycogen becomes depletedand glucose production is primarily from gluconeogenesis, with an increasing proportionfrom the kidney compared to the liver. In extreme situations renal gluconeogenesis cancontribute as much as 45% of glucose production. Thus glycogen is the short term or ‘emergency’fuel source (rule 2), with gluconeogenesis predominating during more prolongedfasts. The following metabolic alterations enable this increase in glucose productionto occur:• Muscle: Glucose uptake and oxidative metabolism are reduced and fatty acid oxidationincreased. Amino acids are released.• Adipose tissue: There are reductions in glucose uptake and triglyceride storage. Theincrease in the activity of the enzyme hormone-sensitive lipase results in hydrolysisof triglyceride to glycerol (a gluconeogenic precursor) and fatty acids, which can bemetabolised.• Liver: Increased cAMP concentrations result in increased glycogenolysis and gluconeogenesisthus increasing hepatic glucose output. The uptake of gluconeogenic precursors(i.e. amino acids, glycerol, lactate and pyruvate) is also increased. Ketone bodies areproduced in the liver from fatty acids. This process is normally inhibited by insulin andstimulated by glucagon, thus the hormonal changes during fasting lead to an increase inketone production. Fatty acids are also a metabolic fuel used by the liver and provide asource of energy for the reactions involved in gluconeogenesis.