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Blood sugar control
The physiological control of blood glucose is complex. While the major role belongs to insulin, a multitude of other hormonal influences apply. It should also be remembered that insulin has other actions beyond the regulation of blood glucose.
Pharmacological control of blood glucose becomes necessary in situations of elevation and depression of blood glucose beyond the homeostatic limits, in other words due to hyperglycaemia or hypoglycaemia. The causes of failure in regulation of blood glucose are given in Figure 38.1.
| Hypoglycaemia | |
| Deficiency of glucose intake and failure of compensatory mechanisms | |
| Excess insulin | insulinoma |
| iatrogenic | |
| Hyperglycaemia | |
| Deficiency of insulin | |
| Decreased end-organ sensitivity to insulin | |
| Excess administration of glucose solutions | |
Treatment of hypoglycaemia is directed towards administration of glucose and removal of the root cause. Treatment of hyperglycaemia includes removal of the cause, administration of insulin in the acute phase and at a later stage augmentation of both the secretion and effect of endogenous insulin.
Insulin receptor
The insulin receptor is a complex of four glycoprotein subunits (ααββ) linked by disulphide bridges to form a cylinder. The α subunits are entirely extracellular and contain the insulin binding site. The β subunit spans the cell membrane, and the intracellular part has tyrosine kinase activity. The α subunit has a repressive effect on this activity that is removed by the conformational change resulting from insulin binding. The tyrosine kinase acts on insulin receptor substrate 1 (IRS-1), triggering a chain of action culminating in the activation of glycogen synthetase, phosphorylase kinase and glycogen phosphorylase. IRS-1 is also a substrate for insulin-like growth factor 1 (IGF-1) receptors. The binding of insulin to the α subunit changes the insulin receptor formation to form a transmembrane tunnel allowing glucose (and other molecules) to pass through the membrane. The activated β subunit autophosphorylates at six or more tyrosine residues and these phosphorylate intracellular proteins, resulting in second-messenger effects on fat, protein and glycogen synthesis. Insulin has a very high affinity for the insulin receptor. This may be due to subsequent binding to the second α subunit. The interaction does not conform to the law of mass action. The insulin–receptor complex is internalised and the receptors recycled, while the insulin itself is degraded in lysosomes.
Glucose
Ideally, glucose should be administered by mouth. Its rapid absorption ensures rapid correction of limited hypoglycaemia. In more severe situations, the unconscious patient requires IV administration. Dextrose 5% has little calorific value (840 kJ L–1). The treatment of hypoglycaemia usually requires a 20% dextrose solution (3.36 MJ L–1) or alternatively a 50% solution (8.4 MJ L–1). Glucose (20%) requires a large vein but can be administered peripherally, but 50% glucose should always be given via a central venous line. Both 20% and 50% solutions can cause damage to the blood vessels and are viscous. Extravasation of concentrated glucose solutions will cause local necrosis.
Glucagon
Glucagon is a polypeptide (smaller than insulin) formed in the A cells of the pancreas and also in the upper gastrointestinal tract. Glucagon has a large number of roles in the regulation of metabolism, all of which are directed to the raising of blood glucose. Although the majority of effects are physiological, glucagon has been used therapeutically in two main areas, for the rapid restoration of blood glucose in severe hypoglycaemia and in cardiogenic shock, due to its positive inotropic effect.
Insulin
Soluble (otherwise known as unmodified) insulin may be given subcutaneously or intravenously. It is short-acting and has a half-life in the circulation of 5 minutes. Subcutaneous administration results in more gradual absorption. Administration of IV insulin allows rapid control in ketoacidotic hyperglycaemia.
Long-term control of diabetes requires a variety of preparations of insulin with differing absorption characteristics for precise control. Longer-acting insulin may be obtained by the formation of insulin complexes using either zinc or protamine or both. The addition of zinc produces a crystalline insulin of intermediate action. The addition of protamine produces isophane insulin, which also has an intermediate duration of action. These insulin preparations may be mixed with soluble insulin (to make biphasic insulins), which will lessen temporal fluctuations in plasma insulin.
Long-acting insulin is produced by combination with both protamine and zinc (protamine zinc insulin). This preparation should not be mixed with soluble insulin because the soluble insulin will combine with any free protamine in the solution. Figure 38.2 gives a guide to the time-related effects of the different categories of insulin.
| Onset (hours) | Peak (hours) | Duration (hours) | |
|---|---|---|---|
| Short-acting | 0.5–1 | 2–4 | 8 |
| Intermediate-acting | 1–2 | 4–12 | 12–24 |
| Long-acting | 2–4 | 24–40 | 36 |
Insulin may be bovine, porcine or human, the animal products being purified by crystallisation. Bovine insulin has three differences from human in its amino acid sequence, and porcine one. These foreign sequences in the insulin or in impurities may be antigenic, leading to insulin resistance and immunoreactivity. To overcome this the insulin is highly purified, but alternatively human insulin may be used. This is the preferred choice in modern therapy. Human insulin is either synthesised by bacteria or created by enzymatic modification of porcine insulin.
Insulin is mainly used in the treatment of diabetes mellitus, but it may also be indicated in parenteral feeding to aid glucose utilisation.
Oral hypoglycaemic agents
Sulphonylureas
Examples – chlorpropamide, glibenclamide, gliclazide, glipizide, tolbutamide
Sulphonylurea drugs act by augmenting endogenous insulin secretion from existing B cells within the islets of Langerhans. Sulphonylureas bind to receptors on the pancreatic B cells and increase the sensitivity of the cells to glucose. The potassium permeability of B cells is reduced by blockade of the ATP-dependent potassium channel. The membrane becomes depolarised, leading to calcium influx and subsequent secretion of insulin.
In excess, sulphonylureas have the propensity to cause hypoglycaemia. Most are metabolised in the liver, resulting in the formation of active metabolites. The sulphonylureas and metabolites are excreted in the urine. They cross the placenta and can cause hypoglycaemia in the newborn. There is competition for albumin binding sites with sulphonamides, aspirin and other highly protein-bound drugs. Factors affecting the action of the sulphonylurea family are given in Figure 38.3.
| Augmented by | Phenylbutazone |
| Salicylates | |
| Alcohol | |
| Monoamine oxidase inhibitors | |
| Diminished by | Thiazides |
| Corticosteroids | |
| Oestrogens | |
| Frusemide |
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