Diabetic ketoacidosis is characterised by marked elevations of catabolic counter-regulatory hormone concentrations:
These increases, often in concert with elevated levels of inflammatory cytokines, occur in the presence of an absolute or relative deficiency of insulin. While insulin may be measurable in plasma it is, by definition, insufficient to maintain a normal metabolic state. Insulin resistance, a reduced biological action of the hormone, is acutely increased in diabetic ketoacidosis, compounding any deficiency in circulating insulin. In patients with type 2 diabetes, residual endogenous insulin secretion serves to protect against ketoacidosis (see Chapter 3). However, suppression of b-cell insulin secretion by catecholamines (via a-adrenergic receptors) may occasionally precipitate ketoacidosis during acute severe illness; this may be especially true of patients with type 2 diabetes of long duration in whom b-cell function may be more compromised. A practical rule of thumb is to regard any patient with insulin-treated diabetes as having major insulin deficiency. This has implications for the management of diabetes during severe intercurrent illness, trauma and surgery (see Chapter 7).
Severe intercurrent illness may precipitate ketoacidosis in patients with type 2 diabetes.
Under experimental conditions, withdrawal of insulin from insulin-dependent patients leads to an early rise in plasma glucagon. As hyperglycaemia and ketoacidosis develop, progressive dehydration and acidosis stimulate the release of catecholamines (adrenaline and nor-adrenaline) and Cortisol. A vicious circle develops in which worsening metabolic decompensation stimulates further secretion of catabolic hormones. Hepatic overproduction of glucose and ketone bodies initiates hyperglycaemia and ketosis, while impaired disposal by peripheral tissues such as muscle and brain maintains and exacerbates hyperglycaemia and hyperketonaemia. The rate of glucose production subsequently decreases towards normal but hyperglycaemia is maintained as the rates of production and utilisation become equal. Insulin withdrawal also results in a progressive increase in ketone body production and utilization. However, the former exceeds the latter, resulting in a progressive rise in plasma ketone bodies.
Insulin deficiency with elevated counter-regulatory hormones initiates hyperglycaemia and ketosis
We will now consider the biochemical disturbances in more detail.
• Hyperglycaemia. Insulin deficiency and elevated plasma levels of catabolic hormones, particularly glucagon and catechol-amines, result in increased rates of hepatic glycogenolysis and gluconeogenesis; in addition, renal gluconeogenesis is enhanced by acidosis, although it contributes quantitatively less to hyperglycaemia. Glucose disposal by tissues such as skeletal muscle and adipocytes is reduced by insulin deficiency; elevated plasma levels of catabolic hormones and non-esterified fatty acids with acidosis induce insulin resistance.
• Hyperketonaemia. In ketoacidosis, serum ketone body levels are often raised to 200-300 times their normal fasting values. Ketone bodies are strong organic acids that are fully dissociated at physiological pH. In turn, this results in equimolar generation of hydrogen ions (H+) outstripping the buffering capacity of fluids and tissues. Metabolic acidosis has a number of serious detrimental physiological effects that account for many of the serious clinical features of ketoacidosis:
o negative inotropic effect on cardiac muscle o exacerbation of systemic hypotension through vasodilatation o exacerbation of insulin resistance o increased risk of ventricular arrhythmias o respiratory depression with severe acidosis.
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