The incretin hormone GLP-1, released by the gut in response to food intake, acts on beta and alpha cells in the pancreatic islets to increase insulin secretion and decrease glucagon secretion, respectively. But the glucose-lowering effects of GLP-1 are glucose dependent. This means that GLP-1 effects are attenuated at low plasma glucose concentrations. Thus, GLP-1 analogues, such as exenatide and liraglutide, and the DPP-4 inhibitors which lower glucose levels by GLP-1 mediated effects, appear to have a very low incidence of hypoglycemia in clinical trials (Figure 13.6). Avoidance of hypoglycemia, especially in comparison with sulphonylureas and insulin, is likely to be the major advantage of these newer treatments for type 2 diabetes.
Tight glycemic control is a risk factor for impaired glucose counter-regulation and hypoglycemia unawareness – lower levels of HbA1c result in a resetting of thresholds for the counter-regulatory and symptomatic responses to hypoglycemia at lower glucose concentrations. In addition, recurrent hypoglycemia exacerbates the defective responses to subsequent hypoglycemia, thus leading to a vicious circle of reduced awareness, increased vulnerability and further episodes of hypoglycemia (Figure 13.7). It is likely that the neurones that initiate the autonomic response adapt to chronic hypoglycemia by increasing glucose transporter expression and glucose uptake. Subsequent hypoglycemia then fails to produce sufficient intracellular glycopenia and therefore no longer elicits a response. There is also evidence that cortisol (released during the counter-regulatory response to hypoglycemia) dampens the hypothalamic sensing of glucose.
Most episodes of hypoglycemia can be self-treated by ingestion of glucose tablets or 20 g of carbohydrate in the form of juice, biscuits or a meal. Parenteral therapy is needed when a hypoglycemic patient is unable or unwilling (because of neuroglycopenia) to take carbohydrate orally.
Intramuscular glucagon is used by family members of patients with type 1 diabetes, but glucagon is less useful in type 2 diabetes because it stimulates insulin secretion as well as glycogenolysis. Continuous subcutaneous insulin infusion (CSII, see Chapter 10) is associated with a lower frequency of hypoglycemia than multiple insulin injection therapy and should be considered as a therapeutic option in those patients with type 1 diabetes with frequent, unpredictable hypoglycemia. Newer insulin analogues may also decrease the risk of hypoglycemia.
Suspected severe hypoglycemia (e.g. in a diabetic patient with impaired consciousness or coma) should be confirmed by blood glucose testing. It should be treated immediately with oral glucose or, if the patient is unconscious or unable to swallow safely, with intravenous glucose or intramuscular or subcutaneous glucagon injection (Figure 13.8). Patients usually recover within minutes.
|Box 13.2 General Principles for Optimizing Glycemic Control and Minimizing the Risk of Hypoglycemia
• Patient education and empowerment
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