Severe hypoglycaemia in type 1 diabetes: impact of the renin-angiotensin system and other risk factors.

Hypoglycaemia is an unavoidable side effect to insulin therapy of diabetes. In daily life some hypoglycaemic episodes are recognised by the patients and corrected by ingestion of glucose, but occasionally unrecognised episodes progress into severe hypoglycaemia with cognitive impairment and the need for assistance from other persons in order to manage the situation. Such episodes represent the most feared side effect to insulin treatment and are regarded as the major limiting factor for achievement of recommended glycaemic targets in type 1 diabetes. The series of studies that constitute this thesis was conducted to assess the significance of severe hypoglycaemia as a clinical problem in the type 1 diabetic population, to evaluate the impact of known risk factors on occurrence of severe hypoglycaemia, and to identify new markers that could contribute to improved prediction of, and inspire to novel preventive measures of, severe hypoglycaemia. Our studies confirm that severe hypoglycaemia is still a major clinical problem in type 1 diabetes. The individual susceptibility to severe hypoglycaemia is highly varying and conventional risk factors - with major contribution from hypoglycaemia unawareness - only account for a limited part of this variation. Results from a case-series suggest that the use of psychoactive substances may be as significant as alcohol for promotion of risk of severe hypoglycaemia - a finding which needs to be confirmed by case-control studies. We identified elevated renin-angiotensin system activity as a novel predictor of risk of severe hypoglycaemia in type 1 diabetes with potential clinical significance. Thus, three sequential renin-angiotensin system-related risk factors were associated with severe hypoglycaemia, and by including these factors in a common model both subjects at low and at high risk within a one-year period were identified. Preliminary data suggest that this is explained by impaired capability of subjects with high renin-angiotensin system activity to maintain cognitive function during hypoglycaemia. The clinical implications of this finding which, however, must await additional independent confirmation, include prediction and possibly some prevention of severe hypoglycaemia. An evaluation of renin-angiotensin system activity may - together with assessment of other risk factors - contribute to rational individualized setting of glycaemic targets and thereby open for prevention of severe hypoglycaemia. Furthermore, subjects with elevated renin-angiotensin system activity and a high rate of severe hypoglycaemia might benefit from pharmacological blockade of the renin-angiotensin system by ACE inhibitors or angiotensin II receptor blockers or even renin blockers. This should be addressed in controlled trials.