Lipolysis during hypoglycemia in patients with typ 1 diabetes mellitus

Research project P 14298 Lipolysis During Hypoglycemia Zlatko TRAJANOSKI 26.6.2000 Background: The Diabetes Control and Complication Trail has demonstrated that intensive therapy of type 1 diabetes mellitus can prevent or delay the late complications of diabetes. However, hypoglycemia incidence is substantially increased during intensive insulin therapy and due to the increased incidence it is also the major limiting factor in achieving euglycemia. It was suggested that lipolysis (hydrolysis of triglycerides to free fatty acids (FFA) and glycerol) may help to correct hypoglycemia by increasing mobilization of glycerol and FFA and thereby inducing peripheral (muscular) insulin resistance in a late phase of hypoglycemic counterregulation, However, the contribution of lipolysis to hypoglycemic glucose counterregulation in patients with type 1 diabetes mellitus has so far not been investigated. Objective: The broad, long-term objective of this proposal is to investigate the mechanisms that regulate hypoglycemic counterregulation and their alteration in patients with type 1 diabetes mellitus by applying minimally invasive and noninvasive techniques for assessment of whole-body and regional metabolism. The specific aims are: 1) to examine the extent of systemic and regional (in muscle and adipose tissue) lipolysis during prolonged moderate hypoglycemia in healthy volunteers and in type 1 diabetes mellitus patients with good long-term metabolic control, and 2) to examine the mobilization of intramycellular lipid content during prolonged moderate hypoglycemia in healthy subjects and patients with type 1 diabetes with good long-term metabolic control. Methods: In the first series of studies we will systemically infuse stable-labeled glycerol to achieve a significant enrichment of glycerol in plasma and in interstitial fluid (ICF) of both, muscle and adipose tissue. ICF will be sampled using open-flow microperfusion in adipose and muscle tissue. Measurement of the tracer dilution will enable us to determine systemic and local glycerol appearance and disappearance. Additionally, we will perfuse locally non-selective a - and b -adrenoceptor blocking agents to block the lipolytic effects of catecholamines. In the second series of studies we will use 1H-NMR spectroscopy to measure nonivasively both intramyocellular and extramyocellular lipid content during hypoglycemia in both study groups. This studies will give significant new insights into the metabolism of key substrates during hypoglycemia and the pathophysiological alterations in patients with type 1 diabetes mellitus. A comprehensive understanding regarding how key factors interact is needed in order to develop strategies to reduce the risk of this major obstacle to successful management.