Glucose Counterregulation in Long Standing Type 1 Diabetes

• Endogenous glucose production [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  

• Endogenous Glucose Production [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  
• Magnitude and Glycemic thresholds for counter-regulatory Hormonal and Symptom Responses [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  
• Magnitude and Glycemic thresholds for counter-regulatory Hormonal and Symptom Responses [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  

The present protocol is designed to determine whether strict hypoglycemia avoidance by real-time continuous glucose monitoring (RT-CGM), can restore endogenous glucose production in response to hypoglycemia in patients with long standing disease. Twelve subjects with long standing type 1 diabetes complicated by hypoglycemia unawareness will undergo assessment of the endogenous glucose production response to insulin-induced hypoglycemia using paired hyperinsulinemic eu- and hypoglycemic clamps with stable glucose isotope infusions before and at 6 and 18 months following initiation of RT-CGM. The primary analysis will be change in the endogenous glucose production response from before to 6 months following initiation of RT-CGM, and a secondary analysis will consider the persistence of any change at 18 months. The clinical significance of any determined changes in the endogenous glucose production response to insulin-induced hypoglycemia will be determined by comparison to responses obtained using paired hyperinsulinemic eu- and hypoglycemic clamps on one occasion in a matched control group of 12 subjects with long-standing type 1 diabetes but no hypoglycemia unawareness, and in a matched control group of 12 nondiabetic subjects.

Hypoglycemia is a major barrier to the achievement of adequate glycemic control for most patients with insulin-dependent diabetes. Type 1 diabetic patients with absolute insulin deficiency (C-peptide negative) are at greatest risk for experiencing severe hypoglycemic events because the near total destruction of insulin producing islet β-cells produces an associated defect in glucagon secretion from neighboring α-cells. Such patients then depend on the sympathoadrenal system as a final defense against hypoglycemia, but unfortunately, recurrent episodes of hypoglycemia blunt sympathoadrenal activation and produce a syndrome of hypoglycemia unawareness that is associated with a twenty-fold increased risk of life-threatening hypoglycemia. Without intact islet or sympathoadrenal (especially epinephrine) responses to hypoglycemia, these patients cannot increase endogenous (primarily hepatic) glucose production to prevent or correct low blood glucose.