Diurnal Profiles Compared:
Healthy vs. T1D

As expected, individuals with T1D had higher blood glucose levels than healthy, nondiabetics throughout the meal cycles (Exhibit 7).

Exhibit 7.jpg

Based on area-under-the-curve (AUC) for the diurnal glucose profiles, T1D exposure to blood glucose was 80% higher than that of nondiabetics.  The AUCs of these diurnal profiles translate into HbA1c levels of 5.4% for nondiabetics and 8.5% for T1D subjects.[1]

T1D subjects have higher average insulin in circulation than nondiabetics receive from endogenous beta-cell secretions (Exhibit 8).

Exhibit 8.jpg

Based on the insulin AUCs, T1D subjects are exposed to 65% more circulating insulin than nondiabetic subjects.  It is well documented that T1D patients are insulin resistant, i.e. display lower sensitivity to the effects of insulin in both hepatic and muscle tissue.  Also, higher circulating exogenous insulin may be needed to compensate for subphysiological levels in the liver; because about 50% of endogenous insulin is extracted by the liver before reaching circulation, endogenous insulin secretion results in intraportal concentrations about twice those in peripheral circulation.

Exhibit 8 also demonstrates that insulin pump infusions do a poor job of mimicking the diurnal profile of endogenous secretions.  In this study, the prandial rate of exogenous insulin increase in T1D appears similar to that of endogenous insulin in nondiabetics, but the rate of clearing infused insulin is slower in T1D. As a result, T1D insulin levels remain elevated at times when nondiabetic insulin concentrations have fallen to basal levels.  Breakfast and lunch peak concentrations are subnormal in T1D, probably because the risk of iatrogenic hypoglycemia constrains mealtime bolus amounts.

Because T1D patients are on average both hyperglycemic and hyperinsulinemic, current thinking in the diabetes field supposes they should demonstrate lower average circulating glucagon levels than nondiabetics do, if their alpha-cell regulation is normal.  As shown in Exhibit 9, this hypothesis is correct: T1D patients have roughly normal levels of glucagon at mealtime, but postabsorption levels are depressed.  Over a complete diurnal cycle, T1D patients are exposed to 18% less daily glucagon than nondiabetics: they are hypoglucagonemic in ABSOLUTE terms.

Exhibit 9.jpg

Since alpha-cells appear to be relatively normal in T1D, this finding that T1D subjects secrete less daily glucagon than healthy subjects points to the following conclusion: the defective counterregulatory response to hypoglycemia characteristic of T1D is NOT caused by depletion of glucagon stores in alpha-cells.  Rather, the counterregulatory defect must be intrinsic to the glucose sensing mechanisms which stimulate the alpha-cell response to hypoglycemia.

Is the T1D postabsorption deficiency in glucagon consistent with levels predicted by their hyperglycemia, if their glycemic regulation of alpha-cells were normal?  More specifically, is an 18% reduction in glucagon exposure a healthy response to an 80% increase in blood glucose exposure?  To answer this question, we need to measure the healthy, nondiabetic dose-response of glucagon to postprandial changes in blood glucose.

The healthy diurnal glucose and glucagon profiles provide the basis for considering two parameters by which circulating glucagon concentrations are determined:

  • Glycemic Alpha-Cell Regulation Model:  We first estimate the degree to which circulating glucagon levels correlate to glucose levels.  If conventional wisdom is correct, higher blood glucose should result in lower blood glucagon. (The “glycemic model.”)

  • Nonglycemic Alpha-Cell Regulation Model:  We then analyze the diurnal deviations of circulating glucagon from levels predicted by the glycemic model.  If consistent meal cycle deviations from the glycemic model are detected, these will be interpreted as indicative of non-glucose sensitive regulation of alpha-cell secretion.  (The “nonglycemic model.”)

Finally, we will combine these two models into an Integrated Alpha-Cell Regulation Model to demonstrate whether the glucagon diurnal profile can be predicted by our empirical modelling.  (The “integrated model.”)

Endnote:

[1] -- Translating the A1C Assay Into Estimated Average Glucose Values; Diabetes Care 31:1473-8 2008.