Diurnal Pattern of Insulin Action in Type 1 Diabetes

Abstract

We recently demonstrated a diurnal pattern to insulin action (i.e., insulin sensitivity [SI]) in healthy individuals with higher SI at breakfast than at dinner. To determine whether such a pattern exists in type 1 diabetes, we studied 19 subjects with C-peptide–negative diabetes (HbA1c 7.1 ± 0.6%) on insulin pump therapy with normal gastric emptying. Identical mixed meals were ingested during breakfast, lunch, and dinner at 0700, 1300, and 1900 h in randomized Latin square of order on 3 consecutive days when measured daily physical activity was equal. The triple tracer technique enabled measurement of glucose fluxes. Insulin was administered according to the customary insulin:carbohydrate ratio for each participant. Although postprandial glucose excursions did not differ among meals, insulin concentration was higher (P < 0.01) and endogenous glucose production less suppressed (P < 0.049) at breakfast than at lunch. There were no differences in meal glucose appearance or in glucose disappearance between meals. Although there was no statistical difference (P = 0.34) in SI between meals in type 1 diabetic subjects, the diurnal pattern of SI taken across the three meals in its entirety differed (P = 0.016) from that of healthy subjects. Although the pattern in healthy subjects showed decreasing SI between breakfast and lunch, the reverse SI pattern was observed in type 1 diabetic subjects. The results suggest that in contrast to healthy subjects, SI diurnal pattern in type 1 diabetes is specific to the individual and cannot be extrapolated to the type 1 diabetic population as a whole, implying that artificial pancreas algorithms may need to be personalized.

Exercise effects on postprandial glucose metabolism in type 1 diabetes: a triple-tracer approach

“…Despite the fact that T1D subjects administered their customary insulin dose at the start of the meal based on the carbohydrate content adjusted for the degree of planned exercise and their premeal glucose levels, it was clearly inadequate to prevent hyperglycemia in the early postprandial (0 -120 min) period. This is corroborated by the observation that the insulin excursion during this period was lower, but glucagon excursion higher, in T1D than healthy subjects, implying that coexisting ␣-cell dysfunction that has been described in T1D (16,26), which likely also contributed to postprandial hyperglycemia in these individuals.…”

“…This could be due to continued increased mobilization of insulin from subcutaneous fat depots, reduced insulin clearance, reduced volume of distribution, or a combination thereof despite prior observations that insulin clearance increases during exercise in T1D subjects (29). This observation assumes even more importance because, in sharp contrast to our recent report in T1D subjects (16) where plasma insulin concentrations returned to baseline preprandial levels in the absence of exercise within 3 h after a mixed meal in our current study, plasma insulin concentrations did not return to baseline even after the completion of exercise and remained substantially higher than premeal concentrations.…”

“…Subjects administered premeal insulin bolus with their CSII, taking into account their customary insulin/carbohydrate ratio adjusted for the ambient glucose concentrations and the planned exercise. To be pragmatic and to reflect as much of a real-world scenario as possible and to facilitate incorporation of these data into closed control simulation, as we have done for previous studies in T1D (16,30), each individual subject was permitted to decide on their prandial insulin dose, as they would have normally done during free-living situation. Basal insulin pump rates were not changed during the study duration.…”

The UVA/PADOVA Type 1 Diabetes Simulator

“…Random sampling form this distribution, conditioned by age of in silico patient, allowed the generation of the duration of T1DM for each in silico subject, while respecting the incidence characteristics of the disease. The choice to include glucagon secretion was based on our recent data in T1DM 23 showing a nonnegligible glucagon secretion. However, since not all the authors report the same slow decline in glucagon secretion found in Lorenzi et al 15 (see, eg, Siafarikas et al), 16 future versions of the simulator may include the possibility for the user to define the residual glucagon secretion in the population.…”

Insulin:Carbohydrate Ratio—Part of the Story

“…A lower insulin:glucagon ratio would stimulate hepatic glucose production, thus increasing plasma glucose concentrations. This effect is compounded in those with type 1 diabetes because the peripherally administered insulin is unable to restore the normal portal vein insulin:glucagon ratio in the presence of the well-characterized a-cell defect that occurs in these individuals, which in turn leads to postprandial hyperglucagonemia 24,25 with resultant hyperglycemia. This is because of two possible reasons: (1) delay in subcutaneously administered insulin reaching adequate concentrations in the portal vein and (2) a large insulin dose needs to be injected subcutaneously to counter the portal hyperglucagonemia, and this would increase the risk for late postprandial hypoglycemia.…”