Diurnal pattern of insulin action in type 1 diabetes: implications for a closed loop system

Hinshaw L, Dalla Man C, Nandy DK, et al. Diurnal pattern of insulin action in type 1 diabetes: implications for a closed loop system. Diabetes. 2013;62(7):2223-2229.

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Design  

This study by Hinshaw and colleagues examined whether a diurnal pattern to insulin secretion exists in type 1 diabetes. 

Subjects (N=19) had C-peptide negative type 1 diabetes and were on an insulin pump.

  • Aged 18-60 years
  • Body mass index <40 kg/m2 
  • A1C ≤8.5%
  • Creatinine ≤1.5 mg/dL
  • Normal gastric emptying to solids and liquids
Subjects received mixed meals for breakfast, lunch, and dinner on three consecutive days in randomized Latin Square order. Using a Latin Square study design allows for control of random variation of two factors and reduces the effect of random factors; in this study, Latin Square design was used to remove confounding effects of unequal glycogen labeling and carry-over effects of residual tracer glucose concentrations in plasma on postprandial glucose that would have occurred if all three of the successive study meals were labeled during one day. 
 
 
Daily physical activity was equal for all subjects and no physical activity was permitted 72 hours before screen and study visits. Insulin was administered in the usual insulin:carbohydrate ratio. Healthy subjects were studied concomitantly.(Click here for slide) 
 
Study Protocol and Meals 

Subjects spent 3 days and 4 nights in a clinical research facility. Participants consumed standard 10 kcal/kg meal (55% carbohydrate, 15% protein, 30% fat) the night before the first study day. No additional food was consumed until the next morning. 

Breakfast, lunch, and dinner were given for 3 consecutive days. Meals consisted of flavored gelatin with dextrose, eggs, and ham or steak slices. One meal/day included 50 glucose as the carbohydrate component. 

Pre-meal insulin bolus with pump was based on the usual insulin:carbohydrate ratio and sensitivity factor was administered. Subjects were continued on basal insulin infusion patterns. Primed-continuous glucose infusion was started 3 hours prior to the first bite of the mixed meal to estimate postprandial glucose kinetics (triple tracer mixed meal). 

Data on body posture and movement were recorded; subjects were inactive 3 hours before the meal and 6 hours after. (Click here for slide)   

Results for Glucose and Hormones (Click here for slide) 

Glucose

  • Preprandial: no difference between meals (P=0.083)
  • Peak postprandial: differed by meal (P=0.010); lower at dinner than at breakfast (P<0.01)

Insulin

  • Preprandial: differed by meal (P=0.002); lunch higher than breakfast or dinner
  • Peak postprandial: no difference between meals (P=0.13)

Glucagon

  • Preprandial: lower at breakfast than lunch (P=0.023) or dinner (P=0.013)
  • Peak postprandial: no difference between meals (P=0.22)

There was no difference between meals for meal glucose appearance and disappearance. Endogenous glucose production was lower at breakfast and lunch at baseline.

Indices of Insulin Action 

When data were compared for healthy subjects1 and individuals with type 1 diabetes, estimated mean profiles for insulin response were shown to be increased from breakfast through dinner in subjects with type 1 diabetes: 5.1 to 7.5 to 7.2 10-4 dL/kg/min per μU/mL for breakfast to lunch to dinner (P=0.34). The opposite occurred among healthy subjects: 11.2 to 7.9 to 8.1 10-4 dL/kg/min per μU/mL for breakfast to lunch to dinner (P<0.05). This suggests that a diurnal pattern to insulin action in type 1 diabetes is individual specific. (Click here for slide) 

Summary of Findings 

Data showed no uniformly identifiable diurnal pattern of postprandial insulin sensitivity that can be generalized to individuals with type 1 diabetes as a whole. Large inter-subject variability was seen, which could be due to greater variability of insulin action in type 1 diabetes. These findings are contrary to recent data from a cohort of healthy subjects.1 (Click here for slide) 

1. Saad A, Dalla Man C, Nandy DK, et al. Diurnal pattern to insulin secretion and insulin action in healthy individuals. Diabetes. 2012;61(11):2691-2700.

 

The pharmacologic agents discussed are approved for use in the United States by the U.S. Food and Drug Administration (FDA) unless otherwise noted. Consult individual prescribing information for approved uses outside of the United States. 

April 2013 

This overview was created by KnowledgePoint360 Group, LLC, and was not associated with funding via an educational grant or a promotional/commercial interest.  

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Last Modified: 8/5/2014