Separating insulin-mediated and non-insulin-mediated glucose uptake during and after aerobic exercise in type 1 diabetes

Abstract

Aerobic exercise in type 1 diabetes (T1D) causes rapid increase in glucose utilization due to muscle work during exercise, followed by increased insulin sensitivity after exercise. Better understanding of these changes is necessary for models of exercise in T1D. Twenty-six individuals with T1D underwent three sessions at three insulin rates (100%, 150%, 300% of basal). After 3-h run-in, participants performed 45 min aerobic exercise (moderate or intense). We determined area under the curve for endogenous glucose production (AUCEGP) and rate of glucose disappearance (AUCRd) over 45 min from exercise start. A novel application of linear regression of Rd across the three insulin sessions allowed separation of insulin-mediated from non-insulin-mediated glucose uptake before, during, and after exercise. AUCRd increased 12.45 mmol/L (CI = 10.33-14.58, P < 0.001) and 13.13 mmol/L (CI = 11.01-15.26, P < 0.001) whereas AUCEGP increased 1.66 mmol/L (CI = 1.01-2.31, P < 0.001) and 3.46 mmol/L (CI = 2.81-4.11, P < 0.001) above baseline during moderate and intense exercise, respectively. AUCEGP increased during intense exercise by 2.14 mmol/L (CI = 0.91-3.37, P < 0.001) compared with moderate exercise. There was significant effect of insulin infusion rate on AUCRd equal to 0.06 mmol/L per % above basal rate (CI = 0.05-0.07, P < 0.001). Insulin-mediated glucose uptake rose during exercise and persisted hours afterward, whereas non-insulin-mediated effect was limited to the exercise period. To our knowledge, this method of isolating dynamic insulin- and non-insulin-mediated uptake has not been previously employed during exercise. These results will be useful in informing glucoregulatory models of T1D. The study has been registered at www.clinicaltrials.gov as NCT03090451.NEW & NOTEWORTHY Separating insulin and non-insulin glucose uptake dynamically during exercise in type 1 diabetes has not been done before. We use a multistep process, including a previously described linear regression method, over three insulin infusion sessions, to perform this separation and can graph these components before, during, and after exercise for the first time.

Keywords: aerobic exercise; clamp study; glucose tracer; insulin-mediated glucose uptake; type 1 diabetes.

Conflict of interest statement

Peter G. Jacobs has a financial interest in Pacific Diabetes Technologies, Inc., a company that may have a commercial interest in the results of this type of research and technology. This potential conflict of interest has been reviewed and managed by OHSU. In addition, he reports research support from Xeris, Dexcom, and Tandem Diabetes Care. Jessica R. Castle has a financial interest in Pacific Diabetes Technologies, Inc., a company that may have a commercial interest in the results of this type of research. This potential conflict of interest has been reviewed and managed by OHSU. In addition, she reports advisory board participation for Zealand Pharma, Novo Nordisk, Insulet, and AstraZeneca, consulting for Dexcom, and a U.S. patent on the use of ferulic acid to stabilize glucagon. Michael C. Riddell reports grant funding from Insulet, nonfinancial support from Dexcom, and personal fees from Medtronic, Novo Nordisk, Lilly, and Zucara. Ahmad Haidar received research support/consulting fees from Eli Lilly, Medtronic, AgaMatrix, Tandem, and Dexcom, and has pending patents in the artificial pancreas area. None of the other authors has any conflicts of interest, financial or otherwise, to disclose.

Figures

Graphical abstract

Figure 1.

Transparent reporting of enrollment, with final study counts. Twenty-six participants underwent three sessions each after successful screening, and one participant completed only the first session before dropping out, for a total of 79 sessions included in the final analysis. Four sessions had to be repeated due to technical difficulties (included in the study counts within parentheses in the lower right table). IIR, insulin infusion rate.

Figure 2.

A: schematic of the Radziuk–Mari two-compartment model. B: method for calculating insulin- vs. non-insulin-mediated glucose uptake. Linear regression was performed at each time point across three different insulin infusion curves. The slope of the line at each point is the insulin-mediated glucose uptake and extrapolating the line to theoretical zero insulin gives the non-insulin-mediated glucose uptake. (C) workflow showing inputs and outputs for each step of data analysis. EGP, endogenous glucose production; k, rate constant; (N)IMGU, (non) insulin-mediated glucose uptake; Q, mass compartment; Rd, glucose rate of disappearance; Ra, glucose rate of appearance; S, glucose species; U, glucose input.

Figure 3.

Interquartile plots of endogenous glucose production (EGP) across insulin conditions and exercise arms. Area under the curve (AUC)EGP was higher in the patients undergoing intense exercise (3.46 mmol/L over baseline, 95% CI = 2.81–4.11, P < 0.001) compared with moderate exercise (1.66 mmol/L over baseline, 95% CI = 1.01–2.31, P < 0.001) with a difference between exercise groups of 2.14 mmol/L (95% CI = 0.91–3.37, P < 0.001). There was no difference in AUCEGP across insulin infusion groups, P = 0.7. Exercise occurred during the shaded interval.

Figure 4.

Interquartile plots of glucose rate of disappearance (Rd) across insulin conditions and exercise arms. Rd was systematically higher for higher basal insulin dosing. AUCRd increased 12.45 mmol/L (95% CI = 10.33–14.58, P < 0.001) during moderate exercise and 13.13 mmol/L (95% CI = 11.01–15.26, P < 0.001) during intense exercise compared with baseline, with a significant effect of insulin infusion rate equal to 0.06 (mmol/L)/% above basal rate (95% CI = 0.05–0.07, P < 0.001). There was no difference in AUCRd between moderate and intense exercise groups, P = 0.34. Exercise occurred during the shaded interval.

Figure 5.

Glucose disposal during 45 min of exercise. Red lines indicate medians, blue boxes indicate 25th–75th percentile, and horizontal black lines indicate lower and upper adjacent. Medians for low, medium, and high insulin infusion rates during moderate exercise are 28.077 (Q1 = 26.474, Q3 = 29.383), 34.160 (Q1 = 32.427, Q3 = 36.583), and 44.505 (Q1 = 40.842, Q3 = 46.300) mmol/L, respectively. For intense exercise, medians were 26.913 (Q1 = 24.485, Q3 = 31.247), 31.844 (Q1 = 27.006, Q3 = 39.720), and 48.558 (Q1 = 43.027, Q3 = 55.838) mmol/L, respectively. Q, mass compartment.

Figure 6.

Insulin-mediated and non-insulin-mediated glucose uptake plotted across the duration of the experiment. Asterisks indicate time points where Rd is significantly different from baseline at minutes 150. Exercise occurred during the shaded time period. 95% confidence intervals are shown in dotted lines.

Figure 7.

Glucose infusion rates for each insulin infusion group and glucose levels across all study participants. A: the upper graph shows the dextrose infusion rate for the low, medium, and high insulin infusion groups, with standard deviations. Dextrose infusion was increased at minutes 150 to limit hypoglycemia and to allow a constant dextrose infusion rate during exercise. B: the lower graph shows average glucose levels for each exercise condition, with gray lines denoting individual study participants. The average for both conditions in shown in bold with bars indicating standard deviations.

Figure 8.

Plasma insulin levels during exercise across insulin infusion groups, showing a rise in insulin plasma levels during exercise, despite a constant intravenous infusion rate of insulin. Shaded area, exercise period; IIR, insulin infusion rate. *P < 0.01 for High vs. Med and High vs. Low. †P < 0.0001 for minutes 200 and minutes 220 insulin plasma levels compared with minute 180 for Low, Med, and High IIR.

Figure 9.

Free fatty acid, glucagon, and catecholamine levels separated by insulin infusion rate and exercise intensity. Shaded area shows the period of exercise.

Figure 10.

Representative Rd traces during two experiments. A: Rd for one participant that shows increase at the start of exercise as is expected. B: Rd for another participant that shows a nonphysiological increase at minute 150 at the time that dextrose was increased to help prevent hypoglycemia during exercise.