1. Highly Correlated Measures of Insulin Sensitivity Thomas Lotz 1, J Geoffrey Chase 1, Kirsten A McAuley 3, Jessica Lin 1, Geoffrey M Shaw 2, Chris E Hann 1, 1 Centre for Bioengineering, University of Canterbury, Christchurch 2 Christchurch School of Medicine and Health Sciences, University of Otago, Christchurch 3 Edgar National Centre for Diabetes Research, Dunedin

2. Up to now… Control of Hyperglycaemia in the ICU  Development of a model-based adaptive control protocol to reduce hyperglycaemia  Development of a physiological model of glucose and insulin kinetics  Model validation with retrospective ICU data

3. Hyperglycaemia – The Problem High Blood Glucose Levels due to impaired insulin secretion by pancreas Typical in Diabetes Mellitus Common in Intensive Care Patients due to the stress of their condition Tight glucose control in ICU reduces mortality by up to 45% –Van den Berghe G. et al., N Engl J Med 2001;345:1359-67 –Tight = 6.1 mmol/L

4. Physiological Model GLUCOSE (Feed) I(t) P(t) G(t) INSULIN (Infusion) Physiological model Blood Glucose Level

5. Physiological Model Endogenous glucose removal (p G ) Insulin mediated glucose removal (S I ) Saturation of glucose removal (α G ) Insulin transport saturation (α I ) Insulin utilisation over time (Q) Insulin clearance (n) Suppression of endogenous insulin secretion Exogenous glucose feed (P) Insulin infusion (u) Patient Specific

6. Fitting of Euglycaemic Clamp Trials Clamp Trial considered the “Gold-Standard“ to measure insulin sensitivity  High IV infusion of insulin and glucose during 120 minutes  “Clamp“ insulin infusion at fixed level (40mU/m 2 /min)  Vary glucose infusion to reach steady-state BG of 4.6 mmol/l  ISI=glucose infusion rate/plasma insulin concentration (at steady state during last 60 minutes) Data from Euglycaemic Clamps performed by McAuley et. al. on 79 normoglycaemic individuals for a 16 week lifestyle intervention study Fitting method: integral based, 2 time-varying piece- wise linear parameters

7. Clamp fit - Results N=140, BMI=33.84 Error in ISI: 3.93 ± 3.01 % (Range: 0.13 - 15.82%) 97% of fits within 10% error

8. Correlation of Insulin Sensitivity Measures Correlation between ISI/G (clamp) and S I (model) Steady state assumptions as in ISI calculation: r= 0.971 60120 60120 Mean S I r= 0.971

9. Transient value of S I at 60 minutes: r= 0.908 60 Mean S I r= 0.908 Correlation of Insulin Sensitivity Measures

10. Common measures of Insulin Sensitivity Definition: “Measure of the body’s response to insulin to enable glucose uptake” Euglycaemic-Hyperinsulinemic Clamp  Steady state, intense, long, “Gold-Standard” IVGTT with Minimal Model analysis  Dynamic, intense, long HOMA (log-HOMA)  Fasting state, quick, lower accuracy QUICKI  Fasting state, quick, lower accuracy

11. Comparisons Correlations calculated using clamp trial data Error in calculating ISI is 6-11% (average = 8%) Common quick tests correlate much worse with clamp ISI (clamp) S I -ss (model) S I -60 (model) Log-HOMAQUICKI ISI (clamp)10.970.90-0.530.51 S I -ss (model)0.9710.94-0.600.57 S I -60 (model)0.900.941-0.620.60 Log-HOMA-0.53-0.60-0.621-0.98 QUICKI0.510.570.60-0.981

12. Comparison of subgroups Before (week 0) and after (week 16) intervention Obese population (BMI=33.8) nSteady state60 minutes ALL 1400.9710.908 Week 0 (BMI=34.4) 670.9440. 897 Week 16 (BMI=33.6) 670.9800.911 BMI < 30 310.9780.923 BMI > 30 1090.9580.869 30 < BMI <35 530.9670.904 BMI > 35 560.9400.800

13. Outlook Development of a new model-based measurement of insulin sensitivity  Accuracy of Clamp  Short duration (~1-2 hours)  Easy & flexible protocol  Low cost Model can give further information about metabolic status, i.e. saturation dynamics, insulin clearance rate

14. Possible test procedure Start test Insulin bolus Glucose bolus 0102030405060908070 Blood Glucose profile Measurements of 1.Glucose 2.Insulin 3.C-Peptide Stop test

15. Possible test procedure Fit model to glucose & insulin profiles  Use highly correlated model parameter S I at ie 60 minutes to calculate insulin sensitivity 60 SISI t Insulin Sensitivity

16. Summary Two compartment model of insulin/glucose kinetics –Includes accumulation and saturation dynamics Long term fitting with retrospective ICU data –Error within measurement error Highly correlated fitting of euglycaemic clamp data –Correlation of insulin sensitivity: r=0.971 New model-based test to assess insulin sensitivity –Accurate measurement –Quick and easy –Low cost

17. Acknowledgements Engineers and Docs Dr Geoff ChaseDr Geoff Shaw Other Minions Maths and Stats Dr Dominic Lee Prof Graeme Wake Questions? The Danes Dr Steen Andreassen Dunedin Prof Jim Mann Dr Kirsten McAuley Jessica Lin Dr Chris Hann