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Highly Correlated Measures of Insulin Sensitivity

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

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Highly Correlated Measures of Insulin Sensitivity

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  1. Highly Correlated Measures of Insulin Sensitivity Thomas Lotz1, J Geoffrey Chase1, Kirsten A McAuley3, Jessica Lin1, Geoffrey M Shaw2, Chris E Hann1, 1Centre for Bioengineering, University of Canterbury, Christchurch 2Christchurch School of Medicine and Health Sciences, University of Otago, Christchurch 3Edgar 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) Blood Glucose Level P(t) Physiological model G(t) I(t) INSULIN (Infusion)

  5. Physiological Model • Endogenous glucose removal (pG) • Insulin mediated glucose removal (SI) • Saturation of glucose removal (αG) • Insulin transport saturation (αI) • 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/m2/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 SI (model) • Steady state assumptions as in ISI calculation: r= 0.971 60 120 r= 0.971 60 120 Mean SI

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

  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

  12. Comparison of subgroups • Before (week 0) and after (week 16) intervention • Obese population (BMI=33.8)

  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. 0 10 20 30 40 50 60 70 80 90 Possible test procedure Blood Glucose profile Measurements of • Glucose • Insulin • C-Peptide Glucose bolus Insulin bolus Start test Stop test Stop test

  15. 60 SI t Possible test procedure • Fit model to glucose & insulin profiles • Use highly correlated model parameter SI at ie 60 minutes to calculate insulin sensitivity 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. The Danes Acknowledgements Engineers and Docs Dunedin Other Minions Jessica Lin Dr Geoff Chase Dr Geoff Shaw Dr Kirsten McAuley Prof Jim Mann Maths and Stats Questions? Prof Graeme Wake Dr Dominic Lee Dr Chris Hann Dr Steen Andreassen

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