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Assessing Insulin Resistance

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Dr Karthik Balachandran
Dr Karthik Balachandran

Assessment of Insulin sensitivity/resistance in clinical and research settings.

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Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Assessing Insulin Resistance Karthik Balachandran Department of Endocrinology,JIPMER Oct 2014 Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Background IR is sine qua non of type 2 Diabetes Reduced ability of insulin to exert its action on target tissues-liver, skeletal muscle and adipose tissue Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Background IR is sine qua non of type 2 Diabetes Reduced ability of insulin to exert its action on target tissues-liver, skeletal muscle and adipose tissue Continuum not a binary Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Figure: Causes of Insulin Resistance 1 1Anwar Borai et al. “Selection of the appropriate method for the assessment of insulin resistance.” BMC medical research methodology 11.1 (Jan. 2011), p. 158. issn: 1471-2288. Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Responsiveness and Sensivitity Responsiveness Maximal effect of insulin Sensitivity Half maximal effect of insulin2 2Ranganath Muniyappa et al. “Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage.” American journal of physiology. Endocrinology and metabolism 294.1 (Jan. 2008), E15–26. issn: 0193-1849. Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Basis of IR Genetic and environmental components Fetal origins Genes in the insulin action pathway Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Dynamic tests Hyperinsulinemic euglycemic clamp Hyperglycemic clamp Insulin tolerance test Frequently Sampled Intravenous GTT(FSIVGTT) Modified FSIVGTT OGTT Continuous infusion of glucose with model assessment(CIGMA) Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperinsulinemic Euglycemic Clamp Hyperinsulinemic Supraphysiological Insulin Euglycemic Normal glucose levels Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperinsulinemic Euglycemic Clamp Hyperinsulinemic Supraphysiological Insulin Euglycemic Normal glucose levels Clamp Hepatic glucose output clamped Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperinsulinemic Euglycemic Clamp Described by DeFronzo et al-1979 Infuse exogenous insulin at 6mIU/kg/min and 20% glucose Check RBS at 5 min intervals Infused insulin suppresses HGO Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperinsulinemic Euglycemic Clamp Once steady state is reached3 rate of infusion of glucose= rate of peripheral glucose disposal 3usally during the last 30-60 min of the test Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperinsulinemic Euglycemic Clamp Once steady state is reached3 rate of infusion of glucose= rate of peripheral glucose disposal Insulin sensitive people require more exogenous glucose, insulin resistant people require less Insulin mediated glucose disposal rate denoted as M 3usally during the last 30-60 min of the test Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperinsulinemic Euglycemic Clamp Sensitive M > 7.5mg/kg/min Resistant M < 4mg/kg/min Intermediate M 4to7.5mg/kg/min Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperinsulinemic Euglycemic Clamp M can be normalized to fat free mass or resting energy expenditure Insulin sensitivity index Si(clamp) derived from data for comparing clamp with minimal model Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperinsulinemic Euglycemic Clamp M can be normalized to fat free mass or resting energy expenditure Insulin sensitivity index Si(clamp) derived from data for comparing clamp with minimal model Hyperinsulinemic euglycemic clamp-gold standard for measuring IR Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Infusion rates-importance Figure: Insulin vs Glucose disposal Figure: Insulin infusion vs GIR Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Clamp-considerations M should be obtained at single infusion rate Multiple stepwise infusion rates-ideal but difficult Difference b/w arterial and venous blood-”arterialised” venous blood Cannulate in retrograde fashion Warm hand with pad to open AV anastomoses Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Clamp-improvements Use of radiolabeled tracers to study hepatic and peripheral insulin sensitivity Glycerol and aminoacids to study fat and protein metabolism w.r.t. insulin sensitivity P31 magnetic resonance spectroscopy - assess rates of insulin-stimulated muscle mitochondrial ATP synthase flux and insulin-stimulated increases in concentrations of intramyocellular inorganic phosphate Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperglycemic Clamp Quantitative measure of
-cell insulin secretion in response to glucose Plasma glucose levels raised to plateau at 7mmol/L above basal and kept for 2 hours Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperglycemic Clamp Quantitative measure of
-cell insulin secretion in response to glucose Plasma glucose levels raised to plateau at 7mmol/L above basal and kept for 2 hours Glucose infused at 5 min intervals Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperglycemic Clamp Quantitative measure of
-cell insulin secretion in response to glucose Plasma glucose levels raised to plateau at 7mmol/L above basal and kept for 2 hours Glucose infused at 5 min intervals Hyperglycemia stimuates insulin secretion Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperglycemic Clamp Quantitative measure of
-cell insulin secretion in response to glucose Plasma glucose levels raised to plateau at 7mmol/L above basal and kept for 2 hours Glucose infused at 5 min intervals Hyperglycemia stimuates insulin secretion Volume of glucose maintenance doses needed to maintain hyperglycemia-a measure of insulin secretion Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperglycemic Clamp M can be calculated as in euglycemic clamp M/I ratio provides a measure of sensitivity to endogenously secreted insulin Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Clamp studies Cons Difficult Suppresses HGO Risk of hypoglycemia Not physiological Pros Gold standard Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Insulin Tolerance Test Oldest measure of insulin sensitivy- 1929 Net effect of insulin on liver and peripheral tissues IV bolus of 0.1 mU/kg given Blood samples are collected 15 and 5 min prior to injection and at 3, 6, 9, 12, 15, 20 and 30 min thereafter At 30 min glucose is injected to stop a continuing fall in blood glucose4 4Anwar Borai, Callum Livingstone, and Gordon a a Ferns. “The biochemical assessment of insulin resistance.” Annals of clinical biochemistry 44.Pt 4 (July 2007), pp. 324–42. issn: 0004-5632. Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Insulin Tolerance Test The rate of glucose disappearance constant is then calculated as the slope of the decline in blood glucose plotted logarithmically KITT = 0.693 t1/2 x100 (1) Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Insulin Tolerance Test The rate of glucose disappearance constant is then calculated as the slope of the decline in blood glucose plotted logarithmically KITT = 0.693 t1/2 x100 (1) I Normal KITT is > 2% I Values < 1.5% are abnormal Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment ITT Limitations Risk of hypoglycemia Can’t localize the site of resistance Antagonism by counter-regulatory hormones Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment ITT Limitations Risk of hypoglycemia Can’t localize the site of resistance Antagonism by counter-regulatory hormones Advantage Cheaper than Clamp studies Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Frequently Sampled Intravenous GTT Baseline blood samples for insulin and glucose are taken at 15, 20, 25, 30 min following placement of an intravenous cannula Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Frequently Sampled Intravenous GTT Baseline blood samples for insulin and glucose are taken at 15, 20, 25, 30 min following placement of an intravenous cannula Glucose (0.3 g/kg of 50%) is then manually injected as a bolus over 1min Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Frequently Sampled Intravenous GTT Baseline blood samples for insulin and glucose are taken at 15, 20, 25, 30 min following placement of an intravenous cannula Glucose (0.3 g/kg of 50%) is then manually injected as a bolus over 1min Blood samples for glucose and insulin measurement are drawn 2, 3, 4, 5, 6, 8,10,12,14,16,19, 22, 25, 30, 40, 50, 60,70, 80, 90,100,120,140, 160 and 180 min after the start of the glucose injection Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Frequently Sampled Intravenous GTT Modified- exogenous insulin also used over 5 min beginning 20 min after the iv glucose bolus Some studies use tolbutamide Data analyzed using miminal model analysis Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Figure: FSIVGTT and Minimal model analysis Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Minimal Model Equations One compartment dG(t) dt = −[p1 + X(t)G(t) + p1Gb (2) Two compartments dX(t) dt = p2X(t) + p3[I(t) − ib] (3) Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Minimal model- assumptions 1 Instantaneous glucose distribution in monocompartmental space Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Minimal model- assumptions 1 Instantaneous glucose distribution in monocompartmental space 2 Glucose disappearance at monoexponential rate Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Minimal model- assumptions 1 Instantaneous glucose distribution in monocompartmental space 2 Glucose disappearance at monoexponential rate 3 Glucose concentration at beginning and end -same Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Minimal model- assumptions 1 Instantaneous glucose distribution in monocompartmental space 2 Glucose disappearance at monoexponential rate 3 Glucose concentration at beginning and end -same 4 Insulin acts from a remote compartment Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Minimal model- assumptions 1 Instantaneous glucose distribution in monocompartmental space 2 Glucose disappearance at monoexponential rate 3 Glucose concentration at beginning and end -same 4 Insulin acts from a remote compartment 5 Glucose disposal in skeletal muscle and HGO-lumped together Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Minimal model- assumptions 1 Instantaneous glucose distribution in monocompartmental space 2 Glucose disappearance at monoexponential rate 3 Glucose concentration at beginning and end -same 4 Insulin acts from a remote compartment 5 Glucose disposal in skeletal muscle and HGO-lumped together 6 Total insulin secretion is above a certain threshold Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Glucose effectiveness and FSIVGTT Glucose effectiveness Ability of glucose per se to promote its own disposal and inhibit HGP in the absence of an incremental insulin effect Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment FSIVGTT-Advantages Insulin sensitivity, glucose effectiveness, and
-cell function can be derived from a single dynamic test Simpler than clamp studies Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Oral glucose tolerance test After an overnight fast, blood samples for deter- minations of glucose and insulin concentrations are taken at 0, 30,60, and 120 min following a standard oral glucose load (75 g). Use of glucose tracer and insulin/C peptide at specific time points - allows calculation of glucose clearance Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment OGTT problems Poor reproducibility Variable gastric emptying Variable glucose absorption Variable incretin effect No adequate information about glucose and insulin dynamics Less physiological Does not distinguish insulin sensitivity from secretion5 5Rita S Patarr˜ao, Wilford Wayne, and Maria Paula. “Revista Portuguesa de Endocrinologia , Diabetes e Metabolismo Assessment of methods and indexes of insulin sensitivity”. 9.1 (2014), pp. 65–73. Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Meal Tolerance Test Physiologic variant of OGTT Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Meal Tolerance Test Physiologic variant of OGTT No artifactual post load hypoglycemia Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Meal Tolerance Test Physiologic variant of OGTT No artifactual post load hypoglycemia Triggers cephalic phase of gastric emptying Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Meal Tolerance Test Physiologic variant of OGTT No artifactual post load hypoglycemia Triggers cephalic phase of gastric emptying Potential to evaluate the physiological effects of incretins Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Meal Tolerance Test Physiologic variant of OGTT No artifactual post load hypoglycemia Triggers cephalic phase of gastric emptying Potential to evaluate the physiological effects of incretins Can measure insulin sensitivity with a modified algorithm based on the minimal model Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Continuous infusion of glucose with model assessment Assesses insulin sensitivity through the evaluation of the near steady-state glucose and insulin con- centrations after a continuous infusion of glucose Mimics postprandial glucose and insulin concentrations The glucose and insulin values used for CIGMA are obtained during the last 15 min of the 60 min continuous glucose infusion (5 mg glucose/kg bw/min) Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment CIGMA Samples are collected at 5 min intervals and the average is then compared with predicted values from the com- puter model The median value for normal subjects is 1.35, and for diabetic patients with mild hyperglycemia is 4.0 Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices HOMA QUICKI Homeostasis Model Assessment Model of interactions between glucose and insulin dynamics, that is then used to predict fasting steady-state glucose and insulin concentrations Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices HOMA QUICKI Homeostasis Model Assessment Model of interactions between glucose and insulin dynamics, that is then used to predict fasting steady-state glucose and insulin concentrations The model assumes a feedback loop b/w liver and
cell Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices HOMA QUICKI Homeostasis Model Assessment Model of interactions between glucose and insulin dynamics, that is then used to predict fasting steady-state glucose and insulin concentrations The model assumes a feedback loop b/w liver and
cell Glucose concentrations are regulated by insulin-dependent hepatic glucose production, while insulin levels depend on the pancreatic
-cellresponse to glucose concentrations Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices HOMA QUICKI HOMA Describes Glucose insulin homeostasis by a set of non linear equations The model predicts fasting steady-state levels of plasma glucose and insulin for any given combination of pancreatic
-cell function (HOMA%B) and insulin sensitivity (HOMA%S). Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices HOMA QUICKI HOMA HOMA = Fasting glucosexFasting insulin 22.5 6 6The denominator of 22.5 is a normalizing factor, i.e., the product of normal fasting plasma insulin of 5 ÎŒIU/ml and normal fasting plasma glucose of 4.5 mmol/l obtained from an “ideal and normal” individual Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices HOMA QUICKI HOMA in type 2 DM Short acting insulin and sulfonylureas can be used Stop NPH the night before7 7Kohei Okita et al. “Homeostasis model assessment of insulin resistance for evaluating insulin sensitivity in patients with type 2 diabetes on insulin therapy”. Endocrine Journal 60.3 (2013), pp. 283–290. issn: 0918-8959. Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices HOMA QUICKI HOMA in type 2 DM Figure: HOMA in type 2 DM8 8Kohei Okita et al. “Homeostasis model assessment of insulin resistance for evaluating insulin sensitivity in patients with type 2 diabetes on insulin therapy”. Endocrine Journal 60.3 (2013), pp. 283–290. issn: 0918-8959. Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices HOMA QUICKI HOMA-2 Assessment of HOMA%S and HOMA%B in subjects with glucose levels 25 mM Accounts for renal glucose losses Assumes reduced suppression of HGP and increased insulin secretion in response to glucose levels 10 mM Allows for the use of total or specific insulin assays Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices HOMA QUICKI Quantitative insulin sensitivity check index Mathematical transformation that uses fasting glucose and fasting insulin Transformation is done as these variables have skewed distribution This makes better correlation with clamp studies -Si(clamp) Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices HOMA QUICKI QUICKI = 1 log(fasting insulin(ÎŒIU/ml)) + log(fasting glucose(mg/dl)) Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices HOMA QUICKI QUICKI Pros Simple Inexpensive Single blood draw More reproducible than HOMA-IR Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices HOMA QUICKI QUICKI Pros Simple Inexpensive Single blood draw More reproducible than HOMA-IR Cons No information on stimulated glucose and insulin systems Mainly tells hepatic IR- less important than peripheral IR Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Cederholm and Wibell index Gutt index Avignon Index Matsuda Index Cederholm and Wibell index Measures peripheral insulin sensitivity and muscular glucose uptake Values found in normal non-obese individuals were reported to be about 79 ± 14 mg l2 /mmol/mIU/min, lower in obese individuals Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Cederholm and Wibell index Gutt index Avignon Index Matsuda Index Cederholm and Wibell index Cederholm and Wibell index ISICederholm = 75000 + (G0 − G120)x1.15x180x0.19xm 120xGmeanxlog(Imean) 9 9where m is body weight and Gmean is mean glucose during OGTT and Imean is mean insulin during OGTT Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Cederholm and Wibell index Gutt index Avignon Index Matsuda Index Gutt Index Derived from Cederholm by omitting constant terms The reference range for lean controls was 89± 39, for obese 58 ±23 and for diabetic patients 23 ±19 mg l2 /mmol/mIU/min Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Cederholm and Wibell index Gutt index Avignon Index Matsuda Index Gutt Index Gutt Index ISI0,120 = 75000 + (G0 − G120)x0.19xm 120xGmeanxlog(Imean) Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Cederholm and Wibell index Gutt index Avignon Index Matsuda Index Avignon Index Avignon proposed 3 insulin sensitivity indices: Sib (derivedfrom fasting plasma insulin and glucose concentrations) Si2h (derived from plasma insulin and glucose concentrations in the120th min of OGTT) and SiM (derived by averaging Sib and Si2h after balancing Sib by a coefficient of 0.137 to give the same weight to both indices10 10Rita S Patarr˜ao, Wilford Wayne, and Maria Paula. “Revista Portuguesa de Endocrinologia , Diabetes e Metabolismo Assessment of methods and indexes of insulin sensitivity”. 9.1 (2014), pp. 65–73, p. 4. Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Cederholm and Wibell index Gutt index Avignon Index Matsuda Index Avignon Index Sib Sib = 108 I0xG0xVD Si2h Si2h = 108 I120xG120xVD SiM SiM = (0.137xSib) + Si2h 2 Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Cederholm and Wibell index Gutt index Avignon Index Matsuda Index Matsuda Index Composite measure of peripheral and hepatic insulin sensitivity Calculated during fasting and OGTT Along with disposition index, has excellent power for prediction of type 2 diabetes Karthik Balachandran Assessing Insulin Resistance
Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Cederholm and Wibell index Gutt index Avignon Index Matsuda Index Matsuda Index Matsuda Index ISIMatsuda = 10, 000 pG0xI0xGmeanxImean Disposition index I0−30 G0−30 Karthik Balachandran Assessing Insulin Resistance
Belfiore Index Compares insulin and glucose values measured (fasting, 0–1–2 h areas or 0–2 h areas) with the defined normal reference values
Belfiore Index Compares insulin and glucose values measured (fasting, 0–1–2 h areas or 0–2 h areas) with the defined normal reference values Values between 0 and 2 Normal - around 1 Overweight,obese,diabetes 1
Belfiore Index Belfiore Index ISIBelfiore= 2 (Gs/GN)x(Is/IN) + 1
Stumvoll index Series of indices calculated using insulin and glucose values during OGTT Uses muliple linear regression
Stumvoll index Stumvoll index ISIStumvoll = 0.222 − 0.00333x BMI - 0.0000779 x I120-0.00541 x age ISIStumvoll = 0.156 − 0.0000459x I120-0.000321 xI0-0.0541 x G120

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Assessing Insulin Resistance

  • 1. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Assessing Insulin Resistance Karthik Balachandran Department of Endocrinology,JIPMER Oct 2014 Karthik Balachandran Assessing Insulin Resistance
  • 2. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Background IR is sine qua non of type 2 Diabetes Reduced ability of insulin to exert its action on target tissues-liver, skeletal muscle and adipose tissue Karthik Balachandran Assessing Insulin Resistance
  • 3. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Background IR is sine qua non of type 2 Diabetes Reduced ability of insulin to exert its action on target tissues-liver, skeletal muscle and adipose tissue Continuum not a binary Karthik Balachandran Assessing Insulin Resistance
  • 4. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Figure: Causes of Insulin Resistance 1 1Anwar Borai et al. “Selection of the appropriate method for the assessment of insulin resistance.” BMC medical research methodology 11.1 (Jan. 2011), p. 158. issn: 1471-2288. Karthik Balachandran Assessing Insulin Resistance
  • 5. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Responsiveness and Sensivitity Responsiveness Maximal effect of insulin Sensitivity Half maximal effect of insulin2 2Ranganath Muniyappa et al. “Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage.” American journal of physiology. Endocrinology and metabolism 294.1 (Jan. 2008), E15–26. issn: 0193-1849. Karthik Balachandran Assessing Insulin Resistance
  • 6. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Basis of IR Genetic and environmental components Fetal origins Genes in the insulin action pathway Karthik Balachandran Assessing Insulin Resistance
  • 7. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Dynamic tests Hyperinsulinemic euglycemic clamp Hyperglycemic clamp Insulin tolerance test Frequently Sampled Intravenous GTT(FSIVGTT) Modified FSIVGTT OGTT Continuous infusion of glucose with model assessment(CIGMA) Karthik Balachandran Assessing Insulin Resistance
  • 8. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperinsulinemic Euglycemic Clamp Hyperinsulinemic Supraphysiological Insulin Euglycemic Normal glucose levels Karthik Balachandran Assessing Insulin Resistance
  • 9. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperinsulinemic Euglycemic Clamp Hyperinsulinemic Supraphysiological Insulin Euglycemic Normal glucose levels Clamp Hepatic glucose output clamped Karthik Balachandran Assessing Insulin Resistance
  • 10. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperinsulinemic Euglycemic Clamp Described by DeFronzo et al-1979 Infuse exogenous insulin at 6mIU/kg/min and 20% glucose Check RBS at 5 min intervals Infused insulin suppresses HGO Karthik Balachandran Assessing Insulin Resistance
  • 11. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperinsulinemic Euglycemic Clamp Once steady state is reached3 rate of infusion of glucose= rate of peripheral glucose disposal 3usally during the last 30-60 min of the test Karthik Balachandran Assessing Insulin Resistance
  • 12. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperinsulinemic Euglycemic Clamp Once steady state is reached3 rate of infusion of glucose= rate of peripheral glucose disposal Insulin sensitive people require more exogenous glucose, insulin resistant people require less Insulin mediated glucose disposal rate denoted as M 3usally during the last 30-60 min of the test Karthik Balachandran Assessing Insulin Resistance
  • 13. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperinsulinemic Euglycemic Clamp Sensitive M > 7.5mg/kg/min Resistant M < 4mg/kg/min Intermediate M 4to7.5mg/kg/min Karthik Balachandran Assessing Insulin Resistance
  • 14. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperinsulinemic Euglycemic Clamp M can be normalized to fat free mass or resting energy expenditure Insulin sensitivity index Si(clamp) derived from data for comparing clamp with minimal model Karthik Balachandran Assessing Insulin Resistance
  • 15. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperinsulinemic Euglycemic Clamp M can be normalized to fat free mass or resting energy expenditure Insulin sensitivity index Si(clamp) derived from data for comparing clamp with minimal model Hyperinsulinemic euglycemic clamp-gold standard for measuring IR Karthik Balachandran Assessing Insulin Resistance
  • 16. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Infusion rates-importance Figure: Insulin vs Glucose disposal Figure: Insulin infusion vs GIR Karthik Balachandran Assessing Insulin Resistance
  • 17. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Clamp-considerations M should be obtained at single infusion rate Multiple stepwise infusion rates-ideal but difficult Difference b/w arterial and venous blood-”arterialised” venous blood Cannulate in retrograde fashion Warm hand with pad to open AV anastomoses Karthik Balachandran Assessing Insulin Resistance
  • 18. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Clamp-improvements Use of radiolabeled tracers to study hepatic and peripheral insulin sensitivity Glycerol and aminoacids to study fat and protein metabolism w.r.t. insulin sensitivity P31 magnetic resonance spectroscopy - assess rates of insulin-stimulated muscle mitochondrial ATP synthase flux and insulin-stimulated increases in concentrations of intramyocellular inorganic phosphate Karthik Balachandran Assessing Insulin Resistance
  • 19. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperglycemic Clamp Quantitative measure of
  • 20. -cell insulin secretion in response to glucose Plasma glucose levels raised to plateau at 7mmol/L above basal and kept for 2 hours Karthik Balachandran Assessing Insulin Resistance
  • 21. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperglycemic Clamp Quantitative measure of
  • 22. -cell insulin secretion in response to glucose Plasma glucose levels raised to plateau at 7mmol/L above basal and kept for 2 hours Glucose infused at 5 min intervals Karthik Balachandran Assessing Insulin Resistance
  • 23. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperglycemic Clamp Quantitative measure of
  • 24. -cell insulin secretion in response to glucose Plasma glucose levels raised to plateau at 7mmol/L above basal and kept for 2 hours Glucose infused at 5 min intervals Hyperglycemia stimuates insulin secretion Karthik Balachandran Assessing Insulin Resistance
  • 25. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperglycemic Clamp Quantitative measure of
  • 26. -cell insulin secretion in response to glucose Plasma glucose levels raised to plateau at 7mmol/L above basal and kept for 2 hours Glucose infused at 5 min intervals Hyperglycemia stimuates insulin secretion Volume of glucose maintenance doses needed to maintain hyperglycemia-a measure of insulin secretion Karthik Balachandran Assessing Insulin Resistance
  • 27. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Hyperglycemic Clamp M can be calculated as in euglycemic clamp M/I ratio provides a measure of sensitivity to endogenously secreted insulin Karthik Balachandran Assessing Insulin Resistance
  • 28. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Clamp studies Cons Difficult Suppresses HGO Risk of hypoglycemia Not physiological Pros Gold standard Karthik Balachandran Assessing Insulin Resistance
  • 29. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Insulin Tolerance Test Oldest measure of insulin sensitivy- 1929 Net effect of insulin on liver and peripheral tissues IV bolus of 0.1 mU/kg given Blood samples are collected 15 and 5 min prior to injection and at 3, 6, 9, 12, 15, 20 and 30 min thereafter At 30 min glucose is injected to stop a continuing fall in blood glucose4 4Anwar Borai, Callum Livingstone, and Gordon a a Ferns. “The biochemical assessment of insulin resistance.” Annals of clinical biochemistry 44.Pt 4 (July 2007), pp. 324–42. issn: 0004-5632. Karthik Balachandran Assessing Insulin Resistance
  • 30. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Insulin Tolerance Test The rate of glucose disappearance constant is then calculated as the slope of the decline in blood glucose plotted logarithmically KITT = 0.693 t1/2 x100 (1) Karthik Balachandran Assessing Insulin Resistance
  • 31. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Insulin Tolerance Test The rate of glucose disappearance constant is then calculated as the slope of the decline in blood glucose plotted logarithmically KITT = 0.693 t1/2 x100 (1) I Normal KITT is > 2% I Values < 1.5% are abnormal Karthik Balachandran Assessing Insulin Resistance
  • 32. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment ITT Limitations Risk of hypoglycemia Can’t localize the site of resistance Antagonism by counter-regulatory hormones Karthik Balachandran Assessing Insulin Resistance
  • 33. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment ITT Limitations Risk of hypoglycemia Can’t localize the site of resistance Antagonism by counter-regulatory hormones Advantage Cheaper than Clamp studies Karthik Balachandran Assessing Insulin Resistance
  • 34. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Frequently Sampled Intravenous GTT Baseline blood samples for insulin and glucose are taken at 15, 20, 25, 30 min following placement of an intravenous cannula Karthik Balachandran Assessing Insulin Resistance
  • 35. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Frequently Sampled Intravenous GTT Baseline blood samples for insulin and glucose are taken at 15, 20, 25, 30 min following placement of an intravenous cannula Glucose (0.3 g/kg of 50%) is then manually injected as a bolus over 1min Karthik Balachandran Assessing Insulin Resistance
  • 36. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Frequently Sampled Intravenous GTT Baseline blood samples for insulin and glucose are taken at 15, 20, 25, 30 min following placement of an intravenous cannula Glucose (0.3 g/kg of 50%) is then manually injected as a bolus over 1min Blood samples for glucose and insulin measurement are drawn 2, 3, 4, 5, 6, 8,10,12,14,16,19, 22, 25, 30, 40, 50, 60,70, 80, 90,100,120,140, 160 and 180 min after the start of the glucose injection Karthik Balachandran Assessing Insulin Resistance
  • 37. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Frequently Sampled Intravenous GTT Modified- exogenous insulin also used over 5 min beginning 20 min after the iv glucose bolus Some studies use tolbutamide Data analyzed using miminal model analysis Karthik Balachandran Assessing Insulin Resistance
  • 38. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Figure: FSIVGTT and Minimal model analysis Karthik Balachandran Assessing Insulin Resistance
  • 39. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Minimal Model Equations One compartment dG(t) dt = −[p1 + X(t)G(t) + p1Gb (2) Two compartments dX(t) dt = p2X(t) + p3[I(t) − ib] (3) Karthik Balachandran Assessing Insulin Resistance
  • 40. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Minimal model- assumptions 1 Instantaneous glucose distribution in monocompartmental space Karthik Balachandran Assessing Insulin Resistance
  • 41. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Minimal model- assumptions 1 Instantaneous glucose distribution in monocompartmental space 2 Glucose disappearance at monoexponential rate Karthik Balachandran Assessing Insulin Resistance
  • 42. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Minimal model- assumptions 1 Instantaneous glucose distribution in monocompartmental space 2 Glucose disappearance at monoexponential rate 3 Glucose concentration at beginning and end -same Karthik Balachandran Assessing Insulin Resistance
  • 43. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Minimal model- assumptions 1 Instantaneous glucose distribution in monocompartmental space 2 Glucose disappearance at monoexponential rate 3 Glucose concentration at beginning and end -same 4 Insulin acts from a remote compartment Karthik Balachandran Assessing Insulin Resistance
  • 44. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Minimal model- assumptions 1 Instantaneous glucose distribution in monocompartmental space 2 Glucose disappearance at monoexponential rate 3 Glucose concentration at beginning and end -same 4 Insulin acts from a remote compartment 5 Glucose disposal in skeletal muscle and HGO-lumped together Karthik Balachandran Assessing Insulin Resistance
  • 45. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Minimal model- assumptions 1 Instantaneous glucose distribution in monocompartmental space 2 Glucose disappearance at monoexponential rate 3 Glucose concentration at beginning and end -same 4 Insulin acts from a remote compartment 5 Glucose disposal in skeletal muscle and HGO-lumped together 6 Total insulin secretion is above a certain threshold Karthik Balachandran Assessing Insulin Resistance
  • 46. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Glucose effectiveness and FSIVGTT Glucose effectiveness Ability of glucose per se to promote its own disposal and inhibit HGP in the absence of an incremental insulin effect Karthik Balachandran Assessing Insulin Resistance
  • 47. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment FSIVGTT-Advantages Insulin sensitivity, glucose effectiveness, and
  • 48. -cell function can be derived from a single dynamic test Simpler than clamp studies Karthik Balachandran Assessing Insulin Resistance
  • 49. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Oral glucose tolerance test After an overnight fast, blood samples for deter- minations of glucose and insulin concentrations are taken at 0, 30,60, and 120 min following a standard oral glucose load (75 g). Use of glucose tracer and insulin/C peptide at specific time points - allows calculation of glucose clearance Karthik Balachandran Assessing Insulin Resistance
  • 50. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment OGTT problems Poor reproducibility Variable gastric emptying Variable glucose absorption Variable incretin effect No adequate information about glucose and insulin dynamics Less physiological Does not distinguish insulin sensitivity from secretion5 5Rita S Patarr˜ao, Wilford Wayne, and Maria Paula. “Revista Portuguesa de Endocrinologia , Diabetes e Metabolismo Assessment of methods and indexes of insulin sensitivity”. 9.1 (2014), pp. 65–73. Karthik Balachandran Assessing Insulin Resistance
  • 51. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Meal Tolerance Test Physiologic variant of OGTT Karthik Balachandran Assessing Insulin Resistance
  • 52. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Meal Tolerance Test Physiologic variant of OGTT No artifactual post load hypoglycemia Karthik Balachandran Assessing Insulin Resistance
  • 53. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Meal Tolerance Test Physiologic variant of OGTT No artifactual post load hypoglycemia Triggers cephalic phase of gastric emptying Karthik Balachandran Assessing Insulin Resistance
  • 54. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Meal Tolerance Test Physiologic variant of OGTT No artifactual post load hypoglycemia Triggers cephalic phase of gastric emptying Potential to evaluate the physiological effects of incretins Karthik Balachandran Assessing Insulin Resistance
  • 55. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Meal Tolerance Test Physiologic variant of OGTT No artifactual post load hypoglycemia Triggers cephalic phase of gastric emptying Potential to evaluate the physiological effects of incretins Can measure insulin sensitivity with a modified algorithm based on the minimal model Karthik Balachandran Assessing Insulin Resistance
  • 56. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment Continuous infusion of glucose with model assessment Assesses insulin sensitivity through the evaluation of the near steady-state glucose and insulin con- centrations after a continuous infusion of glucose Mimics postprandial glucose and insulin concentrations The glucose and insulin values used for CIGMA are obtained during the last 15 min of the 60 min continuous glucose infusion (5 mg glucose/kg bw/min) Karthik Balachandran Assessing Insulin Resistance
  • 57. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Direct Assessment CIGMA Samples are collected at 5 min intervals and the average is then compared with predicted values from the com- puter model The median value for normal subjects is 1.35, and for diabetic patients with mild hyperglycemia is 4.0 Karthik Balachandran Assessing Insulin Resistance
  • 58. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices HOMA QUICKI Homeostasis Model Assessment Model of interactions between glucose and insulin dynamics, that is then used to predict fasting steady-state glucose and insulin concentrations Karthik Balachandran Assessing Insulin Resistance
  • 59. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices HOMA QUICKI Homeostasis Model Assessment Model of interactions between glucose and insulin dynamics, that is then used to predict fasting steady-state glucose and insulin concentrations The model assumes a feedback loop b/w liver and
  • 60. cell Karthik Balachandran Assessing Insulin Resistance
  • 61. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices HOMA QUICKI Homeostasis Model Assessment Model of interactions between glucose and insulin dynamics, that is then used to predict fasting steady-state glucose and insulin concentrations The model assumes a feedback loop b/w liver and
  • 62. cell Glucose concentrations are regulated by insulin-dependent hepatic glucose production, while insulin levels depend on the pancreatic
  • 63. -cellresponse to glucose concentrations Karthik Balachandran Assessing Insulin Resistance
  • 64. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices HOMA QUICKI HOMA Describes Glucose insulin homeostasis by a set of non linear equations The model predicts fasting steady-state levels of plasma glucose and insulin for any given combination of pancreatic
  • 65. -cell function (HOMA%B) and insulin sensitivity (HOMA%S). Karthik Balachandran Assessing Insulin Resistance
  • 66. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices HOMA QUICKI HOMA HOMA = Fasting glucosexFasting insulin 22.5 6 6The denominator of 22.5 is a normalizing factor, i.e., the product of normal fasting plasma insulin of 5 ÎŒIU/ml and normal fasting plasma glucose of 4.5 mmol/l obtained from an “ideal and normal” individual Karthik Balachandran Assessing Insulin Resistance
  • 67. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices HOMA QUICKI HOMA in type 2 DM Short acting insulin and sulfonylureas can be used Stop NPH the night before7 7Kohei Okita et al. “Homeostasis model assessment of insulin resistance for evaluating insulin sensitivity in patients with type 2 diabetes on insulin therapy”. Endocrine Journal 60.3 (2013), pp. 283–290. issn: 0918-8959. Karthik Balachandran Assessing Insulin Resistance
  • 68. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices HOMA QUICKI HOMA in type 2 DM Figure: HOMA in type 2 DM8 8Kohei Okita et al. “Homeostasis model assessment of insulin resistance for evaluating insulin sensitivity in patients with type 2 diabetes on insulin therapy”. Endocrine Journal 60.3 (2013), pp. 283–290. issn: 0918-8959. Karthik Balachandran Assessing Insulin Resistance
  • 69. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices HOMA QUICKI HOMA-2 Assessment of HOMA%S and HOMA%B in subjects with glucose levels 25 mM Accounts for renal glucose losses Assumes reduced suppression of HGP and increased insulin secretion in response to glucose levels 10 mM Allows for the use of total or specific insulin assays Karthik Balachandran Assessing Insulin Resistance
  • 70. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices HOMA QUICKI Quantitative insulin sensitivity check index Mathematical transformation that uses fasting glucose and fasting insulin Transformation is done as these variables have skewed distribution This makes better correlation with clamp studies -Si(clamp) Karthik Balachandran Assessing Insulin Resistance
  • 71. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices HOMA QUICKI QUICKI = 1 log(fasting insulin(ÎŒIU/ml)) + log(fasting glucose(mg/dl)) Karthik Balachandran Assessing Insulin Resistance
  • 72. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices HOMA QUICKI QUICKI Pros Simple Inexpensive Single blood draw More reproducible than HOMA-IR Karthik Balachandran Assessing Insulin Resistance
  • 73. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices HOMA QUICKI QUICKI Pros Simple Inexpensive Single blood draw More reproducible than HOMA-IR Cons No information on stimulated glucose and insulin systems Mainly tells hepatic IR- less important than peripheral IR Karthik Balachandran Assessing Insulin Resistance
  • 74. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Cederholm and Wibell index Gutt index Avignon Index Matsuda Index Cederholm and Wibell index Measures peripheral insulin sensitivity and muscular glucose uptake Values found in normal non-obese individuals were reported to be about 79 ± 14 mg l2 /mmol/mIU/min, lower in obese individuals Karthik Balachandran Assessing Insulin Resistance
  • 75. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Cederholm and Wibell index Gutt index Avignon Index Matsuda Index Cederholm and Wibell index Cederholm and Wibell index ISICederholm = 75000 + (G0 − G120)x1.15x180x0.19xm 120xGmeanxlog(Imean) 9 9where m is body weight and Gmean is mean glucose during OGTT and Imean is mean insulin during OGTT Karthik Balachandran Assessing Insulin Resistance
  • 76. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Cederholm and Wibell index Gutt index Avignon Index Matsuda Index Gutt Index Derived from Cederholm by omitting constant terms The reference range for lean controls was 89± 39, for obese 58 ±23 and for diabetic patients 23 ±19 mg l2 /mmol/mIU/min Karthik Balachandran Assessing Insulin Resistance
  • 77. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Cederholm and Wibell index Gutt index Avignon Index Matsuda Index Gutt Index Gutt Index ISI0,120 = 75000 + (G0 − G120)x0.19xm 120xGmeanxlog(Imean) Karthik Balachandran Assessing Insulin Resistance
  • 78. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Cederholm and Wibell index Gutt index Avignon Index Matsuda Index Avignon Index Avignon proposed 3 insulin sensitivity indices: Sib (derivedfrom fasting plasma insulin and glucose concentrations) Si2h (derived from plasma insulin and glucose concentrations in the120th min of OGTT) and SiM (derived by averaging Sib and Si2h after balancing Sib by a coefficient of 0.137 to give the same weight to both indices10 10Rita S Patarr˜ao, Wilford Wayne, and Maria Paula. “Revista Portuguesa de Endocrinologia , Diabetes e Metabolismo Assessment of methods and indexes of insulin sensitivity”. 9.1 (2014), pp. 65–73, p. 4. Karthik Balachandran Assessing Insulin Resistance
  • 79. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Cederholm and Wibell index Gutt index Avignon Index Matsuda Index Avignon Index Sib Sib = 108 I0xG0xVD Si2h Si2h = 108 I120xG120xVD SiM SiM = (0.137xSib) + Si2h 2 Karthik Balachandran Assessing Insulin Resistance
  • 80. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Cederholm and Wibell index Gutt index Avignon Index Matsuda Index Matsuda Index Composite measure of peripheral and hepatic insulin sensitivity Calculated during fasting and OGTT Along with disposition index, has excellent power for prediction of type 2 diabetes Karthik Balachandran Assessing Insulin Resistance
  • 81. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Cederholm and Wibell index Gutt index Avignon Index Matsuda Index Matsuda Index Matsuda Index ISIMatsuda = 10, 000 pG0xI0xGmeanxImean Disposition index I0−30 G0−30 Karthik Balachandran Assessing Insulin Resistance
  • 82. Belfiore Index Compares insulin and glucose values measured (fasting, 0–1–2 h areas or 0–2 h areas) with the defined normal reference values
  • 83. Belfiore Index Compares insulin and glucose values measured (fasting, 0–1–2 h areas or 0–2 h areas) with the defined normal reference values Values between 0 and 2 Normal - around 1 Overweight,obese,diabetes 1
  • 84. Belfiore Index Belfiore Index ISIBelfiore= 2 (Gs/GN)x(Is/IN) + 1
  • 85. Stumvoll index Series of indices calculated using insulin and glucose values during OGTT Uses muliple linear regression
  • 86. Stumvoll index Stumvoll index ISIStumvoll = 0.222 − 0.00333x BMI - 0.0000779 x I120-0.00541 x age ISIStumvoll = 0.156 − 0.0000459x I120-0.000321 xI0-0.0541 x G120
  • 87. McAuley Index Predicts insulin sensitivity in normal individuals
  • 88. McAuley Index Predicts insulin sensitivity in normal individuals Regression analysis used to estimate the cut-off points and the importance of various data for insulin resistance (fasting concentrations of insulin, triglycerides, aspartate aminotransferase, BMI, waist circumference)
  • 89. McAuley Index Predicts insulin sensitivity in normal individuals Regression analysis used to estimate the cut-off points and the importance of various data for insulin resistance (fasting concentrations of insulin, triglycerides, aspartate aminotransferase, BMI, waist circumference) Bootstrap procedure used to find an index most strongly correlating with insulin sensitivity index, corrected for fat-free mass
  • 90. McAuley Index Predicts insulin sensitivity in normal individuals Regression analysis used to estimate the cut-off points and the importance of various data for insulin resistance (fasting concentrations of insulin, triglycerides, aspartate aminotransferase, BMI, waist circumference) Bootstrap procedure used to find an index most strongly correlating with insulin sensitivity index, corrected for fat-free mass Combination of fasting insulin and triglycerides predicted IR best
  • 91. Oral glucose insulin sensitivity Uses data from OGTT Correlates with HIEC OGIS= f (G0, G90, G120, I0, I90, I120,D0)
  • 92. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Cederholm and Wibell index Gutt index Avignon Index Matsuda Index 1 Background 2 Assessment of IR Direct Assessment 3 Surrogate Markers HOMA QUICKI 4 Insulin Sensitiviy Indices Cederholm and Wibell index Gutt index Avignon Index Matsuda Index Karthik Balachandran Assessing Insulin Resistance
  • 93. Biochemical markers Figure: Biochemical markers11 11Bhawna Singh and Alpana Saxena. “Surrogate markers of insulin resistance: A review.” World journal of diabetes 1.2 (May 2010), pp. 36–47. issn: 1948-9358.
  • 94. Background Assessment of IR Surrogate Markers Insulin Sensitiviy Indices Cederholm and Wibell index Gutt index Avignon Index Matsuda Index Conclusion Measurement of insulin sensitivity - mainly experimental Available resources and expertise dictate choice of marker For resource limited setting, HOMA or QUICKI If IR is main part of study- clamp or FSIVGTT Karthik Balachandran Assessing Insulin Resistance