Assessing Insulin Resistance
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Transcript of Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Assessing Insulin Resistance
Karthik Balachandran
Department of Endocrinology,JIPMER
Oct 2014
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Background
IR is sine qua non of type 2 DiabetesReduced 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
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Background
IR is sine qua non of type 2 DiabetesReduced ability of insulin to exert its action on target tissues-liver,skeletal muscle and adipose tissueContinuum not a binary
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Figure: Causes of Insulin Resistance1
1Anwar Borai et al. “Selection of the appropriate method for the assessmentof insulin resistance.” BMC medical research methodology 11.1 (Jan. 2011),p. 158. issn: 1471-2288.
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Responsiveness and Sensivitity
Responsiveness Maximal effect of insulinSensitivity Half maximal effect of insulin2
2Ranganath Muniyappa et al. “Current approaches for assessing insulinsensitivity and resistance in vivo: advantages, limitations, and appropriateusage.” American journal of physiology. Endocrinology and metabolism 294.1(Jan. 2008), E15–26. issn: 0193-1849.
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Basis of IR
Genetic and environmental componentsFetal originsGenes in the insulin action pathway
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Dynamic testsHyperinsulinemic euglycemic clampHyperglycemic clampInsulin tolerance testFrequently Sampled Intravenous GTT(FSIVGTT)Modified FSIVGTTOGTTContinuous infusion of glucose with modelassessment(CIGMA)
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Hyperinsulinemic Euglycemic Clamp
Hyperinsulinemic Supraphysiological InsulinEuglycemic Normal glucose levels
Clamp Hepatic glucose output clamped
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Hyperinsulinemic Euglycemic Clamp
Hyperinsulinemic Supraphysiological InsulinEuglycemic Normal glucose levels
Clamp Hepatic glucose output clamped
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Hyperinsulinemic Euglycemic Clamp
Described by DeFronzo et al-1979Infuse exogenous insulin at 6mIU/kg/min and 20% glucoseCheck RBS at 5 min intervalsInfused insulin suppresses HGO
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin 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 lessInsulin mediated glucose disposal rate denoted as M
3usally during the last 30-60 min of the testKarthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Hyperinsulinemic Euglycemic Clamp
Once steady state is reached3
rate of infusion of glucose= rate of peripheral glucose disposalInsulin sensitive people require more exogenous glucose,insulin resistant people require lessInsulin mediated glucose disposal rate denoted as M
3usally during the last 30-60 min of the testKarthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Hyperinsulinemic Euglycemic Clamp
Sensitive M > 7.5mg/kg/minResistant M < 4mg/kg/min
Intermediate M 4to7.5mg/kg/min
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Hyperinsulinemic Euglycemic Clamp
M can be normalized to fat free mass or resting energyexpenditureInsulin sensitivity index Si(clamp) derived from data forcomparing clamp with minimal model
Hyperinsulinemic euglycemic clamp-gold standard formeasuring IR
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Hyperinsulinemic Euglycemic Clamp
M can be normalized to fat free mass or resting energyexpenditureInsulin sensitivity index Si(clamp) derived from data forcomparing clamp with minimal modelHyperinsulinemic euglycemic clamp-gold standard formeasuring IR
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Infusion rates-importance
Figure: Insulin vs Glucose disposal Figure: Insulin infusion vs GIR
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Clamp-considerations
M should be obtained at single infusion rateMultiple stepwise infusion rates-ideal but difficultDifference b/w arterial and venous blood-”arterialised” venousblood
Cannulate in retrograde fashionWarm hand with pad to open AV anastomoses
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Clamp-improvements
Use of radiolabeled tracers to study hepatic and peripheralinsulin sensitivityGlycerol and aminoacids to study fat and protein metabolismw.r.t. insulin sensitivityP31 magnetic resonance spectroscopy - assess rates ofinsulin-stimulated muscle mitochondrial ATP synthase fluxand insulin-stimulated increases in concentrations ofintramyocellular inorganic phosphate
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Hyperglycemic Clamp
Quantitative measure of β -cell insulin secretion in response toglucosePlasma glucose levels raised to plateau at 7mmol/L abovebasal and kept for 2 hours
Glucose infused at 5 min intervalsHyperglycemia stimuates insulin secretionVolume of glucose maintenance doses needed to maintainhyperglycemia-a measure of insulin secretion
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Hyperglycemic Clamp
Quantitative measure of β -cell insulin secretion in response toglucosePlasma glucose levels raised to plateau at 7mmol/L abovebasal and kept for 2 hoursGlucose infused at 5 min intervals
Hyperglycemia stimuates insulin secretionVolume of glucose maintenance doses needed to maintainhyperglycemia-a measure of insulin secretion
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Hyperglycemic Clamp
Quantitative measure of β -cell insulin secretion in response toglucosePlasma glucose levels raised to plateau at 7mmol/L abovebasal and kept for 2 hoursGlucose infused at 5 min intervalsHyperglycemia stimuates insulin secretion
Volume of glucose maintenance doses needed to maintainhyperglycemia-a measure of insulin secretion
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Hyperglycemic Clamp
Quantitative measure of β -cell insulin secretion in response toglucosePlasma glucose levels raised to plateau at 7mmol/L abovebasal and kept for 2 hoursGlucose infused at 5 min intervalsHyperglycemia stimuates insulin secretionVolume of glucose maintenance doses needed to maintainhyperglycemia-a measure of insulin secretion
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Hyperglycemic Clamp
M can be calculated as in euglycemic clampM/I ratio provides a measure of sensitivity to endogenouslysecreted insulin
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Clamp studies
ConsDifficultSuppresses HGORisk of hypoglycemiaNot physiological
ProsGold standard
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Insulin Tolerance Test
Oldest measure of insulin sensitivy- 1929Net effect of insulin on liver and peripheral tissuesIV bolus of 0.1 mU/kg givenBlood samples are collected 15 and 5 min prior to injectionand at 3, 6, 9, 12, 15, 20 and 30 min thereafterAt 30 min glucose is injected to stop a continuing fall in bloodglucose4
4Anwar Borai, Callum Livingstone, and Gordon a a Ferns. “The biochemicalassessment of insulin resistance.” Annals of clinical biochemistry 44.Pt 4 (July2007), pp. 324–42. issn: 0004-5632.
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Insulin Tolerance Test
The rate of glucose disappearance constant is then calculated asthe slope of the decline in blood glucose plotted logarithmically
KITT =0.693t1/2
x100 (1)
I Normal KITT is > 2%I Values < 1.5% are abnormal
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Insulin Tolerance Test
The rate of glucose disappearance constant is then calculated asthe slope of the decline in blood glucose plotted logarithmically
KITT =0.693t1/2
x100 (1)
I Normal KITT is > 2%I Values < 1.5% are abnormal
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
ITT
LimitationsRisk of hypoglycemiaCan’t localize the site ofresistanceAntagonism bycounter-regulatory hormones
AdvantageCheaper than Clamp studies
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
ITT
LimitationsRisk of hypoglycemiaCan’t localize the site ofresistanceAntagonism bycounter-regulatory hormones
AdvantageCheaper than Clamp studies
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin 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 abolus over 1minBlood samples for glucose and insulin measurement are drawn2, 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 theglucose injection
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin 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 cannulaGlucose (0.3 g/kg of 50%) is then manually injected as abolus over 1min
Blood samples for glucose and insulin measurement are drawn2, 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 theglucose injection
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin 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 cannulaGlucose (0.3 g/kg of 50%) is then manually injected as abolus over 1minBlood samples for glucose and insulin measurement are drawn2, 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 theglucose injection
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Frequently Sampled Intravenous GTT
Modified- exogenous insulin also used over 5 min beginning 20min after the iv glucose bolusSome studies use tolbutamideData analyzed using miminal model analysis
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Figure: FSIVGTT and Minimal model analysis
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Minimal Model Equations
One compartmentdG(t)
dt = −[p1 + X (t)G(t) + p1Gb (2)
Two compartmentsdX (t)
dt = p2X (t) + p3[I(t)− ib] (3)
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Minimal model- assumptions
1 Instantaneous glucose distribution in monocompartmentalspace
2 Glucose disappearance at monoexponential rate3 Glucose concentration at beginning and end -same4 Insulin acts from a remote compartment5 Glucose disposal in skeletal muscle and HGO-lumped together6 Total insulin secretion is above a certain threshold
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Minimal model- assumptions
1 Instantaneous glucose distribution in monocompartmentalspace
2 Glucose disappearance at monoexponential rate
3 Glucose concentration at beginning and end -same4 Insulin acts from a remote compartment5 Glucose disposal in skeletal muscle and HGO-lumped together6 Total insulin secretion is above a certain threshold
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Minimal model- assumptions
1 Instantaneous glucose distribution in monocompartmentalspace
2 Glucose disappearance at monoexponential rate3 Glucose concentration at beginning and end -same
4 Insulin acts from a remote compartment5 Glucose disposal in skeletal muscle and HGO-lumped together6 Total insulin secretion is above a certain threshold
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Minimal model- assumptions
1 Instantaneous glucose distribution in monocompartmentalspace
2 Glucose disappearance at monoexponential rate3 Glucose concentration at beginning and end -same4 Insulin acts from a remote compartment
5 Glucose disposal in skeletal muscle and HGO-lumped together6 Total insulin secretion is above a certain threshold
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Minimal model- assumptions
1 Instantaneous glucose distribution in monocompartmentalspace
2 Glucose disappearance at monoexponential rate3 Glucose concentration at beginning and end -same4 Insulin acts from a remote compartment5 Glucose disposal in skeletal muscle and HGO-lumped together
6 Total insulin secretion is above a certain threshold
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Minimal model- assumptions
1 Instantaneous glucose distribution in monocompartmentalspace
2 Glucose disappearance at monoexponential rate3 Glucose concentration at beginning and end -same4 Insulin acts from a remote compartment5 Glucose disposal in skeletal muscle and HGO-lumped together6 Total insulin secretion is above a certain threshold
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Glucose effectiveness and FSIVGTT
Glucose effectivenessAbility of glucose per se to promote its own disposal and inhibitHGP in the absence of an incremental insulin effect
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
FSIVGTT-Advantages
Insulin sensitivity, glucose effectiveness, and β-cell functioncan be derived from a single dynamic testSimpler than clamp studies
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Oral glucose tolerance test
After an overnight fast, blood samples for deter- minations ofglucose and insulin concentrations are taken at 0, 30,60, and120 min following a standard oral glucose load (75 g).Use of glucose tracer and insulin/C peptide at specific timepoints - allows calculation of glucose clearance
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
OGTT problems
Poor reproducibilityVariable gastric emptyingVariable glucose absorptionVariable incretin effect
No adequate information about glucose and insulin dynamicsLess physiologicalDoes not distinguish insulin sensitivity from secretion5
5Rita S Patarrao, Wilford Wayne, and Maria Paula. “Revista Portuguesa deEndocrinologia , Diabetes e Metabolismo Assessment of methods and indexes ofinsulin sensitivity”. 9.1 (2014), pp. 65–73.
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Meal Tolerance Test
Physiologic variant of OGTT
No artifactual post load hypoglycemiaTriggers cephalic phase of gastric emptyingPotential to evaluate the physiological effects of incretinsCan measure insulin sensitivity with a modified algorithmbased on the minimal model
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Meal Tolerance Test
Physiologic variant of OGTTNo artifactual post load hypoglycemia
Triggers cephalic phase of gastric emptyingPotential to evaluate the physiological effects of incretinsCan measure insulin sensitivity with a modified algorithmbased on the minimal model
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Meal Tolerance Test
Physiologic variant of OGTTNo artifactual post load hypoglycemiaTriggers cephalic phase of gastric emptying
Potential to evaluate the physiological effects of incretinsCan measure insulin sensitivity with a modified algorithmbased on the minimal model
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Meal Tolerance Test
Physiologic variant of OGTTNo artifactual post load hypoglycemiaTriggers cephalic phase of gastric emptyingPotential to evaluate the physiological effects of incretins
Can measure insulin sensitivity with a modified algorithmbased on the minimal model
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Meal Tolerance Test
Physiologic variant of OGTTNo artifactual post load hypoglycemiaTriggers cephalic phase of gastric emptyingPotential to evaluate the physiological effects of incretinsCan measure insulin sensitivity with a modified algorithmbased on the minimal model
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
Continuous infusion of glucose with model assessment
Assesses insulin sensitivity through the evaluation of the nearsteady-state glucose and insulin con- centrations after acontinuous infusion of glucoseMimics postprandial glucose and insulin concentrationsThe glucose and insulin values used for CIGMA are obtainedduring the last 15 min of the 60 min continuous glucoseinfusion (5 mg glucose/kg bw/min)
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Direct Assessment
CIGMA
Samples are collected at 5 min intervals and the average isthen compared with predicted values from the com- putermodelThe median value for normal subjects is 1.35, and for diabeticpatients with mild hyperglycemia is 4.0
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
HOMAQUICKI
Homeostasis Model Assessment
Model of interactions between glucose and insulin dynamics,that is then used to predict fasting steady-state glucose andinsulin concentrations
The model assumes a feedback loop b/w liver and β cellGlucose concentrations are regulated by insulin-dependenthepatic glucose production, while insulin levels depend on thepancreatic β-cellresponse to glucose concentrations
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
HOMAQUICKI
Homeostasis Model Assessment
Model of interactions between glucose and insulin dynamics,that is then used to predict fasting steady-state glucose andinsulin concentrationsThe model assumes a feedback loop b/w liver and β cell
Glucose concentrations are regulated by insulin-dependenthepatic glucose production, while insulin levels depend on thepancreatic β-cellresponse to glucose concentrations
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
HOMAQUICKI
Homeostasis Model Assessment
Model of interactions between glucose and insulin dynamics,that is then used to predict fasting steady-state glucose andinsulin concentrationsThe model assumes a feedback loop b/w liver and β cellGlucose concentrations are regulated by insulin-dependenthepatic glucose production, while insulin levels depend on thepancreatic β-cellresponse to glucose concentrations
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
HOMAQUICKI
HOMA
Describes Glucose insulin homeostasis by a set of non linearequations
The model predicts fasting steady-state levels of plasmaglucose and insulin for any given combination of pancreaticβ-cell function (HOMA%B) and insulin sensitivity(HOMA%S).
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
HOMAQUICKI
HOMA
HOMA =Fasting glucosexFasting insulin
22.56
6The denominator of 22.5 is a normalizing factor, i.e., the product of normalfasting plasma insulin of 5 µIU/ml and normal fasting plasma glucose of 4.5mmol/l obtained from an “ideal and normal” individual
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
HOMAQUICKI
HOMA in type 2 DM
Short acting insulin and sulfonylureas can be usedStop NPH the night before7
7Kohei Okita et al. “Homeostasis model assessment of insulin resistance forevaluating insulin sensitivity in patients with type 2 diabetes on insulintherapy”. Endocrine Journal 60.3 (2013), pp. 283–290. issn: 0918-8959.
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
HOMAQUICKI
HOMA in type 2 DM
Figure: HOMA in type 2 DM8
8Kohei Okita et al. “Homeostasis model assessment of insulin resistance forevaluating insulin sensitivity in patients with type 2 diabetes on insulintherapy”. Endocrine Journal 60.3 (2013), pp. 283–290. issn: 0918-8959.
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
HOMAQUICKI
HOMA-2
Assessment of HOMA%S and HOMA%B in subjects withglucose levels ≤25 mMAccounts for renal glucose lossesAssumes reduced suppression of HGP and increased insulinsecretion in response to glucose levels> 10 mMAllows for the use of total or specific insulin assays
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
HOMAQUICKI
Quantitative insulin sensitivity check index
Mathematical transformation that uses fasting glucose andfasting insulinTransformation is done as these variables have skeweddistributionThis makes better correlation with clamp studies -Si(clamp)
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
HOMAQUICKI
QUICKI =1
log(fasting insulin(µIU/ml)) + log(fasting glucose(mg/dl))
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
HOMAQUICKI
QUICKI
ProsSimpleInexpensiveSingle blood drawMore reproducible than HOMA-IR
ConsNo information on stimulated glucose and insulin systemsMainly tells hepatic IR- less important than peripheral IR
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
HOMAQUICKI
QUICKI
ProsSimpleInexpensiveSingle blood drawMore reproducible than HOMA-IR
ConsNo information on stimulated glucose and insulin systemsMainly tells hepatic IR- less important than peripheral IR
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Cederholm and Wibell indexGutt indexAvignon IndexMatsuda Index
Cederholm and Wibell index
Measures peripheral insulin sensitivity and muscular glucoseuptakeValues found in normal non-obese individuals were reported tobe about 79 ± 14 mg l2 /mmol/mIU/min, lower in obeseindividuals
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Cederholm and Wibell indexGutt indexAvignon IndexMatsuda 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 Imeanis mean insulin during OGTT
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Cederholm and Wibell indexGutt indexAvignon IndexMatsuda Index
Gutt Index
Derived from Cederholm by omitting constant termsThe 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
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Cederholm and Wibell indexGutt indexAvignon IndexMatsuda Index
Gutt Index
Gutt Index
ISI0,120 =75000 + (G0 − G120)x0.19xm
120xGmeanxlog(Imean)
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Cederholm and Wibell indexGutt indexAvignon IndexMatsuda 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 inthe120th min of OGTT) andSiM (derived by averaging Sib and Si2h after balancing Sib by acoefficient of 0.137 to give the same weight to both indices10
10Rita S Patarrao, Wilford Wayne, and Maria Paula. “Revista Portuguesa deEndocrinologia , Diabetes e Metabolismo Assessment of methods and indexes ofinsulin sensitivity”. 9.1 (2014), pp. 65–73, p. 4.
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Cederholm and Wibell indexGutt indexAvignon IndexMatsuda Index
Avignon Index
Sib
Sib =108
I0xG0xVD
Si2h
Si2h =108
I120xG120xVD
SiM
SiM =(0.137xSib) + Si2h
2
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Cederholm and Wibell indexGutt indexAvignon IndexMatsuda Index
Matsuda Index
Composite measure of peripheral and hepatic insulin sensitivityCalculated during fasting and OGTTAlong with disposition index, has excellent power forprediction of type 2 diabetes
Karthik Balachandran Assessing Insulin Resistance
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Cederholm and Wibell indexGutt indexAvignon IndexMatsuda Index
Matsuda Index
Matsuda Index
ISIMatsuda =10, 000√
G0xI0xGmeanxImean
Disposition index∆I0−30∆G0−30
Karthik Balachandran Assessing Insulin Resistance
Belfiore Index
Compares insulin and glucose values measured (fasting, 0–1–2h areas or 0–2 h areas) with the defined normal referencevalues
Values between 0 and 2Normal - around 1Overweight,obese,diabetes <1
Belfiore Index
Compares insulin and glucose values measured (fasting, 0–1–2h areas or 0–2 h areas) with the defined normal referencevaluesValues between 0 and 2
Normal - around 1Overweight,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 valuesduring OGTTUses muliple linear regression
Stumvoll index
Stumvoll indexISIStumvoll = 0.222− 0.00333x BMI - 0.0000779 x I120-0.00541 xageISIStumvoll = 0.156− 0.0000459x I120-0.000321 xI0-0.0541 x G120
McAuley Index
Predicts insulin sensitivity in normal individuals
Regression analysis used to estimate the cut-off points andthe importance of various data for insulin resistance (fastingconcentrations of insulin, triglycerides, aspartateaminotransferase, BMI, waist circumference)Bootstrap procedure used to find an index most stronglycorrelating with insulin sensitivity index, corrected for fat-freemassCombination of fasting insulin and triglycerides predicted IRbest
McAuley Index
Predicts insulin sensitivity in normal individualsRegression analysis used to estimate the cut-off points andthe importance of various data for insulin resistance (fastingconcentrations of insulin, triglycerides, aspartateaminotransferase, BMI, waist circumference)
Bootstrap procedure used to find an index most stronglycorrelating with insulin sensitivity index, corrected for fat-freemassCombination of fasting insulin and triglycerides predicted IRbest
McAuley Index
Predicts insulin sensitivity in normal individualsRegression analysis used to estimate the cut-off points andthe importance of various data for insulin resistance (fastingconcentrations of insulin, triglycerides, aspartateaminotransferase, BMI, waist circumference)Bootstrap procedure used to find an index most stronglycorrelating with insulin sensitivity index, corrected for fat-freemass
Combination of fasting insulin and triglycerides predicted IRbest
McAuley Index
Predicts insulin sensitivity in normal individualsRegression analysis used to estimate the cut-off points andthe importance of various data for insulin resistance (fastingconcentrations of insulin, triglycerides, aspartateaminotransferase, BMI, waist circumference)Bootstrap procedure used to find an index most stronglycorrelating with insulin sensitivity index, corrected for fat-freemassCombination of fasting insulin and triglycerides predicted IRbest
Oral glucose insulin sensitivity
Uses data from OGTTCorrelates with HIEC
OGIS= f (G0,G90,G120, I0, I90, I120,D0)
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Cederholm and Wibell indexGutt indexAvignon IndexMatsuda Index
1 Background
2 Assessment of IRDirect Assessment
3 Surrogate MarkersHOMAQUICKI
4 Insulin Sensitiviy IndicesCederholm and Wibell indexGutt indexAvignon IndexMatsuda Index
Karthik Balachandran Assessing Insulin Resistance
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.
BackgroundAssessment of IR
Surrogate MarkersInsulin Sensitiviy Indices
Cederholm and Wibell indexGutt indexAvignon IndexMatsuda Index
Conclusion
Measurement of insulin sensitivity - mainly experimentalAvailable resources and expertise dictate choice of markerFor resource limited setting, HOMA or QUICKIIf IR is main part of study- clamp or FSIVGTT
Karthik Balachandran Assessing Insulin Resistance
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