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



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




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




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.




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.




Basis of IR

Genetic and environmental componentsFetal originsGenes in the insulin action pathway




Direct Assessment

Dynamic testsHyperinsulinemic euglycemic clampHyperglycemic clampInsulin tolerance testFrequently Sampled Intravenous GTT(FSIVGTT)Modified FSIVGTTOGTTContinuous infusion of glucose with modelassessment(CIGMA)




Direct Assessment

Hyperinsulinemic Euglycemic Clamp

Hyperinsulinemic Supraphysiological InsulinEuglycemic Normal glucose levels

Clamp Hepatic glucose output clamped




Direct Assessment


Hyperinsulinemic Supraphysiological InsulinEuglycemic Normal glucose levels

Clamp Hepatic glucose output clamped




Direct Assessment


Described by DeFronzo et al-1979Infuse exogenous insulin at 6mIU/kg/min and 20% glucoseCheck RBS at 5 min intervalsInfused insulin suppresses HGO




Direct Assessment


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



Direct Assessment


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



Direct Assessment


Sensitive M > 7.5mg/kg/minResistant M < 4mg/kg/min

Intermediate M 4to7.5mg/kg/min




Direct Assessment


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




Direct Assessment


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




Direct Assessment

Infusion rates-importance

Figure: Insulin vs Glucose disposal Figure: Insulin infusion vs GIR




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




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




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




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




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




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




Direct Assessment

Hyperglycemic Clamp

M can be calculated as in euglycemic clampM/I ratio provides a measure of sensitivity to endogenouslysecreted insulin




Direct Assessment

Clamp studies

ConsDifficultSuppresses HGORisk of hypoglycemiaNot physiological

ProsGold standard




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.




Direct Assessment


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




Direct Assessment


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




Direct Assessment

ITT

LimitationsRisk of hypoglycemiaCan’t localize the site ofresistanceAntagonism bycounter-regulatory hormones

AdvantageCheaper than Clamp studies




Direct Assessment

ITT

LimitationsRisk of hypoglycemiaCan’t localize the site ofresistanceAntagonism bycounter-regulatory hormones

AdvantageCheaper than Clamp studies




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




Direct Assessment


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




Direct Assessment


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




Direct Assessment


Modified- exogenous insulin also used over 5 min beginning 20min after the iv glucose bolusSome studies use tolbutamideData analyzed using miminal model analysis




Direct Assessment

Figure: FSIVGTT and Minimal model analysis




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)




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




Direct Assessment



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




Direct Assessment



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




Direct Assessment



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




Direct Assessment



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




Direct Assessment



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




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




Direct Assessment

FSIVGTT-Advantages

Insulin sensitivity, glucose effectiveness, and β-cell functioncan be derived from a single dynamic testSimpler than clamp studies




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




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.




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




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




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




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




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




Direct Assessment

Continuous infusion of glucose with model assessment

Assesses insulin sensitivity through the evaluation of the nearsteady-state glucose and insulin concentrations 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)




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




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




HOMAQUICKI


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




HOMAQUICKI


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




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).




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




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.




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.




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




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)




HOMAQUICKI

QUICKI =1

log(fasting insulin(µIU/ml)) + log(fasting glucose(mg/dl))




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




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




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







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





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





Gutt Index

Gutt Index

ISI0,120 =75000 + (G0 − G120)x0.19xm

120xGmeanxlog(Imean)





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.





Avignon Index

Sib

Sib =108

I0xG0xVD

Si2h

Si2h =108

I120xG120xVD

SiM

SiM =(0.137xSib) + Si2h

2





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





Matsuda Index

Matsuda Index

ISIMatsuda =10, 000√

G0xI0xGmeanxImean

Disposition index∆I0−30∆G0−30


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)




1 Background

2 Assessment of IRDirect Assessment

3 Surrogate MarkersHOMAQUICKI

4 Insulin Sensitiviy IndicesCederholm and Wibell indexGutt indexAvignon IndexMatsuda Index


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.




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


Thank You

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Assessing Insulin Resistance