Tamara SpaicA fellow forever………….

ObjectivesWhat is insulin resistance/sensitivity ?Insulin SecretionHow is insulin sensitivity related to insulin

secretion?How do we measure?What are the clinical manifestations?What test is the best?

Pathophysiology of diabetes (2)

1.Beta cell function (insulin secretion)2.Insulin resistance/sensitivity3.Hepatic glucose output

Secretion

N ~ 30 U/dayBasal and stimulated insulin secretionBasal – in the absence of exogenous stimuli

(fasting state, 50%), pulsatileStimulated insulin secretion (in response to

glucose)Biphasic

Copyright ©2000 American Physiological Society

Rorsman, P. et al. News Physiol Sci 15: 72-77 2000

FIGURE 1. A: stimulus-secretion coupling of pancreatic {beta}-cells

Measures of Insulin Secretion and Beta Cell Mass

Fasting blood sugar Serum insulin concentration Oral and intravenous glucose tolerance tests Arginine stimulation

Fasting glucose

Fasting condition represents a basal steady state

Glucose is homeostatically maintained in the same range

Insulin levels are not significantly changingHGP is constant (matched whole body

glucose disposal under fasting conditions)Rats : loss of 70% beta cell mass – N glucose

Fasting Insulin Peripheral levels: 50-60% of pancreatic insulin

is removed by liver on first pass effectConfounding effect of anti-insulin antibodiesCross-reactivity of insulin assay with proinsulin

: 20% of circulating “insulin” may be proinsulin (and may be higher in IGT and Type 2DM)

Not good measure of beta cell mass/function but can be used to determine insulin sensitivity

What about C peptide?

C peptide released equimolar with insulinUnder steady-state conditions, reliable as

marker of insulin secretionDue to long half life, C peptide levels in

dynamic situations will not reflect insulin secretion

Arginine stimulationDependent on the prestimulus glucose

concentration

Acute serum insulin response to arginine (AIRarg)

Slope of glucose potentiation of insulin secretion

Maximum serum insulin response

Insulin Resistance (IR)Presence of an impaired biologic response to

either exogenously or endogenously secreted insulin

Manifested by decreased insulin-stimulated glucose transport and metabolism in adipocytes and skeletal muscle and by impaired suppression of hepatic glucose output

Williams textbook of Endocrinology, 2008

Insulin Sensitivity (IS)

The capacity of cells to respond to insulin-stimulated glucose uptake following ingestion of carbohydrates

Influenced by – age, weight, ethnicity, body fat, physical activity, medications

Disease vs not

IR → impaired/decreased IS

Insulin SensitivityThe ability of beta cells to compensate for IR determines

whether one develops DMCompensation – insulin hypersecretion even when N

glucoseTHIS OCCURS ONLY IF BETA CELL SENSITIVITY TO

GLUCOSE IS INCREASD2 factors – number of cells and increased expression of

hexokinase (relative to glucokinase)This shifts the glucose-insulin secretion dose response

curve to the LEFT, leading to increased insulin secretion across a wide range of glucose concentration

Disposition Index

Product of insulin secretion and sensitivityDuring the development of IR insulin

secretion increasesIf DI remains N (N glucose) – able to

compensateOnce DI drops (inadequate secretion in

relation to resistance) – diabetes develops

Zucker Fatty Rat (ZFR) and Diabetic Rat (ZDR)ZFR – obese and resistant, but N glucoseZDR – obese, resistant, overt hyperglycemiaAt 6 weeks (before development of DM)

increased beta cell mass (same in ZFR and ZDR and increased compared to lean control)

Beta cell mass in ZFR increased fourfold vs 2-fold in ZDR as DM develops (failure of beta cell to compensate)

Inhanced beta cell (apoptosis)

Humans……..Shift seen in pregnancy (three fold increase

in F1 and F2 insulin secretion)IGT – flattened response, shift to the right, F1

decreased consistently decreasedDM – F1 absent, further flattening and

coordination of insulin secretory responses during oscillatory glucose infusion is almost lost

Obesity1. Insulin resistance develops2. Insulin secretion increased3. If insulin sensitivity SAME – who will have

higher insulin secretion a) IGT patientb) Normal glucose tolerance patient

Bariatric surgery DI is1. Same2. Decreased3. Increased

Direct measures of ISHyperinsulinemic euglycemic clampOvernight fastInsulin infusionD20% to keep glucose clamped in the normal

rangeNeeds KSteady state (increased disposition to muscle and

adipocytes, HGP inhibited)No net change in glucose concentration then

glucose infusion rate is equal to the glucose disposal rate (M)

Insulin Suppression TestOctreotide or somatostatin infused to

suppress endogenous secretion of insulin and glucagon

Insulin and glucose infusedConstant infusion will determine steady state

plasma insulin (SSPI) and glucose (SSPG) SSPG inversly related to insulin sensitivity

Indirect measures

FSIVGTTOGTT

FSIVGTT (Frequently sampled intravenous glucose tolerance test)

To determine the disappearance rate of glucose per minute

Reflects patient’s ability to dispose of glucose load (first phase)

Screening siblings of DM1 or in pts with GI abnormalities

Bypasses GI (?incretins)Insensitive

ProcedureIV 25% or 50% glucose solution over 2-3

minutesSampling for glucose from indwelling

catheter in the opposite side (0, 10, 15, 20, 30 minutes)

Plasma glucose values plotted against time (rate of fall in % per minute)

75 g OGTTMeasurement of ISReflects the efficiency of the body to dispose of

glucose after oral glucose loadMimics physiologyNot primary screening test(if IFG or BG 5.6 - 6.0 but at risk)Just 0 and 120 min valueFasting for 8 hours prior3 days prior should be on 150-200 g of CHO/day

Surrogate Indexes

1/Fasting Insulin Glucose/Insulin ratioHOMAQUICKI

HOMAHomeostasis model assessmentAssumes feedback loop between liver and

beta cellsHOMA – IR = fasting insulin (uU/ml) x fasting

glucose (mmol/L) /22.5Normal IS HOMA-IR =1Resonable correlation with clamp studiesNot good if significantly impaired beta cell

function

QUICKIQuantitative insulin sensitivity check indexEmpirically derived mathematical

transformation of fasting blood glucose and plasma insulin concentrsation

Very good PPV1/[log(fasting insulin, uU/mL)+ log(fasting

glucose, mg/dL)]Performs best in insulin-resistant subjects

But why do beta cells fail ?

Glucotoxicity

1. Impaired glucose transport into the beta cell thru GLUT2 transporters

2. Reduced glucokinase activity in the beta cell3. Downregulation of insulin transcription factors

LipotoxicityHigh fat diet steatosis: after prolonged high fat

diet TG accumulate in skeletal muscle, islets, liver and elsewhere

FA initially stimulate insulin production

But as more fat enters islets, insulin secretion decreases as beta cells die

Role of islet amyloid polypeptide

High concentrations of amylin decrease glucose uptake and inhibit endogenous insulin secretion, suggesting that amylin may be directly involved in the pathogenesis of type 2 diabetes

Impaired insulin processing

Processing of proinsulin to insulin in the beta cells is impaired in type 2 diabetes, or that there is insufficient time for granules to mature properly so that they release more proinsulin.

Insulin secretion in IGT/DM2Delay in peak insulin responseDose response rate curve shiftes to the rightFirst phase response decreasedDM2 : absent first phase insulin and C-

peptide response to IVG and reduced 2nd phase response

Historic prospectiveHimsworth 1936Vague 1947Initially in patients on insulin that would

develop Ab to insulin (today recombinant human insulin)

IR not any longer a common complication but rather a component of several disorders

Donohues syndrome

(Leprechaunism)

Rabson-Mendenhall syndrome

Major causes of insulin resistance Inherited states of target cell resistance Leprechaunism (insulin-receptor mutations) Rabson-Mendenhall syndrome (insulin-receptor mutations) Type A syndrome of insulin resistance (insulin-receptor mutations in some, unknown

signalling defect in most) Most cases of type 2 diabetes mellitus (unknown inherited defect in vast majority) Some lipodystrophies (unknown primary defect)

Secondary insulin resistance Obesity (free fatty acids and tumor necrosis factor may contribute) Excess counterregulatory hormones (glucocorticoids, catecholamines, growth

hormone, placental lactogen) Type 2 diabetes mellitus (secondary to obesity and other factors) Inactivity Stress, infection (counterregulatory hormones) Pregnancy (placental lactogen) Immune mediated (anti-insulin antibodies, anti-insulin receptor antibodies in type B

syndrome) Miscellaneous (starvation, uremia, cirrhosis, ketoacidosis)

Unknown etiology of insulin resistance Hypertension Polycystic ovary syndrome Metabolic Syndrome (Syndrome X)

MONOGENIC FORMS OF DIABETES

ASSOCIATED WITH INSULIN RESISTANCEMutations in the insulin receptor gene • Type A insulin resistance • Leprechaunism • Rabson-Mendenhall syndrome

Lipoatrophic diabetes Mutations in the PPARγ gene

ASSOCIATED WITH DEFECTIVE INSULIN SECRETION Mutations in the insulin or proinsulin genes Mitochondrial gene mutations Maturity-onset Diabetes of the Young (MODY) HNF-4α (MODY 1) Glucokinase (MODY 2) HNF-1α (MODY 3) IPF-1 (MODY 4) HNF-1β (MODY 5) NeuroD1/Beta2 (MODY 6)

Clinical manifestations of insulin resistance Glucose homeostasis Variable, including overt diabetes, impaired glucose tolerance, normal,

and hypoglycemia Cutaneous Acanthosis nigricans Skin tags Alopecia Reproductive Amenorrhea Hirsutism Virilization Infertility (in women) Linear growth Variable, including normal, impaired, increased Adipose tissue Variable, including normal, lipoatrophy, lipohypertrophy, obesity Musculoskeletal Variable, including normal, cramps, muscle hypertrophy,

pseudoacromegaly Lipid metabolism Normal or hypertriglyceridemia /low HDLAutoimmunity Type B syndrome with variety of immune phenotypes

Abnormal glucose metabolismHypoglycemiaN (majority)IGTDM2

DM2PolygenicEnvironment

IR is associated with progression to IGT/DM2 although diabetes is rarely seen in in IR persons without some degree of beta cell dysfunction.

Acanthosis nigricans

Hyperkeratosis, epidermal papillomatosis, and increased numbers of melanocytes

Reproductive abnormailitiesNot in maleOvarian hyperandrogenismThe basis for the association between insulin

resistance and ovarian hyperandrogenism is not known

The ovary shows the histologic changes of hyperthecosis

overt virilization or hirsutism, amenorrhea, and infertility

GrowthN in adultsPediatricSyndromes (leprechaunism and the Rabson-

Mendenhall syndrome)

Musculoskeletal changes

Some patients with severe tissue resistance to insulin have muscle cramps unrelated to exercise

The severity of cramping can sometimes be reduced by phenytoin

Adipose tissue

ObesityLipodystrophy (primary vs acquired)

Metabolic SyndromeThe US National Cholesterol Education Program

Adult Treatment Panel III (2001) requires at least three of the following:

1.Central obesity: waist circumference ≥ 102 cm (male),

2. ≥ 88 cm (female)3.Dyslipidemia: TG ≥ 1.7 mmol/L 4.Dyslipidemia: HDL-C < 1.0 mmol/L (male), <1.3

mmol/L (female)5.Blood pressure ≥ 130/85 mmHg6.Fasting plasma glucose ≥ 6.1 mmol/L (2004 :

>5.6 mmol/L or hypoglycemic agent)

IS and BMIAssociation of IS and BMI (inverse)Why: abdominal fat is more lipolytically

activeMore resistant to antilipolytic effect of insulinAltered LPL activityGreater flux of FFA 11 beta hydroxysteroid dehydrogenase (more

cortisol)

FFAPredict progression of IGT to DMPeripheral levels not helpful(efficiently extracted by the liver and muscle)Randel hypothesis (ability of FFA to inhibit

muscle glucose utilization)Affect (decrease) glucose transportImpair insulin action