tamara spaic a fellow forever………….. objectives what is insulin resistance/sensitivity ?...
TRANSCRIPT
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