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Tamara Spaic
A fellow forever………….
Objectives
 What is insulin resistance/sensitivity ?
 Insulin Secretion
 How 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/sensitivity
3. Hepatic glucose output
Secretion
 N ~ 30 U/day
 Basal and stimulated insulin secretion
 Basal – in the absence of exogenous stimuli (fasting
state, 50%), pulsatile
 Stimulated insulin secretion (in response to glucose)
 Biphasic
FIGURE 1. A: stimulus-secretion coupling of pancreatic {beta}-cells
Rorsman, P. et al. News Physiol Sci 15: 72-77 2000
Copyright ©2000 American Physiological Society
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 changing
 HGP 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 effect
 Confounding effect of anti-insulin antibodies
 Cross-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 insulin
 Under steady-state conditions, reliable as marker of
insulin secretion
 Due to long half life, C peptide levels in dynamic
situations will not reflect insulin secretion
Arginine stimulation
 Dependent 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 insulinstimulated glucose uptake following ingestion of
carbohydrates
 Influenced by – age, weight, ethnicity, body fat,
physical activity, medications
Disease vs not
 IR → impaired/decreased IS
Insulin Sensitivity
 The ability of beta cells to compensate for IR determines whether one
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develops DM
Compensation – insulin hypersecretion even when N glucose
THIS OCCURS ONLY IF BETA CELL SENSITIVITY TO GLUCOSE IS
INCREASD
2 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 sensitivity
 During the development of IR insulin secretion
increases
 If DI remains N (N glucose) – able to compensate
 Once DI drops (inadequate secretion in relation to
resistance) – diabetes develops
Zucker Fatty Rat (ZFR) and Diabetic Rat
(ZDR)
 ZFR – obese and resistant, but N glucose
 ZDR – obese, resistant, overt hyperglycemia
 At 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 decreased
 DM – F1 absent, further flattening and coordination of
insulin secretory responses during oscillatory glucose
infusion is almost lost
Obesity
Insulin resistance develops
2. Insulin secretion increased
3. If insulin sensitivity SAME – who will have higher
insulin secretion
a) IGT patient
b) Normal glucose tolerance patient
1.
Bariatric surgery
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1.
2.
3.
DI is
Same
Decreased
Increased
Direct measures of IS
 Hyperinsulinemic euglycemic clamp
 Overnight fast
 Insulin infusion
 D20% to keep glucose clamped in the normal range
 Needs K
 Steady 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 Test
 Octreotide or somatostatin infused to suppress
endogenous secretion of insulin and glucagon
 Insulin and glucose infused
 Constant infusion will determine steady state plasma
insulin (SSPI) and glucose (SSPG)
 SSPG inversly related to insulin sensitivity
Indirect measures
 FSIVGTT
 OGTT
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
Procedure
 IV 25% or 50% glucose solution over 2-3 minutes
 Sampling 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 OGTT
 Measurement of IS
 Reflects the efficiency of the body to dispose of glucose
after oral glucose load
 Mimics physiology
 Not primary screening test
(if IFG or BG 5.6 - 6.0 but at risk)
 Just 0 and 120 min value
 Fasting for 8 hours prior
 3 days prior should be on 150-200 g of CHO/day
Surrogate Indexes
 1/Fasting Insulin
 Glucose/Insulin ratio
 HOMA
 QUICKI
HOMA
 Homeostasis model assessment
 Assumes feedback loop between liver and beta cells
 HOMA – IR = fasting insulin (uU/ml) x fasting glucose
(mmol/L) /22.5
 Normal IS HOMA-IR =1
 Resonable correlation with clamp studies
 Not good if significantly impaired beta cell function
QUICKI
 Quantitative insulin sensitivity check index
 Empirically derived mathematical transformation of
fasting blood glucose and plasma insulin
concentrsation
 Very good PPV
 1/[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 cell
3. Downregulation of insulin transcription factors
Lipotoxicity
 High 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/DM2
 Delay in peak insulin response
 Dose response rate curve shiftes to the right
 First phase response decreased
 DM2 : absent first phase insulin and C-peptide
response to IVG and reduced 2nd phase response
Historic prospective
 Himsworth 1936
 Vague 1947
 Initially 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
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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
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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
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Hypertension
Polycystic ovary syndrome
Metabolic Syndrome (Syndrome X)
MONOGENIC FORMS OF DIABETES
ASSOCIATED WITH INSULIN RESISTANCE
Mutations in the insulin receptor gene
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Type A insulin resistance
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Leprechaunism
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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 HDL
Autoimmunity
 Type B syndrome with variety of immune phenotypes
Abnormal glucose metabolism
 Hypoglycemia
 N (majority)
 IGT
 DM2
DM2
 Polygenic
 Environment
 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 abnormailities
 Not in male
 Ovarian hyperandrogenism
 The 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
Growth
 N in adults
 Pediatric
 Syndromes (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
 Obesity
 Lipodystrophy (primary vs acquired)
Metabolic Syndrome
 The 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 mmHg
6. Fasting plasma glucose ≥ 6.1 mmol/L (2004 : >5.6 mmol/L
or hypoglycemic agent)
IS and BMI
 Association of IS and BMI (inverse)
 Why: abdominal fat is more lipolytically active
 More resistant to antilipolytic effect of insulin
 Altered LPL activity
 Greater flux of FFA
 11 beta hydroxysteroid dehydrogenase (more cortisol)
FFA
 Predict progression of IGT to DM
 Peripheral levels not helpful
(efficiently extracted by the liver and muscle)
 Randel hypothesis (ability of FFA to inhibit muscle
glucose utilization)
 Affect (decrease) glucose transport
 Impair insulin action