Transcript Pathophysiology of Type 2 Diabetes

Pathophysiology of
Type 2 Diabetes
Deric Morrison
October 14, 2009
Objectives
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Discuss the Pathophysiology of T2DM
including:
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Insulin Secretion
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Genetic Factors
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Monogenic
Polygenic
Environmental factors
Insulin Resistance
Genetic Factors
 Environmental factors
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Introduction
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Type 2 Diabetes
Hyperglycemia
 Insulin resistance (Skeletal muscle, liver, adipose
tissue) - Early
 Insufficient pancreatic β cell compensation due to
irreversible loss of β cell mass – Late
 Increased hepatic glucose production
 Genetic and environmental factors
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Normal
IGT*
Type 2 diabetes
Insulin
resistance
Increased insulin
resistance
Insulin
secretion
Hyperinsulinemia,
then -cell failure
Post-prandial
glucose
Abnormal
glucose tolerance
Fasting
glucose
Hyperglycemia
*IGT = impaired glucose tolerance
Adapted from Type 2 Diabetes BASICS. International Diabetes Center (IDC), Minneapolis, 2000.
Epidemiology
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T2DM ~90% of DM burden worldwide
~150 million people in 2005
Estimated ~300 million in 2025
Associated Conditions
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Hypertension
High LDL
Low HDL
Obesity
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Metabolic Syndrome
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Cause? Effect?
Pathophysiology
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The precise way genetic, environmental, and
pathophysiologic factors interact to lead to the
clinical onset of T2DM is not known
Most T2DM is polygenic
Some specific monogenic defects largely
confined to the pathways that regulate insulin
action or β cell function cause DM
Monogenic
Monogenic - IR
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Type A insulin resistance
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Leprechaunism
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insulin resistance
acanthosis nigricans
hyperandrogenism
intrauterine growth retardation
fasting hypoglycemia
death within the first 1 to 2 years of life
Rabson-Mendenhall syndrome
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short stature
protuberant abdomen
abnormalities of teeth and nails
Monogenic - IR
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Lipoatrophic diabetes
paucity of fat
 insulin resistance
 hypertriglyceridemia
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Face-sparing partial lipoatrophy (Dunnigan
Syndrome)
Lamin A/C gene mutation (AD)
Congenital generalized lipoatrophy (the SeipBerardinelli syndrome - AR)
Monogenic - IS
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Mutant Insulin Syndromes
Hyperinsulinemia
 Mild DM, but no resistance to exogenous insulin
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Mitochondrial Diabetes
Maternally transmitted
 Diabetes
 Sensorineural hearing loss
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Maturity Onset Diabetes of the
Young
Gene
Molecular Basis
MODY-1
HNF-4α
MODY-2
Glucokinase
Defect in
transcription →
↓insulin
secretion/β-cell
mass
↓ Sn of β-cell to
glucose/ ↓ glucose
→ glycogen
MODY
Gene
Molecular Basis
MODY-3
HNF-1α
MODY-4
IPF-1
Defect in
transcription →
↓insulin
secretion/β-cell
mass
Defect in
transcription →
Abnormal β-cell
development and
function
MODY
Gene
Molecular Basis
MODY-5
HNF-1β
MODY-6
NeuroD1 or β2
Defect in
transcription →
↓insulin
secretion/β-cell
mass
Defect in
transcription →
Abnormal β-cell
development and
function
MODY
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May account for 1-5% of DM
Often mild (especially the most common
MODY-2 Glucokinase)
Family Hx in successive generations
Onset often childhood/adolescence
DM2 Genetics
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High risk in certain ethnic groups
 Pima Indians ~21%
3.5x risk in 1st degree relatives
Monozygotic vs. dizygotic twins
 70 vs. 10% concordance
DM2 Genetics
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Common variant-common disease hypothesis
(i.e. not Mendelian)
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Simultaneous occurrence of common DNA
sequence variations in many genes that in their sum
confer an increased susceptibility toward adverse
environmental factors.
At least 27 (confirmed and potential) T2DM
susceptibility genes have been identified
Genome Wide
Association
Genetics and Insulin Secretion
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Insulin secretion is stimulated by
Glucose
 Incretins
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Glucagon Like Peptide (GLP-1)
 Gastric Inhibitory Polypeptide (GIP)
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Glucose
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Taken up via glucose transporters
Phosphorylated by glucokinase, metabolized
ATP is generated that causes closure of the ATP
sensitive potassium channel
This provokes membrane depolarization and
subsequent opening of a voltage-dependent calcium
channel
Calcium influx raises the cytosolic calcium
concentration, and promotes exocytosis of insulin
granules
Incretins
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In the presence of glucose incretins enhance
insulin secretion
Binding to G protein-coupled transmembrane
receptors activates adenylyl cyclase → cAMP
cAMP activates protein kinase A, which
mediates induction of the insulin gene and
exocytosis of insulin granules
Insulin Secretion Genetics
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Hypothesis: individual differences in insulin
secretion capacity are predominantly determined
by genetics
Strengthened by the finding that 18 among
those 27 genes mentioned affect β-cell function
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CAPN10, CDC123/CAMK1D, CDKAL1, CDKN2A/B, ENPP1, FOXO1, HHEX,
IGF2BP2, JAZF1, KCNJ11, KCNQ1, MTNR1B, PPARGC1A, SGK1, SLC30A8, TCF7L2,
TSPAN8/LGR5 and WFS1
Insulin Secretion
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Some Single Nucleotide Polymorphisms affect:
β-cell response to GLP-1
 GIP/GLP-1 levels
 Proinsulin conversion
 Free Fatty Acid Levels
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Leading to decreased β-Cell function
β Cell Failure
Oversecretion of
insulin to compensate
for insulin resistance1,2
Glucotoxicity2
Chronic
hyperglycemia
Lipotoxicity3
High circulating
free fatty acids
Pancreas
Genetic Mutations
-cell
dysfunction
3Finegood
1Boden
G & Shulman GI. Eur J Clin Invest 2002; 32:14–23.
2Kaiser
N, et al. J Pediatr Endocrinol Metab 2003; 16:5–22.
DT & Topp B. Diabetes Obes Metab 2001; 3 (Suppl. 1):S20–S27.
Insulin Resistance
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Subnormal response to insulin
Genetic β-cell defects only apparent when insulin
requirements > insulin production
Insulin resistance is strongly associated with obesity
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Environmental factors?
Calculating insulin sensitivity
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BG and insulin levels
OGTT
Euglycemic clamp
Isotope tracer methods
Insulin Resistance
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There are obesity independent genetic factors of
insulin resistance
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e.g. PPAR-γ
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2 Isoforms
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PPAR-γ-1: expressed in a number of tissues and cell types at
moderate levels
PPAR-γ-2: largely restricted to adipose tissue, where it represents
a master regulator of fat cell differentiation
Insulin Resistance
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PPAR-γ-2
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P12Avariant ? → ↓ adipose insulin sensitivity→ ↑
release of fatty acids→ ↓ muscle and liver insulin
sensitivity
PPAR-γ is the target of TZDs → ↑ insulin
sensitivity
Insulin Resistance
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May be best predictor of T2DM
↑ with age and weight
? Unmasking defect of β-cell function
Leads to Hyperglycemia
Hyperglycemia has toxic effects on β-cell
Obesity
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Causes peripheral resistance to insulin-mediated glucose
uptake
May ↓ sensitivity of β-cells to glucose
Potential Exacerbating Factors
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Abdominal > Peripheral fat
β-3-adrenergic receptor mutation
↑ c-Jun amino-terminal kinase (JNK) activity
Inflammatory Adipokines
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(leptin, adiponectin, TNF α, and resistin)
↑ Free fatty acids
Leptin
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Produced by adipocytes, secreted in proportion
to adipocyte mass
Signals the hypothalamus about the quantity of
stored fat
Leptin deficiency and leptin resistance →
obesity and insulin
Leptin may be important for the regulation of
beta cell mass/function depending upon diet
and presence of insulin resistance
Adiponectin
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Reduces levels of free fatty acids and associated
with
improved lipid profiles
 better glycemic control
 reduced inflammation in diabetic patients
 inversely associated with risk for diabetes in the nondiabetic population
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Adiponectin
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Lower adiponectin levels are more closely
related to the degree of insulin resistance and
hyperinsulinemia than to the degree of adiposity
and glucose intolerance
Adiponectin is downregulated in obesity
↓ Adiponectin → ↑ TNF-α and ↑ insulin
resistance
TNF-α
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? major role in insulin action impairment
A preliminary study found a strong correlation
between the degree of obesity, hyperinsulinemia,
and TNF-α mRNA in adipose tissue.
In a study of a homogeneous Native Canadian
population plasma TNF-α concentrations were
positively correlated with insulin resistance
Plasminogen activator inhibitor
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An inhibitor of fibrinolysis, is another protein
related to adipocytes.
It is also secreted from endothelial cells,
mononuclear cells, hepatocytes, and fibroblasts
May be associated with an increased risk for
T2DM
Resistin
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In obese mice adipocytes secrete resistin
Administration of resistin decreases insulinmediated glucose uptake by adipocytes
Neutralization of resistin increases insulinmediated glucose uptake by adipocytes
Hypothalamic administration of resistin
enhances glucose production, independent of
changes in glucoregulatory hormones
Retinol-binding protein 4
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Released from adipocytes
Correlates with the degree of insulin resistance
in mice, ? humans
Intrauterine Development
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Low birth weight “Thrifty" genotype hypothesis
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Insulin resistance might improve survival during
states of caloric deprivation but would lead to
diabetes in states of caloric excess or adequacy.
Intrauterine Development
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Thrifty genotype might be induced by IUGR
Inverse relationship between birth weight and
DM in Nurses' Health Study (69,000 women)
Relative risk of T2DM by ascending birth
weight categories decreased progressively
Thinness at birth vs. in adult life have opposing
effects on insulin resistance
Adult, kg/m2
Intrauterine Development
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Higher birth weight (>4.0 kg) may also be associated
with an increased risk of diabetes
A meta-analysis of 14 studies (132,180 babies) of birth
weight and risk of T2DM
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U-shaped relationship between birth weight and diabetes risk
High birth weight was associated with increased risk of
diabetes in later life to the same extent as low birth weight
Prematurity independent of birth weight may also be a
risk factor for insulin resistance
Summary
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Type 2 Diabetes
Hyperglycemia
 Insulin resistance (Skeletal muscle, liver, adipose
tissue) - Early
 Insufficient pancreatic β cell compensation due to
irreversible loss of β cell mass – Late
 Increased hepatic glucose production
 Genetic and environmental factors
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Summary
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Insulin Resistance
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Intrauterine
Low/High birth weight
 Prematurity
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Obesity/Inflammation
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Central, JNK, FFA, adipokines
Genetic
PPAR-γ
 Others
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Summary
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Insulin Secretion/β-cell Function
 Monogenic
 MODY
 Polygenic
 SNPs afffecting
 Response to glucose
 Response to incretins
Selected References
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Williams
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