Download insulin resistance

Glucose homeostasis
All cells in the body use glucose as energy source to make ATP
Blood glucose feedbacks to pancreas:
high blood glucose
insulin- promotes uptake of glucose, conversion of glucose to
glycogen (glycogenesis), to pyruvic acid (glycolysis), suppresses
gluconeogenesis. Also promotes nucleic acid, fatty acid and
protein synthesis. Net effect of reducing blood glucose. (cf
cortisol)
low blood glucose
glucagon- stimulates glucose production (glygenolysis,
gluconeogenesis) and secretion, fat breakdown. Net effect of
increasing blood glucose. (cf to adrenaline)
The stress/exercise hormones:
cortisol, adrenaline, noradrenaline
cortisol- increases gluconeogenesis, glycogenesis, fat
breakdown
adrenaline- increases glucose uptake, glycogenolysis,
fat breakdown
noradrenaline- increases glucose uptake,
glycogenolysis, fat breakdown
Diabetes Mellitus
Heterogeneous syndrome (many features, sliding scale
of severity) in which the central feature is a chronic
elevation of blood glucose (hyperglycemia)
This leads to long term tissue damage, especially of
blood vessels, nerves, heart, kidney and eyes
Due to insulin deficiency or insulin resistance.
However, there are many causes of both deficiency and
resistance
Diabetes Mellitus
Chronic disorder of protein, fat and
carbohydrate metabolism
Type I diabetes mellitus
(insulin dependent diabetes mellitus IDDM)
• Destruction of pancreatic beta cells by autoimmune
process [Beta cells produce insulin in response to
high glucose levels]
• Autoimmune trigger (virus?) and genetic
predisposition (major histocompatability complex)
• Hyperglycemia occurs when about 75% of beta cells
destroyed (tolerance of system)
• Low or absent insulin secretion
• Early onset (childhood)
• Treated with insulin injections
Type II diabetes mellitus
(non-insulin dependent diabetes mellitus NIDDM)
• Multifactoral interaction of genetics, environment
and age
• Inability to respond to insulin-receptor or postreceptor defects
• Insulin hypersecretion in response to high glucose,
eventual failure of beta cell secretion
• Insulin resistance
• Late onset
• Often gradual onset with chronic mild hyperglycemia
• Obese and non-obese types
• Endothelial cell dysfunction
• Leptin physiology dysfuntion
Other specific types of
diabetes mellitus
• Genetic defects of beta cells (MODY)
• Genetic defects of insulin signalling
• Diseases of the pancreas
• Endocrinopathies
• Gestational
Clinical diagnosis and
symptoms
Normal homeostatic mechanisms maintain blood glucose
levels within the range 3.5-6.5 mmol/L
Diabetes (these figures occasionally change...)
random blood glucose  11.1mmol/l
fasting (no food for 8h) blood glucose  7.0mmol/l
oral glucose tolerance test (OGTT) 2h  11.1mmol/l
Classical symptoms also include:
polyuria (excessive urination), polydipsia (thirst), nocturia
(nocturnal urination), lethargy, weight loss
Oral glucose tolerance test
Glucose tolerance curve for a normal person and one with insulin-dependent
diabetes mellitus (IDDM, Type 1 diabetes). The dotted lines indicate the range of
glucose concentration expected in a normal individual.
Impaired glucose tolerance
• Intermediate category
• Hyperglycemia at fasting and after OGTT
but not in diabetic range
• Higher risk of developing type II diabetes
Mechanism
• Loss of insulin effects on main targets of action (liver,
muscles, fat cells):
promotes uptake of glucose, conversion of glucose to
glycogen (glycogenesis), to pyruvic acid (glycolysis),
suppresses gluconeogenesis. Also promotes synthesis
of nucleic acid, fatty acids and protein. Net effect of
reducing blood glucose
• Hypothesized increase in glucagon secretion and
activity:
stimulates glucose production (glygenolysis,
gluconeogenesis) and secretion, fat breakdown. Net
effect of increasing blood glucose
Mechanism
• Direct effects of increased levels of glucose:
while liver, muscles and fat require insulin for glucose uptake,
blood vessels, nerves, kidney and the eye lens do not
require insulin
Thus, increased intracellular levels of glucose in these cells
causes:
•non-enzymatic glycation (glucose binds to proteins) = AGEs (advanced
glycosylation end products)
•oxidative-reductive stress (more free-radicals produced)
•increased polyol pathway activity (sorbitol & fructose accumulates in
cells) → ion pump/osmolality dysfunction
•intracellular myo-inositol depletion (serves as a
“compatible osmolyte” used to control intracellular osmolarity)
•increased protein kinase C activity, due to increased glycolytic activity
Mechanism
•increased blood pressure
•increased blood viscosity & coagubility
•endothelial cell dysfunction
•thickening of basement membranes
Insulin and insulin receptors
Insulin :
two peptide chains, A and B,
linked by two disulphide
bridges
Insulin receptor:
two alpha subunits and
two beta subunits linked
by disulfide bonds
www.chemicalgraphics.com/ paul/vrml2pov/
arbl.cvmbs.colostate.edu/..../insulin_phys.html
insulin-receptor events
•The insulin receptor is a tyrosine kinase.
= an enzyme that transfers phosphate groups from ATP to
tyrosine residues on intracellular target proteins.
•Binding of insulin to receptor causes autophosphorylation,
which activates the catalytic activity of the receptor
•The activated receptor then phosphorylates a number of
intracellular proteins, which either activates or inactivates them
•Several intracellular proteins have been identified as
phosphorylation substrates for the insulin receptor
e.g. insulin receptor substrate 1 (IRS-1)
• IRS-1 serves as a type of docking center for recruitment and
activation of other enzymes
Insulin signalling pathways
Glucagon
Epinephrine / adrenalin
PC
AC
G
PLC
G
PKA
cAMP
Ph K
PP1
Ph K
IP3
Ca2+
Ph K
Endoplasmic
Reticulum
Ca2+
PKA
PP1
DAG
Ca2+
PP1
Gly Ph
P
Inactive
Semi-active
Ph K
Ph K
Ca2+ P
Ca2+
P
PP1
Active
P
P
Gly Ph
Gly Ph
P
[Glucose]
Glycogenolysis
AC
Adenylate Cyclase
G
G Protein
Gly Ph
Glycogen
Phosphorylase
Ph K Glycogen Phosphorylase
IP3
PC
PLC Phospholipase C
Kinase
PKA Protein Kinase A
Inositol 1,4,5-triphosphate
Phosphatidylcholine (PC)
PP1 Protein Phosphatase-1
DAG Diacylglycerol
Insulin signalling pathways
• inactivation of key regulatory enzymes of
glycogenolysis (glycogen → glucose) and
gluconeogenesis (pyruvate → glucose)
• activation of key regulatory enzymes of glycolysis
(glucose → pyruvate) and glycogenesis (glucose →
glycogen)
• glycogen → fatty acids
• amino acids uptake
• protein synthesis
Insulin signalling pathways
http://www.sanger.ac.uk/PostGenomics/signaltransduction/insulin/pathways/ir_itinerary
Insulin signalling pathways
adrenaline diminishes insulin secretion by
beta cells and counters the effects of insulin in
liver and fat cells similar to glucagon via
alpha- and beta-adrenergic receptors
Liver and diabetes mellitus
Growing evidence that diabetes causes liver disease but
difficult to distinguish cause and effect. However, studies
show diabetics have double the risk of having liver
disease compared with controls
e.g.
hepatitis C
non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH)
cirrhosis
hepatocellular carcinoma (HCC)
Hepatitis C
• hepatitis C virus can induce hepatic intracellular fat
(triglycerides) accumulation (steatosis)
• this causes defects in insulin signalling and impairs
the ability of insulin to suppress hepatic glucose
production
• the hepatitis C core protein can disrupt the IRS-1
signalling pathway (increases glucose uptake in
muscle, but not liver -IRS-2....)
non-alcoholic fatty liver disease
(NAFLD) and non-alcoholic
steatohepatitis (NASH)
•insulin resistance → high circulating insulin
•leading to defective fatty acid oxidation in mitochondria
•resulting in intracytoplasmic accumulation of
triglycerides
•accumulated fat induces inflammatory and fibrotic
response
•elevated serum aminotransferase activity
Cirrhosis
definition: damage to liver cells which leads to
impaired structure and function
due to:
fibrosis (scarring)
altered blood and bile flow- constriction of vessels
and ducts leading to build-up and overflow,
cholestasis (build-up of bile in liver)
Hepatocellular carcinoma
(HCC)
•as consequence of insulin resistance → NAFLD →
NASH → cirrhosis → HCC
or
•direct stimulatory effects of insulin on hepatocyte
growth leading to abnormal and uncontrolled cell
growth (neoplasia)