Transcript Mechanisms linking obesity to insulin resistance and type 2 diabetes

Mechanisms linking obesity to
insulin resistance and type 2
diabetes
Reporter: Wen Ying, Chen
Date: 2006, 12, 28
Prevalence of obesity & type 2
diabetes

In the United States, only about a third of adults
are considered to be of “normal” weight, and
similar trends are being observed worldwide.

At the turn of this century 171 million
individuals were estimated to have diabetes, and
this is expected to increase to 366 million by
2030.
Obesity/insulin resistance
Increased β-cell function
Increased β-cell growth
β-cell dysfunction
β-cell apoptosis
Impaired glucose tolerance
Normal glucose tolerance
Compensatory
hyperinsulinaemia
Type 2 diabetes
Obesity
Insulin
resistance
Dysfunction of pancreatic
islet β- cells
Type 2
diabetes
Insulin resistance and obesity

Fluctuations in insulin sensitivity occur during
the normal life cycle
insulin resistance --------puberty, pregnancy and
aging.
lifestyle variation (increased physical activity &
carbohydrate intake)--------enhance insulin
sensitivity.
Insulin resistance and obesity

The most critical factor in the emergence
of metabolic diseases is obesity.
adipose tissue: non-esterified fatty acids
(NEFAs), glycerol, hormones (leptin &
adiponectin), proinflammatory
cytokines-------modulates metabolism
Insulin resistance and obesity
obesity/RBP4
Retinol-binding protein-4 (RBP4)
PI3-kinase
in muscle
phosphoenolpyruvate
carboxykinase
in the liver
Insulin resistance
Insulin resistance and obesity
obesity/adiponectin

Adiponectin (an insulin sensitizer): stimulating
fatty acid oxidation in an AMP-activated protein
kinase (AMPK) and peroxisome proliferator
activated receptor-α (PPAR-α)-dependent
manner.
Insulin resistance and obesity
obesity/TNF-α, IL-6
Upregulation
of
potential mediators
of
inflammation
that can lead to
insulin resistance.
C-Jun aminoterminal kinase
(JNK)
Insulin resistance and obesity
obesity/NEFAs

The release of NEFAs (non-esterified fatty acids) may be the
single most critical factor in modulating insulin sensitivity.
1. inhibition of pyruvate dehydrogenase, phosphofructkinase,
hexokinase II activity.
2. increase in the intracellular metabolism of fatty acid
metabolites (DAG, fatty acyl-CoA, ceramides)-----PI(3)K
------downstream of insulin-receptor signalling
Insulin resistance and obesity
obesity/distribution of body fat

The distribution of body fat is itself a critical
determinant of insulin sensitivity.
1. intra-abdominal fat expresses more genes encoding
secretory proteins and proteins responsible for energy
production.
2. The amount of protein released per adipocyte also
differs according to their location. The secretion of
adiponectin by omental adipocytes is greater than that of
subcutaneous-derived adipocytes.
β- Cell function and mass

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β-cell are markedly plastic in their ability to regulate
insulin release.
The quantity of insulin released by β-cells varies
according to nature, quantity and route of administration
of the stimulus, and the prevailing glucose concentration.
Insulin sensitivity also modulates β-cell function and is
almost always decreased in obesity.
The ability of the β-cell to adapt to changes in insulin
sensitivity seems to result from two parameters: the
functional responsiveness of the cell and β-cell mass.
Relationship between insulin sensitivity and the
β-cell insulin response in nonlinear
In response to the insulin resistance observed in obesity, puberty and pregnancy, human
β-cell can increase insulin release to levels fourflod to fiveflod higher than in insulinsensitive individuals, whereas β-cell volume is only by about 50%.
β- Cell function and mass

The intergration of the β- cell’s response to changes in
insulin sensitivity probably involves increased cellular
glucose metabolism, NEFA signalling and sensitivity to
incretins.

Glucose-stimulated insulin secretion
the metabolism of glucose ----- generation of ATP---increase in the ATP/ADP ratio triggers the closure of the
ATP-sensitive potassium (K+ATP) channel----depolarization of the cell membrane and influx of
calcium through voltage-dependent calcium channels----insulin granule exocytosis.
GLP-1: glucagonlike peptide-1
β- Cell function and mass
A: increase in β- cell glucose metabolism
increase in the activity of glucokinase
B: anaplerosis: glucose-----pyruvate----TCA cycle
------pyruvate
F: humoral factor----intestinal mucosa production-----incretin hormons
β- Cell function and mass
NEFAs are important for normal β- cell function.
D: NEFAs + G-protein-coupled receptor GPR40
activation of intracellular signalling ----increase
in the intracellular calcium -----insulin granule
exocytoisis.
E: generation of fatty acyl-CoA
by PKC activation----insulin granule exocytoisis.
β- Cell function and mass
G: parasympathetic stimulation
acetylcholine + M2 muscarinic receptor----insulin release
H: sympathetic nervous system
increased activity of the α2-adrenergic
component -----decreased insulin release
increased activity of the β-adrenergic
component ----- enhances insulin output
β- Cell function and mass
I: insulin/insulin-like growth factor 1 (IGF-1)
J: incretin GLP-1 (glucagon-like peptide-1)
an insulin secretagogue
increasing β–cell proliferation
reducing β–cell apoptosis
β-cell dysfunction
First: the β- cell is unable to release insulin rapidly in response
to intravenous glucose, despite the fact that β–cells in
type 2 diabetes clearly contain insulin.
Second: delivery of non-glucose secretagogues can acutely
increase insulin release but dose not result in equivalent
responses to those seen with similar stimulation in
healthy subjects.
Third: although the number of β- cell is clearly reduced by
about 50% in type 2 diabetes, this degree of β- cell
loss cannot fully account for the change in the secretory
function, because by the time the diagnostic level for
diabetes occurs, the cell is operating at 25% or loss of its
functional capacity.
Type 2 diabetes is progression, and one of the
main factors responsible for this is a continued
decline in β–cell function
Lipotoxic effects
Glucotoxic effects
Elevated plasma NEFA
Elevated blood glucose
glucolipotoxicity
Pathogenesis of type 2 diabetes
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β-cell function is decreased by about 75% when
fasting hyperglycaemia is present.
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Even when the glucose levels is still within the
normal range, β-cell function decreases
progressively as the fasting glucose level
increases.
Genes and environment
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Many genes interact with the environment to
produce obesity and diabetes.

In the case of obesity/ gene mutation
1. melanocortin-4 receptor---most frequent mutations
2. leptin & leptin receptor
3. prohormone convertase 1 (PC1)
4. pro-opiomelanocortin (POMC)
In the case of obesity/ environmental factors
increase fat/calories & decrease physical activity ----over-nutrition
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Genes and environment
PC1: prohormone convertase 1
POMC: pro-opiomelanocortin
MC4: melanocortin-4
A possible unifying mechanism

Having a single mechanism to explain the
link between obesity, insulin resistance
and type 2 diabetes would be ideal.

A defect in insulin release could by the β–
cell could be crucial.
A possible unifying mechanism
Thank You!