Mechanisms linking obesity to Mechanisms linking obesity to insulin resistance and type 2 insulin resistance and type 2

diabetesdiabetes

Reporter: Wen Ying, ChenReporter: Wen Ying, Chen

Date: 2006, 12, 28Date: 2006, 12, 28

Prevalence of obesity & type 2 Prevalence of obesity & type 2 diabetesdiabetes

In the United States, only about a third of adults In the United States, only about a third of adults are considered to be of “normal” weight, and are considered to be of “normal” weight, and similar trends are being observed worldwide.similar trends are being observed worldwide.

At the turn of this century 171 million At the turn of this century 171 million individuals were estimated to have diabetes, and individuals were estimated to have diabetes, and this is expected to increase to 366 million by this is expected to increase to 366 million by 2030.2030.

Obesity/insulin resistance

Increased β-cell functionIncreased β-cell growth

Normal glucose toleranceCompensatory

hyperinsulinaemia

β-cell dysfunctionβ-cell apoptosis

Impaired glucose tolerance

Type 2 diabetes

Obesity

Insulinresistance

Type 2 diabetes

Dysfunction of pancreatic islet β- cells

Insulin resistance and obesityInsulin resistance and obesity

Fluctuations in insulin sensitivity occur during Fluctuations in insulin sensitivity occur during the normal life cyclethe normal life cycle

insulin resistance --------puberty, pregnancy and insulin resistance --------puberty, pregnancy and aging.aging.

lifestyle variation (increased physical activity & lifestyle variation (increased physical activity & carbohydrate intake)--------enhance insulin carbohydrate intake)--------enhance insulin sensitivity.sensitivity.

Insulin resistance and obesityInsulin resistance and obesity

The most critical factor in the emergence oThe most critical factor in the emergence of metabolic diseases is f metabolic diseases is obesityobesity..

adipose tissue: adipose tissue: non-esterified fatty acids (Nnon-esterified fatty acids (NEFAs), glycerol, hormones (leptin & adipoEFAs), glycerol, hormones (leptin & adiponectin), proinflammatory cytokinnectin), proinflammatory cytokines-es-------modulates metabolism------modulates metabolism

Insulin resistance and obesityInsulin resistance and obesityobesity/RBP4obesity/RBP4

Retinol-binding protein-4 (RBP4)Retinol-binding protein-4 (RBP4)

PI3-kinasein muscle

phosphoenolpyruvate carboxykinase

in the liver

Insulin resistance

Insulin resistance and obesityInsulin resistance and obesity obesity/adiponectinobesity/adiponectin

Adiponectin (an insulin sensitizer): stimulating fAdiponectin (an insulin sensitizer): stimulating fatty acid oxidation in an AMP-activated protein atty acid oxidation in an AMP-activated protein kinase (AMPK) and peroxisome proliferator actikinase (AMPK) and peroxisome proliferator activated receptor-α (PPAR-α)-dependent manner.vated receptor-α (PPAR-α)-dependent manner.

Insulin resistance and obesityInsulin resistance and obesityobesity/TNF-obesity/TNF-α, IL-6α, IL-6

Upregulation of potential mediators of inflammation that can lead to insulin resistance.

C-Jun amino-terminal kinase (JNK)

Insulin resistance and obesityInsulin resistance and obesity obesity/NEFAsobesity/NEFAs

The release of NEFAs (non-esterified fatty acids)The release of NEFAs (non-esterified fatty acids) may be the may be the single most critical factor in modulating insulin sensitivity.single most critical factor in modulating insulin sensitivity.

1. inhibition of pyruvate dehydrogenase, phosphofructkinase,1. inhibition of pyruvate dehydrogenase, phosphofructkinase,

hexokinase II activity.hexokinase II activity.

2. increase in the intracellular metabolism of fatty acid meta2. increase in the intracellular metabolism of fatty acid metabolites (DAG, fatty acyl-CoA, ceramides)-----PI(3)Kbolites (DAG, fatty acyl-CoA, ceramides)-----PI(3)K

------downstream of insulin-receptor signalling ------downstream of insulin-receptor signalling

Insulin resistance and obesityInsulin resistance and obesity obesity/distribution of body fatobesity/distribution of body fat

The distribution of body fat is itself a critical detThe distribution of body fat is itself a critical determinant of insulin sensitivity.erminant of insulin sensitivity.

1. intra-abdominal fat expresses more genes encoding se1. intra-abdominal fat expresses more genes encoding secretory proteins and proteins responsible for energy prodcretory proteins and proteins responsible for energy production.uction.

2. The amount of protein released per adipocyte also diff2. The amount of protein released per adipocyte also differs according to their location. The secretion of adiponecers according to their location. The secretion of adiponectin by omental adipocytes is greater than that of subcutantin by omental adipocytes is greater than that of subcutaneous-derived adipocytes.eous-derived adipocytes.

β- Cell function and massβ- Cell function and mass

β-cell are markedly plastic in their ability to regulate β-cell are markedly plastic in their ability to regulate insulin release.insulin release.

The quantity of insulin released by β-cells varies The quantity of insulin released by β-cells varies according to nature, quantity and route of administration according to nature, quantity and route of administration of the stimulus, and the prevailing glucose concentration.of the stimulus, and the prevailing glucose concentration.

Insulin sensitivity also modulates β-cell function and is Insulin sensitivity also modulates β-cell function and is almost always decreased in obesity. almost always decreased in obesity.

The ability of the β-cell to adapt to changes in insulin The ability of the β-cell to adapt to changes in insulin sensitivity seems to result from two parameters: the sensitivity seems to result from two parameters: the functional responsiveness of the cell and β-cell mass.functional responsiveness of the cell and β-cell mass.

Relationship between insulin sensitivity and the Relationship between insulin sensitivity and the

β-cell insulin response in nonlinearβ-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 insulin-β-cell can increase insulin release to levels fourflod to fiveflod higher than in insulin-sensitive individuals, whereas β-cellsensitive individuals, whereas β-cell volume is only by about 50%.

β- Cell function and massβ- Cell function and mass

The intergration of the β- cell’s response to changes in inThe intergration of the β- cell’s response to changes in insulin sensitivity probably involves increased cellular sulin sensitivity probably involves increased cellular gluglucose metabolism, NEFA signalling and sensitivity to incrcose metabolism, NEFA signalling and sensitivity to incretins.etins.

Glucose-stimulated insulin secretionGlucose-stimulated insulin secretion the metabolism of glucose ----- generation of ATP----incthe metabolism of glucose ----- generation of ATP----inc

rease in the ATP/ADP ratio triggers the closure of the Arease in the ATP/ADP ratio triggers the closure of the ATP-sensitive potassium (KTP-sensitive potassium (K++

ATPATP) channel-----depolarizatio) channel-----depolarization of the cell membrane and influx of calcium through voln of the cell membrane and influx of calcium through voltage-dependent calcium channels-----insulin granule exotage-dependent calcium channels-----insulin granule exocytosis. cytosis.

GLP-1: glucagon-like peptide-1

β- Cell function and massβ- Cell function and mass

A: increase in β- cell glucose metabolism A: increase in β- cell glucose metabolism

increase in the activity of glucokinaseincrease in the activity of glucokinase

B: anaplerosis: B: anaplerosis: glucose-----pyruvate----TCA cycleglucose-----pyruvate----TCA cycle

------pyruvate------pyruvate

F: humoral factor----intestinal mucosa productioF: humoral factor----intestinal mucosa production------incretin hormonsn------incretin hormons

β- Cell function and massβ- Cell function and mass

NEFAs are important for normal β- cell function.NEFAs are important for normal β- cell function.

D: NEFAs + G-protein-coupled receptor GPR40D: NEFAs + G-protein-coupled receptor GPR40

activation of intracellular signalling ----increase iactivation of intracellular signalling ----increase in the intracellular calcium -----insulin granule exn the intracellular calcium -----insulin granule exocytoisis.ocytoisis.

E: generation of fatty acyl-CoAE: generation of fatty acyl-CoA

by PKC activation----insulin granule exocytoisisby PKC activation----insulin granule exocytoisis..

β- Cell function and massβ- Cell function and mass

G: parasympathetic stimulationG: parasympathetic stimulation acetylcholine + M2 muscarinic receptor-----insuacetylcholine + M2 muscarinic receptor-----insu

lin releaselin release

H: sympathetic nervous systemH: sympathetic nervous system increased activity of the increased activity of the αα2-adrenergic compone2-adrenergic compone

nt -----decreased insulin releasent -----decreased insulin release increased activity of the increased activity of the ββ-adrenergic componen-adrenergic componen

t ----- enhances insulin output t ----- enhances insulin output

β- Cell function and massβ- Cell function and mass

I: insulin/insulin-like growth factor 1 (IGF-1)I: insulin/insulin-like growth factor 1 (IGF-1)

J: incretin GLP-1 (glucagon-like peptide-1)J: incretin GLP-1 (glucagon-like peptide-1)

an insulin secretagoguean insulin secretagogue

increasing increasing ββ–cell proliferation–cell proliferation

reducing reducing ββ–cell apoptosis–cell apoptosis

β-cell dysfunctionβ-cell dysfunction

First: the First: the β- β- cell is cell is unable to release insulin rapidlyunable to release insulin rapidly in response in response to intravenous glucose, despite the fact that to intravenous glucose, despite the fact that ββ–cells in –cells in type 2 diabetes clearly contain insulin.type 2 diabetes clearly contain insulin.Second: delivery of non-glucose secretagogues can acutelySecond: delivery of non-glucose secretagogues can acutely increase insulin release but dose not result in equivalentincrease insulin release but dose not result in equivalent responses to those seen with similar stimulation inresponses to those seen with similar stimulation in healthy subjects.healthy subjects.Third: although the number of Third: although the number of β- β- cell is clearly reduced by cell is clearly reduced by about 50% in type 2 diabetes, this degree of about 50% in type 2 diabetes, this degree of β- β- cell cell loss cannot fully account for the change in the secretoryloss cannot fully account for the change in the secretory function, because by the time the diagnostic level for function, because by the time the diagnostic level for diabetes occurs, the cell is operating at 25% or loss of its diabetes occurs, the cell is operating at 25% or loss of its functional capacity.functional capacity.

Type 2 diabetes is progression, and one of the Type 2 diabetes is progression, and one of the main factors responsible for this is a continued main factors responsible for this is a continued

decline in decline in ββ–cell function–cell function

Glucotoxic effectsElevated blood glucose

Lipotoxic effects Elevated plasma NEFA

glucolipotoxicity

Pathogenesis of type 2 diabetesPathogenesis of type 2 diabetes

β-cell function is decreased by about β-cell function is decreased by about 75%75% when when fasting hyperglycaemia is present.fasting hyperglycaemia is present.

Even when the glucose levels is still within the nEven when the glucose levels is still within the normal range, β-cell function decreases progressivormal range, β-cell function decreases progressively as the fasting glucose level increases.ely as the fasting glucose level increases.

Genes and environmentGenes and environment

Many genes interact with the environment to proMany genes interact with the environment to produce obesity and diabetes.duce obesity and diabetes.

In the case of obesity/ gene mutationIn the case of obesity/ gene mutation 1. melanocortin-4 receptor---most frequent mutations1. melanocortin-4 receptor---most frequent mutations 2. leptin & leptin receptor2. leptin & leptin receptor 3. prohormone convertase 1 (PC1)3. prohormone convertase 1 (PC1) 4. pro-opiomelanocortin (POMC)4. pro-opiomelanocortin (POMC) In the case of obesity/ environmental factorsIn the case of obesity/ environmental factors increase fat/calories & decrease physical activity -----increase fat/calories & decrease physical activity ----- over-nutrition over-nutrition

Genes and environmentGenes and environmentPC1: prohormone convertase 1

POMC: pro-opiomelanocortin

MC4: melanocortin-4

A possible unifying mechanismA possible unifying mechanism

Having a single mechanism to explain the Having a single mechanism to explain the link between obesity, insulin resistance link between obesity, insulin resistance and type 2 diabetes would be ideal. and type 2 diabetes would be ideal.

A defect in insulin release could by the β–A defect in insulin release could by the β–cell could be crucial.cell could be crucial.

A possible unifying mechanismA possible unifying mechanism

Thank You!Thank You!