obes dan DM.ppt

7/29/2019 obes dan DM.ppt

1/21

Patogenesis Obesitas dengan

DM


2/21

Lipid storage in adipose tissue represents

excess energy consumption relative to

energy expenditure, which in its

pathological form has been coined

obesity

Obesity is obviously associated with an

increased number and/or size of adiposetissue cells.


3/21


4/21

Obesity results in cellular stress or

metabolic dysfunction leading to insulin

resistance, the mechanism(s) of which is

unknown


5/21

hypothesized

the endoplasmic reticulum (ER), may be

insulted (ie, stressed) by obesity.

This leads to the production of misfolded

or unfolded proteins that accumulate in ER

tubules and impair ER function


6/21


7/21

No stress relief for the ER. The metabolic andinflammatory stresses of obesity disrupt the smoothoperation of the ER and cause protein misfolding. TheER attempts to cope with stress by activating XBP-1, a

transcriptional regulator of the unfolded protein response(UPR). If these responses fail to restore homeostasis,stress-induced IRE1 activates JNK1, a serine kinase thatopposes insulin action. Impaired insulin signaling mightserve to alleviate intracellular stress, but it does so at the

expense of systemic glucose regulation. FFA, free fattyacids; ROS, reactive oxygen species.CREDIT: KATHARINE SUTLIFF/SCIENCE


8/21

the cell mounts an unfolded protein

response (UPR) composed of increased

activity of the pancreatic ER kinase(PERK) that phosphorylates eIF2, the

subunit of translation initiation factor 2, c-

Jun N-terminal kinase (JNK) - a serinephosphorylase, and glucose-

regulated/binding immunoglobulin protein

(GRP78). Results in increased hepatic and

adipose tissue levels of phosphorylated

PERK and eIF2 and JNK and GRP78

consistent with ER stress


9/21


10/21

These cells overproduce hormones, such

as leptin, and cytokines, such as TNF-,

some of which appear to cause cellular

resistance to insulin.

At the same time, the lipid-laden

adipocytes decrease synthesis of

hormones, such as adiponectin, whichappear to enhance insulin responsiveness.


11/21

The insulin resistance in adipose tissue results

in increased activity of the hormone-sensitive

lipase, which is probably sufficient to explain the

increase in circulating NEFAs The high circulating levels of NEFAs may also

contribute to insulin resistance in the muscle and

liver.

Initially, the pancreas maintains glycemic control

by overproducing insulin


12/21

The excess NEFAs are carried to the liver and

converted to triacylglycerol and cholesterol.

Excess triacylglycerol and cholesterol are

released as very-low-density lipoproteinparticles, leading to higher circulating levels of

both triacylglycerol and cholesterol. Eventually,

the capacity of the pancreas to overproduce

insulin declines which leads to higher fastingblood sugarlevels and decreased glucose

tolerance


13/21


14/21


15/21


16/21

others

Disturbances in pathways of lipolysis and

fatty acid handling are of importance in the

aetiology of obesity and type 2 diabetes

mellitus. There is evidence that a loweredcatecholamine-mediated lipolytic response

may play a role in the development and

maintenance of increased adipose tissuestores


17/21

Increased adipose tissue stores, a

disturbed insulin-mediated regulation of

lipolysis and subnormal skeletal muscle

non-esterified fatty acid (NEFA) uptakeunder conditions of high lipolytic rate may

increase circulating NEFA concentrations,

which may promote insulin resistance andcardiovascular complications.


18/21

evidence is increasing that insulin-resistant muscle is characterised by alowered ability to oxidise fatty acids. A

dysbalance between fatty acid uptake andfatty acid oxidation may in turn be a factorpromoting accumulation of lipidintermediates and triacylglycerols within

skeletal muscle, which is stronglyassociated with skeletal muscle insulinresistance.


19/21


20/21


21/21

Terimakasih

obes dan DM.ppt

Documents

Transcript of obes dan DM.ppt