7/29/2019 obes dan DM.ppt
1/21
Patogenesis Obesitas dengan
DM
7/29/2019 obes dan DM.ppt
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.
7/29/2019 obes dan DM.ppt
3/21
7/29/2019 obes dan DM.ppt
4/21
Obesity results in cellular stress or
metabolic dysfunction leading to insulin
resistance, the mechanism(s) of which is
unknown
7/29/2019 obes dan DM.ppt
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
7/29/2019 obes dan DM.ppt
6/21
7/29/2019 obes dan DM.ppt
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
7/29/2019 obes dan DM.ppt
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
7/29/2019 obes dan DM.ppt
9/21
7/29/2019 obes dan DM.ppt
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.
7/29/2019 obes dan DM.ppt
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
7/29/2019 obes dan DM.ppt
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
7/29/2019 obes dan DM.ppt
13/21
7/29/2019 obes dan DM.ppt
14/21
7/29/2019 obes dan DM.ppt
15/21
7/29/2019 obes dan DM.ppt
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
7/29/2019 obes dan DM.ppt
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.
7/29/2019 obes dan DM.ppt
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.
7/29/2019 obes dan DM.ppt
19/21
7/29/2019 obes dan DM.ppt
20/21
7/29/2019 obes dan DM.ppt
21/21
Terimakasih
Top Related