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AMP-ACTIVATED PROTEIN KINASE

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Energy sensing enzymes that are activated by cellular stresses resulting in

ATP depletion.

AMPK is considered to regulate glucose and lipid metabolism

AMPK-activation:-

Switch cells from active ATP consumption (eg. fatty acid and

cholesterol biosynthesis) to active ATP production (eg. fatty acid and

glucose oxidation).

AMPK switches on catabolic pathways that generate ATP, while

switching off ATP-consuming processes such as biosynthesis ,cell growth

and proliferation.

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Chemical activation of AMPK in vivo with 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) improves blood glucose concentrations and lipid profiles, making AMPK an attractive pharmacological target for the treatment of type 2 diabetes and other metabolic disorders.

The two leading diabetic drugs namely, metformin and rosiglitazone show their metabolic effects partially through AMPK.

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It is activated by increases in the cellular AMP:ATP ratio caused by metabolic stresses

Muscle contraction leads to increase in AMP/ ATP and Cr/ pCr levels leading to robust increase in AMPK activity .

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In liver, activation of AMPK results in enhanced fatty acid oxidation and decreased production of glucose, cholesterol, and triglycerides

Other activities Regulation of insulin synthesis and secretion in pancreatic islet

β-cells Modulation of hypothalamic functions involved in the

regulation of satiety.

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STRUCTURE OF AMPK

AMPK is a heterotrimeric protein consists of three subunits namely α,β and ɣ

Both the α and β subunits have two isoforms each, namely α1 & α2 and β1 & β2, while the ɣ subunit exists in three isomeric forms, i.e., ɣ 1, ɣ2 and ɣ3.

AMPK α1 is widely expressed, whereas the α2 subunit isoform is mainly found in the heart, skeletal muscle, and liver.

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PHYSIOLOGICAL FUNCTIONS

AMPK in skeletal muscle Skeletal muscle is the main site for glucose

disposal in the body. Insulin resistance is one of the early defects

detected in the muscle of diabetic patients . Targeting insulin independent pathway to

restore glucose disposal is being explored as an alternative approach to treat diabetes.

Exercise enhances muscle glucose disposal in diabetic patients through an insulin independent mechanism.

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Mimicking exercise like effect through drug could

be an attractive approach to improve blood

glucose level.

A similar effect has been observed with AICAR, an

AMP analogue and known AMPK activator.

AMPK also plays an important role in muscle fat

metabolism.

Upon activation either by exercise or contraction,

AMPK decreases the activity of acetyl CoA

carboxylase (ACC) by inhibiting its transcription

and also through phosphorylation.

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Role of AMPK in liver

Activated AMPK inactivates ACC at transcriptional and post translational level and also inhibits HMG CoA reductase.

Activated AMPK decreases malonyl CoAsynthesis resulting in increased b -oxidation

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Role of AMPK in adipocytokine signalling

Adiponectin and leptin-adipocytokines produced

and secreted from adipose tissues-type 2 diabetes

Adinopectin increases free fatty oxidation through

ACC inhibition, an AMPK target gene and also

enhances insulin sensitivity both in skeletal muscle

and liver

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AMPK is a global target as it regulates different diversified signals in metabolic pathways.

Type 2 diabetic patients are often associated with hypertriglyceridaemia and high cholesterol, the potential risk factors for cardiovascular problems. Activated AMPK could reduce this risk.

AMPK, by inhibiting hepatic glucose output and increasing muscle glucose uptake, could control elevated blood glucose level in the body.

THERAPEUTIC POTENTIAL

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Three different kinds of AMPK activators have been reported so far:

1. PPARg activators:rosiglitazone and pioglitazone, which activate AMPK without direct binding but by increasing cellular AMP/ATP ratio.

2. AICAR, an analogue of natural activator AMP, which activates AMPK through direct binding.

3. Lastly, metformin, an AMPK activator which does not affect AMP/ATP ratios or bind to AMPK, but acts through an unknown mechanism.

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An ideal AMPK activator is expected to: increase muscle glucose transport and muscle

insulin sensitivity enhance fat oxidation in muscle and liver inhibit hepatic gluconeogenesis decrease cholesterol and triglyceride synthesis in

liver should be devoid of problems associated with

present antidiabetic drugs (gastrointestinal problem, body weight increase, etc.)

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(i) AMPK is a heterotrimeric protein and so far no

crystal structure is available

(ii) each subunit contains two or more isoforms

(iii) the AMP binding site is not well defined.

Challenges associated with AMPK

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REFERENCE

1. icmr.nic.in/ijmr/2007/march/0313.pdf2. circres.ahajournals.org/content/100/3/328.long3. themedicalbiochemistrypage.org/ampk.php