The Role of Adiponectin and Leptin in diminishing Insulin Resistance

Introduction

‘A family history, a chemical mystery or a diet and an exercise chemistry’- anything may today

 bring a person down from being healthy. And Diabetes Mellitus is the most common one, more commonly T2DM which is letting millions of people down either due to their sedentary lifestyle or inheritance. Globally, as of 2010, an estimated 285 million people have type 2 diabetes, making up about 90% of the total diabetic cases. There are several deleterious  complications that 

made me throw the spotlight over this aspect like diabetic ketoacidosis, retinopathy, neuropathy, atheroschlerosis, etc.

On reference to many clinical evidences and research papers, obesity happens to be one of the

 most important contributor to the increase in the insulin resistance as well as type 2 diabetes.

 This means insulin resistance is associated with accumulation of body fat like skeletal muscle

 lipid over supply, etc.

ADIPONECTIN

Adiponectin is a protein hormone that modulates a number of metabolic processes, including 

glucose regulation and fatty acid catabolism. Adiponectin is exclusively secreted from adipose

 tissue into the bloodstream and is very abundant in plasma relative to many hormones. Levels

 of the hormone are inversely correlated with body fat percentage in adults .Transgenic mice with increased adiponectin show impaired adipocyte differentiation and increased energy

 expenditure associated with protein uncoupling.  Adiponectin is secreted into the bloodstream

 where it accounts for approximately 0.01% of all plasma protein at around 5-10 μg/mL. Levels of 

adiponectin are reduced in diabetics compared to non-diabetics. Weight reduction significantly increases circulating levels.

Adiponectin automatically self-associates into larger structures. Initially, three adiponectin

 molecules bind together to form a homotrimer. The trimers continue to self-associate and form hexamers or dodecamers.

 Role of Adiponectin in AMPK activation  
 Adiponectin is a protein hormone that has positive metabolic effects like enhancing fatty-acid oxidation and glucose utilization in muscle and adipose tissue as well as in inhibiting gluconeogenesis  in liver where these are associated with the activation of AMPK(1,4) in muscle and liver and the activation of the nuclear factor-kb in muscle cells. Hexameric and HMW forms activate NF-kb in undifferentiated and differentiated c2c12 cells and improve insulin sensitivity in liver whereas trimeric forms activate AMPK in muscle and adipose tissues. (Muscle cells trimeric adiponectin causes a rapid 2-fold increase in 5’-AMP level)AMPK when activated by adiponectin phosphorylates  and inactivates acyl-coA Carboxylase (ACC) which is the enzyme that catalyzes the formation of Malonyl-CoA. Malonyl-CoA is a substrate for the fatty-acid bio-synthesis and inhibits fatty-acid oxidation. AMPK activation by adiponectin results in inhibition of fatty-acids and triglyceride synthesis and stimulation of FA beta-oxidation.

AMPK phosphorylates IRS-1 at ser789 which correlates with a 65% increase in insulin stimulated pl3k activity in c2c12 myotubes, since AMPK activates aPKC which plays a positive role in glucose transport. Adiponectin also increases PPAR-Y ligand activity.

   
Adiponectin and acyl-coA synthase

 Acyl-CoA synthetases catalyze the 1^st step of fatty acid metabolism;

  FA + CoA + ATP ͢Fatty acyl CoA + 5’ AMP +2 Pi and the activation of FFA’s to their CoA derivatives by these enzymes generate 5’ AMP. The resultant formed during the attachment  of FA’s  to CoA would then activate AMPK.( The result is ATP consumption and  AMP production)

LEPTIN

Leptin  is an adipose derived  protein hormone that plays a key role in regulating energy intake and energy expenditure, including appetite and metabolism. It promotes appetite suppressants  like α-MSH and lowers the hunger. Leptin acts directly on the cells of the liver and skeletal muscle where it stimulates the oxidation of fatty acids in the mitochondria. This reduces the storage of fat in those tissues (but not in adipose tissue). The absence of leptin leads to uncontrolled food intake and results in obesity. The obese people have high levels of leptin and consequently result in leptin desensitization. In a report, baseline plasma leptin did not significantly differ between subjects with newly diagnosed or long-standing type 2 diabetes compared with non diabetic controls matched for BMI; however, plasma leptin responsiveness to dexamethasone was impaired in the diabetic groups. Leptin may improve glucose uptake by muscle and decrease hepatic glucose production . Finally, there is evidence that leptin may protect against the adverse effects of fat accumulation within non adipose cells. Less circulating leptin may lead to improved sensitivity to leptin, possibly offsetting the consequences of the reduction.

Role of leptin in AMPK activation
  Leptin  stimulates phosphorylation and activation of the alpha2 catalytic subunit of AMPK           (alpha2 AMPK) in skeletal muscle, thus establishing signalling pathway for leptin. Early activation of AMPK occurs by leptin acting directly on muscle, whereas later activation depends on leptin functioning through the hypothalamic-sympathetic nervous system axis. In parallel with its activation of AMPK, leptin suppresses the activity of ACC, thereby stimulating the oxidation of fatty acids in muscle. AMPK activation inhibits the phosphorylation of ACC stimulated by leptin. We can identify AMPK as a principal mediator of the effects of leptin on fatty-acid metabolism in muscle

COMBINATION OF ADIPONECTIN AND LEPTIN

Through analysis of multi-variated research studies it can be suggested that the combination of

 leptin and adiponectin at the molecular level would completely reverse the insulin resistance syndrome. Other studies have shown that insulin resistance in lip atrophic mice can be effectively reversed by the combination of physiologic doses of adiponectin and leptin, but only partially by

 either alone.

HYPOTHESIS

It has been hypothesised that combination of both adiponectin and leptin would lead to a rapid increase in the AMPK activity rather alone and combining these would double the positive effects in reducing Insulin Resistance. They may suppress the ACC activity at a better potential.

The combination of  the  aspects that lead to insulin sensitivity and addition of these to the

 existing drugs for IR may improve the medication and help many people get away from this

 deadly metabolic syndrome or  may also give rise to a completely new drug to treat T2DM and

 IR. It would also more effectively help in reducing the wide-spread obesity and prevent its further complications.

REFERENCES

       Skeletal muscle lipid deposition and insulin resistance: effect of dietary fatty acids and exercise

       Michael P Corcoran,Stefania Lamon-Fava, and Roger A Fielding

       Intramyocellular lipid kinetics and insulin resistance     ZengKui Guo

       Novel role of FATP1 in mitochondrial fatty acid oxidation in skeletal muscle cells   David Sebastián*§,  Maria Guitart§**, 

         Contraction of insulin-resistant muscle normalizes insulin action in association with increased mitochondrial activity and fatty acid catabolismJohn P. Thyfault1, Melanie G. Cree2, Donghai Zheng3

       Adiponectin and Leptin in Relation to Insulin Sensitivity

GEETHA R. SOODINI, M.D., and OSAMA HAMDY, M.D., Ph.D.

    www.resistantstarch.com/NR/rdonlyres/

    A Potent and Selective AMPK Activator That Inhibits de Novo Lipogenesis

    Efficacy of Metreleptin in Obese Patients With Type 2 Diabetes: Cellular and Molecular Pathways Underlying Leptin Tolerance

-Vaishnavi.NR