Science Voyager

Saturday 5 July 2014

Obesity, type II Diabetes Mellitus and Physical Exercise: A scientific Overview.

This article address the relationship between Obesity and T2DM as well as the prophylactic and therapeutic effect of systematic physical exercise in managing T2DM. The distinguishing feature of T2DM is insulin resistance and higher than average levels of circulating Insulin.According to WHO ,T2DM comprises 90% of people with diabetes around the world and is largely the result of excess body weight and inactivity( 2013).Obesity is considered as one of the primary causes of T2DM in people who are genetically predisposed to it.  Many studies have identified systematic exercise as a prophylactic and therapeutic means for treating T2DM.
                               
Treatment Triad 

Relationship between Obesity and Insulin Resistance. 

According to WHO "a BMI ( Body Mass Index) greater than or equal to 30 in  a person is deemed as obesity. Obesity is a silent epidemic that has deleterious impact on hormonal and bio-energetic storage and metabolism in human body.All though many aspects of  mechanism is yet to know ,Obesity is regraded as both co-morbid condition and one of the precipitating factors of Insulin resistance in patients with T2DM. Besides T2DM obesity has been implicated as a risk factor for Coronary artery diseases , hypertension and certain forms of Cancer.
 In physiological  terms Obesity is characterized by increased adipose tissue mass.Insulin is a critical regulator of virtually all aspects of adipocyte physiology. Under normal physiological circumstances, Insulin promotes adipocytes triglyceride storage by stimulating glucose transport , lipogenesis  and by inhibiting lipolysis. Insulin  also increases the adipocyte uptake of fatty acids derived from circulating lipoproteins  by a cellular cascade mediated by enzyme lipoprotein lipase. Insulin's metabolic effect on adipose tissue are mediated by a broad array of tissue-specific actions , which involve rapid phosphorylation and changes in specific gene expression( BarbaraB.K and J.F .Miller2000). 

A number of mechanisms of insulin resistance have been identified so far in obese patients , in particular obese patients with T2DM. The chief manifestation of insulin resistance in both population are decreased insulin stimulated glucose transport and metabolism in adipocytes and skeletal muscle along with impaired suppression of hepatic glucose output. The major functional  defect that leads to insulin resistance in adipose tissue is the down-regulation   of   insulin responsive glucose transporter GLUT4. In vitro analysis of adipocytes and myocytes of obese T2DM patients have also demonstrated reduction in insulin binding to its receptors , reduced insulin receptor phosphorylation & tyrosine kinase activity as well as reduction in phosphorylation of Insulin receptor substrates (IRSs). A study conducted by Rondinone et all demonstrated that reduced IRS-1 expression results in decreased IRS-1 mediated PI3K activity and IRS-2 becomes the primary docking protein for PI3K. In addition to glucose metabolism PI3K signaling pathway is an important mediator of cell growth proliferation and survival signals. In contrast to Rondinone's findings Goldstin et all demonstrated that in the myocytes of obese T2DM patients IRS-1 and IRS-2 levels are normal but PI3K activity associated with both IRSs are impaired by the catalytic action of an enzyme  called PTP-1B ( 2000). central obesity have been implicated as a chief concern for precipitating Insulin resistance more than peripheral obesity. A study conducted by  CL McTernnan et all  showed an 418%  increase in resistin mRNA expression in  the subcutaneous abdominal and Omental fat. Increased levels of adipocytes derived cytokine Resistin in abdominal fat could lead to increased insulin resistance and increased glucose intolerance (2002). 
Adipocytes also act as an endocrine organ by secreting numerous peptide hormones and cytokines. Through such secreted products adipocytes influence its on biology in autocrine fashion . It has paracrine effect on brain , vasculature, pancreatic beta cells that produce insulin, gonads.  Of these secretory products , one that is chiefly implicated in T2DM and insulin resistance is a cytokine called Tumor Necrosis Factor- alpha ( TNF-Alpha). In addition to Inflammatory cytokine TNF -Alpha,elevated levels of  CRP , Resistin and Leptin  are also noticed in T2DM obese patients as opposed to T2DM non obese patients( D Hansen2010). 

Mechanism of Insulin Resistance in Skeletal Muscle.

In the postprandial state , skeletal muscle is the predominate site of insulin mediated glucose uptake. Skeletal muscle insulin resistance is considered to be the primary defect that manifest decades before the manifestation of overt hyperglycemia result from pancreatic beta cell failure. Gulli et all demonstrated that in patients with T2DM  impaired muscle glycogen synthesis secondary to reduced Glycogen synthase activity is the earliest detectable defect ( 1992). Increased circulating levels of free fatty acids particularly saturated fatty acids affects intracellular signaling pathways in skeletal muscles. Elevated serum saturated fatty acids inhibits insulin mediated intracellular downstream signalling by activating enzyme kinases such as PKCs , IKK beta, JNK and p38 MAP Kinase. They catalyze the phosphorylation of serine residues in IRS-1 inhibiting its activity and directing it for degradation by the proteasome. Such effects culminate with a reduction in the phosphorylation of tyrosin residues of IRS-1 and thus inhibits insulin mediated downwstream signal transduction. This ultimately results in insulin resistance and reduced glucose uptake by the myocytes ( A R Martins et all 2012).                        
     
Physical Activity Improves Insulin Sensitivity.

A large number of studies have corroborated the fact that systematic physical activity reduces insulin resistance and improves insulin sensitivity . American Diabetic Association and ACSM  have recommended systematic exercise as a first line choice for the prevention and treatment of insulin resistance.Systematic exercise is an integral part of any good treatment plan for the management of T2DM along with pharmaco-nutritional interventions. Systematic exercise has an array of benefits in both T2DM patients just as it has in healthy population. In T2DM patients exercise act not only as a catalyst of insulin sensitivity but as a prophylaxis for cardio-vascular complications. The role of exercise in improving insulin sensitivity in skeletal muscle was first reported by Richter et all in 1982 in a study they published in Journal on clinical investigation . The study was conducted on rats in Neil Ruderman's Laboratory. There study showed an increase in insulin sensitivity and glucose uptake lasted for 4 hours post exercise.In 1983 John Ivy et all expanded richter's finding by using  hind limb perfusion to show post exercise glucose uptake lasted for 2 days.  
A very vivid picture of exercise induced glucose uptake by skeletal muscles are yet to unleash. different type of exercise such as aerobic or resistance exercise mediate these process by influencing different cellular signaling pathways of glucose metabolism and uptake in skeletal muscles. 

Aerobic Exercise and Insulin Sensitivity.

Transcapillary  transport of insulin is one of the important determinants of insulin sensitivity. skeletal muscle capilary density is lower in older adults with impaired glucose tolerance.  A study published by S J prior et all in 2014 have demonstrated that 6 months of aerobic training with an emphasis on weight loss and improving insulin sensitivity in older adults with impaired glucose tolerance have demonstrated that increased capillary density caused by exercise induced angeogenesis increases  Insulin sensitivity and glucose tolerance. evidence also suggest that acute aerobic exercise stimulates glucose transport in skeletal muscle by translocating GLUT4 transporters to the cell surface.In skeletal muscles GLUT4 is distributed in two intracellular populations an endosomal pool that remains unaltered in post exercise and a storage population that is markedly GLUT4 depleted in response to both aerobic exercise and insulin treatment. It is this storage compartment that trigger GLUT4 translocation to the cell surface in response to exercise and insulin treatment( Eva T et all 2001).  A meta analysis of RCT's published in Journal Metabolism in 2014 also suggests that systematic aerobic training is therapeutic for patients with T2DM .It helps to significantly reduce systemic inflammatory responses by reducing inflammatory cytokines CRP and IL-6 ( Hayashino.Y et all 2014). exercise professionals and clinicians when recommending aerobic activities for patients , it is salient to follow the guidelines of ACSM and ADA for aerobic exercise prescription for T2DM and Metabolic disorders.However , each client is unique and guidelines should be followed intelligently.

Resistance Training  and Insulin Sensitivity.


Research have only recently been started focusing on the Therapeutic benefits of resistance training for a number of Chronic diseases including T2DM and Obesity. In fact it has been demonstrated to be safe and effective for elderly and obese patients than that of aerobic exercise. Many studies have corroborated the notion that resistance training is just as effective as aerobic training to improve skeletal muscle insulin sensitivity. A study conducted in 1998 by Errickson J et all have concluded that resistance training increases insulin sensitivity primarily by increase in non-oxidative glucose metabolism. Many studies also concluded that resistance training can enhance muscle strength, increase lean muscle mass . In addition to brain , skeletal muscle being the largest site for glucose disposal increased lean muscle mass may significantly improve insulin sensitivity. A different study conducted by Erickson et all to identify the effect of resistance training on T2DM have also concluded that a 2/week progressive resistance training for 3 months results in a significant improvement in HbA1c levels. there subjects pre Intervention levels of HbA1c were 8.8%  and was reduced post exercise to 8.2%. A novel RCT published by Mads.K.Holten et all in journal Diabetes(2004) have concluded that resistance training increases protein content of GLUT4 , Insulin receptor , protein kinase B-a/beta, glycogen synthase and glycogen synthase activity, which are indicators of increased insulin activity in skeleton muscles.In this study they followed a resistance training program that consist of strength training for 30min./3times /week for 6 weeks.A 2007 study has reported that whole body insulin resistance as estimated by the Homeostasis Model Assessment(HOMA-IR) has been shown to improve by 25% after 16 weeks of whole body strength training 3 times per week in older Hispainc adults with T2DM ( N.Brooks et all 2007).

I hope this brief scientific overview of the molecular mechanism of insulin resistance , the link between Obesity and T2DM as well as the therapeutic and prophylactic benefits of systematic exercise will enable practitioners in the area of exercise physiology , clinical exercise physiology and fitness science to develop a better and scientific understanding on the topic. It may also help you to develop more scientific and pragmatic exercise interventions.Once again this article is intended to promote scientific and evidence based practice of exercise science among all the exercise science professionals as well as to enrich my grip on the topic ultimately. I hope this article will be efficacious and informative to all.  



Siby C Chacko BPE,MPE( Exercise Physiology)                                            

References

1) http://www.who.int/mediacentre/factsheets/fs312/en/      

2) Barbara BK and JF Miller , Cellular mechanisms of insulin       resistance. J.Clin.Inves. 
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3) Rondinone CM, Wang LM, Lonnroth .P, IRS-1 reduced and        IRS-2 is the main docking site for PI3K 
     in adipocytes of subjects with NIDDM. 
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4) Goldstein BJ, Bitnner KA , White MF , Harbeck M , Tyrosin       dephosphorylation and deactivation of  IRS-1 by PTB-1B. 
     Possible facilitation by the fromation of ternary 
    complex with the Grb adaptor protein. 
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9) Charles M.Tipton, History of Exercise Physiology, 
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10) http://care.diabetesjournals.org/content/early/2014/02/27/dc13-2358.full.pdf+html

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      The insulin sensitive GLUT4 storage compartment is a
     postendocytic and heterogeneous population Recruited
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12) Erickkson J , tuominnen J, Valle T, Sundberg S et all.
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13)  Erikson J, Timela S, Errickosn K, Parvieaeinen S ,    Peltonen J  and Kujala U Resistance training in the treatment of NIDDM. Int. J. Spot.Med.18(4) 242-246( 1997).

14) MK Holten, Morten Z, M Gaster, C Jauel, Jorgan FPW and F Dela. Strength training increases
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15) N.Brooks , Jennifer EL, PL Gordon, Ronenn R, ME Nelson and CC Scepa, Strength training improves
       muscle quality and insulin sensitivity in Hispanic older adults with T2DM.
       Inta.J.med.Sci 4(1) 19-27( 2007) 

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