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 Presentation

"The Insulin Resistance Syndrome and Cardiovascular Risk in Type 2 Diabetic Patients: Pathophysiology and Implications for Assessment and Management"

Dr. Ivan G. Fantus (biography)
English - 2002-11-16 - 55 minutes
(32 slides)
(44 slides)

Summary :
The increasing prevalence of diabetes around the world is now well documented. This is due almost entirely to Type 2 diabetes and is most dramatic in developping nations. It appears to result, at least in part, from dramatic changes in lifestyle comprising Westernization of diet and decreased physical activity. These changes are associated with the development of obesity and insulin resistance, which are commonly accompanied by other cardiovascular risk factors, e.g., hypertension, dyslipidemia, microalbuminuria. The term “Metabolic Syndrome” has been adopted by the World Health Organization to describe this clinical phenotype.
The central pathophysiologic abnormality of the Metabolic Syndrome is insulin resistance. To understand the etiology of insulin reistance, it is necessary to appreciate the mechanisms and complexity of insulin signaling in the major target tissues; fat, muscle, and liver, as well as the myriad of factors that can regulate this process. Briefly, circulating insulin binds to a specific cell surface receptor, the insulin receptor, which is a transmembrane 4-subunit containing protein. Insulin binding to the extracellular -subunits stimulates the enzymatic tyrosine kinase activity of the cytoplasmic portions of the -subunits. This in turn results in tyr phosphorylation of various substrates called IRSs (insulin receptor substrates). Once phosphorylated , IRS-1 and –2 bind specific domains of various proteins called SH2 (Src homolgy 2) domains. This binding activates the protein to promote further signalling. Once such key metabolic protein is an enzyme, phosphatidylinositol 3-kinase, which phosphorylates membrane phospholipids to generate “second messengers”. The lipid product PI (3,4,5) P3 attracts various enzymes (Ser/Thr kinases) such as PKB (protein kinase B) and PKC- (protein kinase C-), which ultimately activate glucose transport, glycolysis, glycogen synthesis and inhibit lipolysis and gluconeognesis. In addtion to short-term effects, insulin induces changes in gene expression consistent with its anabolic funtion to store energy after meals.
What then can cause insulin resistance? Clearly, the above description is simplified and there are over 100 proteins involved in various aspects of insulin action and, since a number have more than one isoform (e.g., IRSs, PKBs) there are well over 1,000 combinations of protein-protein interaction cascades. One view is to ask whether insulin resistance is genetic. After a great deal of research very few monogenic forms of insulin resistance account for Type 2 diabetes (1-5%). However, it is likely that many susceptibility genes contribute. These polymorphisms occur in the nondiabetic population, so they beomce important in a fertile environment. From the above description of the recent diabetes epidemic, it is clearly this environment that has played a critical role.
Major circulating factors associated with insulin resistance are hormones, e.g., glucocorticoids, catecholamines and high concetrations of insulin iteself; adipocytokines, e.g., TNF- (tumor necrosis factor-), resistin, leptin and decreased adiponectin (Acrp30); and excess metabolic fuels, i.e., FFAs (free fatty acids), glucose and even amino acids. The mechanisms by which these diverse factors impinge on insulin signalling are different, but do overlap. For example, inhibition of IRS-1 tyr phosphorylation and function is observed in TNF-- and FFA-induced insulin resistance, while inhibition at the level of PKB has been observed in FFA- and high glucose-induced insulin resitance. Futhermore, decreased expression of the insulin sensitive glucose transporter (GLUT4) is seen in adipose tissue but not skeletal muscle in Type 2 diabetes and may be mediated by hyperinsulinemia. In most cases, multiple defects are observed since a primary insult will result in secondary changes, which then exacerbate the resistance. Furthermore, effects are time-dependant with additional defects super-imposed on primary events often mediated by changes in gene expression.
Unravelling these mechanisms and the proteins involved will be critical to develop new and relevant therapeutic agents. Thus, inhibition of insulin resistance-inducing circulating factors and/or intracellular signalling molecules or conversely, enhancing those which increase insulin sensitivity is a major focus of the pharmaceutical industry. At the same time, physicians and others involved in public helth policy need to address the modifiable lifestyle, i.e., environmental, contribution to the insulin resistance syndrome and Type 2 diabetes.


Learning objectives :
The participant will learn about the causes and actual and potential treatments of insulin resistance:

- The term “Metabolic Syndrome” has been adopted by the World Health Organization to describe the clinical phenotype comprising obesity and insulin resistance often accompanied by by other cardiovascular risk factors, e.g., hypertension, dyslipidemia, microalbuminuria.

- The central pathophysiologic abnormality of the Metabolic Syndrome is insulin resistance.

- In addition to susceptibility genes there are environmental factors which contribute to insulin resistance, as well as circulating factors such as hormones, high levels of insulin, adipocytokines, FFAs, glucose and amino acids.

- Inhibition of insulin resistance-inducing circulating factors and/or intracellular signaling molecules or conversely, enhancing those which increase insulin sensitivity is a major focus of the pharmaceutical industry.

- Physicians need to focus on the environmental contribution to the development of insulin resistance and type 2 diabetes, i.e., modifiable lifestyle.


Bibliographic references :
1. Zimmet P, Alberti KGMM, Shaw J, Global and societal implications of the diabtes epidemic. Nature 2001; 4145:782-7
2. Virkamaki A, Ueki K, Kahn CR. Protein-protien interaction in insulin signaling and the molecular mechanisms of insulin reistance. J. Clin Invest 1999; 103:931-43
3. Shepherd PR, Kahn BB. Glucose transporters and insulin action: implications for insulin resistance and diabetes mellitus. N Engl J Med 1999; 341:248-57.


   


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