Friday, June 13, 2008

Ancient Insulin... Modern Metabolic Chaos and Cancer

When the Russian empire fell, civil, political, financial chaos ensued. A new book titled McMafia recently came out. The author Misha Glenny recently appeared on Charlie Rose to discuss what his investigative reporting illuminated over the last few years. He made interesting comments about how the ex-KGB were suddenly in essence 'forced' to command new 'mafia-like' outposts after the regime was re-ordered (or dysregulated). Naturally, the public could not rely on the state for policing. Who was more sophisticated and trained? Real mafia or the government-sponsored with access to the latest research, gadgets, military surveillance and satellite technology? Actually, that may be a difficult one to answer... Naturally, a new order was created and in fact so well the author reports that they now run dominant global operations (demonstrating strong entrepreneurial spirit! and franchise facets!).

Similar derangement (and 'reconfiguration' of diseased organs) occurs when carbohydrates are introduced to human metabolism...Chaos, inflammation, blood thickening, increased heart rate, lower TSH, higher cortisol (more neuropsych issues; sodium retained), high uric acid (UA;gout), high blood pressure, decreased vagal tone (more anxiety), vascular tone goes down the drain (leading to plaque an arterial stiffness). Cancer...? Coronary artery disease...? Even mental derangement (like PMS, ADHD, depression)?

Kinda like putting water in your gas tank... Need a little humidity and moisture for petrol/gasoline to flow, however if excessive water mixes in, the engine and carburetor will eventually be ruined.

Approximately ten years ago, Ferrannini et al wrote a revised canon for insulin actions entitled 'Insulin: New Roles for an Ancient Hormone.' Insulin not only has several responsibilities including the process of transporting energy (glucose) into muscles and the liver, but also has many other actions when excessive and over-represented and un-directed. Insulin is an ancient peptide hormone and evolutionarily tightly conserved -- expressed in tissues of all species vertebrate and non-vertebrate... including C.elegans the longevity worm-model. What is the downstream effect of insulin on worms? Shortened lifespan.

The funny thing about this peptide hormone is that there is no direct central controller. It is like a de-centralized satellite KGB agent. No pituitary or hypothalamic hormone flips insulin 'on' or 'off'. The authors wrote insulin's 'release is driven by its substrate, with no apparent central integration.'

Insulin: new roles for an ancient hormone.
Ferrannini E, et al. Eur J Clin Invest. 1999 Oct;29(10):842-52.

Recent research has greatly expanded the domain of insulin action. The classical action of insulin is the control of glucose metabolism through the dual feedback loop linking plasma insulin with plasma glucose concentrations. This canon has been revised to incorporate the impact of insulin resistance or insulin deficiency, both of which alter glucose homeostasis through maladaptive responses (namely, chronic hyperinsulinaemia and glucose toxicity). A large body of knowledge is available on the physiology, cellular biology and molecular genetics of insulin action on glucose production and uptake. More recently, a number of newer actions of insulin have been delineated from in vitro and in vivo studies. In sensitive individuals, insulin inhibits lipolysis and platelet aggregation. In the presence of insulin resistance, dyslipidaemia (HIGH TGs, LOW HDLs, HIGH apoB, HIGH Lp(a)), hyper-aggregation and anti-fibrinolysis may create a pro-thrombotic milieu. Preliminary evidence indicates that hyperinsulinaemia per se may be pro-oxidant both in vitro and in vivo. Insulin plays a role in mediating diet-induced thermogenesis, and insulin resistance may therefore be implicated in the defective thermogenesis of diabetes. In the kidney, insulin spares sodium and uric acid from excretion; in chronic hyperinsulinaemic states, these effects may contribute to high blood pressure and hyperuricaemia. Insulin hyperpolarises the plasma membranes of both excitable and non-excitable tissues, with consequences ranging from baroreceptor desensitisation to cardiac refractoriness (prolongation of QT interval). Under some circumstances insulin is vasodilatory-the mechanism involving both the sodium-potassium pump and intracellular calcium transients. Finally, by crossing the blood-brain barrier insulin exerts a host a central effects (sympatho-excitation, vagal withdrawal, stimulation of corticotropin releasing factor), collectively resembling a stress reaction. Description and understanding of these new roles, their interactions, the interplay between insulin resistance and hyperinsulinaemia, and their implications for cardiovascular disease have only begun. PMID: 10583426

The insulin receptor: a new ANTI-CANCER target for peroxisome proliferator-activated receptor-gamma (PPARgamma) and thiazolidinedione-PPARgamma agonists.

Costa V, et al. Endocr Relat Cancer. 2008 Mar;15(1):325-35.

The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the nuclear hormone receptor superfamily. Ligand activation of PPARgamma is associated with differentiation and inhibition of proliferation in the normal and malignant cells. Herein, we studied the effects of PPARgamma and the PPARgamma agonists thiazolidinediones (TZDs) on the insulin receptor (IR), a cell membrane tyrosine kinase receptor protein, whose role is of paramount importance in mediating the metabolic and growth-promoting effects of the peptide hormone insulin. Overexpression of the PPARgamma1 in human hepatocellular (HepG2) cells was associated with decreased IR gene transcription and protein expression levels, and these reductions were more evident in the presence of TZDs. Since no PPARgamma response elements were identified on the IR promoter, we postulated that PPARgamma adversely affects the IR gene transcription by perturbing the assembly and stability of the transcriptionally active multiprotein-DNA complex identified previously, which includes the high-mobility group A1 protein, the ubiquitously expressed transcription factor (Sp1), the CAAT enhancer-binding protein (C/EBPbeta), and, in some cell lines, the developmentally regulated activator protein-2 (AP-2) transcription factor. Using glutathione S-transferase pull-down assays combined with electrophoretic mobility shift assay and chromatin immunoprecipitation, we demonstrated that by interacting with Sp1, C/EBPbeta, and AP-2, PPARgamma can prevent Sp1/AP-2 protein-protein association and inhibit binding of Sp1 and C/EBPbeta to DNA, thus reducing IR gene transcription. Our results demonstrate that IR is a new target gene of PPARgamma, and support a potential use of TZDs as anti-proliferative agents in selected neoplastic tissues overexpressing IRs. PMID: 18310298