The dysox model of diabetes and de-diabetization potential

Townsend Letter for Doctors and Patients, May, 2007 by Majid Ali

Is diabetes mellitus a sugar problem? No. The abnormalities of blood sugar seen in diabetes are the consequences of the derangements of cellular energetics and toxicity that collectively create what is commonly called diabetes. Is diabetes an insulin problem? No. The abnormalities of insulin functions are the consequences of plasticized (chemicalized) and hardened cell membranes that immobilize the insulin receptors embedded in them. Is diabetes a problem of blood vessels that cause blindness, kidney failure, stroke, heart attacks, and neuropathy? No. The abnormalities of blood vessels are the consequences of oxidizing and deoxygenizing influences in diabetes.

In this column, I marshal evidence for my view that the state of insulin resistance should be regarded as a "hardened cell membrane state." The so-called metabolic syndrome should be visualized as a "gummed-up matrix state." Pre-diabetes should be seen as a "mitochondrial dysfunction state." The strategies for the prevention and reversal of diabetes yield better long-term clinical results if diabetes is recognized as an "dysfunction oxygen signalling" or the dysox state.

In type 1 diabetes, insulin itself becomes a potent autoantigen and initiates autoimmune injury to pancreatic islet cells. (1-3) I will show how this recently documented role of insulin in the pathogenesis of diabetes fits in the dysox model of diabetes presented here. In type-2 diabetes, insulin cannot function--insulin resistance, in the common jargon--and hyperinsulinemia develops, which triggers and amplifies the inflammatory response. (4-6) In all types of diabetes, the endothelial cells produce nitric oxide and other bioactive factors in abnormal quantities and proportions. (7,8) Diabetes causes neuropathy, retinopathy, nephropathy, dementia, stroke, and heart attacks. I will describe how those complications of diabetes can be better understood when the problems are seen through the prism of oxygen signaling.

Strong clinical, epidemiologic, and experimental evidence links the epidemics of obesity with those of diabetes in an ever-increasing number of countries. (9-11) That link is supported by known metabolic roles of non-esterified fatty acids (NEFAs) and altered paracrine and endocrine functions of fat cells (adipocytes) in the energy economy of the body. For example, in a healthy state, NEFAs serve as substrates for adenosine triphosphate (ATP) generation. In obesity, these fatty acids are retained in excess in biomembranes of all cell populations of the body and within adipocytes. NEFAs, along with trans fats and oxidized lipids, then "harden" the cell membranes to clamp down on insulin receptors--rusting and impacting the crank, so to speak--to cause insulin resistance. (12) Those lipids also "gum up" the matrix, blocking molecular cross-talk there. Eventually, those elements, along with other toxins, uncouple respiration from oxidative phosphorylation and impede mitochondrial electron transfer events.

In obesity, the hormonal output of adipocytes is chaotic in the ways in which it further increases cellular fat build-up and sets the stage for the development of diabetes. (13,14) However, the obesity/diabetes link does not prevail in all populations of the world. For instance, in India, there is also an epidemic of low body-weight (LBW) diabetes (15)--a phenomenon that clearly points to the existence of environmental factors unrelated to obesity that are involved in the pathogenicity of diabetes, and supports the dysox model of diabetes.

A growing number of free radicals, transcription factors, enzymes, and proteins has been--and continues to be--implicated in the pathogenesis of diabetes, including: (1) nitric oxide; (16,17) (2) inducible nitric oxide synthase (iNOS); (18) (3) mitochondrial uncoupling proteins (UCPs); (19-21) (4) proinflammatory cytokines; (22-24) (5) resistin; (25,26) (6) leptin; (27,28) (7) adipokines; (29) (8) adiponectin; (30) (9) tumor necrosis factor-alpha (TNF-[alpha]); (31) (10) peroxisome proliferator-activated receptor gamma (PPARgamma); (32-34) (11) nuclear respiratory factor-1 (NRF-1); (35) (12) suppression of cytokine signaling (SOCS) proteins; (36) (13) retinol-binding protein-4 (RBP4); (37) (14) antibodies against glutamic acid decarboxylase; (38) (15) prothrombotic species, including fibrinogen, von Willebrand factor, and plasminogen activator inhibitor (PAI-1), adipsin (complement D), acylation-stimulating protein (ASP); (39-42) (16) heat shock protein 60, voltage-dependent anion channel 1 (VDAC-1), and Grp75; (43) and (17) hypercoagulable platelets. (44) These factors constitute an enormous network of molecular and cellular cross-talk, nearly all aspects of which are linked to oxygen signaling and provide support for the dysox model of diabetes. To cite some examples, over-expression of several antioxidant and oxystatic systems--including superoxide dismutase, catalase, and glutathione peroxidase--in various tissue-organ systems of diabetic animals and humans have been documented. (45) Later in this column, I furnish direct evidence for impaired bioenergetics--altered Krebs cycle chemistry, glycolytic pathways, and mitochondrial functions--in individuals with diabetes, by presenting personal data.