Beyond insulin resistance and syndrome X:

Majid Ali, M.D.

Oxidative – Dysoxygenative Model

of Insulin Toxicity and DiabetesHomeostasis (2001)


 

Beyond insulin resistance and syndrome X: tThe oxidative-dysoxygenative insulin dysfunction (ODID) modelof Insulin Toxicity--Part II. 

Nitric Oxide Dynamics and ODID

Reactive oxygen species (ROS) induce production of reactive nitrogen species (RNS). RNS, in turn, stimulate the generation of reactive oxygen species. The feedback loops provided by ROS-RNS dynamics feed the oxidative fires and inflict oxidative cellular injury. Under physiologic conditions, superoxide dismutase, catalase, glutathione peroxidase, and a host of enzymes support the reduction arm of redox equilibrium. In hyperinsulinemic and hyperglycemic states, the ROS/RNS loops significantly add to cumulative oxidosis. (158-160)

Endothelium-derived nitric oxide exerts several homeostatic effects in the vascular ecology, including regulation of vasomotor tone, inhibition of platelet aggregation, and prevention of adhesion of leukocytes to the endothelial surface (Vane 1990). In animal models as well as in both type 1 and type 2 diabetes, nitric oxide-dependent vasodilation is impaired. (158) Ascorbic acid improved the vasodilatory response in both types of diabetes. (29,30) Endothelium-dependent vasodilation is impaired in healthy subjects after six hours of hyperglycemic clamp. (159) Studies with incremental brachial artery administration of methacholine chloride during euglycemia and hyperglycemia support one of the core tenets of oxidative insulin dysfunction in that hyperglycemia contributes to abnormal endothelial function through production of superoxide anion. (37)

Higher concentrations of insulin in the blood increase blood flow to the skeletal muscle. (164-170) Some of the increase in the cellular glucose uptake has been attributed to that effect of insulin on the blood flow. The precise mechanism of action of insulin in blood vessel musculature has not been elucidated, but the role of nitric oxide in it has been postulated. (167) Other data suggest that the vasodilatory effect in the skeletal muscle is dependent on hyperinsulinemia and not consequent upon changes in carbohydrate metabolism. There is also evidence there is a reduction in insulin-induced vasodilation in insulin resistance associated with obesity. (165,169,170) in other words, insulin facilitates its own delivery to the cell membrane and degradation.

Activation of endothelial NO-synthase in higher concentration is deemed necessary for initiation of the oxidative cascade in endothelial cells that leads to production of excess reactive oxygen species and induction of NF-[kappa]B.

Tumor Necrosis Factor (TNF-[alpha]) and ODID

The secretion of TNT-[alpha] by adipocytes is of special interest to me in the context of the proposed oxidative insulin dysfunction model

of insulin resistance and type 2 diabetes. This cytokine plays many well-established and crucial roles in the inflammatory and immune responses. (94,171-176) It is expressed in excess in adipocytes of obese patients and is known to cause insulin resistance through its effects on insulin-mediated cellular signaling pathways.

Tumor necrosis factor [alpha] (TNF-[alpha]) is a potent inhibitor of insulin signaling in myocytes and adipocytes. (174) Since serum concentrations of TNF-[alpha] are very low in lean as well as obese subjects, this cytokine produced in the muscle and fat cells appears to function in a paracrine fashion. TNT-[alpha] expression is high in the muscle and fat cells of obese and diabetic subjects. Furthermore, the administration of antibodies that neutralize TNF-[alpha] to genetically obese Zucker (fa/fa) rats reverses insulin resistance. (171) That creates another mechanism of insulin resistance in mice. Interestingly, administration of the same antibodies to diabetic patients did not reverse insulin resistance. (175)

All known inflammatory and immunologic responses are initially triggered as well as regulated by oxidative and oxygenative phenomena. (173-175) Blockade of TNF-[alpha] can ameliorate, albeit for limited periods of time, both experimental and clinical forms of antoimmune disorders, such as Crohn's colitis and rheumateid arthritis. (177-180) Hypersecretory TNF-[alpha] responses induced by oxidative stresses are likely to play a role in insulin homeostasis in states of oxidosis associated with hyperinsulinism.

NF-[kappa]B, Endothelial Cells, and ODID

NT-[kappa]B is a potent proinflammatory molecule. (181-133) Blockade of NF-[kappa]B decreases inflammatory responses in experimental and such as Crohn's colitis and rheumatoid arthritis. (184-186) All inflammatory responses create regional oxidosis and most also lead to systemic oxidosis. Such theoretical considerations strongly suggest that NF[kappa]B might play some roles in the pathogenesis of oxidative-dysoxygenative insulin dysfunction.

Thus, it comes as no surprise that high concentrations of glucose (10-30 mM) result in excess generation of reactive oxygen species which, in turn, activate NF-[kappa]B and induce endothelial cell apoptosis. (187) Studies with 3O-methyl-D-glucose (a glucose derivative which is taken up but not metabolized by cells) and L-glucose have shown that endothelial reactivity is mediated by glucose-specific pathways. This finding is of direct relevance to the pathogenesis of oxidative coagulopathy in uncontrolled diabetics. Endothelial apoptosis results in denudation of the nonthrombogenic inner lining of the vessel wall, resulting in the exposition of highly thrombogenic subendothelial matrix.

IGF-1, IGF-2, and ODID

Both insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 2 (IGF-2) have insulin-like effects on glucose transport in the myocyte and adipocyte. (188-190) That is not unexpected in light of close sequence homologies between insulin and both IGF-1 and IGF-2. In addition, there is also a high degree of sequence homology between the insulin receptor and the IGF-1 receptor. Again, not surprisingly, intracellular signaling pathways activated by both receptors are similar. Like insulin, IGF-1 affects translocation of GLUT-4 to the myocyte surface in vitro (188) and exerts a potent hypoglycemic effect. (191)

In health, the glucoregulatory roles of IGF-1 and IGF-2 have been thought not to be significant since these factors arc sequestered by specific binding proteins and their serum concentrations in a free state are low. IGF-1 bypasses the insulin receptor and, under those conditions, exerts a significant glucoregulatory role by facilitating glucose uptake in the myocyte and adipocyte. (192) This has been shown in persons with type 1 and type 2 diabetes as well as in instances of mutations in the insulin receptor.

In the oxidative insulin dysfunction states, however, oxidatively induced alterations in the structure and function of those binding proteins are likely to occur. Indeed, there is some evidence that is so in patients with severe insulin resistance, hyperinsulinemia, and poorly controlled diabetes.

PPAR[gamma] and ODID

Adipocytes are rich in nuclear factor called peroxisome proliferation activator receptor-[gamma] (PPAR[gamma]). This receptor is an important determinant of adipogenesis and stimulates adipogenesis in fibroblasts. (193) Persons heterozygous for a dominant-negative PPAR[gamma] allele suffer from severe insulin resistance. (194) Mice heterozygous for a null PPAR[gamma] allele on a high-fat diet have increased insulin sensitivity and develop adipocyte hypertrophy. (195)

Ligands for PPAR[gamma] include thiazolidinediones (TZDs), a class of drugs for diabetes (discussed later). PPAR[gamma] binding in vitro correlates well with in vivo lowering of blood glucose levels. Non-TZD PPAR[gamma] ligands also increase insulin sensitivity. Furthermore, activators of the PPAR[gamma] heterodimer partner, retinoid X receptor, also increase insulin sensitivity and exert antidiabetic effects. (196)

The antidiabetic effects of some drugs, such as those in the thiazotidinedione class, are due to their ability to decrease insulin resistance. This effect is mediated by a nuclear receptor protein called peroxisome proliferator activated receptor-[gamma] (PPAR[gamma]). This protein is involved in the differentiation of adipocytes and is found in large quantities in those cells. PPAR[gamma] also affects insulin sensitivity by mechanisms that are presumed to involve altered gene dynamics in adipocytes. Specifically, it was thought that some factor like PPAR[gamma] might switch on and off some adipocyte-specific gene involved in insulin-mediated signaling pathways. …

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