TYPE3 DIABETES

Dear Friends,

This is an original article from the Journal of Diabeitc Science and Technology.        I have just presented it as such.

Alzheimer’s Disease is being considered as T3DM

The concept of T3 DM is emerging fast though it has not yet been officially recognized.

Jagannathan

Alzheimer's Disease Is Type 3 Diabetes–Evidence Reviewed

THIS IS AN ORIGINAL ARTICLE FROM THE JOURNAL OF DIABETIC SCIENCE AND TECHNOLOGY

Suzanne M. de la Monte, M.D., M.P.H.and Jack R. Wands, M.D.

Alzheimer's disease (AD) has characteristic histopathological, molecular, and biochemical abnormalities, including cell loss; abundant neurofibrillary tangles; dystrophic neurites; amyloid precursor protein, amyloid-β (APP-Aβ) deposits; increased activation of prodeath genes and signaling pathways; impaired energy metabolism; mitochondrial dysfunction; chronic oxidative stress; and DNA damage.

 Gaining a better understanding of AD pathogenesis will require a framework that mechanistically interlinks all these phenomena. Currently, there is a rapid growth in the literature pointing toward insulin deficiency and insulin resistance as mediators of AD-type neurodegeneration, but this surge of new information is riddled with conflicting and unresolved concepts regarding the potential contributions of type 2 diabetes mellitus (T2DM), metabolic syndrome, and obesity to AD pathogenesis.

 Herein, we review the evidence that

 (1) T2DM causes brain insulin resistance, oxidative stress, and cognitive impairment, but its aggregate effects fall far short of mimicking AD;

 (2) extensive disturbances in brain insulin and insulin-like growth factor (IGF) signaling mechanisms represent early and progressive abnormalities and could account for the majority of molecular, biochemical, and histopathological lesions in AD;

 (3) experimental brain diabetes produced by intracerebral administration of streptozotocin shares many features with AD, including cognitive impairment and disturbances in acetylcholine homeostasis; and

(4) experimental brain diabetes is treatable with insulin sensitizer agents, i.e., drugs currently used to treat T2DM. We conclude that the term “type 3 diabetes” accurately reflects the fact that AD represents a form of diabetes that selectively involves the brain and has molecular and biochemical features that overlap with both type 1 diabetes mellitus and T2DM.

Conclusions

Altogether, the results from these studies provide strong evidence in support of the hypothesis that AD represents a form of diabetes mellitus that selectively afflicts the brain. Positive data stemmed from

(1) direct analysis of postmortem human brains with documented AD;

(2) an experimental animal model in which brain diabetes with cognitive impairment and molecular and pathological features that mimic AD was produced by intracerebral administration of a drug that is commonly used to produce T1DM or T2DM; and

(3) a study showing that PPAR agonists, which are used to treat T2DM, prevent many of the AD-associated neurodegenerative effects of ic-STZ. The data are supported by abundant in vitro experiments that demonstrated essentially the same or similar effects of STZ or oxidative stress treatments of neuronal cells.

 The human and experimental animal model studies also showed that CNS impairments in insulin/IGF signaling mechanisms can occur in the absence of T1DM or T2DM.

 Finally, we demonstrated that although obesity with T2DM causes brain insulin resistance with some features of AD-type neurodegeneration, the effects are relatively modest, not associated with significant histopathological lesions, and lack most of the critical abnormalities that typify AD.

Therefore, T2DM was deemed not sufficient to cause AD, although it could possibly serve as a cofactor in its pathogenesis or progression. Altogether, the data provide strong evidence that AD is intrinsically a neuroendocrine disease caused by selective impairments in insulin and IGF signaling mechanisms, including deficiencies in local insulin and IGF production. At the same time, it is essential to recognize that T2DM and T3DM are not solely the end results of insulin/IGF resistance and/or deficiency, because these syndromes are unequivocally accompanied by significant activation of inflammatory mediators, oxidative stress, DNA damage, and mitochondrial dysfunction, which contribute to the degenerative cascade by exacerbating insulin/ IGF resistance.

 Referring to AD as T3DM is justified, because the fundamental molecular and biochemical abnormalities overlap with T1DM and T2DM rather than mimic the effects of either one. Some of the most relevant data supporting this concept have emerged from clinical studies demonstrating cognitive improvement and/or stabilization of cognitive impairment in subjects with early AD following treatment with intranasal insulin or a PPAR agonist.

 

Thanks,

Jagannathan