Type 2 diabetes as a risk factor for Alzheimer's disease - defective insulin-degrading enzyme as an etiological link?

DailyUpdates 2nd April: There is growing evidence that type-2 diabetes is a risk factor for Alzheimer disease.  In their April American Journal of Pathology article Brigham and Women's Hospital researchers add further evidence to support defects in insulin-degrading enzyme activity as a potential cause of this phenomenon.  This and similar data argues for the development of cross-indication treatments of type-2 diabetes and Alzheimer disease and GSK-3 inhibitors may fit the bill.

According to WHO, there are some 130 million diagnosed diabetics in the world, a figure that is predicted to increase to 300 million by 2025. The majority of patients suffer from type 2 diabetes.  The market for diabetes therapeutics is also rising with global sales reportedly topping $8.1 billion for the 12 months to September 2000, a 19% increase over the previous 12 months (for a full analysis of diabetes therapeutics and market opportunities click here).

Diabetes is associated with a number of other conditions.  For example, around 60-65% of diabetics also have hypertension while diabetes co-exists with dyslipidemia in a third of patients.  Although the treatment of diabetes has traditionally focused on the disease per se, the concurrent treatment of multiple co-existing conditions is rapidly gaining attention.  Such an approach will lower the "pill burden" of individual patients and example of this concept include the development of AGE cross-link breakers for the treatment of type 2 diabetics with hypertension and dual PPAR agonists for the treatment of type 2 diabetes with dyslipidemia (for a full analysis of cross indication treatments click here).   More recently, diabetes has been proposed to be a risk factor for developing Alzheimer disease. Alzheimer disease and type 2 diabetes are characterized by increased prevalence with aging, a genetic predisposition, and comparable pathological features in the islet and brain (amyloid derived from amyloid beta protein in the brain in Alzheimer disease and islet amyloid derived from islet amyloid polypeptide in the pancreas in type 2 diabetes). Evidence is growing to link precursors of amyloid deposition in the brain and pancreas with the pathogenesis of Alzheimer disease and type 2 diabetes, respectively and a recent study has demonstrated that type 2 diabetes is twice as prevalent in Alzheimer disease versus non-Alzheimer disease controls.   The reason for diabetes being a risk fact for Alzheimer disease is unclear however increased beta-amyloid (Abeta) aggregation through inhibition of insulin-degrading enzyme is one hypothesis.   Insulin-degrading enzyme (IDE) has been identified as a principal regulator of Abeta levels in neuronal and microglial cells and human genetic studies have implicated the Insulin-degrading enzyme region of chromosome 10 in both Alzheimer disease and type 2 diabetes.  Last year researchers from Brigham and Women's Hospital reported that mice with homozygous deletions of the insulin-degrading enzyme gene were characterized by a large decrease in Abeta degradation in the brain leading to increased cerebral accumulation of endogenous Abeta as well as hyperinsulinemia and glucose intolerance.   For IDE to remain a valid candidate gene for late-onset AD on functional grounds, it must be shown that partial loss of function of IDE can still alter Abeta degradation, but without causing early, severe elevation of brain Abeta. This has recently been addressed by the Brigham and Women's Hospital group   In their April American Journal of Pathology article, Farris et al report that naturally occurring IDE missense mutations in a well-characterized rat model of type 2 diabetes mellitus result in decreased catalytic efficiency and a 15 to 30% deficit in the degradation of both insulin and Abeta. Endogenously secreted Abeta(40) and Abeta(42) are significantly elevated in primary neuronal cultures from animals with the IDE mutations, but there is no increase in steady-state levels of rodent Abeta in the brain up to age 14 months suggesting that the brain can compensate for the partial deficit during the life span of the rat.   The aging population will contribute to an expansion of the already $30 billion neurodegenerative market. The market for Alzheimer disease therapy is expected to grow from 16 million patients to 21 million by 2010 in the seven major pharmaceutical markets. Between 2005 and 2010, drugs for treating Alzheimer disease could achieve sales of well over $2 billion (for a full analysis of this field click here).    The Brigham and Women's Hospital study adds further weight to the concept that type 2 diabetes may be a risk factor for Alzheimer disease and offers a mechanism for this association.  The development of diabetes therapeutics which are additionally able to limit the progression of Alzheimer disease would be of considerable potential.  Of interest the enzyme, glycogen synthase kinase-3 (GSK-3) has emerged over recent years as a highly promising target for various condition including both diabetes and Alzheimer disease (for a state of the art overview of GSK-3 click here).     GSK-3 negatively regulate several aspects of insulin signaling, and elevated levels of GSK-3 have been reported in skeletal muscle from diabetic rodents and humans. GSK-3 inhibition improves glucose handling in Zucker diabetic fatty rats, lowering fasting hyperglycemia. Likewise GSK-3 inhibitors also improve glucose handling making them promising targets for the treatment of diabetes. Researchers at Chiron, who have developed the field-leading GSK-3 inhibitors CT98014 and CHIR98023 have recently demonstrated that their molecules enhanced insulin-stimulated glucose transport in type 1 skeletal muscle from the insulin-resistant ZDF rats but not from insulin-sensitive lean Zucker rats. Single oral or subcutaneous doses of the inhibitors (30-48 mg/kg) rapidly lowered blood glucose levels and improved glucose disposal after oral or intravenous glucose challenges in ZDF rats and db/db mice, without causing hypoglycemia or markedly elevating insulin.   As in diabetes, GSK-3 is also elevated in Alzheimer disease brain.  Furthermore, GSK-3 inhibitors prevent tau hyperphosphorylation, and also protect cultured neurons from cell death triggered by Abeta. GSK-3 not only provides an additional similarity between Alzheimer disease and diabetes etiology but inhibiting this enzyme may also be of use in treating the two conditions, more so in light of data such as that published by Farris et al supporting the hypothesis that type 2 diabetes is a risk factor for Alzheimer disease.

(Source DailyUpdates 2nd April; for a full abstract of the original papers see  Am J Pathol. 2004 Apr;164(4):1425-34; for further information on diabetes therapeutics and market opportunities click here; for further information on Alzheimer disease click here; and for a state of the art overview of GSK-3 click here)

In this edition of DailyUpdates, LeadDiscovery also highlights ischemic neuroprotection with selective {kappa}-opioid receptor agonist...data showing that disruption of neural STAT-3 causes obesity and diabetes...the role that protein kinase C plays in sildenafil-induced cardioprotection...and much more.