Growing evidence for a link between type 2 diabetes and Alzheimer's disease

There is growing evidence of a link between type-2 diabetes/obesity and Alzheimer disease and two recent articles have strengthened this link further. In one paper, researchers report that diet-induced insulin resistance increases beta amyloid generation, amyloid plaque burden in the brain and behavioural impairment in a model of Alzheimer disease. In another more mechanistic paper Brigham and Women's Hospital researchers present data suggesting insulin-degrading enzyme activity as a potential cause of the link.

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.

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).

As with diabetes 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. Intriguingly recent data has suggested that diabetes and Alzheimer's disease may be linked. 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. Thus a body of evidence exists to suggest that diabetes may in fact be a risk factor for developing Alzheimer disease.

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. In a recent article (Am J Pathol. 2004 Apr;164(4):1425-34), Farris et al from Brigham and Women's Hospital, Harvard and the Mayo Clinic 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 although in these animals compensatory mechanisms appeared to prevent the in vivo build up of Abeta. Importantly, in animals who have an underlying propensity to Abeta build up, defects in insulin pathways may lead to Alzheimer's-line disease.

In a second article published in this Month's edition of FASEB (FASEB J. 2004 May;18(7):902-4) Ho et al report that diet-induced insulin resistance increases amyloidogenic beta-amyloid Abeta1-40 and Abeta1-42 peptide generation in the brain of Tg2576 mice, which model Alzheimer disease-like neuropathology. This corresponded with increased gamma-secretase activities and decreased IDE activities. Moreover, increased Abeta production also coincided with increased Alzheimer disease-type amyloid plaque burden in the brain and impaired performance in a spatial water maze task. This therefore provides indirect evidence to confirm that in susceptible mice insulin resistance and defective IDE activity is related to Alzheimer's-like disease.

Further exploration of the apparent interrelationship of insulin resistance to brain amyloidosis revealed a functional decrease in insulin receptor-mediated signal transduction in the brain, and perhaps more importantly an increase in glycogen synthase kinase (GSK)-3alpha.

GSK-3 negatively regulates 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 and that of Ho et al reporting that increased GSK-3 may play a key role in the relationship between the two conditions (for a state of the art overview of GSK-3 click here).

Entry date Tuesday, June 08, 2004

Adapted from Farris et al, Am J Pathol. 2004 Apr;164(4):1425-34 & Ho et al FASEB J. 2004 May;18(7):902-4