P‐206: Pioglitazone modulates plasma levels of β‐amyloid in glucose intolerant older adults
Year: 2007
Type: article
Study design: Clinical Trial
Abstract: Peroxisome proliferator-activated receptor-γ (PPARγ) agonists improve insulin sensitivity in persons with type 2 diabetes (T2DM), preserve cognition in persons with Alzheimer's disease (AD), and modulate β-amyloid (Aβ) levels in vitro, in animals, and in persons with AD. In contrast, insulin secretagogues, which are also used to treat T2DM, are not known to affect Aβ levels. To compare the effects of the PPARγ agonist pioglitazone and the insulin secretagogue nateglinide on plasma Aβ levels in glucose intolerant older adults. Participants underwent a 2-h oral glucose tolerance test and were classified as glucose intolerant (i.e., impaired glucose tolerant or diabetic, conditions often associated with insulin resistance) based on 2-h plasma glucose levels (2-hpg) ≥140 mg/dl (n = 76; mean[SD]: age = 74.7[5.8] y, 2-hpg = 200.0[40.8] mg/dl) or healthy (n = 26; age = 73.0[5.4] y, 2-hpg = 114.9[15.9] mg/dl). Glucose intolerant participants were randomized to a 4-month course of pioglitazone (30 mg daily), nateglinide (120 mg, 3 times daily), or placebo. Treatment groups did not differ significantly with respect to age or baseline 2-hpg. Blood was acquired at baseline for all participants and at month 4 for treated subjects. Baseline Aβ levels (combined across Aβ species) were higher in glucose intolerant than healthy participants (p=0.027). For healthy controls, higher glucose-stimulated insulin levels were associated with lower Aβ40 levels (p=0.007) and greater Aβ42-to-Aβ40 ratio (p=0.001). For glucose intolerant adults, treatment with pioglitazone increased Aβ40 levels, relative to placebo (p=0.036) or nateglinide (p=0.068). In contrast, pioglitazone decreased Aβ42 levels (p=0.042) and the Aβ42-to-Aβ40 ratio (p=0.009), whereas neither nateglinide nor placebo had a significant effect on these measures. At month 4, Aβ42 levels were positively correlated with 2-hpg (p=0.013) and glycosylated hemoglobin (p=0.019) levels in glucose intolerant adults, indicating that Aβ42 levels rise as glucoregulation declines. These results support the notions that glucose intolerance is associated with elevated plasma Aβ levels and that treating glucose intolerance can modulate plasma Aβ40 and Aβ42 levels. In light of evidence associating diabetes and hyperinsulinemia with AD, treatment with PPAR-γ agonists and other strategies that improve glucose tolerance (and possibly insulin sensitivity) may reduce the risk for AD, in part, through modulation of Aβ.
Source: Alzheimer s & Dementia
Institutions: University of Washington, VA Puget Sound Health Care System
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2582040407