Acute Hyperglycemia Induced by Hyperglycemic Clamp Affects Plasma Amyloid-β in Type 2 Diabetes

Abstract

Background:

Individuals with type 2 diabetes (T2D) have an increased risk of cognitive symptoms and Alzheimer’s disease (AD). Mis-metabolism with aggregation of amyloid-β peptides (Aβ) play a key role in AD pathophysiology. Therefore, human studies on Aβ metabolism and T2D are warranted.

Objective:

The objective of this study was to examine whether acute hyperglycemia affects plasma Aβ_1–40 and Aβ_1–42 concentrations in individuals with T2D and matched controls.

Methods:

Ten participants with T2D and 11 controls (median age, 69 years; range, 66–72 years) underwent hyperglycemic clamp and placebo clamp (saline infusion) in a randomized order, each lasting 4 hours. Aβ_1–40, Aβ_1–42, and insulin-degrading enzyme (IDE) plasma concentrations were measured in blood samples taken at 0 and 4 hours of each clamp. Linear mixed-effect regression models were used to evaluate the 4-hour changes in Aβ_1–40 and Aβ_1–42 concentrations, adjusting for body mass index, estimated glomerular filtration rate, and 4-hour change in insulin concentration.

Results:

At baseline, Aβ_1–40 and Aβ_1–42 concentrations did not differ between the two groups. During the hyperglycemic clamp, Aβ decreased in the control group, compared to the placebo clamp (Aβ_1–40: p = 0.034, Aβ_1–42: p = 0.020), IDE increased (p = 0.016) during the hyperglycemic clamp, whereas no significant changes in either Aβ or IDE was noted in the T2D group.

Conclusions:

Clamp-induced hyperglycemia was associated with increased IDE levels and enhanced Aβ₄₀ and Aβ₄₂ clearance in controls, but not in individuals with T2D. We hypothesize that insulin-degrading enzyme was inhibited during hyperglycemic conditions in people with T2D.