Characterization of the Meal-Stimulated Incretin Response and Relationship With Structural Brain Outcomes in Aging and Alzheimer's Disease.

Jill K Morris,Melissa E Petersen,Jeffrey M Burns,Casey S John,Ashwini Kamat,Xiaowan Wang,Zachary D Green,Russell S Swerdlow,Eric D Vidoni,Sid E O’Bryant,Heather M Wilkins,Robyn A Honea

doi:10.3389/fnins.2020.608862

Abstract

BackgroundIndividuals with Alzheimer’s Disease (AD) are often characterized by systemic markers of insulin resistance; however, the broader effects of AD on other relevant metabolic hormones, such as incretins that affect insulin secretion and food intake, remains less clear.MethodsHere, we leveraged a physiologically relevant meal tolerance test to assess diagnostic differences in these metabolic responses in cognitively healthy older adults (CH; n = 32) and AD (n = 23) participants. All individuals also underwent a comprehensive clinical examination, cognitive evaluation, and structural magnetic resonance imaging.ResultsThe meal-stimulated response of glucose, insulin, and peptide tyrosine tyrosine (PYY) was significantly greater in individuals with AD as compared to CH. Voxel-based morphometry revealed negative relationships between brain volume and the meal-stimulated response of insulin, C-Peptide, and glucose-dependent insulinotropic polypeptide (GIP) in primarily parietal brain regions.ConclusionOur findings are consistent with prior work that shows differences in metabolic regulation in AD and relationships with cognition and brain structure.

Highlights

Insulin resistance and Type 2 Diabetes (T2D) increase with age, and over 60% of older adults ( > 65 years) in the United States exhibit impaired fasting glucose or T2D (Cowie et al, 2006)
peptide tyrosine tyrosine (PYY), glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted peripherally from the gastrointestinal tract, they cross the blood-brain barrier (Banks and Kastin, 1998; Kastin et al, 2002; Nonaka et al, 2003; Dogrukol-Ak et al, 2004) and have receptors in many brain regions, including those involved in the metabolic response and affected in Alzheimer’s Disease (AD), such as the hypothalamus, temporal and parietal cortex, and hippocampus (Martel et al, 1990a; Usdin et al, 1993; Dumont et al, 1996; Jhamandas et al, 2011).Change in peripheral metabolic hormone secretion has the potential to modulate both central nervous system (CNS) and peripheral metabolic function
cognitively healthy (CH) and AD diagnosis groups did not differ by age, sex, body mass index (BMI), body weight, Apolipoprotein epsilon 4 (APOE4) carrier status, education or blood pressure (Table 1)

Summary

Introduction

Insulin resistance and Type 2 Diabetes (T2D) increase with age, and over 60% of older adults ( > 65 years) in the United States exhibit impaired fasting glucose or T2D (Cowie et al, 2006) These conditions are known risk factors for Alzheimer’s Disease (AD) Insulin resistance is related to dysfunction in a broader, integrated network of metabolic hormones beyond insulin, including peptide tyrosine tyrosine (PYY), glucagon like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP). These peptides are released by the gastrointestinal tract to stimulate the insulin response and control blood glucose regulation. Individuals with Alzheimer’s Disease (AD) are often characterized by systemic markers of insulin resistance; the broader effects of AD on other relevant metabolic hormones, such as incretins that affect insulin secretion and food intake, remains less clear

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