MRI May Show how Androgen-Lowering Prostate Cancer Therapy Raises Risk of Diabetes and Heart Disease

Lay Summary

MRI may show how androgen-lowering prostate cancer therapy raises risk of diabetes and heart disease

This study will explore how androgen deprivation therapy (ADT) for treating prostate cancer may increase men’s risk for developing type 2 diabetes. Studies indicate that men with prostate cancer who are treated with drugs or surgery to suppress male hormones called androgens have a markedly increased risk of developing type 2 diabetes. Just how therapy that suppresses androgens leads to metabolic dysregulation and type 2 diabetes is not yet known. But scientists do know that androgens ordinarily restrain the activation of “glial” “cells (which support brain cells). They also know that unregulated glial cell activation leads to inflammation, called “gliosis,” in the hypothalamus, where metabolic energy balance is regulated. Animal studies show that hypothalamic gliosis precedes the development of obesity and insulin resistance in response to a high-fat diet, and inhibition of gliosis attenuates obesity. So, investigators anticipate that when ADT reduces androgens, it promotes inflammatory gliosis and increases metabolic risk for developing type 2 diabetes. They will test this by comparing MRI imaging in men with prostate cancer receiving ADT versus radiation only.

The investigators hypothesize, therefore, that men receiving ADT will have metabolic dysregulation while men receiving only radiation will not. They further hypothesize that ADT prostate cancer therapy leads to a strikingly elevated risk of cardiometabolic disease by increasing gliosis in the mediobasalhypothalamus and dysregulating metabolism. They will test this hypothesis in a total of 50 men with prostate cancer by: 1) conducting MRI studies in men before they begin treatment with–ADT (25 men) or with radiation alone (25 men)–and serially thereafter for six months; 2) assessing systemic insulin resistance by measuring insulin and glucose concentrations during this time; and 3) measuring fat deposition through MRI imaging of the abdomen. They also will try to determine whether insulin resistance precedes or follows inflammatory gliosis because prevention approaches will vary depending upon the sequence of events.

We will not be able to look specifically at brain insulin resistance in this study.

Abstract

MRI may show how androgen-lowering prostate cancer therapy raises risk of diabetes and heart disease

Prostate cancer is a highly prevalent cancer in men. A cornerstone of treatment is androgen deprivation therapy (ADT), which improves survival but confers substantially elevated cardiometabolic risk including markedly increased risk of type 2 diabetes. The mechanisms through which ADT leads to metabolic dysregulation remain incompletely understood. An emergent field of obesity research has demonstrated that non-neuronal (glial) cells play a pivotal role in diet-induced obesity. In animal studies, high-fat feeding induces gliosis - activation of glial cells – in the mediobasal hypothalamus (MBH), the anatomical locus of energy balance regulation. Further, interventions that reduce MBH gliosis attenuate diet-induced obesity. State-of-the-art MRI techniques allow in vivo quantitation of MBH gliosis in humans, and reproducible associations have been shown between MBH gliosis and both adiposity and insulin resistance. MBH gliosis also correlates with low circulating testosterone levels in men and is induced by gonadectomy in male mice. The central premise of the proposed work is that androgens restrain MBH gliosis, and this constitutes a key mechanism through which ADT increases metabolic risk. Men with newly diagnosed prostate cancer will be prospectively followed during ADT and compared to controls undergoing radiation alone. Quantitative structural imaging via brain MRI will be performed serially to measure MBH gliosis. In parallel, insulin resistance will be assessed, and visceral adiposity will be measured via abdominal MRI. This clinical study would be the first to examine centrally mediated mechanisms of ADT-induced metabolic dysregulation and could generate novel interventions for mitigating risk of diabetes and obesity in men.