Michael Stitzel, Ph.D., is advancing the understanding of Type 2 diabetes and its risk identifiers, which now include dysfunction in the powerhouse of the cell, the mitochondria.
Type 2 diabetes (T2D) is a complex disease that occurs when cells in the muscle, fat and liver become insulin resistant. T2D places a significant burden on both medical and public health systems in the United States, with roughly 37 million cases (about 1 in 10 people). In an effort to unravel the mysteries of T2D, Associate Professor Michael Stitzel, Ph.D., and his team are conducting innovative genomic research to shed light on the condition’s risk factors and genetic underpinnings. His research focuses on decoding the regulatory mechanisms of human pancreatic and metabolic cells as well as identifying how gene expression and cellular function differ between healthy and T2 diabetic individuals. Supported by an R01 grant from the National Institute for Diabetes and Digestive and Kidney Diseases, Stitzel is investigating mitochondria, which drive cellular metabolism, to determine how their dysfunction could be an early indicator for T2D onset.
Generating most of the chemical energy needed to power cellular biochemical reactions, mitochondria play a central role in fueling and maintaining pancreatic islet β-cells (the cells responsible for balancing glucose levels and producing insulin). Findings suggests that mitochondrial dysfunction precedes the development of T2D in pre-diabetic individuals. A range of variants have been associated with the disease and have been shown to impact normal gene expression patterns, compromising mitochondria health within pancreatic cells. By combining genomic and cellular analyses, the Stitzel lab will study both human islet cells and T2D mouse models to determine how gene expression patterns influence mitochondrial function and impairment in islet cells.
A twofold action plan
The primary suspect of Stitzel’s investigation lies within non-coding areas of the genome. These areas contain single nucleotide polymorphisms (SNPs), where a single base of DNA naturally varies from person to person. Specific SNPs have been identified as contributors to T2D as they seem to alter gene regulation in the cell. And as they modify the expression of active genes, these SNPs are expected to be the key instigators of poor mitochondrial health. To examine the connections between SNPs, regulatory elements and effector genes, Stitzel plans to use a specific form of CRISPR (clustered regularly interspaced short palindromic repeats) gene editing technology, CRISPR-QTL, and genome-wide association studies (GWAS) to map exactly where these genomic modifications affecting mitochondrial function lie hidden within the genomic landscape. He also intends to study how these pinpointed genetic alterations contribute to pancreatic β-cell’s glycemic control, function and metabolism.
The study promises to establish new connections between genetic variants and T2D. Offering insights into the molecular and cellular mechanisms of the disease as well as identifying a new risk identifier, Stitzel’s work may lead to the identification of novel therapeutic targets and strategies for preventing T2D-related pancreatic islet cell failure.