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Genetics and epigenetics help unravel mechanisms of insulin resistance


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Amit R. Majithia, MD
Amit R. Majithia, MD

Insulin resistance remains a mystery. Clinical heterogeneity is the rule, with some healthy individuals showing greater insulin resistance than some individuals with overt diabetes. Insulin resistance also plays a role in type 2 diabetes, cardiovascular disease, fatty liver disease, polycystic ovaries, and other conditions. And, clinicians and researchers recognize multiple insulin-responsive tissues, particularly adipose, skeletal muscle, liver, and arteries, but the spleen, ovaries, and uterus have the greatest expansion of insulin receptors.

“These tissues all talk to each other, which creates even more complexity,” said Amit R. Majithia, MD, Assistant Professor of Medicine and of Pediatrics, University of California, San Diego, School of Medicine. “There are multiple intracellular signaling pathways that can differentially affect different tissues.”

Dr. Majithia opened a basic research symposium, Understanding Human Insulin Resistance Using (epi) Genetics in Diverse Populations, on Sunday, June 5, with an exploration of new opportunities and approaches to quantify and understand insulin resistance. The session was livestreamed and can be viewed on-demand by registered meeting participants at If you haven’t registered for the 82nd Scientific Sessions, register today to access the valuable meeting content through September 5.

Genome-wide association studies (GWAS) and other genetic tools can help tease out the genetic basis of insulin resistance. The average gene has about 30 variants, Dr. Majithia said, most of which have no functional effect on gene products. Using deep mutational scanning to identify variants that have a functional effect, then tracking functional variants back to biobank samples can help identify clinically relevant phenotypes associated with specific variants.

J. Andrew Pospisilik, PhD
J. Andrew Pospisilik, PhD

About 1 in 500 individuals in the UK BioBank have rare missense variants of the peroxisome proliferator-activated receptor gamma gene. One variant is protective against type 2 diabetes, apparently by altering lipid metabolism with enhanced PCSK9 expression, a potential new therapeutic target.

Genetic variation itself is being revised. Traditional models view a phenotype as a combination of genetics and environment, explained J. Andrew Pospisilik, PhD, Chair and Professor of Epigenetics, Van Andel Institute. Few models acknowledge variation in phenotypes from the same genetic and environmental inputs.

“We know that twins can be discordant,” Dr. Pospisilik said. “Up to half of genetic variation is internal, molecular switches, molecular drift, stochastic developmental variation, and errors. Traditional models largely ignore those internal factors.”

Loss of function of neuronatin, for example, triggers excess growth in both mice and humans. Overgrowth can follow two different paths, he explained. Type A is excess body mass due to adiposity with unchanged or reduced lean mass. Type B is excess body mass plus adiposity as measured by body mass index (BMI).

“We stumbled upon what could be two major molecular phenotypes of obesity,” Dr. Pospisilik said. “Switch-like epigenetic programs can determine metabolic disease outcomes.”

Thomas Coffman, MD
Thomas Coffman, MD

Genetic influences also affect end-stage renal disease (ESRD), most often the result of diabetic kidney disease (DKD).

“Diabetic kidney disease and ESRD are a massive public health problem that is still not understood,” said Thomas Coffman, MD, Dean, Duke University-National University of Singapore Medical School and the James R. Clapp Professor of Medicine, Duke University School of Medicine. “Singapore has the highest prevalence of ESRD in the world and the incidence varies by ethnicity. Singaporeans of Malay background are at highest risk, Chinese Singaporeans are at moderate risk, and Singapore East Indians at lowest risk.”

The Diabetes Study in Nephropathy and Other Microvascular Complications, based in Singapore, is attempting to identify new pathways in DKD, discover new treatment targets, and define new biomarkers to stratify risk of DKD in people with type 2 diabetes.

Angiotensin II receptor blockers can help reverse kidney pathology in DKD. New work in mouse models suggests the primary impact is to extinguish albuminuria, which can adversely affect proximal tubule function by altering the tricarboxylic acid cycle (TCA).

“TCA dysfunction may be a biomarker of epithelial stress from proteinuria, perhaps triggered by enhanced exposure to urinary proteins,” Dr. Coffman said. “We are testing that hypothesis now.”

Another approach to unraveling genetic influences combines human genetics, gene perturbations in animal models, cellular phenotyping in human cell culture, and biobanked tissue samples.

Anna Gloyn, DPhil
Anna Gloyn, DPhil

“Gene regulation is context specific,” explained Anna Gloyn, DPhil, Professor of Pediatrics and Genetics, Stanford University School of Medicine. “It matters which cell type it is happening in, which developmental stage, and whether it is under a particular stimulus. We can have the same locus giving risk to very different regulatory effects.”

Dr. Gloyn described a combined human/animal model/human model/human primary tissue approach with the RREB1 gene, responsible for ras-responsive element-binding protein 1. This zinc finger transcription factor is involved in cell proliferation, transcriptional regulation, and DNA repair and is over-expressed in pancreatic cancer.

In human cell models, loss of RREB1 alters beta cell function to reduce insulin gene expression and protein as well as glucose-stimulated insulin secretion after forskolin stimulation. Loss of RREB1 expression affects more than 2,000 genes—56% upregulated and most involved in insulin secretion and pancreatic cell development, Dr. Gloyn continued.

Comparisons across the 500,000-plus human genomes and samples in the UK BioBank showed associations with height, A1C levels, BMI, waist-hip ratio, and bone mineral density (BMD). Similarly, RREB1 knockout mice are insulin-sensitive, shorter, weigh less, and have less fat mass, smaller adipocytes, and higher BMD compared to wildtype mice.

Loss of RREB1 is metabolically protective, Dr. Gloyn noted.

“We are not sure if loss of function matters over time or whether it’s desirable, but it could be therapeutically exciting because it is working in the right metabolic direction,” she said.