Human islets expressing HNF1A variant have defective β cell transcriptional regulatory networks

• Published in: The Journal of clinical investigation Vol. 129; no. 1; pp. 246 - 251
• Main Authors: Haliyur, Rachana, Tong, Xin, Sanyoura, May, Shrestha, Shristi, Lindner, Jill, Saunders, Diane C, Aramandla, Radhika, Poffenberger, Greg, Redick, Sambra D, Bottino, Rita, Prasad, Nripesh, Levy, Shawn E, Blind, Raymond D, Harlan, David M, Philipson, Louis H, Stein, Roland W, Brissova, Marcela, Powers, Alvin C
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 02-01-2019
• Subjects: Adolescent; Adult; Beta cells; Biomedical research; Concise Communication; Deoxyribonucleic acid; Diabetes; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - pathology; DNA; Gene expression; Genetic Variation; Glucose; Hepatocyte Nuclear Factor 1-alpha - biosynthesis; Hepatocyte Nuclear Factor 1-alpha - genetics; Heterozygote; Homeostasis; Humans; Insulin; Insulin secretion; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Insulitis; Male; Mutation; Nucleotide sequence; Pancreas; Proteins; Secretion; Transcription; Transcription factors; Transcription, Genetic; Islet cells; Diabetes; Insulin; Endocrinology
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI121994

Using an integrated approach to characterize the pancreatic tissue and isolated islets from a 33-year-old with 17 years of type 1 diabetes (T1D), we found that donor islets contained β cells without insulitis and lacked glucose-stimulated insulin secretion despite a normal insulin response to cAMP-evoked stimulation. With these unexpected findings for T1D, we sequenced the donor DNA and found a pathogenic heterozygous variant in the gene encoding hepatocyte nuclear factor-1α (HNF1A). In one of the first studies of human pancreatic islets with a disease-causing HNF1A variant associated with the most common form of monogenic diabetes, we found that HNF1A dysfunction leads to insulin-insufficient diabetes reminiscent of T1D by impacting the regulatory processes critical for glucose-stimulated insulin secretion and suggest a rationale for a therapeutic alternative to current treatment.