α Cell Function and Gene Expression Are Compromised in Type 1 Diabetes

Many patients with type 1 diabetes (T1D) have residual β cells producing small amounts of C-peptide long after disease onset but develop an inadequate glucagon response to hypoglycemia following T1D diagnosis. The features of these residual β cells and α cells in the islet endocrine compartment are...

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Published in:Cell reports (Cambridge) Vol. 22; no. 10; pp. 2667 - 2676
Main Authors: Brissova, Marcela, Haliyur, Rachana, Saunders, Diane, Shrestha, Shristi, Dai, Chunhua, Blodgett, David M., Bottino, Rita, Campbell-Thompson, Martha, Aramandla, Radhika, Poffenberger, Gregory, Lindner, Jill, Pan, Fong Cheng, von Herrath, Matthias G., Greiner, Dale L., Shultz, Leonard D., Sanyoura, May, Philipson, Louis H., Atkinson, Mark, Harlan, David M., Levy, Shawn E., Prasad, Nripesh, Stein, Roland, Powers, Alvin C.
Format: Journal Article
Language:English
Published: United States Elsevier Inc 06.03.2018
Elsevier
Subjects:
Adolescent
Adult
alpha cells
Animals
Case-Control Studies
Cellular Reprogramming
Child
Diabetes Mellitus, Type 1 - genetics
Female
Gene Expression Regulation
glucagon
Glucagon - metabolism
Glucagon-Secreting Cells - metabolism
Glucagon-Secreting Cells - pathology
human
Humans
insulin
Insulin Secretion
Insulin-Secreting Cells - metabolism
Insulin-Secreting Cells - pathology
Male
Mice
Middle Aged
pancreatic islet
Phenotype
Tissue Donors
Transcription Factors - metabolism
type 1 diabetes
Young Adult
glucagon
type 1 diabetes
pancreatic islet
insulin
human
alpha cells
ISSN:2211-1247, 2211-1247
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Summary:Many patients with type 1 diabetes (T1D) have residual β cells producing small amounts of C-peptide long after disease onset but develop an inadequate glucagon response to hypoglycemia following T1D diagnosis. The features of these residual β cells and α cells in the islet endocrine compartment are largely unknown, due to the difficulty of comprehensive investigation. By studying the T1D pancreas and isolated islets, we show that remnant β cells appeared to maintain several aspects of regulated insulin secretion. However, the function of T1D α cells was markedly reduced, and these cells had alterations in transcription factors constituting α and β cell identity. In the native pancreas and after placing the T1D islets into a non-autoimmune, normoglycemic in vivo environment, there was no evidence of α-to-β cell conversion. These results suggest an explanation for the disordered T1D counterregulatory glucagon response to hypoglycemia. [Display omitted] •T1D β cells appear to maintain several aspects of regulated insulin secretion•T1D α cells have impaired glucagon secretion and altered gene expression•Unlike in rodents, α-to-β cell conversion in human T1D is a very rare event•T1D α cell identity factors improve in a non-autoimmune, normoglycemic environment Brissova et al. find that β cells in the type 1 diabetic (T1D) pancreas maintain several functional and molecular features, but α cells have impaired glucagon secretion and an altered gene expression profile. These findings provide insight into the mechanism of α cell dysfunction in T1D.
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These authors contributed equally
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2018.02.032