Cell Rep. 2018 Mar 6;22(10):2667-2676. doi: 10.1016/j.celrep.2018.02.032.

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

Brissova M¹, Haliyur R², Saunders D², Shrestha S³, Dai C⁴, Blodgett DM⁵, Bottino R⁶, Campbell-Thompson M⁷, Aramandla R⁴, Poffenberger G⁴, Lindner J⁴, Pan FC⁸, von Herrath MG⁹, Greiner DL¹⁰, Shultz LD¹¹, Sanyoura M¹², Philipson LH¹², Atkinson M⁷, Harlan DM¹⁰, Levy SE³, Prasad N³, Stein R¹³, Powers AC¹⁴.

Author information

1: Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: marcela.brissova@vanderbilt.edu.
2: Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
3: HudsonAlpha Institute for Biotechnology, Huntsville, AL, USA.
4: Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA.
5: Department of Medicine, Diabetes Division, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA; Math and Science Division, Babson College, Wellesley, MA 02457, USA.
6: Institute of Cellular Therapeutics, Allegheny-Singer Research Institute, Allegheny Health Network, Pittsburgh, PA, USA.
7: Department of Pathology, University of Florida Diabetes Institute, College of Medicine, Gainesville, FL, USA.
8: Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
9: Type 1 Diabetes Center, the La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA.
10: Department of Medicine, Diabetes Division, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA.
11: The Jackson Laboratory, Bar Harbor, ME, USA.
12: Departments of Medicine and Pediatrics, Section of Endocrinology, Diabetes, and Metabolism, University of Chicago, Chicago, IL, USA.
13: Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
14: Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA; Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA. Electronic address: al.powers@vanderbilt.edu.

Abstract

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.

KEYWORDS:

alpha cells; glucagon; human; insulin; pancreatic islet; type 1 diabetes

PMID:: 29514095
PMCID:: PMC6368357
DOI:: 10.1016/j.celrep.2018.02.032

Free PMC Article

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Figure 1

T1D β Cells in Recent-Onset T1D Retain Secretory Properties and Gene Expression Pattern Similar to Normal β Cells

(A and B) Insulin secretion was assessed in islets isolated from donors with recent-onset T1D (n = 4; ages 12–22 years; donors nos. 1, 3, 4, and 5) and compared to normal controls (n = 7; ages 7–21 years); G 5.6–5.6 mM glucose, G 16.7–16.7 mM glucose, G 16.7 + IBMX 100–16.7 mM glucose + 100 µM isobutylmethylxanthine (IBMX), G 1.7 + Epi 1–1.7 mM glucose + 1 µM epinephrine, KCl 20–20 mM potassium chloride.
(A) Insulin secretion normalized to overall islet cell volume (expressed as islet equivalents [IEQs]); ****p < 0.0001.
(B) Insulin secretion normalized to islet insulin content; ***p = 0.0005. Data in (A) and (B) were compared by two-way ANOVA.
(C) Insulin content of control (3.873 ± 0.763 ng/IEQ) and T1D islets (1.131 ± 0.660 ng/IEQ); p = 0.0394; data are represented as mean ± SEM.
(D) Expression of β-cell-enriched transcription factors by qRT-PCR in whole T1D islets (n = 3 donors; ages 12–22 years; donors nos. 1, 4, and 5) and controls (n = 3 donors; ages 11–29 years) was normalized to endogenous control and INS expression; ***p < 0.0007.
(E–G) Expression of β-cell-enriched transcription factors in the native pancreatic tissue from donors with recent-onset T1D (n = 2; ages 12–22 years; donors nos. 1 and 5) was compared to 58-year-old donor with 31 years of T1D duration (donor no. 8) and controls (n = 7; ages 8–55 years). The pancreas of 58-year-old T1D donor did not have any insulin+ islets; only rare β cells were found in exocrine parenchyma. T1D β cells (n = 3 donors; ages 12–58 years; donors nos. 1, 5, and 8) had normal expression of β-cell-enriched transcription factors PDX1 (E) and NKX6.1 (F) but decreased expression of NKX2.2 (G) compared to controls (n = 7 donors; ages 8–55 years); ****p < 0.0001; ns, not significant.
Data in (C)–(G) were compared by two-tailed Student’s t test. Data in (A)–(G) are shown as mean ± SEM. The scale bar in (E) represents 10 µm and also corresponds to (F) and (G). See also .

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

Cell Rep. 2018 Mar 6;22(10):2667-2676.