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

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.

Characterisation of the endocrine pancreas in type 1 diabetes: islet size is maintained but islet number is markedly reduced

“…Surprisingly, this process of beta cell loss has not so far been explored in T1D. Similar to the finding of PDX1 reactivity in the nuclei in a proportion of the alpha cells reported herein, a recent publication on impaired alpha cell function in T1D showed that most alpha cells in donors with T1D do not express the alpha cell transcription factors MAFB and ARX, but low levels of NKX6.1 [28]. Cells of a similar phenotype produce trace amounts of insulin, too low for detection by ordinary analysis [29].…”

“…Pancreatic biopsies were obtained from six patients with recent-onset T1D, included in the DiViD study. Mean age was 28 years (range [24][25][26][27][28][29][30][31][32][33][34][35]. Biopsies were taken laparoscopically from the pancreas tail 3-9 weeks after diagnosis.…”

Cystic fibrosis–related diabetes is caused by islet loss and inflammation

“…Human islets were perifused within 24 hours of arrival at Vanderbilt, as previously described (32,71,76), with DMEM supplemented with the following glucose concentrations and test agents: 5.6 mM glucose, 16.7 mM glucose, 16.7 mM glucose plus 100 μm IBMX, 1.7 mM glucose plus 1 μm epinephrine (MilliporeSigma), and 5.6 mM glucose plus 20 mM KCl (MilliporeSigma). Human insulin and glucagon secretion and content was measured in fractions and extracts by radioimmunoassay from MilliporeSigma (catalog no.…”

Time zones of pancreatic islet metabolism

“…81 Therefore, studies of α-cell physiology, regulation of glucagon secretion and most importantly molecular and functional interactions between αand β-cells have increasingly caught attention, in particular with respect to the development and management of diabetes mellitus. [82][83][84][85][86][87][88] Although fundamental aspects concerning the circadian control of transcription and functional regulation in the context of the intact pancreatic islet have been largely explored (as highlighted in the previous chapter), studies aiming to zoom into pancreatic islet cells in order to decipher circadian clock function in different islet cell types have only recently emerged. Our own recent study focuses on the molecular characterization of the αand β-cellular clocks, their interactions, impact on gene transcription and islet hormone secretion.…”