scholarly journals Substance Use Affects Type 1 Diabetes Pancreas Pathology: Implications for Future Studies

2021 ◽  
Vol 12 ◽  
Author(s):  
Brittany S. Bruggeman ◽  
Martha Campbell-Thompson ◽  
Stephanie L. Filipp ◽  
Matthew J. Gurka ◽  
Mark A. Atkinson ◽  
...  

Access to human pancreas samples from organ donors has greatly advanced our understanding of type 1 diabetes pathogenesis; however, previous studies have shown that donors have a high rate of substance use, and its impact on pancreatic histopathology in this disease is not well described. One-hundred-thirty-one type 1 diabetes and 111 control organ donor pancreata from persons 12-89 years of age (mean 29.8 ± 15.5 years) within the Network for Pancreatic Organ donors with Diabetes (nPOD) were examined for insulin positivity, insulitis, amyloid staining, acute and chronic pancreatitis, and chronic exocrine changes (acinar atrophy, fibrosis, fatty infiltration, or periductal fibrosis); findings were compared by history of substance use. A secondary analysis compared exocrine pancreatic histopathologic findings in type 1 diabetes versus control organ donors regardless of substance use history. We observed a high but congruent rate of substance use in type 1 diabetes and control organ donors (66.4% and 64% respectively). Among donors with type 1 diabetes (but not controls), islet amyloid (OR 9.96 [1.22, 81.29]) and acute pancreatitis (OR 3.2 [1.06, 9.63]) were more common in alcohol users while chronic exocrine changes (OR 8.86 [1.13, 69.31]) were more common in cocaine users. Substance use impacted the pancreata of donors with type 1 diabetes more than controls. Overall, despite similar rates of substance use, acute pancreatitis (15.3% versus 4.5%, p=0.0061), chronic pancreatitis (29.8% versus 9.9%, p=0.0001), and chronic exocrine changes (73.3% versus 36.9%, p<0.0001) were more common in type 1 diabetes donors than controls. Alcohol and/or cocaine use in type 1 diabetes organ donors increases exocrine pancreas pathology and islet amyloid deposition but does not affect insulitis or insulin positivity. Exocrine pathology in type 1 diabetes donors is common, and further study of the pathophysiology of these changes is needed.

Diabetes ◽  
2021 ◽  
Vol 70 (Supplement 1) ◽  
pp. 927-P
Author(s):  
ANA CREO ◽  
SWETHA SRIRAM ◽  
LISA VAUGHAN ◽  
AMY WEAVER ◽  
SEEMA KUMAR

2021 ◽  
Vol 12 ◽  
Author(s):  
Laurie G. Landry ◽  
Amanda M. Anderson ◽  
Holger A. Russ ◽  
Liping Yu ◽  
Sally C. Kent ◽  
...  

Proinsulin is an abundant protein that is selectively expressed by pancreatic beta cells and has been a focus for development of antigen-specific immunotherapies for type 1 diabetes (T1D). In this study, we sought to comprehensively evaluate reactivity to preproinsulin by CD4 T cells originally isolated from pancreatic islets of organ donors having T1D. We analyzed 187 T cell receptor (TCR) clonotypes expressed by CD4 T cells obtained from six T1D donors and determined their response to 99 truncated preproinsulin peptide pools, in the presence of autologous B cells. We identified 14 TCR clonotypes from four out of the six donors that responded to preproinsulin peptides. Epitopes were found across all of proinsulin (insulin B-chain, C-peptide, and A-chain) including four hot spot regions containing peptides commonly targeted by TCR clonotypes derived from multiple T1D donors. Of importance, these hot spots overlap with peptide regions to which CD4 T cell responses have previously been detected in the peripheral blood of T1D patients. The 14 TCR clonotypes recognized proinsulin peptides presented by various HLA class II molecules, but there was a trend for dominant restriction with HLA-DQ, especially T1D risk alleles DQ8, DQ2, and DQ8-trans. The characteristics of the tri-molecular complex including proinsulin peptide, HLA-DQ molecule, and TCR derived from CD4 T cells in islets, provides an essential basis for developing antigen-specific biomarkers as well as immunotherapies.


Diabetologia ◽  
2016 ◽  
Vol 59 (4) ◽  
pp. 865-867 ◽  
Author(s):  
Tetsuro Kobayashi ◽  
Kaoru Aida ◽  
Tomoyasu Fukui ◽  
Erika Jimbo ◽  
Akira Shimada ◽  
...  

Diabetes Care ◽  
2001 ◽  
Vol 24 (12) ◽  
pp. 2156-2157 ◽  
Author(s):  
T. Taniguchi ◽  
J. Tanaka ◽  
S. Seko ◽  
K. Okazaki ◽  
M. Okamoto

2018 ◽  
Vol 60 (2) ◽  
pp. R57-R75 ◽  
Author(s):  
Heather C Denroche ◽  
C Bruce Verchere

Islet amyloid polypeptide (IAPP), the main component of islet amyloid in type 2 diabetes and islet transplants, is now recognized as a contributor to beta cell dysfunction. Increasingly, evidence warrants its investigation in type 1 diabetes owing to both its immunomodulatory and metabolic actions. Autoreactive T cells to IAPP-derived epitopes have been described in humans, suggesting that IAPP is an islet autoantigen in type 1 diabetes. In addition, although aggregates of IAPP have not been implicated in type 1 diabetes, they are potent pro-inflammatory stimuli to innate immune cells, and thus, could influence autoimmunity. IAPP aggregates also occur rapidly in transplanted islets and likely contribute to islet transplant failure in type 1 diabetes through sterile inflammation. In addition, since type 1 diabetes is a disease of both insulin and IAPP deficiency, clinical trials have examined the potential benefits of IAPP replacement in type 1 diabetes with the injectable IAPP analogue, pramlintide. Pramlintide limits postprandial hyperglycemia by delaying gastric emptying and suppressing hyperglucagonemia, underlining the possible role of IAPP in postprandial glucose metabolism. Here, we review IAPP in the context of type 1 diabetes: from its potential involvement in type 1 diabetes pathogenesis, through its role in glucose metabolism and use of IAPP analogues as therapeutics, to its potential role in clinical islet transplant failure and considerations in this regard for future beta cell replacement strategies.


2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Fujiko Egashira ◽  
Midori Kawashima ◽  
Ai Morikawa ◽  
Minami Kosuda ◽  
Hisamitsu Ishihara ◽  
...  

PLoS ONE ◽  
2015 ◽  
Vol 10 (8) ◽  
pp. e0135663 ◽  
Author(s):  
Tanya C. Burch ◽  
Margaret A. Morris ◽  
Martha Campbell-Thompson ◽  
Alberto Pugliese ◽  
Jerry L. Nadler ◽  
...  

2010 ◽  
Vol 46 (2) ◽  
pp. S59 ◽  
Author(s):  
Jessica Pan ◽  
Sherry Van Blyderveen ◽  
Zubin Punthakee ◽  
Christina Grant

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