Table 1.

Dogmas or long-standing beliefs that have come under change, or seen correction in recent years, largely if not significantly due to studies of the human pancreas.

Long-Standing Dogma	Reality	References
T1D occurs when 85–95% of β-cells are destroyed	The degree of β-cell loss resulting in symptomatic disease is quite variable (i.e., 40–95% loss).	33,104,215
Individuals with longstanding T1D are devoid of insulin positive β-cells	Proinsulin and insulin expression can be detected within scattered single cells as well as small clusters of islets in pancreas from donors with longstanding T1D.	33,104,121,138,215–217
T1D represents a singular disease	T1D likely represents a collective of distinct disorders (i.e., endotypes) with commonalities of insulinopenia and loss of β-cells. Heterogeneity exists in the degree of β-cell cell loss at onset, rate of insulitis, age and onset, and more.	22,77,218,219
β-cells are subject to replication	In those without T1D, β-cell replication rates are highest in the neonatal period and decline exponentially throughout childhood with little to no replication observed in human adults. Limited evidence exists that such replication occurs in settings of T1D.	144,220–222
T1D is an autoimmune disease, with limited pathogenic contributions of β-cells	An extensive number of β-cell alterations preceed T1D onset and may contribute toward autoimmunity (e.g., ER stress, oxidative stress, protein misfolding, neoepitope formation, impaired autophagy, aberrant prohormone processing, senescence, and increased expression of MHC-I and PD-L1).	15,35,53,74,87,99,104,111,113,115,116,120,216,223–237
The exocrine pancreas is unaffected by T1D	Reduced pancreas organ mass and volume, as well as reduced exocrine pancreatic enzyme levels in serum, are characteristics of recent-onset and pre- T1D. T1D donors also exhibit reduced acinar tissue area and increase acinar cell density.	40,104,175,178,180,183,187,188,238,239
Insulitis is a chronic and predominant feature in the natural history of T1D	Insulitis is restricted to insulin containing islets and has been primarily reported in individuals with recent-onset T1D, with rare cases of insulitis observed in pancreata from persons with single autoantibody positivity, with slightly more in those with multiple islet autoantibodies.	33,34,40,43,44,89,104,106,215,240,241
T1D and T2D are distinct in terms of pancreatic features	Reductions in islet number, pancreas size, β-cell mass, and β-cell function have been observed in both T1D and T2D. Genetic analyses have provided new insight into the contribution of specific polymorphisms, including how the presence of variants associated with T2D can influence the phenotype of donors with T1D.	27,192–194
Insulitis, as reflected in NOD mice, is representative of human disease	Compared to NOD mice, human insulitis is far less severe (fewer immune cells per inflammed islet), less pervasive (fewer islets affected) and occurs in a patchy “mosaic” pattern	37,40,89,111,242–244