Beta-cell destruction and preservation in childhood and adult onset type 1 diabetes

Abstract

Previous studies describing the symptomatic onset of type 1 diabetes (T1D) and rate of beta-cell loss (C-peptide) support the notion that childhood onset T1D exhibits more severe beta-cell depletion compared to adult onset T1D. To test this notion, we performed whole pancreas analyses in two T1D cases; one of childhood onset (7-yr old, onset at 1.5-yr) along with an adult onset case (43-yr old with onset at 27-yr). Both cases were matched for age and gender with control subjects. Striking regional differences in beta-cell loss were observed in both T1D cases, with severity of loss in the order of tail>body>head regions. In contrast, pancreatic alpha- and delta-cell mass was similar in controls and T1D patients. In the childhood onset T1D case, no intra-islet beta-cells were detected while in the adult onset case, beta-cell containing islets were found, exclusively in the head region. In the latter case, considerable numbers of small cellular clusters negative for three major endocrine hormones were observed, in islets with or without beta-cells. Ultrastructural analysis suggests these cells correspond to degenerating beta-cells, with empty granular membranes and abnormal morphology of nuclei with intranuclear pseudoinclusions, adjacent to healthy alpha- and delta-cells. These results support a hypothesis that during T1D development in childhood, beta-cells are more susceptible to autoimmune destruction or immune attack is more severe, while beta-cell death in the adult onset T1D may be more protracted and incomplete. In addition, T1D may be associated with the formation of “empty” beta-cells; an interesting population of cells that may represent a key facet to the disorder's pathogenesis.

Persistent elevations in circulating INS DNA among subjects with longstanding type 1 diabetes

“…However, INS DNA concentrations were not different when compared by sex or race within either control or T1D subject groups, and values for our controls were consistent with previously reported adult control values . Children diagnosed with T1D have consistently been shown to have a more severe disease course than adults, with increased rates of C‐peptide loss postdiagnosis . Because a significant portion of our population were diagnosed as adults, these subjects theoretically could have a larger remaining β cell mass and therefore higher circulating unmethylated INS DNA levels.…”

Beta cell heterogeneity: an evolving concept

“…In contrast to the situation in rodents, human islet composition and function appear to be similar in all regions of the pancreas, although islet density is higher in the tail compared with the head or body [9]. Interestingly, in human type 1 diabetes, the severity of beta cell loss is greater in the tail of the pancreas compared with the head [10], whereas, in type 2 diabetes, beta cell loss is observed mostly in the head of the pancreas [9], suggesting functional differences between islets from different regions of the pancreas.…”

Dynamics of diabetes and obesity: Epidemiological perspective

“…The self-proteins can be subjected to attack not only by autoreactive T cells but also by autoantibodies to GAD, thus the β-cells of the pancreas will be destroyed. Genetics play a large role in causing T1DM and early-onset condition [23, 24]. …”

“…However, it varies and β-cells function may be retained for several years. So T1DM patients ultimately lead their life by taking intramuscular insulin injections for survival [24, 27, 28]. …”

“…The pathology of DM is complex pathogenic process where autoimmune destruction of the β-cells of the pancreas causes insulin deficiency and the attributed abnormalities resulting to insulin resistance (IR) [17–19, 24]. Metabolic derangements that are associated with IR are based on outcome of metabolic function of insulin on carbohydrate, fat, and protein that are being metabolized in living organisms.…”