Development of Type 1 Diabetes may occur through a Type 2 Diabetes mechanism

Abstract

BackgroundAt diagnosis of Type 1 Diabetes (T1D), 30% of the beta cells are dormant, i.e. alive, but inactive. This could reduce beta cell destruction, as cellular stress contributes to beta cell damage. However, the beta cells, that are still active, must produce more insulin and are therefore more vulnerable. The inactive beta cells represent a potential for restoring the insulin secretion.MethodsWe analyzed the expression of selected genes in islets from live, newly diagnosed T1D patients from the DiViD study and organ doners with longer duration of T1D, type 2 diabetes (T2D), or no diabetes from the nPOD study. Additionally, analysis of polymorphisms was performed on all the investigated genes.FindingsVarious possibilities were considered for the inactivity of the beta cells: secretion defect, fetal state, hibernation, and insulin resistance. We analyzed genes related to the ceramide and sphingomyelin synthesis and degradation, secretion, circadian rhythm and insulin action, and found changes in T1D islets that resemble fetal dedifferentiation and asynchrony. Furthermore, we found low levels of insulin receptor mRNA in the islets. No polymorphisms were found.InterpretationOur findings suggest a secretion defect, but also fetal dedifferentiation and desynchronization in the inactive beta cells. Together with previous evidence, that predisposing factors for T2D are also present for T1D development, we raise the idea to treat individuals with ongoing T1D development prophylactically with T2D medicine like GLP-1 receptor agonists, metformin, or others, combined with anti-inflammatory compounds, in order to reactivate the dormant beta cells, and to prevent autoimmune destruction. T2D mechanisms during T1D development should be investigated further.

Influence of sphingolipid enzymes on blood glucose levels, development of diabetes, and involvement of pericytes

“…At the time of T1D diagnosis, roughly one‐third of the beta cells have been destroyed, one‐third are infiltrated by immune cells, mainly lymphocytes, and one‐third are ‘sleeping’; these appear microscopically normal but produce no insulin and are not infiltrated 14 . We have found among newly diagnosed T1D patients, that the insulin receptors were 53.4% of the value for the control persons ( p = 0.00003) 11 . In contrast to the study of Kahn, 10 a recent study using living animals showed that lack of insulin receptors on the beta cells increased the insulin production and secretion 32 …”

“…14 We have found among newly diagnosed T1D patients, that the insulin receptors were 53.4% of the value for the control persons (p = 0.00003). 11 In contrast to the study of Kahn, 10 a recent study using living animals showed that lack of insulin receptors on the beta cells increased the insulin production and secretion. 32 The beta-cell mass adapts to a lower activity level, for example, after a pregnancy or other situations, when the insulin need is reduced.…”

“…The reason for the inactivity of the beta-cells could partly be due to the low number of insulin receptors, which indeed is the case. 10,11 Also, the incretin hormones GLP-1 and GIP are important for the insulin secretion, and their receptors at the beta cells are studied here.…”

Importance of C24:2 sulfatide

“…In humans, it has been discussed that certain cells can enter a hibernation-like state during an extreme rest. This might be seen in beta cells in newly diagnosed type 1 diabetes patients [11]. This suggests the potential importance of C24:2 sulfatide in certain tissues.…”

Insulitis in human type 1 diabetes: lessons from an enigmatic lesion

“… 37 Thus, in these older children, type 1 diabetes is manifested symptomatically when significant numbers of β-cells are still present and the extent of insulitis is modest. In this situation, it is feasible that a defect in insulin secretion may contribute significantly to the reduction in circulating insulin concentrations 42 rather than this being caused solely by the annihilation of β-cells, as in younger children. This does not mean that β-cell demise is not a feature of older onset type 1 diabetes because these cells are undoubtedly lost (especially with increasing disease duration).…”