Diabetes is not a single and homogeneous disease, but a cluster of metabolic diseases characterized by the common feature of hyperglycemia. The pathogenesis of type 1 diabetes (T1D) and type 2 diabetes (T2D) (and all other intermediate forms of diabetes) involves the immune system, in terms of inflammation and autoimmunity. The past decades have seen an increase in all types of diabetes, accompanied by changes in eating habits and consequently a structural evolution of gut microbiota. It is likely that all these events could be related and that gut microbiota alterations might be involved in the immunomodulation of diabetes. Thus, gut microbiota seems to have a direct, even causative role in mediating connections between the environment, food intake, and chronic disease. As many conditions that increase the risk of diabetes modulate gut microbiota composition, it is likely that immune-mediated reactions, induced by alterations in the composition of the microbiota, can act as facilitators for the onset of diabetes in predisposed subjects. In this review, we summarize recent evidence in the field of gut microbiota and the role of the latter in modulating the immune reactions involved in the pathogenesis of diabetes.
Aims/hypothesis
Endoplasmic reticulum (ER) stress and beta cell dedifferentiation both play leading roles in impaired insulin secretion in overt type 2 diabetes. Whether and how these factors are related in the natural history of the disease remains, however, unclear.
Methods
In this study, we analysed pancreas biopsies from a cohort of metabolically characterised living donors to identify defects in in situ insulin synthesis and intra-islet expression of ER stress and beta cell phenotype markers.
Results
We provide evidence that in situ altered insulin processing is closely connected to in vivo worsening of beta cell function. Further, activation of ER stress genes reflects the alteration of insulin processing in situ. Using a combination of 17 different markers, we characterised individual pancreatic islets from normal glucose tolerant, impaired glucose tolerant and type 2 diabetic participants and reconstructed disease progression.
Conclusions/interpretation
Our study suggests that increased beta cell workload is accompanied by a progressive increase in ER stress with defects in insulin synthesis and loss of beta cell identity.
Graphical abstract
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