An obesity-driven type 2 diabetes (T2D) epidemic is ongoing with an estimated 600 million patients affected by 2035. T2D induces significant morbidity and mortality through the development of micro- and macrovascular complications and is projected to be one of the leading causes of death in 2030, making the need for better treatment essential. Failure of pancreatic beta cells is the cause for development and progression of the disease. Thus, therapeutic aims to reverse or stabilize beta-cell function in T2D are critical to slow the course of this devastating disease.
The cause for beta-cell loss is unknown but seems related to a chronic inflammatory process driven by cytokines, macrophages and the innate immune system. The triggers involved in this process, however, are incompletely understood. However, in order to specifically target beta-cell inflammation, the processes that initiate and drive the influx of these immune cells into pancreatic beta cells need to be unraveled.
Recent research indicates that intestinal microbiota composition is associated with development of T2D in large epidemiological studies. Notably, bacterial-derived endotoxins, in particular lipopolysaccharides (LPS) derived from intestinal Gram-negative bacteria, show a transient rise following a meal that is limited in lean control subjects but pronounced in metabolically impaired individuals. The prevailing hypothesis is that high energy/fat intake leads to gut microbiota dysbiosis and alterations in circulating bacteria and endotoxins through leakage. Thus, direct exposure of beta cells to Gram-negative bacteria as well as their toxins might trigger beta-cell inflammation in T2D.
A critical receptor in this respect may be the Toll-like receptor (TLR), predominantly subtype 4 (TLR4). As such, LPS binds to TLR-4, which is expressed on many tissues including the beta cell. Many studies have linked exposure to LPS to impaired glucose and lipid metabolism through TLR4-related mechanisms. Specifically, for beta cells, infusion of LPS in mice was recently shown to impair glucose-stimulated insulin secretion (GSIS) and insulin production through TLR-4 related pathways. In addition, in TLR4-/- mice, both LPS and a high-fat diet were unable to elicit an inflammatory response in pancreatic islets. In particular, macrophage infiltration was absent as well as production of IL-1β. Moreover, the detrimental effects of inflammation on insulin production and secretion were also mitigated.
Taken together, these data suggest that altered intestinal microbiota, likely secondary to the consumption of a high-fat diet, and enhanced translocation of bacteria and their toxins could serve as an important trigger of TLR-4 mediated low-grade inflammation in the pancreas resulting in beta-cell dysfunction. Thus modulation of microbiota composition/translocation could potentially halt the decline in beta-cell function characterized of type 2 diabetes mellitus.
Overview of the action:
1. To determine whether increased translocation of (Gram-negative) bacteria and concomitant TLR4 upregulation occurs in the pancreas of humans with T2D patients, and to identify the specific microorganisms involved.
2a. To determine the effect of the identified, most abundant pathogenic bacteria (from Objective 1) on glucose metabolism, beta-cell function and inflammation, by introducing the cultured microorganisms to mice.
2b. To determine the role of TLR4 in glucose dysregulation, beta-cell dysfunction and inflammation, induced by the most abundant pathogenic bacteria (from Objective 1) in mice.
