Type 2 diabetes and β-cell function

Our main research focus is to unravel molecular mechanisms ensuring β-cell function.

Type 2 diabetes (T2D) compromises ~90% of all diabetics and currently afflicts nearly 400 million individuals and increases globally with an expected increase by ~200 millions within the next 20 years. Although T2D is a polygenetic disorder there is a strong environmental influence from obesity and the current world wide epidemic increase in T2D is unequivocally strongly associated with the escalating global increase in obesity, which in turn is provoked by today’s western life-style with increased calorie intake and reduced physical activity. The development of overt T2D is attributed to two distinct metabolic dysfunctions; insulin resistance and β-cell failure. Although insulin resistance is intimately linked to obesity and generally believed to precede dysglycemia it is not sufficient to provoke overt diabetes as long as compensatory β-cell function is maintained. Various mechanisms, including mitochondrial dysfunction, oxidative and ER stress, as well as gluco- and/or lipotoxicity, have been proposed to underlie the progressive decline in β-cell function and/or survival in the context of obesity and insulin resistance, eventually resulting in development of overt T2D.

β-cell failure: β-cell pathology in T2D is characterized by accumulation of the aggregate prone, amyloidgenic protein Islet Amyloid Polypeptide (IAPP); 90% of all type 2 diabetics have amyloid deposits in at least one islet, and in some type 2 diabetics up to 90% of the islets show evidence of amyloid deposits. Insulin resistance, provoked by obesity and lipid accumulation, exacerbates amyloid formation in β-cells. Nonetheless, the role IAPP amyloid formation, if any, in deterioration of β-cell function is poorly understood and although accumulating data implicate a role(s) for unresolved ER stress, reduced autophagy, increased inflammation, and/or dedifferentiation as a consequence of amyloid formation, IAPP amyloid formation might simply be a mere consequence of, rather than a causal factor in, β-cell deterioration. Part of the reason why the role for IAPP aggregation and amyloid formation in β-cell deterioration is poorly understood is due to the fact that most studies on β-cell function and integrity have been performed using rodent β-cell lines, isolated rodent islets, and/or rodent animal models. In contrast to human IAPP (hIAPP), i.e. the major component of amyloid in T2D β-cells, rodent IAPP homolog does not form toxic oligomers and amyloid, which largely has obviated studies on the mechanistic role of IAPP amyloidogenesis in β-cell degeneration during development of T2D. Consequently, the mechanisms underlying initiation of IAPP aggregation and amyloid formation in β-cells is also not well understood.

We recently showed that mice lacking Insulin-degrading enzyme (Ide), which degrades insulin and a variety of other small, amyloidogenic peptides have increased levels of IAPP, insulin, and α-synuclein in pancreatic islets. Additionally, Ide mutant mice have impaired β-cell function, i.e. impaired glucose-stimulated insulin secretion, reduced β-cell autophagic flux, and decreased β-cell microtubule content. Taken together, our results provide evidence that Ide is a key β-cell gene, and that impaired Ide function leads to perturbed insulin secretion and reduced autophagy as a consequence of impaired neutralization of α -synuclein monomers in β-cells.

One important function of autophagy is removal of aggregated proteins, sometimes referred to as aggrephagy, and attenuation of basal autophagy results in accumulation of toxic protein aggregates that may perturb cell function and integrity. Consequently, perturbed autophagy is associated with reduced turnover of aggregate prone proteins, which in turn leads to intracellular accumulation of aggregate-prone, disease-related proteins that ultimately provokes cell degeneration, as observed in neurodegenerative disorders like Alzheimer’s, Huntington’s, and Parkinson’s disease. Our current working model is that a functional Ide gene may antagonize protein aggregation and amyloid formation via three distinct Ide dependent processes, or most likely combinations thereof. We use a combination of in vivo, ex vivo, and in vitro model systems to elucidate the mechanism(s) by which Ide, and other factors, ensures autophagy and β-cell function.


Page Editor: Lina Sollén

Print page

Helena Edlund

Helena Edlund

Image: Mattias Pettersson

Contact Information

Professor

Umeå Centre for Molecular Medicine (UCMM)
By. 6M 4th floor
Umeå University, S-901 87 Umeå, Sweden
E-mail: helena.edlund@umu.se
Phone: +46 (0)90 785 44 29
Fax: +46-(0)90 785 44 00