As most cellular processes are regulated by multi-protein complexes, abolishing or enhancing a protein-protein interaction may have a profound impact and possibly manifests in distinct disease
s. Since protein-protein interactions are critical events for a wide range of physiological and pathological processes, the precise control of these interactions and their biological consequences present a major challenge and opportunity for modern drug design[
8]. Hyperphosphorylation and glycosylation might induce impairment of the protein interaction machinery. As protein expression deficiencies of SNARE members have been demonstrated in the brain at the Lewy body variant of AD patients[
9], there might exist forms of T2DM in which pancreatic β-cells undergo similar expression deficiencies, but this is still a matter of investigation.
In contrast to neuronal transmitters, insulin does not undergo a reuptake into β-cells. The premature insulin granules[
10] have to be transported to the cell periphery along microtubules
via an energy-consuming process using kinesin[
11]. In this respect, microtubular dynamics as well as microtubule-associated protein tau (MAPT), also named tau, play an important role. Abnormalities in tau protein structure such as tangles and hyperphosphorylated tau aggregates were identified in the brains of AD patients[
12,
13] about 30 years ago. This has led to the technical term tauopathy and has been defined as detergent insoluble tau aggregates forming tangels and neuritic plaques[
14]. Very recently, hyperphosphorylated tau, representing a factor responsible for the inhibition of microtubule assembly and microtubule disruption[
15], has been identified in pancreatic islets of Langerhans of T2DM patients[
16]. In contrast, this was not found in pancreatic islets of healthy individuals. Such data have been confirmed by in vitro studies using insulinoma tissue and cell lines from rodents[
17]. At least six individual tau isoforms have been identified in these rodent β-cell lines, of which two are of higher molecular weight than the brain derived isoforms. Insoluble aggregates were isolated and demonstrated. Most interestingly, a slight but not significant up-regulation of tau[
18] expression could be defined at the gene level using expression screens when comparing normal age matched donor islets with pancreatic islets from T2DM patients.
Although tau has become an important molecule in defining AD pathology, it is not solely responsible for disease development[
19]. In the brain, extracellular beta amyloid deposits are the second main hallmark of AD pathology. Interestingly, a homologous protein[
20] named islet amyloid polypeptide (IAPP)[
21] is present in beta cells, which is intriguing in this respect. It is co-expressed and secreted with insulin by pancreatic beta cells[
22,
23]. The IAPP has a propensity to misfold and aggregate into cytotoxic oligomers, which result in islet amyloid deposits found in T2DM patients[
24]. Oligomers of human IAPP are known to cause membrane disruption[
25], and are therefore involved in the mediation of β-cell apoptosis in T2DM. Interestingly, the single amino acid mutation (proline substitution) in rodent IAPP hinders the formation of IAPP deposits[
22], and rodents do not spontaneously develop diabetes characterized by islet amyloid deposits[
26]. This, in turn, has led to the development of transgenic rats expressing the human variant of IAPP[
27]. The transgenic rat model indeed resembles the T2DM of humans closely, and provides proof that this molecule is involved in derangement of β-cell function. It is of note that, using these models, it has been shown that the toxic effect of human IAPP on β-cell apoptosis is initiated by a threshold-dependent effect[
26].
CELLS