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(1) Background and aims: Amyloidosis due to aggregation of amyloid-β (Aβ42) is a key pathogenic event in Alzheimer's disease (AD), whereas aggregation of mature islet amyloid polypeptide (IAPP37) in human islets leads to β-cell dysfunction. The aim of this study is to uncover potential biomarkers that might additionally point to therapy for early AD patients. (2) Methods: We used bioinformatic approach to uncover novel IAPP isoforms and developed a quantitative selective reaction monitoring (SRM) proteomic assay to measure their peptide levels in human plasma and CSF from individuals with early AD and controls, as well as postmortem cerebrum of clinical confirmed AD and controls. We used Thioflavin T amyloid reporter assay to measure the IAPP isoform fibrillation propensity and anti-amyloid potential against aggregation of Aβ42 and IAPP37. (3) Results: We uncovered hominid-specific IAPP isoforms: hIAPPβ, which encodes an elongated propeptide, and hIAPPγ, which is processed to mature IAPP25 instead of IAPP37. We found that hIAPPβ was significantly reduced in the plasma of AD patients with the accuracy of 89%. We uncovered that IAPP25 and a GDNF derived DNSP11 were nonaggregating peptides that inhibited the aggregation of IAPP37 and Aβ42. (4) Conclusions: The novel peptides derived from hIAPP isoforms have potential to serve as blood-derived biomarkers for early AD and be developed as peptide based anti-amyloid medicine. [ABSTRACT FROM AUTHOR]

While endocannabinoids (ECs) and cannabis were primarily studied for their nervous system effects, it is now clear that ECs are also produced in the periphery where they regulate several physiological processes, including energy storage, glucose and lipid metabolism, insulin secretion and synthesis, and hepatocyte function. Within islet of Langerhans there is an autonomous EC system (ECS). Beta (β)-cells contain all the enzymes necessary for EC synthesis and degradation; ECs are generated in response to cellular depolarization; their paracrine influence on β-cells is mostly through the cannabinoid 1 receptor (CB1R) that is present on all β-cells; they modulate basal and glucose- and incretin-induced insulin secretion, and β-cell responses to various stressors. Furthermore, there is now accumulating evidence from preclinical studies that the autonomous islet ECS is a key player in obesity-induced inflammation in islets, and β-cell damage and apoptosis from many causes can be mitigated by CB1R blockers. We will thoroughly review the literature relevant to the effects of ECs and their receptors on β-cells and the other cell types within islets. Therapeutic potential of agents targeting EC/CB1R and CB2R is highly relevant because the receptors belong to the druggable G protein-coupled receptor superfamily. Present research in the ECS must be considered preliminary, especially with regards to human islet physiology, and further research is needed in order to translate basic cellular findings into clinical practice and the use of safe, clinically approved CBR modulators with and without glucose lowering combinations presently in therapeutic use for diabetes and obesity needs to be studied. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are involved in intercellular communication and are a topic of increasing interest due to their therapeutic potential. The aim of this study was to determine whether human islet-derived EVs contain insulin, and if so, what role do they play in glucose stimulated insulin secretion. We isolated EVs from human islets culture and plasma to probe for insulin. Plasma from hyperglycemic glucose clamp experiments were also used to isolate and measure EV insulin content in response to a secretory stimulus. We performed immunogold electron microscopy for insulin presence in EVs. Co-culture experiments of isolated EVs with fresh islets were performed to examine the effect of EV cargo on insulin receptor signaling. EVs isolated from culture medium contained insulin. Glucose treatment of islets increased the level of EV insulin. Hyperglycemic glucose clamp experiments in humans also lead to increased levels of insulin in plasma-derived EVs. Immunogold electron microscopy and proteinase K-digestion experiments demonstrated that insulin in EVs predominantly associated with the exterior surface of EVs while western blot analyses uncovered the presence of only preproinsulin in EVs. Membrane-bound preproinsulin in EVs was capable of activating insulin signaling pathway in an insulin receptor-dependent manner. The physiological relevance of this finding was observed in priming of human naïve islets by EVs during glucose stimulated insulin secretion. Our data suggest that (1) human islets secret insulin via an alternate pathway (EV-mediated) other than conventional granule-mediated insulin secretion, and (2) EV membrane bound preproinsulin is biologically active. [ABSTRACT FROM AUTHOR]