Amyloid deposits localized to the islets of Langerhans are typical of non-insulin-dependent human diabetes mellitus and of diabetes mellitus in adult cats. Amyloid deposits also commonly occur in insulin-producing pancreatic tumors. We have purified a major protein-insulinoma or islet amyloid polypeptide (IAPP)-from human and cat islet amyloid and from amyloid of a human insulinoma. IAPP from human insulinoma contained 37 amino acid residues and had a theoretical molecular mass of 3850 Da. The amino acid sequence is unique but has >40% identity with the human calcitonin gelie-related peptide. A partial amino acid sequence of cat islet IAPP corresponding to positions 1-27 of human insulinoma IAPP was identical to the human IAPP except for substitutions in three positions. An antiserum raised to a synthetic human insulinoma IAPP-(7-17) undecapeptide showed specific immunohistochemical reactivity with human and cat islet amyloid and with islet B cells.

SUMMARY Sensory neurons adopt distinct morphologies and functional modalities to mediate responses to specific stimuli. Transcription factors and their downstream effectors orchestrate this outcome but are incompletely defined. Here, we show that different classes of mechanosensory neurons in C. elegans are distinguished by the combined action of the transcription factors MEC-3, AHR-1, and ZAG-1. Low levels of MEC-3 specify the elaborate branching pattern of PVD nociceptors, whereas high MEC-3 is correlated with the simple morphology of AVM and PVM touch neurons. AHR-1 specifies AVM touch neuron fate by elevating MEC-3 while simultaneously blocking expression of nociceptive genes such as the MEC-3 target, the claudin-like membrane protein HPO-30, that promotes the complex dendritic branching pattern of PVD. ZAG-1 exercises a parallel role to prevent PVM from adopting the PVD fate. The conserved dendritic branching function of the Drosophila AHR-1 homolog, Spineless, argues for similar pathways in mammals.

This review highlights current tissue engineering and novel therapeutic approaches to axonal regeneration following spinal cord injury. The concept of developing 3-dimensional polymer scaffolds for placement into a spinal cord transection model has recently been more extensively explored as a solution for restoring neurologic function after injury. Given the patient morbidity associated with respiratory compromise, the discrete tracts in the spinal cord conveying innervation for breathing represent an important and achievable therapeutic target. The aim is to derive new neuronal tissue from the surrounding, healthy cord that will be guided by the polymer implant through the injured area to make functional reconnections. A variety of naturally derived and synthetic biomaterial polymers have been developed for placement in the injured spinal cord. Axonal growth is supported by inherent properties of the selected polymer, the architecture of the scaffold, permissive microstructures such as pores, grooves or polymer fibres, and surface modifications to provide improved adherence and growth directionality. Structural support of axonal regeneration is combined with integrated polymeric and cellular delivery systems for therapeutic drugs and for neurotrophic molecules to regionalize growth of specific nerve populations.

The islet in type 2 diabetes mellitus (T2DM) is characterized by a deficit in ␤ cells and islet amyloid derived from islet amyloid polypeptide (IAPP), a protein coexpressed with insulin by ␤ cells. It is increasingly appreciated that the toxic form of amyloidogenic proteins is not amyloid but smaller membrane-permeant oligomers. Using an antibody specific for toxic oligomers and cryo-immunogold labeling in human IAPP transgenic mice, human insulinoma and pancreas from humans with and without T2DM, we sought to establish the abundance and sites of formation of IAPP toxic oligomers. We conclude that IAPP toxic oligomers are formed intracellularly within the secretory pathway in T2DM. Most striking , IAPP toxic oligomers appear to disrupt membranes of the secretory pathway , and then when adjacent to mitochondria , disrupt mitochondrial membranes. Toxic oligomer-induced secretory pathway and mitochondrial membrane disruption is a novel mechanism to account for cellular dysfunction and apoptosis in T2DM. Type 2 diabetes (T2DM) is characterized by a progressive deficit in ␤ cell function and mass with increased ␤ cell apoptosis.1,2 In common with several neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, the loss of ␤ cells in T2DM is associated with accumulation of locally expressed misfolded proteins that share a propensity to form amyloid.3 Islet amyloid in T2DM is composed primarily of a 37-amino acid protein, islet amyloid polypeptide (IAPP).3 IAPP is co-expressed and secreted with insulin by pancreatic ␤ cells, and is thought to play a paracrine inhibitory role in regulation of insulin secretion. 4,5 The property of IAPP to form amyloid fibrils depends on IAPP 20-29 . This sequence is closely homologous in humans, nonhuman primates and cats, 6 all of which spontaneously develop T2DM characterized by a deficit in ␤ cell mass and islet amyloid. In contrast, rodent IAPP (mouse and rat) does not have the propensity to form amyloid fibrils due to proline substitutions in IAPP 20-29 and wild-type mice and rats do not spontaneously develop T2DM.There is accumulating evidence that the toxic form of amyloidogenic protein aggregates is distinct from amyloid fibrils. The latter tend to accumulate extracellularly where they are relatively inert.3,7 Abnormal non-fibrillar intracellular IAPP aggregates were noted in human insulinoma tissue adjacent to disrupted intracellular membranes.

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