Vesiculin derived from IGF-II drives increased islet cell mass in a mouse model of pre-diabetes.

Pancreatic islet-cell function and volume are both key determinants of the maintenance of metabolic health. Insulin resistance and islet-cell dysfunction often occur in the earlier stages of type 2 diabetes (T2D) progression. The ability of the islet cells to respond to insulin resistance by increasing hormone output accompanied by increased islet-cell volume is key to maintaining blood glucose control and preventing further disease progression.

Glucoregulatory activity of vesiculin in insulin sensitive and resistant mice.

Pancreatic islet-derived peptide hormones play key roles in the maintenance of systemic energy homeostasis and glucose balance and defects in their regulation are strongly implicated in the pathogenesis of obesity and diabetes. Peptides have also been used as lead compounds for therapeutics targeting metabolic disease. It is therefore important to understand the activity and function of islet hormones in both their target tissues and the whole organism.

Quantitative data describing the impact of the flavonol rutin on in-vivo blood-glucose and fluid-intake profiles, and survival of human-amylin transgenic mice.

Here we provide data describing the time-course of blood-glucose and fluid-intake profiles of diabetic hemizygous human-amylin (hA) transgenic mice orally treated with rutin, and matched control mice treated with water. We employed "parametric change-point regression analysis" for investigation of differences in time-course profiles between the control and rutin-treatment groups to extract, for each animal, baseline levels of blood glucose and fluid-intake, the change-point time at which blood glucose (diabetes-onset) and fluid-intake (polydipsia-onset) accelerated away from baseline, and the rate of this acceleration. The parametric change-point regression approach applied here allowed a much more accurate determination of the exact time of onset of diabetes than do the standard diagnostic criteria.

Rutin suppresses human-amylin/hIAPP misfolding and oligomer formation in-vitro, and ameliorates diabetes and its impacts in human-amylin/hIAPP transgenic mice.

Pancreatic islet β-cells secrete the hormones insulin and amylin, and defective β-cell function plays a central role in the pathogenesis of type-2 diabetes (T2D). Human amylin (hA, also termed hIAPP) misfolds and forms amyloid aggregates whereas orthologous mouse amylin does neither. Furthermore, hA elicits apoptosis in cultured β-cells and β-cell death in ex-vivo islets.

Monodisperse 130 kDa and 260 kDa Recombinant Human Hemoglobin Polymers as Scaffolds for Protein Engineering of Hemoglobin-Based Oxygen Carriers.

A recombinant 130 kDa dihemoglobin which is made up of a single-chain tetra-α globin and four β globins has been expressed as a soluble protein in E. coli. The sequence of the single chain tetra-α is: αI-Gly-αII-(SerGlyGly)5Ser-αIII-Gly-αIV.

The chaperone proteins HSP70, HSP40/DnaJ and GRP78/BiP suppress misfolding and formation of β-sheet-containing aggregates by human amylin: a potential role for defective chaperone biology in Type 2 diabetes.

Misfolding of the islet β-cell peptide hA (human amylin) into β-sheet-containing oligomers is linked to β-cell apoptosis and the pathogenesis of T2DM (Type 2 diabetes mellitus). In the present study, we have investigated the possible effects on hA misfolding of the chaperones HSP (heat-shock protein) 70, GRP78/BiP (glucose-regulated protein of 78 kDa/immunoglobulin heavy-chain-binding protein) and HSP40/DnaJ. We demonstrate that hA underwent spontaneous time-dependent β-sheet formation and aggregation by thioflavin-T fluorescence in solution, whereas rA (rat amylin) did not.

Tetracycline treatment retards the onset and slows the progression of diabetes in human amylin/islet amyloid polypeptide transgenic mice.

Objective: Aggregation of human amylin/islet amyloid polypeptide (hA/hIAPP) into small soluble beta-sheet-containing oligomers is linked to islet beta-cell degeneration and the pathogenesis of type 2 diabetes. Here, we used tetracycline, which modifies hA/hIAPP oligomerization, to probe mechanisms whereby hA/hIAPP causes diabetes in hemizygous hA/hIAPP-transgenic mice.

Research Design And Methods: We chronically treated hemizygous hA/hIAPP transgenic mice with oral tetracycline to determine its effects on rates of diabetes initiation, progression, and survival.

Novel peptide antagonists of adrenomedullin and calcitonin gene-related peptide receptors: identification, pharmacological characterization, and interactions with position 74 in receptor activity-modifying protein 1/3.

Human adrenomedullin (AM) is a 52-amino acid peptide belonging to the calcitonin peptide family, which also includes calcitonin gene-related peptide (CGRP) and AM2. The two AM receptors, AM(1) and AM(2), are calcitonin receptor-like receptor (CL)/receptor activity-modifying protein (RAMP) (RAMP2 and RAMP3, respectively) heterodimers. CGRP receptors comprise CL/RAMP1.

The aggregation potential of human amylin determines its cytotoxicity towards islet beta-cells.

Human amylin is a small fibrillogenic protein that is the major constituent of pancreatic islet amyloid, which occurs in most subjects with type 2 diabetes. There is evidence that it can elicit in vitro apoptosis in islet beta-cells, but the physical properties that underpin its cytotoxicity have not been clearly elucidated. Here we employed electron microscopy, thioflavin T fluorescence and CD spectroscopy to analyze amylin preparations whose cytotoxic potential was established by live-dead assay in cultured beta-cells.

Thiol reducing compounds prevent human amylin-evoked cytotoxicity.

Human amylin (hA) is a small fibrillogenic protein that is the major constituent of pancreatic islet amyloid, which occurs in most subjects with type-2 diabetes mellitus (T2Dm). There is growing evidence that hA toxicity towards islet beta-cells is responsible for their gradual loss of function in T2Dm. Preventing hA-mediated cytotoxicity has been proposed as a route to halt the progression of this disease, although this has not yet been demonstrated in vivo.

Suppression by polycyclic compounds of the conversion of human amylin into insoluble amyloid.

There is a significant correlation between the occurrence of pancreatic islet amyloid and beta-cell failure in advanced type II diabetes mellitus. Islet amyloid is composed primarily of the fibrillar form of the pancreatic hormone, amylin. Using thioflavin-T fluorescence binding and radioprecipitation assays, we investigated whether or not a series of small tricyclic compounds, tetracycline or Congo Red could interfere with the conversion of synthetic human amylin into its insoluble amyloid form.