Amyloid-related degenerative diseases are associated with the accumulation of misfolded proteins as amyloid fibrils in tissue. In Alzheimer disease (AD), accumulates several distinct types insoluble plaque deposits, intracellular Abeta and soluble oligomers relationships between these deposits their pathological significance remains unclear. Conformation dependent antibodies have been reported that specifically recognize assembly states amyloids, including prefibrillar fibrils.We immunized...

Controversy exists regarding the potential regenerative influences of incretin therapy on pancreatic β-cells versus possible adverse proliferative effects. Examination pancreata from age-matched organ donors with type 2 diabetes mellitus (DM) treated by (n = 8) or other 12) and nondiabetic control subjects 14) reveals an ∼40% increased mass in DM therapy, both exocrine cell proliferation (P < 0.0001) dysplasia (increased intraepithelial neoplasia, P 0.01). Pancreata were notable for α-cell...

Endoplasmic reticulum (ER) stress-induced apoptosis may be a common cause of cell attrition in diseases characterized by misfolding and oligomerisation amyloidogenic proteins. The islet type 2 diabetes is amyloid derived from polypeptide (IAPP) increased beta-cell apoptosis. We questioned the following: 1) whether IAPP-induced mediated ER stress 2) beta-cells are stress.The mechanism was investigated INS-1 cells human IAPP (HIP) transgenic rats. humans C/EBP homologous protein (CHOP)...

OBJECTIVE The aim of this study was to elucidate whether age plays a role in the expansion or regeneration β-cell mass. RESEARCH DESIGN AND METHODS We analyzed capacity 1.5- and 8-month-old mice response high-fat diet, after short-term treatment with glucagon-like peptide 1 (GLP-1) analog exendin-4, streptozotocin (STZ) administration. RESULTS Young responded diet by increasing mass proliferation maintaining normoglycemia. Old mice, contrast, did not display any increases became diabetic. To...

Type 2 diabetes (T2D) is characterized by a deficiency in β cell mass, increased apoptosis, and extracellular accumulation of islet amyloid derived from polypeptide (IAPP), which cells coexpress with insulin. IAPP expression the context insulin resistance, major risk factor for developing T2D. Human potentially toxic, especially as membrane-permeant oligomers, have been observed to accumulate within patients T2D rodents expressing human IAPP. Here, we determined that content regulated...

The islet in type 2 diabetes is characterized by a deficit β-cell mass, increased apoptosis, and impaired insulin secretion. Also, islets often contain deposits of amyloid derived from polypeptide (IAPP), 37–amino acid protein cosecreted with β-cells. Several lines evidence suggest that proteins capacity to develop fibrils may also form small toxic oligomers can initiate apoptosis. amino sequence IAPP rats mice identical differs humans substitution proline residues the amyloidogenic so no...

OBJECTIVE We sought to establish the extent and mechanisms by which sitagliptin metformin singly in combination modify islet disease progression human amyloid polypeptide transgenic (HIP) rats, a model for type 2 diabetes. RESEARCH DESIGN AND METHODS HIP rats were treated with sitagliptin, metformin, plus or no drug as controls 12 weeks. Fasting blood glucose, insulin sensitivity, β-cell mass, function, turnover measured each group. RESULTS Sitagliptin had synergistic effects preserve mass...

OBJECTIVE—Islets in type 2 diabetes are characterized by a deficit β-cells, increased β-cell apoptosis, and islet amyloid derived from polypeptide (IAPP). The toxic form of amyloidogenic protein oligomers distinct smaller than fibrils act disrupting membranes. Using antibodies that bind to IAPP (but not monomers or fibrils) vaccination-based approach, we sought establish whether intra- extracellularly vaccination induce anti-toxic oligomer prevents IAPP-induced apoptosis human (h-IAPP)...

Type 2 diabetes mellitus (T2DM) is characterized by an approximately 60% deficit in beta-cell mass, increased apoptosis, and islet amyloid derived from polypeptide (IAPP). Human IAPP (hIAPP) forms oligomers, leading to either fibrils or toxic oligomers aqueous solution vitro. Either application of hIAPP on overexpression cells induces apoptosis. It remains controversial whether the smaller induce Rifampicin prevents fibril formation has been proposed as a potential target for prevention...

Insulin is secreted as discrete insulin secretory bursts at ~5-min intervals into the hepatic portal vein, these pulses being attenuated early in development of type 1 and 2 diabetes mellitus (T2DM). Intraportal infusions (pulsatile, constant, or reproducing that T2DM) indicated pattern pulsatile secretion delivered via vein important for action and, therefore, presumably signaling. To test this, we examined signaling rat livers exposed to same three patterns delivery by use sequential liver...

The islet in type 2 diabetes (T2DM) is characterized by a deficit β-cells, increased β-cell apoptosis, and extracellular amyloid deposits derived from polypeptide (IAPP). In the absence of longitudinal studies, it unknown if low mass T2DM precedes onset (is risk factor for diabetes) or develops as consequence disease process. Although insulin resistance T2DM, most individuals who are resistant do not develop diabetes. By inference, an workload results some but all individuals. We propose...

The islet in type 2 diabetes is characterized by an approximately 60% beta-cell deficit, increased apoptosis, and amyloid derived from polypeptide (IAPP). Human IAPP (hIAPP) but not rodent (rIAPP) forms toxic oligomers fibrils aqueous environment. We previously reported that overexpression of hIAPP transgenic rats triggered endoplasmic reticulum (ER) stress-induced apoptosis beta-cells. In the present study, we sought to establish whether cytotoxic effects depend on its propensity...

The islet in type 2 diabetes is characterized by β-cell apoptosis, endoplasmic reticulum stress, and amyloid deposits derived from polypeptide (IAPP). Toxic oligomers of IAPP form intracellularly β-cells humans with diabetes, suggesting impaired clearance misfolded proteins. In this study, we investigated whether human-IAPP (h-IAPP) disrupts the reticulum-associated degradation/ubiquitin/proteasome system.We used pancreatic tissue without isolated islets h-IAPP transgenic rats, human islets,...

OBJECTIVE Obesity is a known risk factor for type 2 diabetes. However, most obese individuals do not develop diabetes because they adapt to insulin resistance by increasing β-cell mass and secretion. Islet pathology in characterized loss, islet amyloid derived from polypeptide (IAPP), increased apoptosis endoplasmic reticulum (ER) stress. We hypothesized that IAPP-induced ER stress distinguishes successful versus unsuccessful adaptation resistance. RESEARCH DESIGN AND METHODS To address...

Abstract The islet in type 2 diabetes (T2D) is characterized by amyloid deposits derived from polypeptide (IAPP), a protein co-expressed with insulin β-cells. In common amyloidogenic proteins implicated neurodegeneration, human IAPP (hIAPP) forms membrane permeant toxic oligomers misfolded stress. Here, we establish that hIAPP stress activates HIF1α/PFKFB3 signaling, this increases glycolysis disengaged oxidative phosphorylation mitochondrial fragmentation and perinuclear clustering,...

Background: Type 2 diabetes mellitus (T2DM) is characterized by a deficit in β-cell mass, increased apoptosis, and islet amyloid derived from polypeptide (IAPP). Human IAPP (h-IAPP) applied to β-cells forms toxic oligomers that induce apoptosis. Thiazolidinediones, ligands of peroxisome proliferator-activated receptor-γ (PPAR-γ), can delay the onset T2DM.

The islet in type 2 diabetes (T2DM) and the brain neurodegenerative diseases share progressive cell dysfunction, increased apoptosis, accumulation of locally expressed amyloidogenic proteins (islet amyloid polypeptide (IAPP) T2DM). Excessive activation Ca(2+)-sensitive protease calpain-2 has been implicated as a mediator oligomer-induced death dysfunction diseases. To establish if human IAPP toxicity is mediated by comparable mechanism, we overexpressed rat insulinoma cells freshly isolated...

Vesicular monoamine transporter 2 (VMAT2) is expressed in pancreatic beta cells and has recently been proposed as a target for measurement of cell mass vivo. We questioned, (1) What proportion express VMAT2? (2) Is VMAT2 by other endocrine or non-endocrine cells? (3) the relationship between insulin expression disturbed type 1 (T1DM) diabetes (T2DM)? Human pancreas (7 non-diabetics, 5 T2DM, 10 T1DM) was immunostained insulin, hormones. Most VMAT2. not changed presence diabetes. In tail...

Type 2 diabetes involves aberrant misfolding of human islet amyloid polypeptide (h-IAPP) and resultant pancreatic deposits. Curcumin, a biphenolic small molecule, has offered potential benefits in other protein diseases, such as Alzheimer's disease. Our aim was to investigate whether curcumin alters h-IAPP protects from cellular toxicity at physiologically relevant concentrations. The effect on vitro investigated by electron paramagnetic resonance spectroscopy, ThT fluorescence microscopy....

The islet in type 2 diabetes mellitus (T2DM) is characterized by a deficit β-cells and increased β-cell apoptosis attributable at least part to intracellular toxic oligomers of IAPP (islet amyloid polypeptide). individuals with T2DM are also accumulation polyubiquitinated proteins deficiency the deubiquitinating enzyme UCHL1 (ubiquitin carboxyl-terminal esterase L1 [ubiquitin thiolesterase]), accounting for dysfunctional ubiquitin/proteasome system. In present study, we used mouse genetics...

Abstract Type 2 diabetes is characterized by β and α cell dysfunction. We used phasor-FLIM (Fluorescence Lifetime Imaging Microscopy) to monitor oxidative phosphorylation glycolysis in living islet cells before after glucose stimulation. In healthy cells, enhanced suppressed cells. diabetes, increased only partially FLIM uncovers key perturbations induced metabolism provides a sensitive tool for drug discovery diabetes.