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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Islet amyloid peptide (IAPP) or amylin is a recently discovered polypeptide without settled physiology in man. We present a patient with an endocrine pancreatic tumor secreting huge amounts of IAPP-like immunoreactivity (20,000 mol/l) and a concomitant development of diabetes mellitus. The release of insulin and pancreatic polypeptide (PP) was totally absent after an oral glucose load and a mixed meal, respectively. Tumor secretion of IAPP-like immunoreactivity seemed to be influenced by cholinergic mechanisms and by nutrients. The observed effects on insulin and PP secretion by high circulating levels of IAPP-like immunoreactivity may be of beneficial value for further studies of the physiology of IAPP in man.
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PMID:Islet amyloid polypeptide-producing pancreatic islet cell tumor. A clinical and biochemical characterization. 132 85

Islet amyloid may have a pathological role in the development of Type 2 (non-insulin-dependent) diabetes mellitus. The prevalence of islet amyloid has been investigated on post-mortem pancreatic tissue from both diabetic and non-diabetic Pima Indian subjects who had previously been assessed by oral glucose tolerance tests. Islets were examined for amyloid deposits and for cellular immunoreactivity to pancreatic hormones and islet amyloid polypeptide, the constituent peptide of islet amyloid. Twenty of 26 diabetic subjects (77%) had islet amyloid, compared with one of 14 non-diabetic subjects (7%). Twelve of the diabetic subjects (46%) had amyloid in more than 10% of their islets, whereas only 4% of islets were affected in a single non-diabetic subject. Positive immunoreactivity for islet amyloid peptide was present in the islet amyloid and in islet cells in 54% of the diabetic and 50% of the non-diabetic subjects. Islet amyloid in diabetic Pima Indians may indicate a primary Beta-cell defect which interacts with insulin resistance to produce diabetes, or may develop as a result of Beta-cell dysfunction induced by insulin resistance and hyperglycaemia.
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PMID:Islet amyloid polypeptide in diabetic and non-diabetic Pima Indians. 219 87

Islet amyloid peptide (or diabetes-associated peptide), the major component of pancreatic islet amyloid found in type-2 diabetes, has been identified by electron-microscopic immunocytochemistry in pancreatic B-cells from five non-diabetic human subjects, and in islets from five type-2 diabetic patients. The greatest density of immunoreactivity for islet amyloid peptide was found in electron-dense regions of some lysosomal or lipofuscin bodies. The peptide was also localised by quantification of immunogold in the secretory granules of B-cells, and was present in cytoplasmic lamellar bodies. Acid phosphatase activity was also demonstrated in these organelles. Immunoreactivity for insulin was found in some lysosomes. These results suggest that islet amyloid peptide is a constituent of normal pancreatic B-cells, and accumulates in lipofuscin bodies where it is presumably partially degraded. In islets from type-2 diabetic subjects, amyloid fibrils and lipofuscin bodies in B-cells showed immunoreactivity for the amyloid peptide. Abnormal processing of the peptide within B-cells could lead to the formation of islet amyloid in type-2 diabetes.
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PMID:Localisation of islet amyloid peptide in lipofuscin bodies and secretory granules of human B-cells and in islets of type-2 diabetic subjects. 254 70

Amyloid deposits occurring in the islets of Langerhans in patients with noninsulin-dependent diabetes mellitus and some insulinomas contain a 37-amino acid peptide that is structurally related to calcitonin gene-related peptide. We have identified three cDNA clones encoding islet amyloid polypeptide (IAPP) or diabetes-associated peptide (DAP) by oligonucleotide screening of a lambda gt10 human insulinoma cDNA library. Two of the three cDNAs contained a domain encoding IAPP/DAP but had an intron-like sequence in their 5' region. The other cDNA contained an open reading frame encoding an 89-amino acid precursor having a typical signal peptide followed by a small prohormone-like sequence containing within it the IAPP/DAP peptide bracketed at its NH2 and COOH termini by Lys-Arg and Gly-Lys-Arg, respectively. These data indicate that this amyloid peptide is generated by proteolytic processing similar to that for proinsulin and other islet prohormones and also that the peptide may be carboxyamidated. The isolation of cDNA clones having 5'-unprocessed intron-like sequences suggests that inefficient or alternative splicing of this mRNA occurred in the insulinoma.
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PMID:An islet amyloid peptide is derived from an 89-amino acid precursor by proteolytic processing. 305 5

We investigated the association of amyloid beta-protein precursor (APP) and platelet derived microparticles in 20 normal controls and 91 patients with various diseases causing a thrombotic tendency. Compared with the controls, the mean percentage of APP-positive microparticles was significantly greater in the patients with cerebral infarction (39.1 +/- 17.7%, p < 0.001), diabetes (31.1 +/- 12.6%, p < 0.001), and uremia (30.1 +/- 14.7%, p < 0.01), but not in those with hypertension (8.2 +/- 6.3%, p = NS). Sixteen patients with cerebral infarction, 20 with diabetes, and 11 with uremia had microparticles with very high APP levels. In normal controls, 7.2 +/- 3.7% of the microparticles were positive for P-selectin, while the percentage in cerebral infarction, diabetes, uremia, and hypertension was respectively 43.5 +/- 15.1%, 40.0 +/- 12.8%, 31.8 +/- 12.2%, and 11.6 +/- 7.3%. There was a significant correlation between P-selectin and APP positivity of microparticles. Our results suggest that microparticle APP may have a regulatory influence on coagulation abnormalities.
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PMID:Amyloid beta-protein precursor-rich platelet microparticles in thrombotic disease. 753 36

beta-Amyloid (beta A) is normally produced as a nontoxic soluble peptide. In Alzheimer disease, beta A aggregates and accumulates in the brain as inert diffuse plaques or compact plaques associated with neurodegenerative changes. To determine the relationship of neurotoxicity to the physical state of beta A, we created (i) nonamyloidogenic amorphous aggregates of beta A [amorphous beta A (Am-beta A)] analogous to diffuse plaques and (ii) amyloidogenic fibrils of beta A [fibrillar beta A (Fib-beta A)] analogous to compact plaques. In primary rat hippocampal culture, Fib-beta A was neurotoxic, whereas Am-beta A was not toxic. Fib-beta A caused significant loss of synapses in viable neurons, while Am-beta A had no effect on synapse number. The amyloid fibril-binding dye Congo red inhibited Fib-beta A neurotoxicity by inhibiting fibril formation or by binding to preformed fibrils. Congo red also inhibited the pancreatic islet cell toxicity of diabetes-associated amylin, another type of amyloid fibril. These results indicate that beta A neurotoxicity requires fibril formation. These findings and our previous demonstration that amylin fibrils are toxic suggest that a common cytopathic effect of amyloid fibrils may contribute to the pathogenesis of Alzheimer disease and other amyloidoses.
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PMID:Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. 799 13

The 37-amino-acid polypeptide amylin is the principal constituent of the amyloid deposits that form in the islets of Langerhans in patients with type-2 diabetes mellitus, but its role in the pathogenesis of this disease is unresolved. In view of the fact that the beta-amyloid protein that forms fibrils in Alzheimer's disease is toxic to neurons, we have investigated whether amylin fibrils could be toxic to pancreatic islet cells. We show here that human amylin is toxic to insulin-producing beta-cells of the adult pancreas of rats and humans. This toxicity is mediated by the fibrillar form of the amylin peptide and requires direct contact of the fibrils with the cell surface. The mechanism of cell death involves RNA and protein synthesis and is characterized by plasma membrane blebbing, chromatin condensation and DNA fragmentation, indicating that amylin induces islet cell apoptosis. These findings indicate that amylin fibril formation in the pancreas may cause islet cell dysfunction and death in type-2 diabetes mellitus.
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PMID:Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus. 815 88

Alzheimer disease is characterized by the presence of beta-amyloid protein deposits, neurofibrillary tangles and cholinergic dysfunction throughout the hippocampal region. In addition, the hippocampus, hypothalamus and olfactory bulb--the three areas where the insulin receptors are most dense--are also subject to neurodegeneration. The exact cause of the beta-amyloid deposits and NFTs is unknown. However, it is our intention to explicate the various pathogenic pathways through which Alzheimer disease arises. Fundamentally, the structural and metabolic damage found in Alzheimer disease is due to sustained elevation of interleukin-1 beta, a feature which is also found in insulin-dependent diabetes mellitus. Similarly, the beta-AP deposits found in the Alzheimer brain share the same molecular structure as the amylin deposits found in the pancreatic beta-cells in non-insulin-dependent diabetes mellitus (NIDDM), and are equally neurotoxic. These, and other pathophysiological parallels, afford some insight into the probably cause of Alzheimer disease and, as such, forms the basis of the causal hypothesis advanced in this paper.
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PMID:Interleukin-1 beta: a common cause of Alzheimer's disease and diabetes mellitus. 877 Oct 51

The requirements for amyloidogenesis, as it is currently understood, include an adequate amyloid precursor pool, a nidus for fibrillogenesis, interactions with a set of common components (most of which are involved in basement membrane structure) and amyloid turnover. These factors serve as the basis for therapeutic attack. General strategies focusing on each of these factors are presented with examples from the experimental and clinical literature. These include reducing the amyloid precursor protein pool in familial amyloid polyneuropathy by liver transplantation, inhibiting nidus formation in familial Mediterranean fever by the use of colchicine, inhibiting amyloid precursor protein/heparan sulphate interaction in experimental inflammation-associated amyloidosis by the use of novel small molecule anionic sulphates and sulphonates, and the use of new analogues of doxorubicin in light chain amyloidosis to accelerate amyloid removal. The potential significance of local and systemic amyloid deposits is discussed in the light of new information on the genetics of Alzheimer's disease, observations made in patients receiving long term dialysis for renal failure, and the potential involvement of amyloid deposits in the pathogenesis of non-insulin-dependent diabetes mellitus.
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PMID:Anti-amyloid drugs: potential in the treatment of diseases associated with aging. 884 88

For more than a century amyloid was considered to be an interesting, unique, but inconsequential pathologic entity that rarely caused significant clinical problems. We now recognize that amyloid is not one entity. In vivo it is a uniform organization of a disease, or process, specific protein co-deposited with a set of common structural components. Amyloid has been implicated in the pathogenesis of diseases affecting millions of patients. These range from Alzheimer's disease, adult-onset diabetes, consequences of prolonged renal dialysis, to the historically recognized systemic forms associated with inflammation and plasma cell disturbances. Strong evidence is emerging that even when deposited in local organ sites significant physiologic effects may ensue. With emphasis on A beta amyloid, we review the present definition, classification, and general in vivo pathogenetic events believed to be involved in the deposition of amyloids. This encompasses the need for an adequate amyloid precursor protein pool, whether precursor proteolysis is required prior to deposition, amyloidogenic amino acid sequences, fibrillogenic nucleating particles, and an in vivo microenvironment conducive to fibrillogenesis. The latter includes several components that seem to be part of all amyloids. The role these common components may play in amyloid accumulation, why amyloids tend to be associated with basement membranes, and how one may use these findings for anti-amyloid therapeutic strategies is also examined.
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PMID:A beta amyloidogenesis: unique, or variation on a systemic theme? 938 10


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