Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is suggestive evidence that amylin acts physiologically in an autocrine manner within the islet to restrain insulin secretion, but conversely there is little indication that this action of amylin plays any role in the development of NIDDM. Deposition of amylin within pancreatic islets is a feature in patients with NIDDM but is of sufficient degree to disrupt beta-cell function in only a small minority of individuals. Current evidence suggests that amylin does not have any physiologically important extra-islet metabolic effects. The potential exists for the development of amylin antagonists as pharmacological agents to enhance insulin secretion in NIDDM but antagonism of systematic CGRP would need to be avoided. There is little, if any, indication that either replacement of amylin or treatment with amylin agonists are likely to have any beneficial role in patients with IDDM.
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PMID:Islet amyloid polypeptide: does it play a pathophysiological role in the development of diabetes? 770 17

Islet amyloid polypeptide (IAPP) is the main proteinaceous component of pancreatic islet amyloid, which is a characteristic feature of type 2 diabetes. The factors responsible for amyloid deposition are unclear. Patients with end-stage renal failure (ESRF) on dialysis treatment have increased insulin resistance which is associated with hypersecretion of beta-cell products. Furthermore, elevated concentrations of circulating IAPP are found in these patients due to reduced renal clearance of IAPP. To determine the prevalence of islet amyloid in this group of patients, pancreas was examined from 23 non-diabetic [aged 62 (29-79) years, median and range] and four type 2 diabetic [aged 67 (56-72) years] patients with ESRF on dialysis treatment. Pancreatic specimens from 30 non-diabetic control subjects [aged 67.5 (56-86) years] and 14 type 2 diabetic subjects without renal disease [aged 69 (48-86) years] were used as control groups. Islet amyloid was present in all type 2 diabetic patients with ESRF and in 12 out of 14 type 2 diabetic control subjects (86 per cent). Amyloid deposits were found in 8 out of 23 non-diabetic patients with ESRF (35 per cent), which was a higher prevalence than that found in non-diabetic control subjects (3 per cent) (P < 0.01). This may be related to undiagnosed (pre)diabetes. Elevated secretion rates of IAPP due to insulin resistance and high circulating IAPP concentrations as a result of severely reduced renal clearance of IAPP will cause high pericellular concentrations of IAPP. This condition is likely to enhance amyloid fibril formation in pancreatic islets similar to that observed in type 2 diabetes.
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PMID:High prevalence of pancreatic islet amyloid in patients with end-stage renal failure on dialysis treatment. 773 22

The most characteristic morphologic features of the pancreatic islets of human non-insulin-dependent diabetes mellitus (NIDDM, or type 2 diabetes mellitus) and of similar forms of diabetes in cats and macaques are the deposition of amyloid (islet amyloid) and the loss of beta cells. Islet amyloid is derived from islet amyloid polypeptide (IAPP), which is a normal secretory product of the beta cells. Therefore, knowledge of the IAPP gene is of potential importance in defining the pathogenesis of NIDDM. To identify the feline chromosome(s) on which the IAPP gene is located, we screened genomic DNA obtained from 38 feline-rodent hybrid cell lines that have a known feline chromosome content. Feline IAPP DNA was amplified and detected using the polymerase chain reaction technique. Discordancy analysis for each feline chromosome showed that chromosome B4 had the lowest discordancy (P < 0.0001). Feline chromosome B4 shows an extensive conserved syntenic relationship with human chromosome 12, on which the human IAPP gene is located. This study therefore extends and confirms the homology between human chromosome 12 and feline chromosome B4 and provides an additional genetic marker for feline chromosome B4.
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PMID:Assignment of islet amyloid polypeptide (IAPP) gene to feline chromosome B4 using the polymerase chain reaction technique on feline-rodent hybrid cell lines. 777 Oct 63

Amylin is a 37 amino-acid peptide mainly produced by the islet beta-cell. Aggregation of amylin is partly responsible for amyloid formation. Amyloid deposits occur both extracellularly and intracellularly and may contribute to beta-cell degeneration. Amylin is packed in beta-cell granules and cosecreted with insulin in response to the same stimuli but, unlike other beta-cell products, it is produced from specific a gene on chromosome 12. Basal, plasma amylin concentrations are around 5 pM, and increase fourfold after meals or glucose. Higher levels are found in cases of insulin resistance, obesity, gestational diabetes and in some patients with NIDDM. Low or absent levels are found in insulin-dependent diabetic patients. There are similarities between amylin and non beta-cell peptides such as calcitonin gene related peptides (CGRP). They may bind to the same receptor, determine similar post-receptor phenomena and qualitatively similar actions but with different degree of potency. The actions of amylin are multiple and mostly exerted in the regulation of fuel metabolism. In muscle, amylin opposes glycogen synthesis, activates glycogenolysis and glycolysis (increasing lactate production). Consequently, amylin increases lactate output by muscle and increases the plasma lactate concentration. In fasting conditions, this lactate may serve as a gluconeogenic substrate for the liver, contributing to replenish depleted glycogen stores and to increase glucose production. In non-fasting conditions, lactate can be transformed by liver in triglycerides. It is not clear at present whether amylin actions on the liver are direct or mediated by changes in circulating metabolites. A probably indirect effect of amylin in muscle is to decrease insulin- (or glucose)-induced glucose uptake, which may contribute to insulin resistance. Other actions include inhibition of glucose-stimulated insulin secretion and, in general, actions mimicking CGRP effects. Some of these actions are seen at supraphysiological concentrations. The physiopathological consequences of amylin deficiency, or excess are under active by investigated.
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PMID:Amylin/islet amyloid polypeptide: biochemistry, physiology, patho-physiology. 778 40

Amyloidosis is a heterogeneous group of disorders characterized by extracellular deposition of abnormal protein fibrils which are derived from different proteins in different forms of the disease. Asymptomatic amyloid deposition in a variety of tissues is a universal accompaniment of ageing, and clinical amyloidosis is not rare. Intracerebral and cerebrovascular beta-protein amyloid deposits are a hallmark of the pathology of both sporadic and familial Alzheimer's disease, beta 2-microglobulin-derived amyloid is a common complication of long term haemodialysis, and islet amyloid polypeptide is the fibril protein in the universal islet amyloidosis of type II diabetes mellitus. New fibril proteins have lately been identified in hereditary amyloidosis, including variants of gelsolin, apolipoprotein AI, lysozyme and fibrinogen. The development of radiolabelled serum amyloid P component (SAP) scintigraphy has allowed amyloid to be diagnosed non-invasively in vivo for the first time, provided unique insight into the distribution and size of amyloid deposits, and yielded novel information on the natural history and the effects of treatment. Amyloid deposits are in a state of dynamic turnover and can regress if new fibril formation is halted. The recent elucidation of the three dimensional structure of human SAP may enable the design of specific therapeutic agents.
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PMID:Amyloidosis. 786 80

Islet amyloid polypeptide ("amylin") is the major protein component of amyloid deposits in pancreatic islets of type 2 (non-insulin-dependent) diabetic patients. Islet amyloid polypeptide consists of 37 amino acids, is co-produced and co-secreted with insulin from islet beta-cells, can act as a hormone in regulation of carbohydrate metabolism, and is implicated in the pathogenesis of islet amyloid formation and of type 2 diabetes mellitus. Rat islet amyloid polypeptide differs from human islet amyloid polypeptide particularly in the region of amino acids 25-28, which is important for amyloid fibril formation. In rat and mouse, diabetes-associated islet amyloid does not develop. To study the genetic organization and biosynthesis of islet amyloid polypeptide, we have isolated and analyzed the human and rat islet amyloid polypeptide gene and corresponding cDNAs. Both genes contain 3 exons, encoding precursor proteins of 89 amino acids and 93 amino acids, respectively. Apart from a putative signal sequence, these precursors contain amino- and carboxy-terminal flanking peptides in addition to the mature islet amyloid polypeptide. To understand regulation of islet amyloid polypeptide gene expression, we have identified several potential cis-acting transcriptional control elements that influence beta-cell-specific islet amyloid polypeptide gene expression. Using antisera raised against synthetic human islet amyloid polypeptide we developed a specific and sensitive radioimmunoassay to measure levels of islet amyloid polypeptide in plasma and tissue extracts. Also antisera raised against the flanking peptides will be used in studying human islet amyloid polypeptide biosynthesis. Elevated plasma islet amyloid polypeptide levels have been demonstrated in some diabetic, glucose-intolerant, and obese individuals, as well as in rodent models of diabetes and obesity. To examine the potential role of islet amyloid polypeptide overproduction in the pathogenesis of islet amyloid formation and type 2 diabetes, we generated transgenic mice that overproduce either the amyloidogenic human islet amyloid polypeptide or the nonamyloidogenic rat islet amyloid polypeptide in their islet beta-cells. Despite moderately to highly (up to 15-fold) elevated plasma islet amyloid polypeptide levels, no marked hyperglycemia, hyperinsulinemia or obesity was observed. This suggests that chronic overproduction of islet amyloid polypeptide "per se" does not cause insulin resistance. No islet amyloid deposits were detected in mice up to 63 weeks of age, but in every mouse producing human islet amyloid polypeptide (as in man), accumulation of islet amyloid polypeptide was observed in beta-cell lysosomal bodies. This may represent an initial phase in intracellular amyloid fibril formation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Molecular physiology of the islet amyloid polypeptide (IAPP)/amylin gene in man, rat, and transgenic mice. 792 17

To elucidate the pathogenesis of diabetes in spontaneously diabetic Chinese hamsters (CHAD strain), a longitudinal study from just after weaning to overt diabetic state was performed. Fasting and non-fasting plasma glucose, non-fasting plasma insulin and pancreatic hormone contents (insulin, glucagon and amylin) were measured, and light microscopic examination of pancreatic islets by immunohistochemical technique and pancreas perfusion study were performed. No insulitis was found in the islets of the CHAD strain. In animals aged 1 month, there was no significant difference in the percentage of B-cell area to islet area between the CHAD strain and the control. At this stage, hyperinsulinemia was observed despite normal plasma glucose levels both in fasting and non-fasting states. In the animals of the CHAD strain aged 2-4 months, insulin secretion from the pancreas, pancreatic insulin content and non-fasting plasma insulin level decreased in proportion to the decrease of B-cell mass. In animals aged about ten months, severe hyperglycemia and hypoinsulinemia were observed. We demonstrated the existence of amylin-like immunoreactivity in the B-cells of Chinese hamsters. However, no amyloid deposit was observed in the islets of the CHAD strain. After the onset of diabetes, amylin secretion from the pancreas and pancreatic amylin content in the CHAD strain were significantly lower than those in the control. We demonstrated the natural history of B-cell dysfunction in the CHAD strain. It could mean the process of B-cell exhaustion. The profile of the CHAD strain is similar to some types of human NIDDM. Therefore, the CHAD strain is a useful diabetic model in the study of NIDDM.
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PMID:Natural history of B-cell dysfunction in spontaneously diabetic Chinese hamsters. 798 44

Aberrant expression of the IAPP gene may be involved in the pathogenesis and islet amyloid formation of type 2 (non-insulin dependent) diabetes mellitus. We sequenced 536 basepairs in the 5'-upstream sequence of the gene of 35 Japanese with this disease and 3 patients with maturity-onset diabetes in the young. The sequences corresponding to both alleles of the gene were identical to one another and to the sequence of subjects without diabetes mellitus except for one allelic variation of 'A' and 'C' at the position -230. Analysis by allele specific polymerase chain reaction revealed no significant difference in frequency of the variation at this position between normal and type 2 diabetic subjects. We conclude that the 5' region of the IAPP gene is highly conserved and only 1 DNA polymorphism is detected and that this polymorphism does not associate with type 2 diabetes mellitus.
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PMID:Islet amyloid polypeptide gene: no evidence of abnormal promoter region in thirty-five type 2 diabetic patients. 820 Mar 2

Islet amyloid polypeptide (IAPP or amylin) was first identified as the major peptide constituent of amyloid deposited in the islets of Langerhans in patients with type-2 diabetes mellitus or in insulinomas. It was subsequently shown that IAPP is produced by the pancreatic beta-cells, co-stored and co-released with insulin. IAPP is homologous with the neuropeptide calcitonin gene-related peptide (CGRP) and has therefore been assumed to have a function as an endocrine, paracrine or autocrine hormone. This has prompted the search for its physiological function as well as a putative pathogenic role in type 2 diabetes mellitus.
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PMID:Islet amyloid polypeptide--hen or egg in type 2 diabetes pathogenesis? 832 56

To search for a possible relationship between islet amyloid polypeptide (IAPP)/amylin and the pathophysiology of type 2 diabetes mellitus, we examined IAPP contents in the pancreata of genetically obese and diabetic mice (C57BL/6J ob/ob and KK mice), at 24 weeks of age, using a specific radioimmunoassay. IAPP and insulin contents were noticeably increased in the ob/ob mice with marked obesity and moderate hyperglycemia. These contents slightly, but significantly increased in the KK mice with mild obesity and hyperglycemia. Thus, IAPP production is possibly influenced by factors coded by mutant genes and a possible relationship between IAPP and hyperglycemia in the strains of mice deserves further attention.
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PMID:Islet amyloid polypeptide/amylin contents in pancreata increase in genetically obese and diabetic mice. 834 41


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