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)

Amylin, also called islet amyloid polypeptide (IAPP), or diabetes-associated peptide (DAP) is a recently discovered 37 amino acid polypeptide which has been shown to be co-secreted with insulin from the pancreatic beta-cell. The peptide turned out to be the major constituent of pancreatic amyloid deposits which are frequently found in the pancreas of type II diabetic patients. Therefore, a role for amylin in the aetiology of type II diabetes was hypothesized. To investigate this possibility, several studies have been performed to elucidate whether amylin is able to impair insulin secretion and action, two characteristic features of type II diabetes mellitus. These studies suggest that it is unlikely that amylin has a direct inhibitory effect on insulin secretion. Amyloid deposits, however, which are derived from the in situ polymerization and precipitation of amylin, may impair beta-cell function during type II diabetes by damaging and covering beta-cells. Furthermore, it has been shown that amylin has the potential to antagonize the action of insulin on glucose metabolism by increasing hepatic glucose production and by decreasing muscle, but not adipocyte glucose uptake. For these reasons, it has been suggested that amylin might be involved in the pathophysiology of type II diabetes and obesity, disease states which are characterized by abnormal beta-cell function and insulin resistance. In addition, amylin was shown to induce hypocalcaemia by inhibiting osteoclast-mediated bone resorption in a calcitonin-like manner. Therefore, amylin is likely to be involved in both the modulation of glucose and calcium metabolism.
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PMID:Biological action of pancreatic amylin: relationship with glucose metabolism, diabetes, obesity and calcium metabolism. 140 45

Amylin is a 37 amino-acid peptide which is secreted from the pancreatic islets of Langerhans. It has major sequence homology with calcitonin gene related peptide. Amylin can precipitate out in these cells to form amyloid. Amylin is secreted by similar stimuli to those that secrete insulin. Amylin has a number of effects that may counteract the effect of secreted insulin, i.e., decreased second phase insulin secretion, increased hepatic glucose output, and inhibition of insulin effects on skeletal muscle. It must, however, be recognized that in many cases the doses necessary to produce these effects appear to be supraphysiological. The putative role of amylin in the hyperglycemia of aging and Type II diabetes mellitus therefore remains controversial. Amylin has a number of other effects including inhibition of osteoclastic activity, vasodilatation, anorectic effects and enhanced memory retention. This review postulates a role for amylin in the pathogenesis of a number of age-related changes.
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PMID:Amylin. 145 75

Non-insulin-dependent diabetes mellitus (NIDDM) results from an imbalance between insulin sensitivity and insulin secretion. Both longitudinal and cross-sectional studies have demonstrated that the earliest detectable abnormality in NIDDM is an impairment in the body's ability to respond to insulin. Because the pancreas is able to appropriately augment its secretion of insulin to offset the insulin resistance, glucose tolerance remains normal. With time, however, the beta-cell fails to maintain its high rate of insulin secretion and the relative insulinopenia (i.e., relative to the degree of insulin resistance) leads to the development of impaired glucose tolerance and eventually overt diabetes mellitus. The cause of pancreatic "exhaustion" remains unknown but may be related to the effect of glucose toxicity in a genetically predisposed beta-cell. Information concerning the loss of first-phase insulin secretion, altered pulsatility of insulin release, and enhanced proinsulin-insulin secretory ratio is discussed as it pertains to altered beta-cell function in NIDDM. Insulin resistance in NIDDM involves both hepatic and peripheral, muscle, tissues. In the postabsorptive state hepatic glucose output is normal or increased, despite the presence of fasting hyperinsulinemia, whereas the efficiency of tissue glucose uptake is reduced. In response to both endogenously secreted or exogenously administered insulin, hepatic glucose production fails to suppress normally and muscle glucose uptake is diminished. The accelerated rate of hepatic glucose output is due entirely to augmented gluconeogenesis. In muscle many cellular defects in insulin action have been described including impaired insulin-receptor tyrosine kinase activity, diminished glucose transport, and reduced glycogen synthase and pyruvate dehydrogenase. The abnormalities account for disturbances in the two major intracellular pathways of glucose disposal, glycogen synthesis, and glucose oxidation. In the earliest stages of NIDDM, the major defect involves the inability of insulin to promote glucose uptake and storage as glycogen. Other potential mechanisms that have been put forward to explain the insulin resistance, include increased lipid oxidation, altered skeletal muscle capillary density/fiber type/blood flow, impaired insulin transport across the vascular endothelium, increased amylin, calcitonin gene-related peptide levels, and glucose toxicity.
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PMID:Pathogenesis of NIDDM. A balanced overview. 153 77

To investigate the involvement of islet amyloid polypeptide (IAPP) and amyloid deposits in the pathophysiology of this disease, we studied the relationship between IAPP-derived amyloid deposition and the clinical features in type 2 diabetes mellitus. We examined pancreata obtained from 37 type 2 diabetic subjects and 12 non-diabetic ones by immunohistochemical techniques using two specific antibodies to IAPP. IAPP-derived deposits occurred in 1 of the 12 (8.3%) non-diabetic subjects and 28 of the 37 (75.7%) diabetics. When diabetic patients were divided into categories according to the presence of the deposits, the duration of the disease was significantly longer in patients with amyloid than that in the patients without it. The odds ratio of type 2 diabetes mellitus of at least 14-years-duration to the deposition was significantly high, and a body weight of at least 120% maximal ideal body weight was relatively high. In conclusion, IAPP-derived amyloid deposition increases along with the duration of type 2 diabetes mellitus and obesity may further enhance these deposits, hence hypersecretion of IAPP may be involved in the progression of this disease.
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PMID:Islet amyloid polypeptide-derived amyloid deposition increases along with the duration of type 2 diabetes mellitus. 154 Dec 30

To investigate the possible role of islet amyloid polypeptide (IAPP) in the development of type 2 diabetes mellitus, we examined the IAPP content and secretion in pancreatic islets isolated from ventromedial hypothalamic (VMH)-lesioned rats and genetically obese Zucker rats, using a specific radioimmunoassay for IAPP. Obesity and hyperinsulinemia were observed in rats 21 days after VMH lesioning. IAPP content was increased in the islets of VMH-lesioned rats compared with findings in the sham-operated controls (100.9 +/- 6.6 vs 72.8 +/- 3.85 fmol/islet; P less than 0.01). Isolated islets of VMH-lesioned rats secreted larger amounts of IAPP in the presence of 2.8 and 16.7 mM glucose (2.99 +/- 0.98 and 11.2 +/- 0.29 fmol islet-1 3 h-1) than was noted in sham-operated rats (ND and 6.65 +/- 0.78 fmol islet-1 3 h-1). In the obese Zucker rats, aged 14 weeks, IAPP concentrations in the islets were elevated compared with lean rats (133.3 +/- 10.6 vs 84.4 +/- 8.5 fmol/islet; P less than 0.01). The isolated islets secreted larger amounts of IAPP in response to 2.8 and 16.7 mM glucose (2.83 +/- 0.88 and 15.81 +/- 1.35 fmol islet-1 3 h-1) than did those from lean control rats (0.36 +/- 0.19 and 12.49 +/- 1.20 fmol islet-1 3 h-1). These results strongly suggest that overproduction and hypersecretion of IAPP occur in animals with obesity and hyperinsulinemia.
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PMID:Hypersecretion of IAPP from the islets of VMH-lesioned rats and obese Zucker rats. 154 Dec 31

Amylin, a 37 amino acid polypeptide, has been suggested to play a prominent role in the pathogenesis of insulin resistance in type II diabetes mellitus. Various studies have demonstrated most recently that amylin is cosecreted with insulin. No data are available on the elimination of amylin from the circulation. We therefore tested plasma levels of amylin, insulin and C-peptide in 49 non-obese, non-diabetic patients (27 male/22 female) with various degree of renal impairment (Group A: CCr less than 20 ml/min, n = 20; Group B: CCr 20-89 ml/min, n = 18; and Group C: CCr greater than 80 ml/min, n = 9). We found a significant increase of plasma amylin when kidney function, expressed by creatinine clearance fell below 20 ml/min (17.9 +/- 1.7 vs. 12.2 +/- 0.8 vs. 8.8 +/- 1.2 pg/ml; p = 0.0005). Plasma amylin correlated closely with serum C-peptide (r = .764; p = 0.0001), and to a lesser extent with insulin (r = .595; p = 0.0001) underlining its postulated cosecretion with these peptides. The data indicate that amylin might be eliminated by renal mechanisms. Our data show that besides type II diabetes mellitus, advanced renal failure is another clinical situation with enhanced plasma amylin levels. Whether amylin plays any pathogenetic role in renal patients remains to be elucidated.
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PMID:Increased levels of plasma amylin in advanced renal failure. 156 16

Amyloid deposits characteristically associated with pancreatic islets of those species (e.g., humans, cats, and monkeys) that develop age-associated forms of diabetes have been shown to represent a concentrated and polymerized form of a previously unknown islet-derived protein identified either as IAPP or amylin. IAPP, a highly conserved and carboxy-terminally amidated 37 amino acid polypeptide with approximately 45% amino acid sequence identity to CGRP, is produced by islet beta cells and is cosecreted with insulin in response to glucose and other secretagogues. Prepro-IAPP is synthesized in beta cells as an 89 to 93 amino acid molecule, and mature IAPP appears to be formed by enzymatic processing similar to that involved in the formation of insulin. Glucose-stimulated IAPP secretion generally parallels that of insulin and, on a molar basis, IAPP represents about 1% of the amount of insulin secreted. A significant dissociation of IAPP and insulin secretion (associated with relatively greater upregulation of IAPP secretion) is observed in response to marked hyperglycemia, suggesting that IAPP and insulin expression are differentially regulated. The amyloidogenicity of IAPP in only a very limited number of species is importantly related to the amino acid residues inherently found in the 20-29 region of IAPP from those species. The 25-28 region of human and cat IAPP is identical in structure and appears to be the most important amyloidogenic sequence common to the human and cat. In vitro fibrillogenesis studies have shown that amino acid substitutions in this region especially affect the amyloidogenicity of IAPP. Studies in dogs and cats suggest that aberrations in beta cell synthesis (or processing) of IAPP may lead to an increased concentration of IAPP in the local milieu, thus providing a second prerequisite for the self aggregation of IAPP to form islet amyloid. IAPP has been implicated to have physiological roles in glucose regulation, hemodynamics, calcium homeostasis, and as an anorectic agent. The major current interest in IAPP concerns its potential relationships to glucose metabolism and the development of type 2 diabetes. Evidence has been provided which indicates that IAPP can inhibit glucose-stimulated insulin secretion by beta cells, and that IAPP can also potentially contribute to the pathogenesis of type 2 diabetes by increasing hepatic glucose output and by inducing peripheral insulin resistance.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Islet amyloid polypeptide: mechanisms of amyloidogenesis in the pancreatic islets and potential roles in diabetes mellitus. 157 49

Atypical carcinoid tumor of the lung with amyloid stroma seen in a 43-year-old woman is reported. The 47 x 45 x 33 mm tumor, located at the periphery of the S8 segment of the resected left lower lobe, revealed Dylon-positive amyloid deposition in the stroma. The argyrophilic tumor cells with occasional mitoses and focal venous involvement predominantly showed immunoreactivity of cytokeratin, neuron-specific enolase, cystatin C, chromogranin A, calcitonin and neuropeptide Y (NPY). Fewer cells were immunoreactive for calcitonin gene-related peptide (CGRP), the alpha-subunit of human chorionic gonadotropin, gastrin-releasing peptide, serotonin, methionine-enkephalin and gastrin. Immunoreactive CGRP or NPY were co-localized in calcitonin-positive cells. The amyloid substance was positively labeled only for CGRP. Immunostaining for amylin, a polypeptide isolated from insular amyloid in type II diabetes mellitus or insulinoma showing a 50% homology with CGRP, was negative. The specificity of immunostaining for calcitonin, CGRP and amylin was confirmed by immunoabsorption tests using synthetic human antigens. Immunoelectron microscopic studies disclosed peptide localization in neurosecretory-type granules and CGRP immunoreactivity in extracellular amyloid fibrils. This is the first report describing CGRP as a component of amyloid of endocrine origin.
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PMID:Atypical carcinoid tumor of the lung with amyloid stroma. 160 16

Amylin, a peptide found in pancreatic amyloid deposits, may be involved in NIDDM. The effects of biosynthetic human amylin on multiple aspects of carbohydrate metabolism were studied in freshly isolated and cultured liver cells (rat hepatocytes and HepG2 cells). Acute exposure of culture liver cells to amylin had no effect on glucose incorporation into glycogen. Amylin directly reduced glucose oxidation through the hexose monophosphate shunt. The glycolytic pathway was unaffected. Amylin stimulated both glycogenolysis and gluconeogenesis. These effects were largest at amylin concentrations of 1-10 pM. Insulin partially inhibited both of these responses. Glucagon stimulated glycogenolysis and gluconeogenesis to a similar extent as amylin but required concentrations 100- to 500-fold as high. Thus, amylin, at physiologic concentrations, can impair some aspects of glucose use in liver cells and is also capable of directly stimulating glucose production, suggesting a possible involvement of amylin in the impaired glucose disposal and elevated hepatic glucose output of NIDDM.
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PMID:In vitro effects of amylin on carbohydrate metabolism in liver cells. 162 73

Islet amyloid polypeptide (IAPP) has been recently identified as the principal constituent of amyloid deposits in pancreatic islets of patients with type 2 (non-insulin-dependent) diabetes mellitus and causes insulin resistance in some target cells. In addition, glucose-induced insulin secretion is inhibited by IAPP. We studied the effect of IAPP on proinsulin biosynthesis in rat insulinoma (RINr) cells. Glucose at concentrations of 0, 15, 30, 60, 100, and 300 mg/dl stimulated proinsulin biosynthesis in a dose-responsive and and actino-mycin D-inhibitable manner after 6 h of incubation. At a glucose concentration of 300 mg/dl, IAPP decreased the mean responses of proinsulin biosynthesis to 61.2 and 29% at concentrations of 0.1 and 1 microM, respectively, compared with the IAPP-free control. In conclusion, IAPP inhibits glucose-induced proinsulin biosynthesis in RINr cells. IAPP might play an important role in the pathogenesis of type 2 diabetes mellitus.
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PMID:Inhibitory effect of islet amyloid polypeptide of glucose-induced proinsulin biosynthesis in rat insulinoma cells. 164 90


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