Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The islet amyloid polypeptide (IAPP) was originally identified by chemical analysis of the amyloid component in a human pancreatic islet cell tumor. It consists of 37 amino acids and displays about 50% homology with the neuropeptide calcitonin gene-related peptide (CGRP). In the pancreatic islets the IAPP is confined to the beta-cells, co-stored with insulin in the secretory granules and apparently co-secreted with insulin on glucose stimulation. In beta-cell depletion states such as streptozotocin diabetes in animals and in human type I diabetes mellitus both the IAPP and the insulin levels display reduction or are even absent. Within the mature IAPP molecule the amino acid sequence 23-29 shows considerable amino acid heterogenicity among various mammalian species. The amino acid composition of human IAPP in this specific region promotes the development of pancreatic islet amyloidosis, a phenomenon related to the ability to develop type II diabetes in that particular species. However, as type II diabetes is an inherited disease affecting a subpopulation of humans, not only the gene coding mature IAPP, but also one or several other hereditary factors of unknown origin are needed for the disease to develop. We have established a radioimmunoassay for plasma measurements of IAPP. During screening investigations of a large material of endocrine tumors we found a patient with extremely elevated plasma levels of IAPP, about 20,000 pmol/l. Immunohistochemical investigations confirmed the IAPP content and also revealed amyloid deposits. While performing an oral glucose tolerance test insulin levels remained unchanged whereas there was an increase in the glucose and IAPP levels. It is thus concluded that IAPP can be used as a tumor marker in pancreatic islet cell tumors and that high plasma levels of IAPP can inhibit glucose stimulated insulin secretion.
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PMID:Islet amyloid polypeptide (IAPP). A short review. 185 2

Family studies suggest a strong genetic component in the aetiology of non-insulin dependent diabetes (NIDDM), with evidence for a major gene of co-dominant or dominant effect. A gene-dosage effect, whereby diabetes develops earlier in people with two susceptibility genes than in those with one susceptibility gene is likely. The search for the diabetes gene has led to the cloning and characterization of many genes involved in controlling glucose homeostasis. These include the insulin, insulin receptor, glucose transporter, amylin and glucokinase genes. Molecular techniques have permitted rapid screening of these genes in NIDDM patients and controls. There is now a rather contradictory genetic literature for NIDDM, with weak disease associations reported and refuted for most candidate genes. However, pedigree analyses and DNA sequencing of available candidate genes and their regulatory regions have failed to implicate any of these in the common form of diabetes, NIDDM. Methodical application of random clones in well-defined NIDDM families may be the strategy of choice in finding the NIDDM genes, given the wide range of genes potentially involved in the glucose and lipoprotein metabolic disturbances seen in NIDDM.
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PMID:Genetics of non-insulin dependent diabetes mellitus in 1990. 189 73

Amylin, the major peptide component of the islet amyloid commonly found in the pancreases of patients with type 2 (non-insulin-dependent) diabetes mellitus (NIDDM), is a recently discovered islet polypeptide. This peptide has many structural and functional features suggesting that it is a novel hormone, which may control carbohydrate metabolism in partnership with insulin and other glucoregulatory factors. Amylin is synthesised in, and probably secreted from, the beta-cells of the islets of Langerhans, where it has recently been immunolocalised to secretory granules. DNA cloning studies indicate that in the human and the rat, amylin is generated from a precursor, preproamylin, which displays a typical signal peptide followed by a small prohormone-like sequence containing the amylin sequence. The presence of the signal peptide suggests that amylin is secreted and plays a physiological role. Amylin is probably generated by proteolytic processing similar to that for proinsulin and other islet prohormones. The human amylin gene encodes the complete polypeptide precursor in two exons which are separated by an intron of approx. 5 kb, and is located on chromosome 12. Amylin is a potent modulator of glycogen synthesis and glucose uptake in skeletal muscle, and is capable of inducing an insulin-resistant state in this tissue in vitro, and perhaps also in the liver in vivo. In normal metabolism, amylin could act in concert with insulin as a signal for the body to switch the site of carbohydrate disposal from glycogen to longer-term stores in adipose tissue, by making skeletal muscle relatively insulin-resistant, whilst at the same time leaving rates of insulin-stimulated carbohydrate metabolism in adipose tissue unaltered. Several lines of evidence now implicate elevated amylin levels in the pathogenic mechanisms underlying NIDDM, and suggest to us that the obesity which frequently accompanies this syndrome is a result of, rather than a risk factor for, NIDDM. Following the beta-cell destruction which occurs in type 1 (insulin-dependent) diabetes mellitus (IDDM), it is probable that amylin secretion disappears in addition to that of insulin. As patients with insulin-treated IDDM frequently experience problems with hypoglycaemia, and as amylin acts to modulate the action of insulin in various tissues, it is possible that amylin deficiency may contribute to morbidity in insulin-treated IDDM, perhaps through the loss of a natural damping mechanism which guards against hypoglycaemia under conditions of normal physiology.
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PMID:Amylin and the amylin gene: structure, function and relationship to islet amyloid and to diabetes mellitus. 269 Sep 58

Cats are one of the few species that develop a form of diabetes mellitus that is clinically and histologically analogous to human type 2 diabetes mellitus. Figure 9 summarizes the etiologic factors thought to be involved in the development of feline and human type 2 diabetes. The main metabolic characteristics of type 2 diabetes mellitus are impaired insulin secretion and resistance to the action of insulin in its target tissues. Impaired beta cell function occurs before histologic changes become evident. The characteristic histologic finding in cats with type 2 diabetes is deposition of amyloid in pancreatic islets. Amyloid deposition occurs before the onset of clinical signs, but does not seem to be the primary defect. Pancreatic amyloid is derived form the recently discovered pancreatic hormone amylin. Amylin is synthesized in pancreatic beta cells, and is co-stored and co-secreted with insulin. Amylin has been postulated to be involved in the pathogenesis of feline diabetes mellitus both through its metabolic effects, which include inhibition of insulin secretion and induction of insulin resistance, and via progressive amyloid deposition and beta cell degeneration. Increased amylin concentration has been documented intracellularly in cats with impaired glucose tolerance and in the plasma of diabetic cats, and supports the hypothesis that amylin is involved in the pathogenesis of type 2 diabetes. Obesity is a common finding in diabetic felines and is a contributing factor to the insulin resistance present in type 2 diabetes. Clinical signs of diabetes develop once total insulin secretion decreases to 20% to 25% of normal levels. Many diabetic cats have been treated successfully with oral hypoglycemics, but 50% to 70% of diabetic cats are insulin dependent. Based on histologic evidence, this is the result of extensive amyloid deposition and subsequent beta cell degeneration, rather than autoimmune destruction of pancreatic beta cells associated with type 1 diabetes. Alternative ways of treating type 2 diabetes currently are being investigated. Amylin antagonists recently have been proposed as a novel treatment to reverse the deleterious effects of excessive amylin concentrations. The gastrointestinal hormone glucagon-like peptide-1 may also prove useful in treating diabetic cats, because of its stimulatory effect on insulin secretion and synthesis, and the absence of significant hypoglycemic effect.
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PMID:Pathogenesis of feline diabetes mellitus. 766 May 30

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

Amylin is normally secreted in a regulated fashion by the pancreatic beta-cells in parallel with insulin and has been reported to have bone-conserving properties. Type I diabetes mellitus results in a low-turnover osteopenia in the presence of decreased amylin, which is in contrast to type II diabetes where less bone loss, in the presence of high amylin levels, occurs. We investigated the effects of amylin on bone mineral metabolism in normal and diabetic (streptozotocin-induced) rats, in order to ascertain whether amylin would modify the streptozotocin-induced diabetic osteopenia. Ten-week-old male Sprague-Dawley rats were randomized as follows: group A (n = 18) received normal saline; group B (n = 18) received amylin; group C, diabetic rats (n = 23), received normal saline; and group D, diabetic rats (n = 23), received amylin. Amylin (100 pmol/100 g b.w.) was administered by a daily subcutaneous injection. Double calcein-labeled tibiae were removed for histomorphometric analysis followed sacrifice on day 19. Results showed no difference in blood ionized calcium between groups. Blood glucose remained above 600 mg/dl in the diabetic animals and was not affected by the administration of amylin. Serum osteocalcin, insulin-like growth factor-1 (IGF-1), parathyroid hormone (PTH), and 1,25 dihydroxyvitamin D [1,25(OH)2D] were significantly lower in the diabetic rats compared with control group A by day 19. Amylin produced higher levels of serum osteocalcin in group B on day 9 (P < 0.05) compared with controls but returned to control values (group A) by day 19; no such change occurred in the diabetic group.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Amylin increases bone volume but cannot ameliorate diabetic osteopenia. 779 48

The Calcitonin Gene-Related Peptide (CGRP) is a 37 aminoacid peptide displaying about 50% homology with amylin which is secreted from the pancreatic islets of Langerhans. The main form, the beta-CGRP, is produced by the enteric nervous system and perivascular nerves of the vasa vasorum. It represents the most powerful vasodilator yet discovered but its role is not yet completely clarified. Recently it has been implicated in the control of regional blood flow and some authors have hypothesized its role in the development of Non Insulin Dependent Diabetes Mellitus (NIDDM). CGRP and amylin seem to inhibit the release of insulin from beta-cells and to play a role in local paracrine control of insulin secretion. In addition it is also shown to decrease the uptake of glucose by striated muscle. This has led to the suggestion that CGRP might be a circulating hormone implicated in the regulation of peripheral insulin sensitivity. In this review we examine the possible role of CGRP in the development of peripheral insulin resistance and altered insulin secretion which is characteristic of NIDDM.
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PMID:[Calcitonin gene-related peptide in diabetes mellitus type 2: a possible etiopathogenetic role]. 854 54

To evaluate the pancreatic amylin in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM), we determined the pancreatic amylin (IRA) and insulin (IRI) contents of pancreata obtained at autopsy from diabetics and nondiabetics. IRA was extracted from the tail of the pancreas using formic acid and assayed with a human amylin kit. Following gel filtration of amylin on a Sephadex G-50 column, it was eluted in a similar fraction to insulin. The pancreatic IRA content was significantly higher (p < 0.01) in NIDDM subjects compared with nondiabetics, with the mean values being 4.25 +/- 1.62 and 0.085 +/- 0.022 microgram/g, respectively. The IRA content of two IDDM pancreata was low. No significant relationship was found between the IRA and the IRI contents or between the IRA content and the duration of diabetes. However, there was a tendency for the IRA content to increase in longstanding diabetes. Men had a significantly higher pancreatic IRA content than women. The four subjects with very high IRA levels ( > 10 micrograms/g) were all elderly men with a long duration of diabetes. Thus, although the pancreatic amylin content was increased in NIDDM, no significant relationship to the clinical features of the disease was found.
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PMID:Pancreatic amylin content in human diabetic subjects and its relation to diabetes. 857 86

Amylin has been reported to decrease glycogen storage in rodent skeletal muscles and produce insulin resistance in intact rats. To test the acute effect of a human amylin analog (AC137) on glucose metabolism in man, seven IDDM patients were infused in a randomized, double blind, cross-over study with AC137 (100 micrograms/h, n = 1; 50 micrograms/h, n = 6) or placebo for 330 min during a two-step euglycemic clamp (insulin infusion rates, 0.2 and 0.6 mU/kg.min; basal and hyperinsulinemic period, respectively) followed by a hyperinsulinemic hypoglycemic clamp (insulin infusion rate, 1.5 mU/kg.min; hypoglycemic period). During euglycemia, no differences were found in glucose disposal (step 1, 2.43 +/- 0.20 vs. 2.03 +/- 0.26; step 2, 4.28 +/- 0.54 vs. 4.11 +/- 0.45 mg/kg.min; AC137 vs. placebo, mean +/- SEM), arteriovenous substrate balances across the forearm, or hepatic glucose production. During hypoglycemia, glucose fluxes were also similar. However, lactate release from the forearm was more pronounced (P < 0.05) with the analog than with placebo (area under the curve, -11.2 +/- 4.6 vs. -1.4 +/- 2.2 mmol/min.L). Despite similar plasma glucose nadirs (2.7 +/- 0.0 vs. 2.6 +/- 0.1 mmol/L; AC137 vs. placebo), circulating cortisol and GH rose to significantly higher levels during hypoglycemia with the amylin analog (P < 0.05). In conclusion, acute administration of the amylin analog AC137 did not influence insulin-stimulated glucose metabolism during euglycemic conditions. During imposed hypoglycemia, lactate release from skeletal muscle was, however, enhanced, and the rise in cortisol and GH was augmented.
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PMID:Acute effects of the human amylin analog AC137 on basal and insulin-stimulated euglycemic and hypoglycemic fuel metabolism in patients with insulin-dependent diabetes mellitus. 877 80

Many studies suggest that amylin, which is cosecreted with insulin from islet beta-cells, is a biologically active peptide and modulates plasma glucose levels. We therefore scanned the amylin gene for mutations in 294 Japanese NIDDM patients by single-strand conformational polymorphism, and we found a single heterozygous missense mutation (Ser-->Gly at position 20: S20G mutation) in 12 NIDDM patients (frequency 4.1%). None of the 187 nondiabetic subjects or 59 IDDM patients had the mutation. Of 12 patients carrying the mutation, 8 were diagnosed as having NIDDM at a relatively early age (< or = 35 years), and they had severe diabetes and strong family histories of late-onset NIDDM. On the other hand, the remaining four patients were diagnosed as having NIDDM after age 51, and they had mild diabetes without family histories of diabetes. In high-performance liquid chromatography analysis, a small amount (16%) of amylin immunoreactivity appeared in the position corresponding to normal amylin and a much larger amount (84%) appeared in the position corresponding to mutant amylin. These findings suggest that the S20G mutation of the amylin gene may play a partial role in the pathogenesis of early-onset NIDDM in the Japanese population and may also provide an important model to investigate the true physiological action of amylin.
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PMID:Missense mutation of amylin gene (S20G) in Japanese NIDDM patients. 877 35


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