Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both human and rat islet amyloid polypeptide with COOH-terminal amide (IAPP-NH2) dose-dependently displaced the specific binding of 125I-labeled [Tyr0] rat alpha-calcitonin gene-related peptide (CGRP) to rat liver plasma membranes, whereas human IAPP (IAPP-COOH) had no effect. Conversely, human or rat IAPP-NH2 but not human IAPP-COOH evoked dose-dependent activation of adenylate cyclase in the membranes, and these effects were significantly inhibited by the CGRP-receptor antagonist human CGRP-1(8-37). Moreover, the dose of human or rat IAPP-NH2 necessary for producing half-maximal activation of adenylate cyclase was comparable with that for producing a half-maximal inhibition of the label binding. Thus, IAPP-NH2 but not IAPP-COOH appears to induce adenylate cyclase activation via CGRP receptors on rat liver plasma membranes.
Diabetes 1990 Jul
PMID:Activation of adenylate cyclase by islet amyloid polypeptide with COOH-terminal amide via calcitonin gene-related peptide receptors on rat liver plasma membranes. 216 4

Aberrant expression of the islet amyloid polypeptide (IAPP) gene might be involved in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM). Here, we report that IAPP promoter-luciferase constructs revealed tissue-specific activity. This activity was not mediated by cAMP. Sequential 5' deletions of the IAPP promoter caused a progressive derepression of the IAPP gene promoter in IAPP-producing cells. Comparison of the nucleotide sequence of the IAPP promoter with that of the insulin promoter (both active in pancreatic beta-cells) reveals two sequence elements of putative importance: an insulin enhancer-like sequence and an element which corresponds to a protected domain in rat insulin I gene promoter footprint experiments.
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PMID:IAPP/amylin gene transcriptional control region: evidence for negative regulation. 217 4

Amylin-amide has been implicated in the pathogenesis of type II diabetes due to its proposed inhibitory effect on insulin release from beta cells of the pancreatic islets, and on glucose uptake by the skeletal muscle. In experiments with rats and rabbits we failed to demonstrate these anti-insulin actions of amylin and amylin-amide. A single bolus dose of the two peptides (500 pmol) administered i.v. failed to suppress plasma insulin levels or to elevate blood glucose levels. The continuous infusion of amylin-amide into rabbits also failed to suppress the release of insulin in response to hyperglycaemia produced by an i.v. bolus injection of glucose. These in vivo observations imply that the amylin peptides may not have a primary physiological role in carbohydrate metabolism, but in view of our previous findings, we speculate that the peptide has a more prominent role in calcium homeostasis.
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PMID:Amylin and amylin-amide lack an acute effect on blood glucose and insulin. 217 52

Islet amyloid polypeptide (IAPP), also known as amylin, has previously been demonstrated to occur in amyloid deposits in pancreatic islets in type 2 diabetics, and, therefore, the peptide has been suggested to be involved in the pathogenesis of diabetes. The 37 amino acid peptide shows approximately 50% homology with the intrapancreatic neuropeptide calcitonin gene-related peptide (CGRP), a peptide that inhibits insulin secretion. We therefore examined, in model experiments in mice and rats, if IAPP also exerts this effect. IAPP was given intravenously, at dose levels at which CGRP previously has been shown to inhibit insulin secretion. Thus, in mice, IAPP was injected at 0.85 and 4.25 nmol kg-1, and in rats IAPP was infused at 17 or 68 pmol min-1. However, neither basal nor glucose-stimulated insulin release was inhibited by IAPP under these experimental conditions. We also investigated if IAPP (10(-11) to 10(-6) M), when incubated in vitro with isolated, overnight-cultured rat islets, could affect insulin secretion induced by glucose (3.3, 8.3 or 11.7 mM). However, also in vitro no effect by IAPP on insulin release was observed. Hence, in mice and rats, IAPP does not inhibit insulin secretion under experimental conditions identical to those previously used to demonstrate an inhibition by CGRP. Therefore, we conclude (1) that the homologous amino acid sequence within IAPP and CGRP does not seem to be sufficient for inducing inhibition of insulin release in mice and rats and (2) that the possible involvement of IAPP in the pathogenesis of diabetes type 2 still remains speculative.
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PMID:Failure of islet amyloid polypeptide to inhibit basal and glucose-stimulated insulin secretion in model experiments in mice and rats. 218 42

Islet amyloid polypeptide is a 37 amino acid hormone-like peptide which is the major protein component of islet amyloid deposits commonly found in patients with Type 2 (non-insulin-dependent) diabetes mellitus. Recent studies indicate that a physiologically active form of this peptide appears to be carboxyamidated and secreted from the insulin-producing beta cell. In order to clarify the possible in vivo actions of islet amyloid polypeptide, we have studied the effects of synthesized islet amyloid polypeptide-amide on peripheral glucose utilization by performing hyperinsulinaemic euglycaemic glucose clamp studies on dogs. Exogenously administered islet amyloid polypeptide-amide (an infusion from 1.0 to 100 micrograms.kg-1.h-1, over 2 h) inhibited the insulin-stimulated glucose disposal rate in a dose dependent manner. Twenty-five micrograms.kg-1.h-1 of islet amyloid polypeptide-amide infused via a peripheral vein significantly lowered the glucose disposal rate by 20% (from 17.4 +/- 1.7 to 14.4 +/- 1.7 mg.kg-1.min-1, n = 5, p less than 0.01). These findings suggest that islet amyloid polypeptide-amide causes peripheral insulin resistance in vivo.
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PMID:Islet amyloid polypeptide amide causes peripheral insulin resistance in vivo in dogs. 218 60

Islet amyloid polypeptide (IAPP) has been identified as the major constituent of the pancreatic amyloid of non-insulin-dependent diabetes mellitus (NIDDM) and is also present in normal beta-cell secretory granules. To determine whether IAPP is a pancreatic secretory product, we measured the quantity of IAPP-like immunoreactivity (IAPP-LI), insulin, and glucagon released into 5 ml of incubation medium during a 2-h incubation of monolayer cultures (n = 5) of neonatal (3- to 5-day-old) Sprague-Dawley rat pancreases under three conditions: 1.67 mM glucose, 16.7 mM glucose, and 16.7 mM glucose plus 10 mM arginine and 0.1 mM isobutylmethylxanthine (IBMX). The quantity of IAPP-LI, insulin, and glucagon in the cell extract was also determined. Mean +/- SE IAPP-LI in the incubation medium increased from 0.041 +/- 0.003 pmol in 1.67 mM glucose to 0.168 +/- 0.029 pmol in 16.7 mM glucose (P less than 0.05) and 1.02 +/- 0.06 pmol in 16.7 mM glucose plus arginine and IBMX (P less than 0.05 vs. 1.67 or 16.7 mM glucose). Insulin secretion increased similarly from 4.34 +/- 0.27 to 20.2 +/- 0.6 pmol (P less than 0.05) and then to 135 +/- 5 pmol (P less than 0.05 vs. 1.67 or 16.7 mM glucose). Glucagon release tended to decrease with the increase in glucose concentration (0.39 +/- 0.01 vs. 0.33 +/- 0.02 pmol, P less than 0.1), whereas with the addition of arginine and IBMX to high glucose, glucagon release increased to 1.32 +/- 0.03 pmol (P less than 0.05 vs. 1.67 or 16.7 mM glucose).(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1990 May
PMID:Evidence of cosecretion of islet amyloid polypeptide and insulin by beta-cells. 218 12

Recent interest has focused on the potential role of amylin in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM). This 37-amino acid peptide is found in extracellular amyloid deposits in approximately 50% of pancreatic islets of patients with NIDDM and has been shown to inhibit skeletal muscle glycogen synthesis in vitro. Immunocytochemical studies have colocalized amylin and insulin within beta-cell secretory granules in nondiabetic humans, provoking the following questions. Is amylin cosecreted with insulin? Are circulating amylin concentrations higher in patients with NIDDM either before or after food ingestion? To answer these questions, we developed a sensitive and specific immunoassay to measure plasma concentrations of amylin in humans. Use of this assay indicated that, in lean nondiabetic subjects, glucose ingestion resulted in an increase (P less than 0.001) in the plasma concentration of amylin (from 2.03 +/- 0.22 to 3.78 +/- 0.39 pM) and insulin (from 48.3 +/- 3.1 to 265 +/- 44 pM). There was a significant correlation between the concentrations of insulin and amylin (r = 0.74, P less than 0.001) and the increase in insulin and amylin concentration (r = 0.65, P less than 0.005). Fasting concentrations of amylin did not differ in diabetic and weight-matched nondiabetic subjects and showed a similar pattern of change after ingestion of a mixed meal. We conclude that amylin is secreted in response to ingestion of either glucose or a mixed meal and circulates at concentrations that do not differ in patients with NIDDM and nondiabetic subjects. It remains to be determined whether amylin at physiological concentrations influences carbohydrate metabolism and if so whether its effects differ in diabetic and nondiabetic humans.
Diabetes 1990 Jun
PMID:Effects of meal ingestion on plasma amylin concentration in NIDDM and nondiabetic humans. 218 68

We examined the effects of rat islet amyloid polypeptide (IAPP) on insulin biosynthesis and secretion by isolated rat islets of Langerhans. Culture of islets for 24 h in the presence of 10(-6) M IAPP and 5.5 mM glucose had no effect on insulin mRNA levels. Similarly, the rates of proinsulin biosynthesis were not altered in islets incubated in 10(-4)-10(-9) M IAPP and 5.5 mM glucose, nor was the rate of conversion of proinsulin to insulin changed at 10(-6) M IAPP. Addition of 10(-5) M IAPP to islets incubated in 11 mM glucose decreased the fractional insulin secretion rate; however, the secretion of newly synthesized proinsulin and insulin was not affected. These data indicate that it is unlikely that IAPP is a physiologically relevant modulator of insulin biosynthesis or secretion.
Diabetes 1990 Jul
PMID:Lack of islet amyloid polypeptide regulation of insulin biosynthesis or secretion in normal rat islets. 219 89

Islet amyloid polypeptide (IAPP) is a recently discovered pancreatic islet hormone which is stored with insulin in beta cell granules. IAPP may have a significant role in the development of Type 2 diabetes mellitus due to its propensity to form islet cell-disrupting amyloid deposits, and by opposing the action of insulin in peripheral tissues. Most evidence to-date suggests that an intrinsic structural motif of IAPP is linked to the amyloidogenicity of IAPP, and that this motif occurs only in those species (e.g., humans and cats) that also develop age-associated or Type 2 diabetes We utilized polymerase chain reaction methodology in this study to obtain the IAPP nucleotide and protein sequences of the dog, a species not known to develop islet amyloid. We show that dog IAPP contains the same putative amyloidogenic sequence (GAILS) at residues 24-28 as human and cat IAPP, and that although dogs do not develop islet amyloid they do develop IAPP-derived amyloid in association with neoplastic beta cells (i.e., insulinomas). These results provide strong evidence that the amyloidogenicity of IAPP is linked to at least two prerequisites: a species-specific amyloidogenic structural motif, and aberrations in the synthesis (or processing) of IAPP which leads to increased concentration of IAPP in the local milieau.
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PMID:Canine IAPP cDNA sequence provides important clues regarding diabetogenesis and amyloidogenesis in type 2 diabetes. 219 9

Islet amyloid polypeptide (IAPP), a putative polypeptide hormone, is a product of pancreatic beta-cells and the major constituent of the amyloid deposits seen mainly in islets of type 2 diabetic humans and diabetic cats. The connection between IAPP amyloid formation and diabetes is unknown, but a limited segment of the IAPP molecule, positions 20-29, seems responsible for the aggregation to fibrils. Differences in the amino acid sequence of this region probably determine whether or not islet amyloid can develop in a particular species. Amyloid fibril formation can be mimicked in vitro with the aid of synthetic peptides. With this technique we show that peptides corresponding to IAPP positions 20-29 of human and cat, species that develop IAPP-derived islet amyloid, form amyloid-like fibrils in vitro. The corresponding IAPP segment from three rodent species that do not develop IAPP-derived amyloid did not give rise to fibrils. Substitution of the human IAPP-(20-29) decapeptide with one or two amino acid residues from species without islet amyloid generally reduced the capacity to form fibrils. We conclude that the sequence Ala-Ile-Leu-Ser-Ser, corresponding to positions 25-29 of human IAPP, is strongly amyloidogenic and that a proline-for-serine substitution in position 28, as in several rodents, almost completely inhibits formation of amyloid fibrils.
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PMID:Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation. 219 44


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