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P Westermark

Publications and source records attributed to P Westermark.

At least 91 records · Page 5Linked to original sources
PubMed1993

Islet amyloid polypeptide: a review of its biology and potential roles in the pathogenesis of diabetes mellitus.

Islet amyloidosis (IA) is the principal lesion in the endocrine pancreas of human beings with non-insulin-dependent diabetes mellitus (NIDDM) and in the similar forms of diabetes mellitus in domestic cats and macaques. As such, the delineation of the pathogenesis of this form of amyloidosis may be crucial to the understanding of the development and progression of NIDDM. Islet amyloid polypeptide (IAPP) is a recently discovered polypeptide that is the principal constituent of IA in human beings, cats, and macaques. IAPP is produced by the pancreatic beta-cells and is co-packaged with insulin in the beta-cell secretory vesicles. Immunohistochemical and physiologic evidence supports the notion that the beta-cells are heterogenous with respect to their relative contents of insulin and IAPP. Therefore, although IAPP is co-secreted with insulin in response to a variety of well-known insulin secretagogues, the molar ratio of these two proteins that is released from the islets may vary, depending upon the glucose concentration and prevailing metabolic milieu. IAPP is highly conserved among mammalian species and has about 45% homology to another neuropeptide, calcitonin gene-related peptide. IAPP is encoded by a single-copy gene located, in the human being, on chromosome 12. IAPP is expressed as a 93 (murine)-89 (human)-amino acid prepropolypeptide that is processed enzymatically, resulting in the removal of amino- and carboxy-terminal propeptide segments. The 20-29 region of the IAPP molecule is most important in the ability of IAPP to form amyloid fibrils. The role of IAPP and IA in the pathogenesis of human NIDDM and similar forms of diabetes mellitus in cats and macaques may involve several possible mechanisms, including 1) direct physical/chemical damage to beta-cells, resulting in necrosis and loss of functional islet tissue, 2) biologic activities of IAPP that oppose those of insulin or abnormally suppress insulin secretion, and 3) interference by IA deposits of passage of insulin out of beta-cells and/or entrance of glucose and other secretogogues into the islet. The roles of each of these possible mechanisms have yet to be demonstrated. In addition, the physiological significance of the apparent IAPP deficiency in both insulin-dependent diabetes mellitus and NIDDM is currently unknown.

Amino Acid Sequence↗
PubMed1993

Islet amyloid polypeptide--hen or egg in type 2 diabetes pathogenesis?

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.

Amyloid↗
PubMed1992

The N-terminal segment of protein AA determines its fibrillogenic property.

The amyloid fibril protein AA consists of a varying long N-terminal part of the precursor protein serum AA. By using synthetic peptides corresponding to human and murine protein AA segments and cyanogen bromide fragments of human protein AA, we show evidence that the amyloidogenic part of the molecule is the first 10-15 amino acid long segment. Amino acid substitutions in this part of the molecule may explain why only one of the two mouse SAA isoforms is amyloidogenic.

Amino Acid Sequence↗
PubMed1992

Seminal vesicle amyloid: the first example of exocrine cell origin of an amyloid fibril precursor.

Amyloid fibrils have been extracted from seminal vesicles, and a dominant 14 kD amyloid fibril protein has been identified. An antiserum to this protein reacted both with amyloid and with epithelial cells in some normal seminal vesicles. These reactions were blocked with seminal vesicle secretion and seminal vesicle amyloid fibril protein, but not by degraded amyloid fibrils or fibril protein from other types of amyloid. It is concluded that seminal vesicle amyloid is derived from secretory proteins of the seminal vesicles. As such, it is the first amyloid described which appears to be the product of an exocrine secretory cell.

Aged↗
PubMed1992

Human islet amyloid polypeptide at pharmacological levels inhibits insulin and phorbol ester-stimulated glucose transport in in vitro incubated human muscle strips.

Human islet amyloid polypeptide, at concentrations of 1-100 nmol/l, has been demonstrated to inhibit the insulin-stimulated increase in rat muscle glycogen content. However, at physiological concentrations (1-10 pmol/l) of islet amyloid polypeptide, no effects have been reported. We tested the effect of a wide range of concentrations of human islet amyloid polypeptide on insulin- and phorbol ester-stimulated 3-0-methylglucose transport in in vitro incubated human skeletal muscle. Muscle specimens from the quadriceps femoris muscle were obtained from 23 healthy subjects with the use of a newly-developed open muscle biopsy technique. Human islet amyloid polypeptide at a concentration of 100 nmol/l had no effect on basal glucose transport, but inhibited the stimulatory effect of a maximal insulin concentration (1000 microU/ml) by 69% (p less than 0.001). The presence of human islet amyloid polypeptide at 1, 10 and 100 nmol/l decreased the effect of 100 microU/ml of insulin on glucose transport by 61% (p less than 0.05), 78% (p less than 0.05) and 76% (p less than 0.05), respectively. Similarly, human islet amyloid polypeptide at a concentration of 10 nmol/l inhibited phorbol ester-stimulated glucose transport by 100% (p less than 0.05). The inhibitory effects of human islet amyloid polypeptide on glucose transport were present in the muscle strips despite no net changes in glycogen content. Human islet amyloid polypeptide at 10 and 100 pmol/l had no effect on the rate of insulin-stimulated glucose transport.(ABSTRACT TRUNCATED AT 250 WORDS)

3-O-Methylglucose↗
PubMed1992

Homologous islet amyloid polypeptide: effects on plasma levels of glucagon, insulin and glucose in the mouse.

We examined the effects of a single intravenous injection of homologous islet amyloid polypeptide (IAPP) on the plasma levels of glucagon, insulin and glucose in the freely fed mouse. It was observed that IAPP suppressed basal glucagon levels concomitant with a decrease of the blood glucose concentrations. Basal plasma insulin levels were not affected. IAPP did not appreciably modulate the plasma concentration of glucose, insulin or glucagon after an intravenous glucose load. Further, IAPP inhibited the insulin secretory response to beta 2-adrenoceptor stimulation. IAPP also lowered the plasma glucagon levels following beta 2-adrenoceptor stimulation, whereas no apparent effect on plasma levels of glucose was observed. The data suggest that IAPP suppresses glucagon secretion and lowers blood glucose levels in the freely fed mouse. It might also exhibit a negative feedback inhibition on beta 2-adrenoceptor-induced insulin secretion, but has little influence on glucose-induced insulin release. Since IAPP is co-secreted with insulin, it is not inconceivable, that in the freely fed mouse, IAPP may act to amplify the blood glucose lowering effect of insulin through a direct suppression of glucagon secretion via the islet microcirculation.

Amyloid↗
PubMed1992

Chromogranin A immunoreactivity compared with argyrophilia, calcitonin immunoreactivity, and amyloid as tumour markers in the histopathological diagnosis of medullary (C-cell) thyroid carcinoma.

Applying the WHO criteria for the histopathological diagnosis of medullary thyroid carcinoma (MTC)--as well as the criterion that a significant amount of argyrophil cells, amyloid deposits, or calcitonin (CT) immunoreactive cells shall be present--122 cases were identified from the files of the Swedish Cancer Registry. Both non-occult (n = 110) and "occult" (less than 1 cm in diameter) (n = 12) MTCs were included. Both primary tumours (n = 91) and metastatic lesions (n = 31) were investigated. The specimens available were all only conventionally formalin-fixed and paraffin-embedded. The presence of neoplastic cells immunoreactive with antisera against chromogranin A (Chr A) was compared with that of the other three MTC markers. Chr A immunoreactive cells were present in practically all the cases. Similar results were obtained when the argyrophil reaction alone and CT immunoreactivity alone were used as markers. When two of the three MTC markers were combined, it was found that virtually everyone of the 122 tumours could be identified as a MTC. In contrast, the presence of amyloid deposits was found to be a less constant MTC marker; whereas 94% of the primary tumours had amyloid deposits, they were present in only approximately 70% and 60% of the metastatic and "occult" tumours respectively. No differences in the staining reaction patterns were found between familial (n = 18) and the sporadic (n = 104) types of MTC.(ABSTRACT TRUNCATED AT 250 WORDS)

Amyloid↗
PubMed1992

The complete amino acid sequence of bovine serum amyloid protein A (SAA) and of subspecies of the tissue-deposited amyloid fibril protein A.

Bovine serum amyloid A (SAA) was isolated from the acute phase high density lipoprotein (HDL) fraction of a cow suffering from acute mastitis. The elucidated primary structure revealed a protein consisting of 112 amino acid residues. Compared with SAA proteins from other species, the bovine protein was shown to have an insertion of nine amino acid residues between positions 69 and 70. No microheterogeneity could be observed in the protein. Amyloid fibrils extracted from the kidneys were found to contain at least three subspecies of protein AA, consisting of 68, 81 and about 110 amino acid residues. The amino acid sequences established for the protein AA subspecies revealed no microheterogeneity, and were identical to that elucidated for protein SAA.

Amino Acid Sequence↗
PubMed1992

Pulmonary vascular amyloidosis in aged dogs. A new form of spontaneously occurring amyloidosis derived from apolipoprotein AI.

The N-terminus of a mutant form of apolipoprotein AI [apoAI] has previously been shown to be the subunit protein of amyloid fibrils in a human kindred with a form of familial amyloid polyneuropathy (FAP, type III) and in a recently reported kindred with a form of non-neuropathic hereditary amyloidosis. In this study, we demonstrate by amino-acid sequence analysis, that a form of vascular amyloidosis occurring in the lungs of aged dogs is derived from a N-terminal fragment of apoAI and that no amino acid substitution is present in this confirmed sequence. This represents the first documentation of apoAI as a precursor for a form of amyloidosis in animals, and provides the first documentation of apoAI as a precursor for amyloid fibrils in a form of age-associated ("senile") amyloidosis. Secondary structure prediction analysis of the N-terminal regions of normal human and dog apoAI indicated a propensity for beta-pleated sheet conformation, and thus amyloidogenesis, in 40 and 45% of the respective sequences. These results suggest that apoAI (like transthyretin) may serve as an amyloid precursor protein for both familial and senile forms of amyloidosis. ApoAI should, therefore, be considered as a potential amyloid precursor when forms of human senile amyloidosis of unknown origin are evaluated.

Aging↗
PubMed1992

Senile aortic amyloid. Evidence for two distinct forms of localized deposits.

Aortic tissues obtained at autopsy were examined from 84 patients (age, 18-96 years). Amyloid deposits were present in the media in 61 of 63 (97%) of the patients above the age of 50. In addition, intimal amyloid deposits were present in 35% of this group. Intimal amyloid differed from medial amyloid both in its morphologic characteristics and its association with atherosclerosis. An antiserum raised to a low molecular weight protein extracted from amyloid fibrils of the aortic media reacted specifically with medial amyloid but did not react with intimal deposits. Neither type of amyloid reacted with anti-ATTR (Senile systemic amyloid), anti-AANF (isolated atrial amyloid), or antisera to other known forms of amyloid. These findings are consistent with the presence of two separate forms of localized amyloid in the aging aorta.

Adolescent↗
PubMed1992

Islet amyloid polypeptide: mechanisms of amyloidogenesis in the pancreatic islets and potential roles in diabetes mellitus.

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)

Amino Acid Sequence↗
PubMed1991

The transthyretin cDNA sequence is normal in transthyretin-derived senile systemic amyloidosis.

A variety of mutations leading to amino acid substitutions have been described in the transthyretin gene in association with different familial amyloidoses and have been implicated to be involved in the pathogenesis of amyloid deposits. However, there has been disagreement whether or not a transthyretin mutation is present in the most common form of transthyretin-derived amyloid, namely senile systemic amyloidosis. Therefore, the cDNA sequence of liver transthyretin was determined in a 91-year-old patient with typical senile systemic amyloidosis. This sequence was completely normal and lacked any variation. We conclude that in senile systemic amyloidosis factors other than the presence of a sequentially variant transthyretin must determine the amyloid fibril formation.

Aged↗
PubMed1991

Normal transthyretin and synthetic transthyretin fragments form amyloid-like fibrils in vitro.

In two general forms of amyloidosis, senile systemic amyloidosis and several familial amyloidoses the amyloid fibrils are built up by transthyretin and fragments of the molecule. It has previously been demonstrated that other amyloid fibril proteins e.g. atrial natriuretic factor and islet amyloid polypeptide form amyloid-like fibrils in vitro. In this study we used normal transthyretin and synthetic polypeptides corresponding to segments of the transthyretin molecule. We show that normal transthyretin and two of our tested polypeptides, which corresponded to the beta-strands A and G, easily form amyloid-like fibrils in vitro.

Amino Acid Sequence↗
PubMed1991

Senile systemic amyloidosis: a clinico-pathological study of twelve patients with massive amyloid infiltration.

Hearts from 12 patients, 82-92 years old, with immunohistochemically verified pronounced senile systemic amyloidosis, were studied postmortem. Sections from the left ventricle, atrioventricular and sinus nodes and atrioventricular bundle were studied using the light microscope. The weights of the hearts varied between 310 and 870 grams. In the studied parts of the conduction system, the amounts of amyloid were considerably smaller than in the surrounding myocardium. Clinical data were taken from available case records. Eight of the patients had a history of uncomplicated congestive heart failure, but only two had been in hospital with cardiac symptoms prior to their last admission. The electrocardiogram showed atrial fibrillation in nine cases, left bundle branch block in three, right bundle branch block in two and left anterior hemiblock in one. No evidence of atrioventricular dissociation was seen and, in no case, was death considered to be due to conduction disturbances. Amyloidosis was a contributing cause of death in 7 patients, while the remaining patients died of other diseases. Amyloidosis is rarely diagnosed before death and was not suspected during life in any of our patients.

Aged↗
PubMed1991

Amyloid in the pancreatic islets of the cougar (Felis concolor) is derived from islet amyloid polypeptide (IAPP).

1. Islet amyloid isolated from the pancreas of a 20-year-old cougar (Felis concolor) was dissolved and purified by gel permeation and reversed phase HPLC for amino acid sequence analysis. 2. N-Terminal amino acid sequence analysis of the purified protein revealed a primary structure (positions 1-28) identical to islet amyloid polypeptide (IAPP) from domesticated cats. 3. IAPP from the cougar, like IAPP from the human and domesticated cat, incorporates an inherently amyloidogenic AILS sequence at positions 25-28.

Amino Acid Sequence↗
PubMed1991

Fibronectin and basement membrane components in renal amyloid deposits in patients with primary and secondary amyloidosis.

Kidney biopsies from one patient with primary (AL) and three with secondary (AA) amyloidosis were used for an ultrastructural study of the collocalization of basement membrane proteins and the extracellular matrix protein fibronectin within amyloid deposits. Antibodies against amyloid P component, laminin, and heparan sulphate proteoglycan core protein all reacted with the basement membranes and the amyloid depositions in AA and AL amyloidosis. Monoclonal and polyclonal antibodies against collagen type IV reacted only with the basement membranes. Anti-fibronectin reaction was found in association with the basement membranes in all four cases, while labelling of amyloid depositions was found only in one of the AA amyloid cases and in the AL amyloid depositions. It is concluded that basement membrane components may be of importance for the formation of amyloid fibrils.

Amyloidosis↗