Malignant melanoma vs benign tumors in the young.
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Age Factors↗
Biomedical subjects
P Westermark
Publications and source records attributed to P Westermark.
Effect of insulin treatment on circulating islet amyloid polypeptide in patients with NIDDM.
The objective was to evaluate the effect of insulin treatment on circulating islet amyloid polypeptide (IAPP). Twelve patients with NIDDM and secondary failure were studied on oral agents and then switched to insulin treatment. Fasting and postprandial IAPP concentrations were measured on oral treatment and on insulin treatment. In 5 of the patients no postprandial concentrations were determined. In the 7 patients who were investigated both fasting and postprandially the fasting IAPP concentration was 6.5 +/- 1.2 pmol l(-1) (mean +/- SEM) during oral treatment with a rise to 13.5 +/- 3.1 90 min after breakfast (p = 0.028). On insulin treatment HbA1c decreased from 8.6 +/- 0.5 to 7.5 +/- 0.4% (p< 0.03) and plasma C-peptide concentration was significantly lowered (p< 0.01). There was a close correlation using simple regression between the per cent change of IAPP concentration and the per cent change of C-peptide concentration during this period (r = 0.88; p< 0.01). In the total patient material of 12 patients there was a significant correlation using simple regression analysis between per cent change of IAPP concentration and per cent change of C-peptide concentration using all 48 measurements available (r = 0.58: p< 0.001). These data suggest that secretion of IAPP is lowered when endogenous insulin secretion is lowered by administration of exogenous insulin in patients with NIDDM. Thus, if IAPP secretion has a pathogenetic role in the development of beta cell failure in NIDDM, insulin treatment might delay this deterioration.
Aged↗
Dissociated secretion of islet amyloid polypeptide and insulin in serum-free culture media conditioned by human pancreatic adenocarcinoma cell lines.
CONCLUSION: The cosecretion of insulin and islet amyloid polypeptide (IAPP) is altered when isolated rat pancreatic islets are incubated in culture media conditioned by human pancreatic cancer cells. BACKGROUND: Pancreatic cancer is usually associated with impaired glucose tolerance. This study investigates the tumor-derived influence on beta-cell secretion of pancreatic islets. METHODS: Four conditioned media were prepared from two human pancreatic cancer cell lines (Panc-1 and HPAF), a hamster pancreatic cancer cell line (PC-1), and a fibroblast cell line (Ag1523). Isolated rat pancreatic islets were incubated first in the conditioned media or nonconditioned control medium for 24 h, then in the same kind of media containing 100 microM carbamylcholine for 90 min. Insulin and IAPP secretion were measured by radioimmunoassay. RESULTS: Islets in media conditioned by Panc-1 and HPAF cells demonstrated dissociation of insulin and IAPP secretion. During 24-h incubation, the dissociation was expressed as selectively decreased insulin secretion. With addition of 100 microM carbamylcholine, the dissociation was expressed as normal secretion of insulin and hypersecretion of IAPP. As a result, the IAPP/insulin molar ratios were increased in both groups during both time periods. The islets in PC-1 and Ag1523 media did not show any significant changes in insulin and IAPP secretion.
Adenocarcinoma↗
Altered immunoreactivity of islet amyloid polypeptide (IAPP) may reflect major modifications of the IAPP molecule in amyloidogenesis.
We have developed a mouse monoclonal antibody against rat/mouse islet amyloid polypeptide (IAPP). The antibody recognises an epitope in the N-terminal part of the molecule, which is conserved between different species. The antibody immunohistochemically labelled beta cells in normal islets of most different mammalian species including man and in one avian species. Previous immunohistochemical studies of human pancreatic tissue from individuals with non-insulin-dependent diabetes mellitus (NIDDM) have revealed a paradoxical and unexplained lack of IAPP immunoreactivity in beta cells close to amyloid in spite of the presence of IAPP mRNA. In contrast to these findings we show that the newly developed monoclonal IAPP antibody strongly labels such beta cells while islet amyloid deposits which are labelled by polyclonal antisera do not bind the monoclonal antibody. These findings with the polyclonal antisera and the monoclonal antibody indicate that IAPP undergoes one or several structural changes during the amyloidogenesis. Knowledge of these structural changes that may include abnormal folding or chemical modification of IAPP is probably important for the understanding of the amyloidogenesis and the pathogenesis of the islet lesion in NIDDM.
Amino Acid Sequence↗
Prolactin-derived amyloid in the aging pituitary gland.
Small amyloid deposits occur commonly in different organs in association with aging. As in other amyloids, the fibrils in the age-associated forms are built up by specific proteins, unique to every histological type. The amyloid proteins that have been identified in localized amyloid of human endocrine organs have all been of polypeptide hormone nature, and these include calcitonin, islet amyloid polypeptide (amylin), and atrial natriuretic factor. In the present study, we add prolactin to the increasing group of known amyloid proteins and show that this hormone constitutes the amyloid fibrils of pituitary glands of aging individuals.
Aged↗
Islet amyloid polypeptide in Psammomys obesus (sand rat): effects of nutritionally induced diabetes and recovery on low-energy diet or vanadyl sulfate treatment.
We investigated the possible relationship between islet amyloid polypeptide (IAPP) and the hyperinsulinemia and/or hyperglycemia that is seen in the desert-adapted gerbil Psammomys obesus, when the animal is transferred from a low-energy (LE) diet to a high-energy (HE) diet. The effects of vanadyl sulfate and transition from a HE to a LE diet on the diabetic state of the Psammomys were also studied. Psammomys maintained on a LE diet, showing normoinsulinemia and normoglycemia (group A), were used as controls. IAPP and insulin immunoreactivity in the islets of Langerhans was studied using the peroxidase-antiperoxidase technique and plasma levels of the two hormones were determined by radioimmunoassays. The islet immunoreactivity of both IAPP and insulin was significantly weaker in the hyperinsulinemic and hyperglycemic Psammomys (group C) compared to group A. Transfer to a LE diet resulted in complete recovery of the IAPP- and insulin-staining pattern to that seen in group A [group A--Rec (nutrition)]. The plasma IAPP levels of the group C animals were not significantly higher than in group A, while after vanadyl sulfate treatment the IAPP levels and IAPP/insulin ratios remained significantly higher [group A--Rec (vanadyl)]. At the same time the circulating levels of glucose and insulin were restored to normal. Conclusively, islet IAPP and insulin immunoreactivity disappeared and reappeared in parallel in Psammomys transferred to a HE diet and back to a LE diet. Furthermore, vanadyl sulfate treatment of the hyperinsulinemic and hyperglycemic animals normalized circulating glucose and insulin levels, but not IAPP levels, possibly due to a negative feedback effect of IAPP on insulin release.
Amyloid↗
A protein AA-variant derived from a novel serum AA protein, SAA1 delta, in an individual from Papua New Guinea.
A major protein AA amyloid protein was purified and characterised from a Papua New Guinnean individual. This AA protein differed from all previously characterised SAA variants by the combination of Ala52, Val57, Asn60, Phe68, Phe69 and Gly72. Since the prevalence of AA-amyloidosis is unusually high in Papua New Guinea this AAdelta must originate from a novel SAAdelta which may represent a particularly amyloidogenic variant.
Adult↗
Effects of beta cell granule components on human islet amyloid polypeptide fibril formation.
Formation of amyloid-like fibrils in a solution of human islet amyloid polypeptide (hIAPP) with and without the presence of other beta-cell granule components was studied in vitro. Insulin at less than equimolar concentration strongly inhibited hIAPP fibrillogenesis. Proinsulin had a weaker inhibitory effect while C-peptide, Ca2+ and Zn2+ each individually enhanced fibril formation. C-peptide combined with Ca2+ had an inhibitory effect. Since IAPP was found almost exclusively in the halo fractions of isolated islet secretory granules, primarily the concentrations of C-peptide, Ca2+ and possibly proinsulin may be crucial for the native state of IAPP. It is concluded that an imbalance between fibril formation enhancers and inhibitors may be of importance in the pathogenesis of amyloid in the islets of Langerhans.
Amyloid↗
Ageing and amyloid fibrillogenesis: lessons from apolipoprotein AI, transthyretin and islet amyloid polypeptide.
The age-associated (or senile) amyloidoses encompass a heterogeneous group of systemic or localized forms of amyloidosis. In this paper we present an overview of three age-associated amyloid forms derived from transthyretin, apolipoprotein AI and islet amyloid polypeptide. Mutations in the respective genes give rise to transthyretin and apolipoprotein AI forms of familial amyloidosis while senile forms of amyloid are associated with the wild-type proteins. Different mechanisms are probably of importance in the fibrillogenesis associated with these three amyloid types. It is also possible that different amyloidogenic pathways exist for a single amyloidogenic protein. Thus, limited proteolysis may be necessary in the fibrillogenesis in senile transthyretin amyloidosis but not in most familial transthyretin amyloidoses. Other factors in the pathogenesis of amyloidosis such as local concentration, nidus formation and glycation are also discussed.
Aging↗
Primary localized amyloidosis of the eyelid: two cases of immunoglobulin light chain-derived proteins, subtype lambda V respectively lambda VI.
Primary localized amyloidosis has been described in many different organs in the body. Studies by immunohistochemical techniques have suggested an immunoglobulin light chain origin of the amyloid material. Only in a limited number of cases has the amyloid protein been characterized by amino acid sequence analysis as subtypes of immunoglobulin light chain or heavy chain. In this report, two cases of primary localized amyloidosis of the eyelid are presented. The amyloid substance has been extracted and a major fibril protein subjected to amino acid sequence analysis. Both amyloid proteins were part of the variable region of immunoglobulin light chains, subtype lambda V and subtype lambda VI, respectively. While lambda VI has been shown to be a common subtype in systemic immunoglobulin light chain-amyloidosis, it has never been demonstrated in localized amyloid. Very few lambda V immunoglobulin light chains have been characterized and the subgroup has never been found in amyloid before.
Aged↗
Increased storage and secretion of islet amyloid polypeptide relative to insulin in the spontaneously diabetic GK rat.
We have investigated whether a possible dysregulation of the storage and function of islet amyloid polypeptide (IAPP) in the endocrine pancreas of 4-month-old spontaneously diabetic Goto-Kakizaki (GK) rats might contribute to the impairment of glucose-induced insulin secretion previously reported in these rats. Immunocytochemical studies indicated a significantly lower degree of labeling per beta-cell granule of insulin but not of IAPP in GK islets compared to control islets. Further, the GK rats displayed lower plasma levels of both insulin and IAPP in the fasting state. The pancreatic concentrations of both IAPP and insulin were also significantly lower in the GK rats than in the controls. Following an intraperitoneal glucose injection, the plasma IAPP and insulin concentration of the GK rats did not increase at all, whereas a significant increase in both IAPP and insulin concentration was recorded in the control animals. However, the plasma IAPP/insulin ratio was significantly higher in the GK rats at both 30 and 60 min after glucose injection, which may be a reflection of an increased negative feedback effect of IAPP on insulin release. A relative hypersecretion of IAPP might be one of several factors contributing to the impairment of glucose-induced insulin secretion in this rat model of non-insulin-dependent diabetes mellitus. This is further supported by our electron microscopic observations showing disproportionate IAPP/insulin labeling of beta-cell granules in the GK islets.
Amyloid↗
Chronic infusion of islet amyloid polypeptide causes anorexia in rats.
Islet amyloid polypeptide (IAPP) is a hormonal peptide that at high doses has been shown to reduce food intake. In the present study, the dose-response effects of subcutaneous infusion of IAPP (0, 2, 7, and 25 pmol.kg-1.min-1) for 8 days on food intake and meal patterns in rats were investigated. At the end of the experiment, plasma was obtained and levels of IAPP were measured by radioimmunoassay. IAPP dose-dependently and transiently inhibited food intake. The minimal effective dose (2 pmol.kg-1.min-1) caused a small but significant (up to 14%, P < 0.01) inhibition of food intake that lasted 5 days. The highest dose administered (25 pmol.kg-1.min-1) had the greatest effect (up to 44%, P < 0.001), which lasted throughout the 8-day period. Reductions in feeding during light and dark phases occurred through a decrease in number of meals consumed rather than meal size or meal duration. IAPP also decreased body weight gain and water intake dose dependently. IAPP infusion of 2, 7, and 25 pmol.kg-1.min-1 increased plasma IAPP concentrations from a basal level of 10.3 +/- 0.7 pM to 35.1 +/- 5.4, 78.1 +/- 11.2, and 236.6 +/- 23.6 pM, respectively, values that are likely to be close to physiological and within the pathophysiological ranges. Thus IAPP may play an important physiological or pathophysiological role in control of food intake.
Amyloid↗
Increased plasma levels of islet amyloid polypeptide in patients with primary hyperparathyroidism.
Amylin, also named islet amyloid polypeptide (IAPP), is a protein that is processed and released from pancreatic beta-cells in parallel with insulin. Islet amyloid polypeptide is currently studied with regard to a role for insulin resistance in non-insulin-dependent diabetes. To elucidate a possible function of IAPP for impaired glucose tolerance in primary hyperparathyroidism (pHPT), we studied plasma IAPP levels during an oral glucose tolerance test (OGTT) in seven pHPT patients before and 8 weeks after surgery and in six healthy subjects. The B-glucose level of the patient groups was 4.34 +/- 0.12 mmol/l before and 3.97 +/- 0.16 mmol/l after surgery (NS), while the serum level of insulin was significantly higher before (16.9 +/- 2.8 mlU/l) than after (8.9 +/- 1.9 mlU/l) the operation (p < 0.05), indicating a moderately increased insulin resistance in pHPT. The basal plasma levels of IAPP were significantly higher in pHPT patients before than 8 weeks after surgery (9.71 +/- 1.05 and 4.30 +/- 0.82 pmol/l, respectively: p < 0.01). When compared to the plasma IAPP level of the controls at 1.80 +/- 0.38 pmol/l, pHPT patients had higher IAPP values both before (p < 0.01) and at 8 weeks after (p < 0.05) operation. There was a significant correlation between the serum levels of insulin and plasma levels of IAPP in pHPT patients before (r = 0.87, p < 0.01) as well as 8 weeks after surgery (r = 0.69, p < 0.05). The area under the curve for IAPP during OGTT in pHPT patients was 1872.4 +/- 187.7 pmol.min/l, which is significantly higher than after surgery (1010.8 +/- 93.7 pmol.min/l) (p<0.05) and compared to the area for the controls at 840.3 +/- 49.9 pmol.min/l (p<0.01). In conclusion, pHPT is associated with an increased plasma level of IAPP, correlated to the serum insulin level, but persistently higher than in controls also 8 weeks after surgery. Possibly, increased IAPP levels can have a role for impaired glucose tolerance in pHPT. The hyperparathyroid state might have a specific role for the release of this peptide, otherwise closely connected to insulin secretion
Adult↗
Macular posterior pigmentary incontinence: its relation to macular amyloidosis and notalgia paresthetica.
Patients with clinical features of dorsal macular amyloidosis but without subepidermal amyloid deposits were followed for 2-11 years. The clinical appearance was fairly stable during this period of time, with little tendency of healing. Only 2 of the patients developed typical macular amyloidosis during the follow-up. It is concluded that a condition strongly resembling macular amyloidosis but without amyloid is an entity, and the designation "macular posterior pigmentary incontinence" is proposed. The relationship between macular posterior pigmentary incontinence and the two conditions macular amyloidosis and notalgia paresthetica is discussed.
Adult↗
Effects of acute and chronic infusion of islet amyloid polypeptide on food intake in rats.
BACKGROUND: Islet amyloid polypeptide (IAPP), also called amylin, is a hormonal peptide produced by the islet beta-cells of the pancreas. Because the peptide is co-stored and co-released with insulin, attention has been focused on IAPP's ability to interfere with glucose metabolism. However, IAPP also has other effects, such as a reduction of food intake. METHODS: In this study we investigated the dose-response effect of acute systemic administration of rat and human IAPP on food intake, and the cumulative effect of chronically increased circulating IAPP concentrations on food intake and body weight in the rat. RESULTS: All doses of rat IAPP investigated acutely inhibited food intake. The lowest infusion rate of 8 pmol/kg/min caused an 28% inhibition of the food intake at 2 h (p < 0.05). No effect of human IAPP was observed. Chronic administration of rat IAPP via an osmotic minipump during a 6-day period caused prolonged inhibitory effects on food intake and reduced body weight. During the first 3 days of infusion the food intake of the IAPP group was only 44% of the food intake of the control group (p < 0.001). The body weight of the IAPP group had fallen 18.6 +/- 2.7 g by day 3, in contrast to a small increase in the control group (4.0 +/- 3.1 g; p < 0.001). The reduction in food intake was sustained throughout the last 3 days of study (IAPP, 16.7 +/- 1.1 g/day; control, 20.6 +/- 1.5; p < 0.05). Similarly, the body weight still differed at the end of day 6 and, compared with day 0, was -8.7 +/- 3.7 g for the IAPP group and +10.9 +/- 4.8 for the control group (p < 0.01). CONCLUSIONS: These findings show that chronic increase of circulating IAPP levels can cause a marked reduction in both food intake and body weight and, together with the reduced food intake seen after acute administration of the peptide, indicates the possibility of IAPP functioning as a satiety factor.
Amyloid↗
Amyloidosis: a global problem common in Papua New Guinea.
The increase in different precursor proteins that have been shown to form amyloid fibrils and the identification of common properties have not yet led to any unifying theory or mechanism for the pathogenesis of amyloidogenesis. Papua New Guinea holds a unique place in the story of amyloidosis and in this article we review the current status of amyloidosis research indicating how this relates to those forms relevant to Papua New Guinea. This review concentrates on secondary reactive amyloid (AA), which is found in the highest frequency in the world in parts of Papua New Guinea, and kuru, in which the amyloid protein itself is infectious. The history, pathogenesis and future prospects for these diseases are discussed in the light of what is known about other forms of amyloidosis.
Amyloid↗
Islet pathology of non-insulin-dependent diabetes mellitus (NIDDM).
Islet amyloid polypeptide (IAPP) gives rise to islet amyloid fibrils in NIDDM. Islet amyloid tends to replace islet cells, especially beta-cells and may act as a diffusion barrier. It has also been proposed that IAPP amyloid fibrils are beta-cell cytotoxic. The pathogenesis of islet amyloid is not clear and several factors are probably necessary for amyloid formation. One factor is an amyloidogenic amino acid sequence of IAPP and a second is probably a high local concentration of IAPP. Islet amyloid is not seen in the normal human pancreas and has not been described in the pancreata of transgenic mice over-expressing human IAPP. However, islet amyloid is rapidly deposited in in vitro cultivated islets from these transgenic animals and in isolated normal human islets transplanted into nude mice. Consequently, besides an amyloidogenic structure and high production of IAPP, further factors are necessary for islet amyloid formation in NIDDM.
Amino Acid Sequence↗
Rapid deposition of amyloid in human islets transplanted into nude mice.
Human islets of Langerhans were transplanted to the subcapsular space of the kidneys of nude mice which were either normoglycaemic or made diabetic with alloxan. After 2 weeks, the transplants were processed for light and electron microscopical analyses. In all transplants, islet amyloid polypeptide (IAPP)-positive cells were found with highest frequency in normoglycaemic animals. IAPP-positive amyloid was seen in 16 out of 22 transplants (73%), either by polarisation microscopy after Congo red staining or by immune electron microscopy. At variance with previous findings of amyloid deposits exclusively in the extracellular space of islets of non-insulin-dependent diabetic patients, the grafted islets contained intracellular amyloid deposits as well. There was no clear difference in occurrence of amyloid between diabetic and non-diabetic animals. The present study indicates that human islets transplanted into nude mice very soon present IAPP-positive amyloid deposits. This technique may provide a valuable model for studies of the pathogenesis of islet amyloid and its impact on islet cell function.
Adolescent↗