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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Acta diabetologica 33 (1996), S. 295-297 
    ISSN: 1432-5233
    Keywords: Neuropeptide Y (NPY) ; Impaired glucose tolerance ; Insulin sensitivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Neuropeptide Y (NPY) has been shown to be associated with insulin resistance, since central administration of the peptide induces muscular insulin resistance. NPY also occurs in pancreatic nerves and inhibits insulin secretion. In this study, we examined the plasma NPY levels in 10 women, aged 57–59 years, with impaired glucose tolerance (IGT), which is often accompanied by a combination of reduced insulin sensitivity and impaired insulin secretion. They were 145±4.1 pmol/l compared with 143±4.3 pmol/l in 10 age-matched women with normal glucose tolerance (NGT) (NS). Furthermore, the plasma NPY did not correlate with fasting glucose or insulin levels, the 2-h glucose value after a 75 g oral glucose challenge or insulin sensitivity as determined by the euglycemic, hyperinsulinemic clamp technique. This suggests that plasma NPY is not altered in IGT.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Acta diabetologica 33 (1996), S. 295-297 
    ISSN: 1432-5233
    Keywords: Key words Neuropeptide Y (NPY) ; Impaired glucose tolerance ; Insulin sensitivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Neuropeptide Y (NPY) has been shown to be associated with insulin resistance, since central administration of the peptide induces muscular insulin resistance. NPY also occurs in pancreatic nerves and inhibits insulin secretion. In this study, we examined the plasma NPY levels in 10 women, aged 57–59 years, with impaired glucose tolerance (IGT), which is often accompanied by a com-bination of reduced insulin sensitivity and impaired insulin secretion. They were 145 ± 4.1 pmol/l compared with 143 ± 4.3 pmol/l in 10 age-matched women with normal glucose tolerance (NGT) (NS). Furthermore, the plasma NPY did not correlate with fasting glucose or insulin levels, the 2-h glucose value after a 75 g oral glucose challenge or insulin sensitivity as determined by the euglycemic, hyperinsulinemic clamp technique. This suggests that plasma NPY is not altered in IGT.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0428
    Keywords: Islet amyloid polypeptide ; amylin ; insulin ; dexamethasone ; rat ; pancreatic islets ; in situ hybridization ; gene expression ; mRNA
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Islet amyloid polypeptide (IAPP), a novel islet hormone candidate, has been reported to be over-expressed relative to insulin in rats following dexamethasone treatment. In order to investigate the expression of IAPP and insulin following dexamethasone treatment of rats for 12 days, we applied in situ hybridization and immunocytochemistry, allowing us to evaluate islet changes in gene expression and morphology. Tissue concentrations of IAPP and insulin were measured by radioimmunoassay. A low dose of dexamethasone (0.2 mg/kg daily) increased the islet levels of IAPP and insulin mRNA to 249±13% and 150±24% of controls, respectively (p〈0.001 and p〈0.01). A high dose of dexamethasone (2.0 mg/kg daily) increased the islet levels of IAPP and insulin mRNA to 490±13% and 203±9% of controls, respectively (p〈0.001 and p〈0.001). The pancreatic concentration of IAPP increased more than that of insulin (p〈0.05). Morphometric analysis revealed that dexamethasone treatment induced both hyperplasia and hypertrophy of insulin cells. Changes in the cellular localization of IAPP and insulin mRNA were not observed. Thus, we conclude that the increased level of IAPP mRNA is due to both an increase at the cellular level as well as hyperplasia/hypertrophy of insulin cells. In contrast, the increased level of insulin mRNA appears to be due to hyperplasia/hypertrophy of insulin cells, since insulin gene expression decreased at the cellular level (p〈0.001 vs controls). These observations provide further evidence that IAPP and insulin gene expression are regulated in a non-parallel fashion, which may be relevant to the pathogenesis of non-insulin-dependent diabetes mellitus
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0428
    Keywords: Keywords Islet amyloid polypeptide (IAPP) ; amylin ; insulin ; messenger RNA (mRNA) ; in situ hybridization ; streptozotocin ; dexamethasone.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Islet amyloid polypeptide (IAPP) is over-expressed relative to insulin under several experimental conditions relevant to diabetes mellitus, including the immediate phase (7 days) following induction of streptozotocin diabetes. In the present study, IAPP and insulin gene expression were examined in chronic streptozotocin diabetes (3 weeks) in rats. Quantitative in situ hybridization, determining grain areas and optical densities of mRNA labelling, revealed that IAPP and insulin expression were reduced at the islet level at both low and high streptozotocin doses, partly due to reduced beta-cell mass. In contrast, the cellular levels of IAPP mRNA were either increased or unaffected at the low and high streptozotocin doses, respectively, whereas those of insulin mRNA were unaffected or reduced. When dexamethasone was administered to rats given the low streptozotocin dose, IAPP expression was increased, whereas that of insulin was markedly reduced. Immunocytochemistry revealed that IAPP predominantly occurred in insulin cells and to a lesser extent in somatostatin cells at all treatments examined. Our findings demonstrate that IAPP and insulin gene expression are differentially regulated; the over-expression of IAPP relative to insulin is augmented when the beta-cell insult is aggravated, in our experiments represented by massive beta-cell destruction (high streptozotocin dose) or a combination of moderate beta-cell damage and peripheral insulin resistance (low streptozotocin dose and dexamethasone). An over-expression of IAPP relative to insulin may therefore be involved in diabetes pathogenesis, contributing to its metabolic perturbations, possibly through the capacity of IAPP to restrain insulin release and action and to form islet amyloid. [Diabetologia (1996) 39: 649–657]
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-0428
    Keywords: Keywords Insulin secretion ; glucagon secretion ; islet function ; insulin sensitivity ; dexamethasone.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. To establish whether islet compensation to deterioration of insulin action depends on inherent insulin sensitivity. Methods. We examined insulin and glucagon secretion after iv arginine (5 g) at fasting, 14 and greater than 25 mmol/l glucose concentrations before and after lowering of insulin sensitivity by oral dexamethasone (3 mg twice daily for 2 1/2 days) in 10 women with normal glucose tolerance, aged 58 or 59 years. Five women had high insulin sensitivity as shown by euglycaemic, hyperinsulinaemic clamp (99 ± 12 nmol glucose · kg body weight–1· min–1/pmol insulin · l–1; means ± SD) whereas five women had low insulin sensitivity (34 ± 15 nmol glucose · kg body weight–1· min–1/pmol insulin · l–1). Results. Dexamethasone reduced insulin sensitivity in both groups. Fasting insulin concentration increased by dexamethasone in high insulin sensitivity (72 ± 10 vs 49 ± 9 pmol/l, p = 0.043) but not in low insulin sensitivity (148 ± 63 vs 145 ± 78 pmol/l) whereas the fasting glucose concentration increased in low insulin sensitivity (6.5 ± 0.8 vs 5.8 ± 0.6 mmol/l, p = 0.043) but not in high insulin sensitivity (5.3 ± 0.8 vs 5.3 ± 0.6 mmol/l). Fasting glucagon concentration was not changed. Plasma insulin concentrations after raising glucose to 14 and more than 25 mmol/l and the insulin response to arginine at more than 25 mmol/l glucose were increased by dexamethasone in high insulin sensitivity (p 〈 0.05) but not changed by dexamethasone in low insulin sensitivity. Furthermore, in high but not in low insulin sensitivity, dexamethasone reduced the glucagon response to arginine (p = 0.043). Conclusion/interpretation. The results show that adaptation in islets function to dexamethasone-induced short-term reduction in insulin sensitivity is lacking in subjects with low inherent insulin sensitivity. [Diabetologia (1999) 42: 936–943]
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-0428
    Keywords: Islet amyloid polypeptide (IAPP) ; amylin ; insulin ; messenger RNA (mRNA) ; in situ hybridization ; streptozotocin ; dexamethasone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Islet amyloid polypeptide (IAPP) is over-expressed relative to insulin under several experimental conditions relevant to diabetes mellitus, including the immediate phase (7 days) following induction of streptozotocin diabetes. In the present study, IAPP and insulin gene expression were examined in chronic streptozotocin diabetes (3 weeks) in rats. Quantitative in situ hybridization, determining grain areas and optical densities of mRNA labelling, revealed that IAPP and insulin expression were reduced at the islet level at both low and high streptozotocin doses, partly due to reduced beta-cell mass. In contrast, the cellular levels of IAPP mRNA were either increased or unaffected at the low and high streptozotocin doses, respectively, whereas those of insulin mRNA were unaffected or reduced. When dexamethasone was administered to rats given the low streptozotocin dose, IAPP expression was increased, whereas that of insulin was markedly reduced. Immunocytochemistry revealed that IAPP predominantly occurred in insulin cells and to a lesser extent in somatostatin cells at all treatments examined. Our findings demonstrate that IAPP and insulin gene expression are differentially regulated; the over-expression of IAPP relative to insulin is augmented when the beta-cell insult is aggravated, in our experiments represented by massive beta-cell destruction (high streptozotocin dose) or a combination of moderate beta-cell damage and peripheral insulin resistance (low streptozotocin dose and dexamethasone). An over-expression of IAPP relative to insulin may therefore be involved in diabetes pathogenesis, contributing to its metabolic perturbations, possibly through the capacity of IAPP to restrain insulin release and action and to form islet amyloid.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-0428
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-0428
    Keywords: Keywords IAPP ; amylin ; insulin secretion ; glucose elimination ; glucose tolerance ; transgenic mice
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Islet amyloid polypeptide (IAPP) is synthesized in islet beta cells and has been implicated in diabetes pathogenesis because it can inhibit insulin secretion and action and form fibrils leading to islet amyloidosis. Its physiological function has, however, not been established. We therefore examined insulin secretion and glucose elimination after i. v. or gastric gavage of glucose in transgenic mice overexpressing human IAPP (hIAPP) resulting in considerably increased circulating IAPP concentrations. The insulin response to and the glucose elimination after i. v. glucose (1 g/kg) were not different in transgenic mice compared with wild type animals, neither in males nor in females. In contrast, the insulin response to gastric glucose (150 mg/mouse) was reduced and the glucose elimination was inhibited in both male and female transgenic mice. The area under the 30 min insulin curve (AUCinsulin) was 21 ± 2 nmol/l in 30 min in transgenic males (n = 24) vs 43 ± 3 nmol/l in 30 min in wild type males (n = 26; p 〈 0.001) and the respective areas under the glucose curve (AUCglucose) were 1.90 ± 0.12 and 1.62 ± 0.09 mol/l in 120 min (p 〈 0.05). Similarly, in females, the AUCinsulin was 17 ± 2 nmol/l in 30 min in transgenic mice vs 25 ± 3 nmol/l in 30 min in wild type mice (p 〈 0.05) and the respective AUCglucose was 1.62 ± 0.7 and 1.12 ± 0.07 mol/l in 120 min (p 〈 0.001). Hence, endogenous hIAPP inhibits insulin secretion and glucose elimination after gastric glucose gavage in both male and female mice, indicating that overexpression of hIAPP could be a diabetogenic factor, via effects on the intestinal tract or the gut-islet axis or both. [Diabetologia (1998) 41: 1374–1380]
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1432-0428
    Keywords: Keywords IAPP ; Amylin ; transgenic mice ; ob/ob mice ; insulin resistance ; insulin insufficiency ; islet amyloid ; diabetogenic factor.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aims/hypothesis. Type II (non-insulin-dependent) diabetes mellitus is a multifactorial disease in which pancreatic islet amyloid is a characteristic histopathological finding. Islet amyloid fibrils consist of the beta-cell protein “islet amyloid polypeptide” (IAPP)/“amylin”. Unlike human IAPP (hIAPP), mouse IAPP cannot form amyloid. In previously generated transgenic mice, high expression of hIAPP as such did not induce islet amyloid formation. To further explore the potential diabetogenic role of amyloidogenic IAPP, we introduced a diabetogenic trait (“ob” mutation) in hIAPP transgenic mice. Methods. Plasma concentrations of IAPP, insulin and glucose were determined at 3.5 (t1), 6 (t2), and 16–19 months of age (t3). At t3, the mice were killed and the pancreas was analysed (immuno)histochemically. Results. In non-transgenic ob/ob mice, insulin resistance caused a compensatory increase in insulin production, normalizing the initial hyperglycaemia. In transgenic ob/ob mice, concurrent increase in hIAPP production resulted in extensive islet amyloid formation (more often and more extensive than in transgenic non-ob/ob mice), insulin insufficiency and persistent hyperglycaemia: At t3, plasma insulin levels in transgenic ob/ob mice with amyloid were fourfold lower than in non-transgenic ob/ob mice (p 〈 0.05), and plasma glucose concentrations in transgenic ob/ob mice were almost twofold higher (p 〈 0.05). In addition, the degree of islet amyloid formation in ob/ob mice was positively correlated to the glucose:insulin ratio (r s = 0.53, p 〈 0.05). Conclusion/interpretation. Islet amyloid is a secondary diabetogenic factor which can be both a consequence of insulin resistance and a cause of insulin insufficiency. [Diabetologia (1999) 42: 427–434]
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1432-0428
    Keywords: Keywords Insulin secretion ; glucagon secretion ; islet function ; impaired glucose tolerance ; non-insulin-dependent diabetes mellitus ; pathogenesis.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To study the islet adaptation to reduced insulin sensitivity in normal and glucose intolerant post-menopausal women, we performed a euglycaemic, hyperinsulinaemic clamp in 108 randomly selected women, aged 58–59 years. Of the 20 women with the lowest insulin sensitivity, 11 had impaired glucose tolerance (IGT) whereas 9 had normal glucose tolerance (NGT). These women together with 15 women with medium insulin sensitivity and 16 women with high insulin sensitivity and NGT were further examined with arginine stimulation at three glucose levels (fasting, 14 and 〉 25 mmol/l). In NGT, the acute insulin response (AIR) to 5 g i. v. arginine at all three glucose levels and the slopeAIR, i. e. the glucose potentiation of insulin secretion, were markedly increased in the women with the lowest insulin sensitivity and NGT compared to those with medium or high insulin sensitivity. In contrast, in low insulin sensitivity, AIR was significantly lower in IGT than in NGT (at glucose 14 mmol/l p = 0.015, and at 〉 25 mmol/ l p = 0.048). The potentiation of AIR induced by low insulin sensitivity in women with NGT was reduced by 74 % (AIR at 14 mmol/l glucose) and 57 % (AIR at 〉 25 mmol/l glucose), respectively, in women with IGT. Also the slopeAIR was lower in IGT than in NGT (p = 0.025); the increase in slopeAIR due to low insulin sensitivity was abolished in IGT. In contrast, glucagon secretion was not different between women with IGT as opposed to NGT. We conclude that as long as there is an adequate beta-cell adaptation to low insulin sensitivity with increased insulin secretory capacity and glucose potentiation of insulin secretion, NGT persists. [Diabetologia (1996) 39: 1099–1107]
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