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PubMed2004

Over-expression of sterol-regulatory-element-binding protein-1c (SREBP1c) in rat pancreatic islets induces lipogenesis and decreases glucose-stimulated insulin release: modulation by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR).

Accumulation of intracellular lipid by pancreatic islet beta-cells has been proposed to inhibit normal glucose-regulated insulin secretion ('glucolipotoxicity'). In the present study, we determine whether over-expression in rat islets of the lipogenic transcription factor SREBP1c (sterol-regulatory-element-binding protein-1c) affects insulin release, and whether changes in islet lipid content may be reversed by activation of AMPK (AMP-activated protein kinase). Infection with an adenovirus encoding the constitutively active nuclear fragment of SREBP1c resulted in expression of the protein in approx. 20% of islet cell nuclei, with a preference for beta-cells at the islet periphery. Real-time PCR (TaqMan) analysis showed that SREBP1c up-regulated the expression of FAS (fatty acid synthase; 6-fold), acetyl-CoA carboxylase-1 (2-fold), as well as peroxisomal-proliferator-activated receptor-gamma (7-fold), uncoupling protein-2 (1.4-fold) and Bcl2 (B-cell lymphocytic-leukaemia proto-oncogene 2; 1.3-fold). By contrast, levels of pre-proinsulin, pancreatic duodenal homeobox-1, glucokinase and GLUT2 (glucose transporter isoform-2) mRNAs were unaltered. SREBP1c-transduced islets displayed a 3-fold increase in triacylglycerol content, decreased glucose oxidation and ATP levels, and a profound inhibition of glucose-, but not depolarisation-, induced insulin secretion. Culture of islets with the AMPK activator 5-amino-4-imidazolecarboxamide riboside decreased the expression of the endogenous SREBP1c and FAS genes, and reversed the effect of over-expressing active SREBP1c on FAS mRNA levels and cellular triacylglycerol content. We conclude that SREBP1c over-expression, even when confined to a subset of beta-cells, leads to defective insulin secretion from islets and may contribute to some forms of Type II diabetes.

Acetyltransferases↗
PubMed2004

Characterization of melanosomes in murine Hermansky-Pudlak syndrome: mechanisms of hypopigmentation.

The Hermansky-Pudlak syndrome is a genetically heterogeneous autosomal recessive disorder affecting mice and humans, which causes oculocutaneous albinism, prolonged bleeding, and in some cases, pulmonary fibrosis or granulomatous colitis. We previously demonstrated that the gene defects causing murine Hermansky-Pudlak syndrome cause blocks in melanosome biogenesis and/or trafficking in 10 Hermansky-Pudlak syndrome strains. Here, we report an in vivo quantitative analysis on five additional murine models of the Hermansky-Pudlak syndrome. We demonstrate that all strains examined here except for ashen have defects in morphogenesis, the most severely affected is sandy, muted, and buff followed by subtle gray. The ashen strain only has a defect in secretion, as indicated by retention of melanosomes in melanocytes. We document three cellular mechanisms contributing to the hypopigmentation seen in the Hermansky-Pudlak syndrome: (1) exocytosis of immature hypopigmented melanosomes from melanocytes with subsequent keratinocyte uptake; (2) decreased intramelanocyte steady-state numbers of melanosomes available for transfer to keratinocytes; and (3) accumulation of melanosomes within melanocytes due to defective exocytosis, as seen in ashen. We also report that melanosomes in the DBA/2J strain, the parental strain of the Hermansky-Pudlak syndrome strain sandy, are abnormal, indicating that aberrant biogenesis of melanosomes may play a part in the pathogenesis of pigmentary glaucoma observed in these mice.

Animals↗
PubMed1999

A defect late in stimulus-secretion coupling impairs insulin secretion in Goto-Kakizaki diabetic rats.

A widely accepted genetically determined rodent model for human type 2 diabetes is the Goto-Kakizaki (GK) rat; however, the lesion(s) in the pancreatic islets of these rats has not been identified. Herein, intact islets from GK rats (aged 8-14 weeks) were studied, both immediately after isolation and after 18 h in tissue culture. Despite intact contents of insulin and protein, GK islets had markedly deficient insulin release in response to glucose, as well as to pure mitochondrial fuels or a non-nutrient membrane-depolarizing stimulus (40 mmol/l K+). In contrast, mastoparan (which activates GTP-binding proteins [GBPs]) completely circumvented any secretory defect. Basal and stimulated levels of adenine and guanine nucleotides, the activation of phospholipase C by Ca2+ or glucose, the secretory response to pertussis toxin, and the activation of selected low-molecular weight GBPs were not impaired. Defects were found, however, in the autophosphorylation and catalytic activity of cytosolic nucleoside diphosphokinase (NDPK), which may provide compartmentalized GTP pools to activate G-proteins; a deficient content of phosphoinositides was also detected. These studies identify novel, heretofore unappreciated, defects late in signal transduction in the islets of our colony of GK rats, possibly occurring at the site of activation by NDPK of a mastoparan-sensitive G-protein-dependent step in exocytosis.

Animals↗
PubMed1994

Identification and preliminary characterization of temperature-sensitive mutations affecting HlyB, the translocator required for the secretion of haemolysin (HlyA) from Escherichia coli.

We have carried out a genetic analysis of Escherichia coli HlyB using in vitro(hydroxylamine) mutagenesis and regionally directed mutagenesis. From random mutagenesis, three mutants, temperature sensitive (Ts) for secretion, were isolated and the DNA sequenced: Gly10Arg close to the N-terminus, Gly408Asp in a highly conserved small periplasmic loop region PIV, and Pro624Leu in another highly conserved region, within the ATP-binding region. Despite the Ts character of the Gly10 substitution, a derivative of HlyB, in which the first 25 amino acids were replaced by 21 amino acids of the lambda Cro protein, was still active in secretion of HlyA. This indicates that this region of HlyB is dispensable for function. Interestingly, the Gly408Asp substitution was toxic at high temperature and this is the first reported example of a conditional lethal mutation in HlyB. We have isolated 4 additional mutations in PIV by directed mutagenesis, giving a total of 5 out of 12 residues substituted in this region, with 4 mutations rendering HlyB defective in secretion. The Pro624 mutation, close to the Walker B-site for ATP binding in the cytoplasmic domain is identical to a mutation in HisP that leads to uncoupling of ATP hydrolysis from the transport of histidine. The expression of a fully functional haemolysin translocation system comprising HlyC,A,B and D increases the sensitivity of E. coli to vancomycin 2.5-fold, compared with cells expressing HlyB and HlyD alone. Thus, active translocation of HlyA renders the cells hyperpermeable to the drug. Mutations in hlyB affecting secretion could be assigned to two classes: those that restore the level of vancomycin resistance to that of E. coli not secreting HlyA and those that still confer hypersensitivity to the drug in the presence of HlyA. We propose that mutations that promote vancomycin resistance will include mutations affecting initial recognition of the secretion signal and therefore activation of a functional transport channel. Mutations that do not alter HlyA-dependent vancomycin sensitivity may, in contrast, affect later steps in the transport process.

ATP-Binding Cassette Transporters↗
PubMed2004

Adrenal medullary function and expression of catecholamine-synthesizing enzymes in mice with hypothalamic obesity.

The mechanisms underlying the onset of obesity are complex and not completely understood. An imbalance of autonomic nervous system has been proposed to be a major cause of great fat deposits accumulation in hypothalamic obesity models. In this work we therefore investigated the adrenal chromaffin cells in monosodium glutamate (MSG)-treated obese female mice. Newborn mice were injected daily with MSG (4 mg/g body weight) or saline (controls) during the first five days of life and studied at 90 days of age. The adrenal catecholamine content was 56.0% lower in the obese group when compared to lean controls (P < 0.0001). Using isolated adrenal medulla we observed no difference in basal catecholamine secretion percentile between obese and lean animals. However, the percentile of catecholamine secretion stimulated by high K+ concentration was lower in the obese group. There was a decrease in the tyrosine hydroxylase enzyme expression (57.3%, P < 0.004) in adrenal glands of obese mice. Interestingly, the expression of dopamine beta-hydroxylase was also reduced (47.0%, P < 0.005). Phenylethanolamine N-methyltransferase expression was not affected. Our results show that in the MSG model, obesity status is associated with a defective adrenal chromaffin cell function. We conclude that in MSG obesity the low total catecholamine content is directly related to a decrease of key catecholamine-synthesizing enzymes, which by its turn may lead to a defective catecholamine secretion.

Adrenal Medulla↗
PubMed1993

Hematopoietic stem-cell defects underlying abnormal macrophage development and maturation in NOD/Lt mice: defective regulation of cytokine receptors and protein kinase C.

The immunopathogenesis of autoimmune insulin-dependent diabetes in NOD mice entails defects in the development of macrophages (M phi s) from hematopoietic precursors. The present study analyzes the cellular and molecular basis underlying our previous finding that the Mø growth factor colony-stimulating factor 1 (CSF-1) promotes a reduced level of promonocyte proliferation and M phi development from NOD bone marrow. CSF-1 stimulation of NOD marrow induced Møs to differentiate to the point that they secreted levels of tumor necrosis factor alpha equivalent to that of controls. However, CSF-1 failed to prime NOD M phi s to completely differentiate in response to gamma-interferon, as shown by their decreased lipopolysaccharide-stimulated interleukin 1 secretion. These defects, in turn, were associated with an inability of CSF-1 to up-regulate c-fms (CSF-1 receptor) and Ifgr (gamma-interferon receptor) expression. Even though the combination of CSF-1 and gamma-interferon up-regulated c-fms and Ifgr transcript levels in NOD M phi s to levels induced in control M phi s by CSF-1 alone, the protein kinase C activities coupled to these receptors remained 4-fold lower in NOD M phi s than in M phi s derived from the marrow of diabetes-resistant NON and SWR control mice. Despite expressing the diabetogenic H-2g7 haplotype, M phi s derived from cytokine-stimulated marrow of the NON.H-2g7 congenic stock were functionally more mature than similarly derived M phi s from NOD mice. Whereas diabetes resistance was abrogated in 67% of irradiated (NOD x NON)F1 females reconstituted with NOD marrow, no recipients became diabetic after reconstitution with a 1:1 mixture of marrow from NOD and the congenic stock. Thus, failure to develop functionally mature monocytes may be of pathogenic significance in NOD mice.

Animals↗
PubMed1989

Normal insulin receptors in mitochondrial myopathies with ophthalmoplegia.

Seven patients with histologically proven mitochondrial myopathy with ophthalmoplegia (OMM), 6 of them nondiabetic, 1 affected by diabetes mellitus (DM), were submitted to a study of glucose tolerance and of insulin receptors on peripheral mononuclear cells and cultured skin fibroblasts. The diabetic patient, who had the typical features of the Kearns-Sayre syndrome (KSS) and deleted muscle mitochondrial DNA (mtDNA) presented a low insulin secretion rate under physiological stimuli (intravenous glucose and glucagon) whereas the insulin receptor parameters were found normal. The other patients showed a normal glucose tolerance and normal insulin receptors. Our data support the hypothesis that insulin receptors are not involved in the pathogenesis of DM associated with mitochondrial encephalomyopathies, in contrast to other neuromuscular inherited disorders. The clinical and biological features of DM presented by our KSS patient show normal insulin receptor parameters in spite of a defective insulin secretion, possibly depending on mitochondrial dysfunction.

Adult↗
PubMed1990

Cellular mechanisms of intrahepatic cholestasis.

Most forms of intrahepatic cholestasis are caused by a failure of hepatocytes to secrete osmotically active bile constituents into the minute channels of bile canaliculi. This overall vectorial bile secretory process is dependent upon a variety of polarised active transport functions at the basolateral (sinusoidal and lateral) and canalicular plasma membrane domains, as well as upon the coordinated vectorial movement of intracellular vesicles. Although considerable progress has been made in recent years in the identification, characterisation and exact localisation of a number of polarised hepatocellular transport systems, the primary mechanisms and targets leading to defective bile secretion and cholestasis are still not completely understood. For example, not all reported experimental data are compatible with the concept that estrogen-induced cholestasis represents a predominant sinusoidal disease process. In addition, the pathophysiological significance of disturbed transcytotic pathways and/or disrupted intracellular calcium homeostasis are not yet clear. For many forms of cholestasis, it remains uncertain as to whether leaky tight junctions represent a primary cause rather than a secondary phenomenon of the cholestatic state. However, the ongoing progress in the understanding of the normal mechanisms involved in the establishment, maintenance and regulation of ion homeostasis and polar transport functions in hepatocytes will, undoubtedly, improve our knowledge of the pathogenesis of intrahepatic cholestasis and, it is hoped, lead to better therapeutic strategies in the near future.

Bile↗
PubMed1988

Islet dysfunction in non-insulin-dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus is characterized by fasting hyperglycemia associated with defects in the pancreatic islet, the liver, and the peripheral tissues, which together comprise a feedback loop responsible for maintenance of glucose homeostasis. This review focuses on the key role of the endocrine pancreas A and B cells to coordinate glucose output from the liver with glucose utilization. The basal rate of hepatic glucose production is elevated in subjects with non-insulin-dependent diabetes mellitus and this is positively correlated with the degree of fasting hyperglycemia. This increased rate of glucose release by the liver results from impaired hepatic sensitivity to insulin and reduced insulin secretion. Though basal insulin levels in patients with non-insulin-dependent diabetes mellitus may appear normal when compared with those of healthy persons, islet function testing at matched glucose levels reveals impairments of basal and stimulated insulin secretion due to a reduction in B cell secretory capacity. The degree of impaired beta-cell responsiveness to glucose is closely related to the degree of fasting hyperglycemia but in a curvilinear fashion. The efficiency of glucose uptake by the peripheral tissues is also impaired due to a combination of decreased insulin secretion and defective cellular insulin action. This impairment becomes more important to the hyperglycemia as the islet dysfunction declines. Therapeutic interventions either improve islet dysfunction and raise plasma insulin levels, reduce hepatic glucose production, or improve the efficiency of tissue glucose uptake. All result in a decline in the fasting glucose level regardless of the cause of hyperglycemia. It is concluded that non-insulin-dependent diabetes mellitus is characterized by a steady-state re-regulation of plasma glucose concentration at an elevated level in which islet dysfunction plays a necessary role.

Blood Glucose↗
PubMed1999

Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants.

Chronic exposure of pancreatic islets to supraphysiologic concentrations of glucose causes adverse alterations in beta cell function, a phenomenon termed glucose toxicity and one that may play a secondary pathogenic role in type 2 diabetes. However, no mechanism of action has been definitively identified for glucose toxicity in beta cells. To ascertain whether chronic oxidative stress might play a role, we chronically cultured the beta cell line, HIT-T15, in medium containing 11.1 mM glucose with and without the antioxidants, N-acetyl-L-cysteine (NAC) or aminoguanidine (AG). Addition of NAC or AG to the culture medium at least partially prevented decreases in insulin mRNA, insulin gene promoter activity, DNA binding of two important insulin promoter transcription factors (PDX-1/STF-1 and RIPE-3b1 activator), insulin content, and glucose-induced insulin secretion. These findings suggested that one mechanism of glucose toxicity in the beta cell may be chronic exposure to reactive oxygen species, i.e., chronic oxidative stress. To ascertain the effects of these drugs on diabetes, NAC or AG was given to Zucker diabetic fatty rats, a laboratory model of type 2 diabetes, from 6 through 12 weeks of age. Both drugs prevented a rise in blood oxidative stress markers (8-hydroxy-2'-deoxyguanosine and malondialdehyde + 4-hydroxy-2-nonenal), and partially prevented hyperglycemia, glucose intolerance, defective insulin secretion as well as decrements in beta cell insulin content, insulin gene expression, and PDX-1 (STF-1) binding to the insulin gene promoter. We conclude that chronic oxidative stress may play a role in glucose toxicity, which in turn may worsen the severity of type 2 diabetes.

Acetylcysteine↗
PubMed1991

Mechanisms for hyperglycemia in type II diabetes mellitus: therapeutic implications for sulfonylurea treatment--an update.

Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by fasting hyperglycemia associated with defects in the pancreatic islet, the liver, and the peripheral tissues, which together comprise a feedback loop responsible for maintenance of glucose homeostasis. This review focuses on the key role of the endocrine pancreas alpha and beta cells to coordinate glucose output from the liver with glucose utilization. The basal rate of hepatic glucose utilization. The basal rate of hepatic glucose production is elevated in subjects with NIDDM, and this is positively correlated with the degree of fasting hyperglycemia. This increased rate of glucose release by the liver results from impaired hepatic sensitivity to insulin, reduced insulin secretion, and increased glucagon secretion. Though basal immunoreactive insulin levels in patients with NIDDM may appear normal when compared with healthy individuals, islet function testing at matched glucose levels reveals impairments of basal, steady-state, and stimulated insulin secretion due to a reduction in beta-cell secretory capacity and a reduced ability of glucose to suppress glucagon. The degree of impaired beta-cell responsiveness to glucose is closely related to the degree of fasting hyperglycemia but in a curvilinear fashion. The efficiency of glucose uptake by the peripheral tissues is also impaired due to a combination of decreased insulin secretion and defective cellular insulin action. This impairment becomes more important to the hyperglycemia as the islet alpha- and beta-cell function declines. Therapeutic interventions, to be effective, must reduce hepatic glucose production either by improving islet dysfunction and raising plasma insulin levels, or improving the effectiveness of insulin on the liver. Both result in a decline in the fasting glucose levels regardless of the cause of hyperglycemia. We conclude that NIDDM is characterized by a steady-state re-regulation of plasma glucose concentration at an elevated level in which islet dysfunction plays a necessary role. Treatment should be based on this physiologic understanding.

Diabetes Mellitus, Type 2↗
PubMed1990

[Nocturnal growth hormone secretion in children with constitutional and acquired developmental delay].

We investigated the spontaneous secretion of GH during sleep (20.00 to 8.00) in 76 children with short statute. No difference could be found between a group of 12 children with familiar short stature or a group of 28 children with familial delay of growth and development: mean GH level 5.88:5.71 maxima 26.9:25.4 ng/ml, and integrated concentration of GH 2360:2617 ng x min/ml. 14 children with severe growth hormone deficiency proven by 2 stimulation tests, secreted significantly lower amounts of GH (mean 0.83 ng/ml, maximum 2.9 ng/ml, integrated concentration 371 ng x min/ml). 22 children with nonfamilial delay of growth and development presented values being lower than the first two groups, but higher than the group of GH deficiency patients (mean 3.07 ng/ml, maximum 13.8 ng/ml, integrated concentration 1429 ng x min/ml). Since in these children the anamnesis revealed events like breech delivery, shock or commotio cerebri as the history of patients with GH deficiency does, these events apparently cause the defective GH secretion in nonfamilial delay of growth and development.

Adolescent↗
PubMed1993

Gliclazide. An update of its pharmacological properties and therapeutic efficacy in non-insulin-dependent diabetes mellitus.

Gliclazide is a second generation sulphonylurea oral hypoglycaemic agent used in the treatment of non-insulin-dependent diabetes mellitus (NIDDM). It improves defective insulin secretion and may reverse insulin resistance observed in patients with NIDDM. These actions are reflected in a reduction in blood glucose levels which is maintained during both short and long term administration, and is comparable with that achieved by other sulphonylurea agents. Gradually accumulating evidence suggests that gliclazide may be useful in patients with diabetic retinopathy, due to its haemobiological actions, and that addition of gliclazide to insulin therapy enables insulin dosage to be reduced. Thus, gliclazide is an effective agent for the treatment of the metabolic defects associated with NIDDM and may have the added advantage of potentially slowing the progression of diabetic retinopathy. These actions, together with its good general tolerability and low incidence of hypoglycaemia have allowed gliclazide to be well placed within the array of oral hypoglycaemic agents available for the control of NIDDM.

Animals↗
PubMed2000

The diabetes autoantigen ICA69 and its Caenorhabditis elegans homologue, ric-19, are conserved regulators of neuroendocrine secretion.

ICA69 is a diabetes autoantigen with no homologue of known function. Given that most diabetes autoantigens are associated with neuroendocrine secretory vesicles, we sought to determine if this is also the case for ICA69 and whether this protein participates in the process of neuroendocrine secretion. Western blot analysis of ICA69 tissue distribution in the mouse revealed a correlation between expression levels and secretory activity, with the highest expression levels in brain, pancreas, and stomach mucosa. Subcellular fractionation of mouse brain revealed that although most of the ICA69 pool is cytosolic and soluble, a subpopulation is membrane-bound and coenriched with synaptic vesicles. We used immunostaining in the HIT insulin-secreting beta-cell line to show that ICA69 localizes in a punctate manner distinct from the insulin granules, suggesting an association with the synaptic-like microvesicles found in these cells. To pursue functional studies on ICA69, we chose to use the model organism Caenorhabditis elegans, for which a homologue of ICA69 exists. We show that the promoter of the C. elegans ICA69 homologue is specifically expressed in all neurons and specialized secretory cells. A deletion mutant was isolated and found to exhibit resistance to the drug aldicarb (an inhibitor of acetylcholinesterase), suggesting defective neurotransmitter secretion in the mutant. On the basis of the aldicarb resistance phenotype, we named the gene ric-19 (resistance to inhibitors of cholinesterase-19). The resistance to aldicarb was rescued by introducing a ric-19 transgene into the ric-19 mutant background. This is the first study aimed at dissecting ICA69 function, and our results are consistent with the interpretation that ICA69/RIC-19 is an evolutionarily conserved cytosolic protein participating in the process of neuroendocrine secretion via association with certain secretory vesicles.

Amino Acid Sequence↗
PubMed1998

Decreased bone mineral density in prepubertal children with sickle cell disease: correlation with growth parameters, degree of siderosis and secretion of growth factors.

Patients with sickle cell disease (SCD) frequently have bone disorders of multifactorial aetiology. We attempted to analyse the relationships between bone mineral density (BMD) on the one hand and auxologic parameters, degree of siderosis, function of the growth hormone (GH)/insulin-like growth factor-I (IGF-I)/IGF-binding protein 3 (IGFBP3) axis, and calcium-phosphate balance in 28 prepubertal children with SCD and 15 age-matched children with constitutional short stature (CSS). Children with SCD had significantly decreased BMD (77.9 +/- 11.9 per cent of normal BMD for age and sex) and circulating concentrations of IGF-I (91 +/- 31 ng/ml) and IGFBP3 (1.7 +/- 0.44 mg/l) compared with the control group (BMD = 93.5 +/- 8.2 per cent of normal BMD for age and sex, IGF-I = 221 +/- 48 ng/ml, and IGFBP3 = 2.3 +/- 0.34 mg/ml). GH response to provocation was defective (peak below 10 micrograms/l) in 40 per cent of children with SCD. Those with SCD with defective GH secretion had significantly lower circulating IGF-I concentration and BMD than those with normal GH secretion. Serum calcium, phosphate and alkaline phosphatase concentrations were normal in all children with SCD. BMD was correlated significantly with height, weight, and body mass index as well as with the circulating concentrations of IGF-I and IGFBP3. It is suggested that increasing the circulating IGF-I concentration, either through increasing the caloric intake of subjects and/or via GH/IGF-I therapy, may improve growth and bone mineralization in these patients.

Anemia, Sickle Cell↗
PubMed2005

Restitution of defective glucose-stimulated insulin secretion in diabetic GK rat by acetylcholine uncovers paradoxical stimulatory effect of beta-cell muscarinic receptor activation on cAMP production.

Because acetylcholine (ACh) is a recognized potentiator of glucose-stimulated insulin release in the normal beta-cell, we have studied ACh's effect on islets of the Goto-Kakizaki (GK) rat, a spontaneous model of type 2 diabetes. We first verified that ACh was able to restore the insulin secretory glucose competence of the GK beta-cell. Then, we demonstrated that in GK islets 1) ACh elicited a first-phase insulin release at low glucose, whereas it had no effect in Wistar; 2) total phospholipase C activity, ACh-induced inositol phosphate production, and intracellular free calcium concentration ([Ca2+]i) elevation were normal; 3) ACh triggered insulin release, even in the presence of thapsigargin, which induced a reduction of the ACh-induced [Ca2+]i response (suggesting that ACh produces amplification signals that augment the efficacy of elevated [Ca2+]i on GK exocytosis); 4) inhibition of protein kinase C did not affect [Ca2+]i nor the insulin release responses to ACh; and 5) inhibition of cAMP-dependent protein kinases (PKAs), adenylyl cyclases, or cAMP generation, while not affecting the [Ca2+]i response, significantly lowered the insulinotropic response to ACh (at low and high glucose). In conclusion, ACh acts mainly through activation of the cAMP/PKA pathway to potently enhance Ca2+-stimulated insulin release in the GK beta-cell and, in doing so, normalizes its defective glucose responsiveness.

Acetylcholine↗
PubMed1997

Altered neuroendocrine control of GH secretion in normal women of advanced reproductive age.

BACKGROUND: Previous studies have suggested that the neuroendocrine control of growth hormone (GH) secretion changes with increasing age in women with normal menstrual cycles and sex steroid levels. METHODS: In order to verify this hypothesis, 8 younger (22-32 years) and 8 older (41-45 years) women with normal menstrual function and gonadal steroid levels were tested with the serotonergic agent sumatriptan (6 mg in a subcutaneous bolus), the GABAergic agonist sodium valproate (800 mg orally), the dopaminergic compound L-Dopa (500 mg orally) and placebos. Furthermore, all women were tested with GH-releasing hormone (GH-RH 1 microgram/kg body weight in an intravenous (i.v.) bolus) to determine whether GH secretion in response to its specific releasing factor was preserved. Serum GH levels were recorded over 2 hours in all tests and IGF-I levels in basal samples. RESULTS: Plasma IGF-I concentrations and the GH responses to sumatriptan, sodium valproate and L-Dopa were significantly lower in older than in younger women. Also, the GH-RH-induced GH response was significantly lower in older than in younger subjects. When peak GH responses to releasing stimuli were compared with age, significant negative correlations were found in all tests. CONCLUSIONS: These data did not show a specific neurotransmitter change underlying defective GH secretion in older aged reproductive women. On the other hand, the results indicated that age-related changes in the secretory machinery of GH, such as a reduced pituitary sensitivity to GH-RH and/or a reduction in the pituitary GH secretory capacity, affect women during the last years of the reproductive period.

Adult↗
PubMed1990

Bile secretion of trace elements in rats with a congenital defect in hepatobiliary transport of glutathione.

Bile secretion of trace elements, analyzed by proton-induced x-ray emission, was studied in rats with a congenital defect in hepatobiliary transport of organic anions [Groningen Yellow (GY) rats], in which the process of bile secretion resembles that of the neonatal period. Bile flow (-41%) and biliary glutathione secretion (-99%) were drastically impaired in GY rats compared with controls. Plasma concentrations of all detectable trace elements (Fe, Cu, Zn, Mo, Br, and Se), as well as that of simultaneously determined Ca, were similar in GY and age-matched control Wistar rats. Bile concentrations of Fe, Mo, Br, and Ca were also similar in both groups, resulting in a approximately 40% reduction of their secretion rates in GY rats. The concentrations of Zn (-62%) and Mn (-64%) were significantly lower in GY rats in contrast to that of Cu, which was 50% higher. Se could not be detected in bile of either group. Recovery in bile (% dose/3 h) after i.v. injection of MnCl2, CuSO4, or SeO2 (1 mg metal/kg) was lower in GY rats than in controls: Mn, 26 and 35%; Cu, 2.6 and 5%; and Se, 1.5 and 5%, respectively. Injection of ZnSO4 did not lead to increased Zn secretion in GY rats, and only 1.1% of the dose was recovered in controls. Thus, the hepatic handling of different endogenous and exogenously administered trace metals is affected to a variable extent in the GY rat. For a number of metals (e.g. Fe, Mo), this may be related to the reduced bile flow; for others (e.g. Zn, Mn, Cu), other regulatory factors appear to be responsible.

Animals↗