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At least 793 records · Page 44Linked to original sources
PubMed1997

A prospective multicenter trial of octreotide in 24 patients with visual defects caused by nonfunctioning and gonadotropin-secreting pituitary adenomas. French Multicenter Octreotide Study Group.

OBJECTIVE: The somatostatin analog octreotide has been demonstrated to improve optic tract compression caused by pituitary macroadenomas within hours of its administration and/or reduce tumor size in some patients. We report the results of a prospective multicenter study of the effects of octreotide on visual function and tumor size in patients with nonfunctioning pituitary adenomas or gonadotropin-secreting adenomas. METHODS: Twenty-four patients with visual defects caused by histologically confirmed macroadenomas were administered octreotide via continuous subcutaneous infusion, as follows: 100 micrograms the 1st day and, if necessary, 200 micrograms the 2nd and then 100 or 200 micrograms three times daily if visual function improved. Vision was assessed after 4 days, 1 month, and 2 months, including tumor size evaluation. Visual improvement was defined by a net gain of at least 2/10 in acuity and/or of more than 20% of the surface of one isopter (a reduction in tumor volume of > or = 20% of the initial measurement); opposite changes were defined as deterioration. RESULTS: Visual improvement was noted in 13 of 24 patients, 10 of 23 patients and 9 of 22 patients, and was not noted in 11 of 24 patients, 14 of 23 patients, and 13 of 22 patients after 4 days, 1 month, and 2 months, respectively. After 2 months, three adenomas had shrunk, three had not changed in size, and one had increased; visual function improved in the seven patients with these adenomas. Octreotide was discontinued in 13 patients for lack of efficacy. CONCLUSION: The incidence of visual improvement and tumor shrinkage noted in this study was higher than previously reported. Our data suggest that early onset of visual improvement might help in deciding which patients profit from octreotide. However, concomitant gain in visual acuity with deterioration in visual fields or visual improvement with an increase (moderate) in tumor size can occur.

Adenoma↗
PubMed2006

Serum calcium is independently associated with insulin sensitivity measured with euglycaemic-hyperinsulinaemic clamp in a community-based cohort.

AIMS/HYPOTHESIS: Diabetes mellitus type 2 is associated with altered calcium metabolism. Moreover, in diseases with supranormal serum calcium levels, such as primary hyperparathyroidism, the prevalence of diabetes is increased. Relatively little is known about the relationship between serum calcium concentration and the underlying causes of diabetes-insulin resistance and defective insulin secretion-in the normocalcaemic general population. MATERIALS AND METHODS: We investigated associations between serum calcium concentration and insulin sensitivity and secretion in a population-based cohort of elderly men (Uppsala Longitudinal Study of Adult Men, n = 961). Insulin sensitivity index (M/I; glucose disposal rate [M] divided by mean insulin concentration [I]) was assessed using euglycaemic-hyperinsulinaemic clamp, and insulin secretion was estimated from the early insulin response (EIR) during an OGTT. RESULTS: In a multivariable linear regression model adjusting for BMI, physical activity, smoking, consumption of tea, alcohol, coffee and dietary calcium, serum phosphate and serum creatinine, 1 SD increase in serum calcium was associated with 0.17 mg kg(-1) min(-1) (mU/l)(-1) x 100 (0.024 mg kg(-1) min(-1) [pmol/l](-1) x 100) decrease in M/I (p = 0.01). The results remained robust in individuals with normal fasting glucose, normal glucose tolerance and serum calcium within the normal range (n = 413, regression coefficient for 1 SD increase -0.45, p = 0.001). Serum calcium was not associated with EIR. Dietary intake of calcium was not independently associated with insulin sensitivity or EIR. CONCLUSION/INTERPRETATION: Our data support the notion that endogenous calcium may be involved early in the development of diabetes and that this effect is mediated mainly through effects on insulin sensitivity rather than defective insulin secretion. Dietary intake of calcium does not seem to influence insulin sensitivity.

Aged↗
PubMed2006

Early impairment of beta-cell function and insulin sensitivity characterizes normotolerant Caucasian women with previous gestational diabetes.

BACKGROUND AND AIMS: Women with previous gestational diabetes (pGDM) are at high risk of developing type 2 diabetes mellitus. The aim of this study was to evaluate insulin action and insulin secretion in women with pGDM. METHODS AND RESULTS: One hundred and fifty-three pGDM women and 45 with normal glucose tolerance during pregnancy (controls) were studied 1-3years after delivery. Insulin sensitivity (ISI) and beta-cell secretory capacity (beta-index) were derived from 75-g OGTT. Disposition Index was calculated as the product of beta-index and ISI. One hundred and twenty-two pGDM were normotolerant (NGT) and 31 had impaired glucose regulation (IGR) i.e. impaired glucose tolerance and/or impaired fasting glucose. NGT-pGDM, as compared to controls, had significant impairment in insulin action (ISI: 5.46+/-2.81 vs. 7.38+/-3.68, P<0.01) and insulin secretion (beta-index: 4.68+/-1.01 vs. 5.24+/-0.82 pmol/min/m(2); P<0.01). A further impairment was apparent in IGR-pGDM for beta-index (4.16+/-1.09; P<0.05). The disposition index was reduced in NGT-pGDM as compared to controls (33.9%) and further reduced in IGR-pGDM (28.6%, vs. NGT-pGDM; ANOVA P<0.001). In women of normal weight, ISI and beta-index were significantly (P<0.01) impaired in NGT-pGDM compared to controls and further reduced in IGR-pGDM, although a more pronounced defect in insulin secretion was apparent in these women (beta-index: 4.02+/-0.9; P<0.05). CONCLUSIONS: Normotolerant women with pGDM show both impairment in insulin secretion and action irrespective of body weight. A more pronounced defect in insulin secretion seems to characterize normal weight women while a more prominent defect in insulin action is found in overweight women.

Adult↗
PubMed1979

Two abnormalities of glucose-induced insulin secretion: dose-response characteristics and insulin sensitivity.

To characterize the defect of insulin secretion in diabetes, the response to different iv glucose loads has been studied in women who have had gestational diabetes and are, by definition, latent diabetic (LD). Women who have produced a large-for-dates baby, but who were not known to have been diabetic (LFD), have been investigated to determine if they have abnormal metabolism. Both groups were found to have raised fasting plasma glucose concentrations. Only the LD had glucose intolerance, which was associated with a reduced first phase insulin response to all glucose loads with a decreased maximal secretory capacity (low V max). The LFD women appeared to include a distinct abnormality in which the beta cells had decreased sensitivity to glucose (high Km), with diminished secretory response to small but normal response to large loads. Whereas the LD probably have disordered beta cell function, some of the LFD women may represent the upper end of the normal range of the glucose "set" of beta cell function. Neither group had insulin resistance, as measured by the hypoglycaemic response to an iv insulin bolus. A woman who has produced a LFD, but who was not known to be diabetic, does not necessarily have a diabetic tendency.

Adult↗
PubMed2004

Induction of beta-cell rest by a Kir6.2/SUR1-selective K(ATP)-channel opener preserves beta-cell insulin stores and insulin secretion in human islets cultured at high (11 mM) glucose.

In health, most insulin is secreted in pulses. Type 2 diabetes mellitus (TTDM) is characterized by impaired pulsatile insulin secretion with a defect in insulin pulse mass. It has been suggested that this defect is partly due to chronic overstimulation of beta-cells imposed by insulin resistance and hyperglycemia, which results in depletion of pancreatic insulin stores. It has been reported that in TTDM overnight inhibition of insulin secretion (induction of beta-cell rest) leads to quantitative normalization of pulsatile insulin secretion upon subsequent stimulation. Recently, decreased orderliness of insulin secretion has been recognized as another attribute of impaired insulin secretion in TTDM. In the current studies we sought to address at the level of the isolated islet whether chronic elevated glucose concentrations induce both defects involved in impaired insulin secretion in TTDM: deficiency and decreased orderliness of insulin secretion. We use the concept of beta-cell rest, induced by a novel beta-cell selective K(ATP)-channel opener (KCO), NN414 (6-chloro-3-(1-methylcyclopropyl)amino-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide), to test whether preservation of insulin stores leads to normalization of both processes in response to glucose stimulation. Human islets were isolated from three cadaveric organ donors and studied in perifusion experiments and static incubation. Acute activation of K(ATP)-channels suppressed insulin secretion from perifused human islets by approximately 90% (P < 0.0001). This KCO also inhibited glucagon secretion in a dose-dependent manner (P = 0.01). Static incubation at 11 and 16 vs. 4 mM glucose for 96 h decreased islet insulin stores by approximately 80% and 85% (P < 0.0001, respectively). In subsequent perifusion experiments, total insulin secretion ( approximately 30%; P < 0.01) from these islets and insulin pulse mass ( approximately 40%; P < 0.05) were both decreased (11 vs. 4 mM). The inhibition of insulin secretion during static incubation with KCO reduced the loss of islet insulin stores in a dose-dependent manner (P < 0.0001) and resulted in increased total insulin secretion (2.6-fold; P < 0.01) and insulin pulse mass (2.5-fold; P < 0.05) during subsequent perifusion. The orderliness of insulin secretion was significantly reduced after chronic incubation of human islets at 11 mM glucose (P = 0.04), but induction of beta-cell rest at 11 mM failed to normalize the regularity of insulin secretion during subsequent perifusion. We conclude that physiological increased glucose concentrations (11 mM), which are frequently observed in diabetes, lead to a loss of islet insulin stores and defective pulsatile insulin secretion as well as reduced orderliness of insulin secretion. Induction of beta-cell rest by selective activation of beta-cell K(ATP)-channels preserves insulin stores and pulsatile insulin secretion without restoring the orderliness of insulin secretion. Therefore, the concept of beta-cell rest may provide a strategy to protect beta-cells from chronic overstimulation and to improve islet function. Impaired glucose-regulated insulin secretion in TTDM may, however, partially involve mechanisms that are distinct from insulin stores and insulin secretion rates.

Adenosine Triphosphate↗
PubMed1986

Defect of the first-phase insulin secretion to glucose stimulation in the perfused pancreas of the nonobese diabetic (NOD) mouse.

To investigate the development of impaired insulin secretion in type I diabetes mellitus, the pancreata of ICR and NOD mice (10-50 wk of age) were perfused. According to insulin responses to 30 mM glucose and to 19 mM arginine, we classified the NOD mice into four groups: those having normal insulin secretion to glucose and to arginine similar to that of control ICR mice (group 1); those with a defect in the first-phase insulin secretion to glucose stimulation but with almost normal insulin secretion to arginine, total insulin release to glucose being significantly smaller than that of group 1 (group 2); those having only a small insulin response to either stimulus, but a fasting plasma glucose level still within the normal range (group 3); and those being overtly diabetic, showing no insulin response to either stimulus (group 4). The severity of insulitis and insulin concentration of the pancreas in each group of NOD mice was well correlated with the insulin release from the perfused pancreas. These results indicate that the initial sign of B-cell damage in NOD mice is a defect of the first phase of glucose-induced insulin secretion, which is followed by a total loss of ability to respond to glucose or arginine stimulation.

Animals↗
PubMed1991

Regulation of hypothalamic gonadotropin-releasing hormone secretion in experimental uremia: in vitro studies.

Defective regulation of hypothalamic gonadotropin-releasing hormone (GnRH) secretion is the primary defect leading to the inhibition of pituitary gonadotropin secretion and its consequences such as androgen deficiency and infertility in experimental uremia. Previous studies using indirect methods to study presumptive GnRH release and the function of GnRH-secreting neurons have suggested functional disturbances of GnRH neurosecretion; however, the precise biochemical mechanisms involved were not defined. Therefore, in order to clarify the mechanisms of aberrant regulation of hypothalamic GnRH secretion in experimental uremia, we examined basal secretion of GnRH from mediobasal hypothalamus (MBH) in vitro and the GnRH-secretory responses to naloxone, an opiate receptor antagonist in experimental uremia. Using a static incubation system, adult male rats, either intact or castrate, with subtotal nephrectomy demonstrated a significant reduction of GnRH secretion by 25% in intact and by 40% in castrate uremic male rats compared with their nonuremic controls. In contrast, hypothalamic GnRH content of uremic animals was increased significantly (6% in intact and 14% in castrate uremic rats). Despite the fall in basal GnRH release from MBH, the MBH GnRH release response to in vitro stimulation by an opioid blocker (naloxone) and a membrane-depolarizing agent (veratrine) were not diminished in uremic male rats. These findings suggest that the inhibition of pituitary gonadotropin secretion in experimental uremia is likely to be due to a functional defect in suprahypothalamic regulation of GnRH secretion rather than an intrinsic defect in the GnRH-secreting neurons. Further studies are required to clarify the nature of the neuromodulator interactions involved.

Animals↗
PubMed1984

The dark mink: a model of male infertility.

Breeding mink for a fine dark fur has coselected male infertility, which may be manifest at the onset of breeding (primary infertility) or after one or more fertile breeding seasons (secondary infertility). Mink with primary infertility have low LH and testosterone levels. However, they respond to exogenous GnRH with increases in LH production and in the number and size of LH and FSH positive gonadotropes in the anterior pituitary. Exogenous human CG also induces testosterone secretion. Thus, mink with primary infertility are probably defective in GnRH secretion, which is due either to abnormal hypothalamic function or its control mechanisms. Autoimmune orchitis with testicular immune complexes are frequent in mink with secondary infertility, suggesting an autoimmune etiology. In contrast, fertile dark mink and fertile mink with the opaline and pastel fur have normal serum LH and testosterone levels; their testes are also normal. In mink with secondary infertility, the frequency and degree of orchitis and testicular immune complexes increased from March (peak sexual activity) to April (onset of testicular regression). Thus, testicular autoimmunity most likely develops during testicular regression. Antisperm antibodies also increased in frequency during testicular regression in the fertile dark mink and in dark mink with primary and secondary infertility. Thus, antisperm antibody per se is insufficient to induce autoimmune orchitis. It is concluded that the infertile mink is a useful model of human male infertility, involving both endocrinological and immunological mechanisms.

Animals↗
PubMed1992

Progressive and concurrent deterioration of vagus-stimulated and hypoglycemia-induced glucagon secretion in streptozotocin-diabetic rats.

The effects of left cervical vagus nerve stimulation on glucagon secretion were studied in streptozotocin-diabetic and age-matched control adult male rats. At two-week intervals, after the induction of streptozotocin-diabetes, streptozotocin-diabetic and age-matched control rats were anesthetized with chloral hydrate (350 mg/kg, ip). Left cervical vagus nerves were electrically stimulated via a Grass stimulator with 5-volt monophasic pulses of 3 msec duration at a frequency of 20 Hz for 1, 2, and 4 min. Arginine-induced glucagon secretion was also determined. Vagus nerve-stimulated (2 and 4 min) glucagon secretion deteriorated as the duration of streptozotocin-diabetes increased. Glucagon secretion in response to vagus nerve stimulation was virtually absent by 12 weeks of streptozotocin-diabetes. However, arginine-induced glucagon secretion was unaffected. Subsequent experiments showed that the defect in glucagon secretion from vagal stimulation occurred concurrently with that seen from insulin-induced hypoglycemia. These results indicate that the impaired hypoglycemia-induced glucagon secretion in long-term streptozotocin-diabetic rats may be correlated with the deterioration of the parasympathetic nervous system transmission in streptozotocin-diabetes.

Animals↗
PubMed2004

Short-term intensive insulin therapy in newly diagnosed type 2 diabetes.

OBJECTIVE: Type 2 diabetes is associated with defects in insulin secretion and insulin action. Hyperglycemia may aggravate these defects, a feature known as glucose toxicity. Previous studies have shown that acute correction of hyperglycemia in subjects with long-standing type 2 diabetes gives only short-term improvement in glycemic control after discontinuation of insulin. The current study attempts to identify any characteristics of patients with newly diagnosed type 2 diabetes (fasting glucose >11.0 mmol/l) who would have a long-term benefit, in terms of glycemic control, from a brief course of insulin therapy. RESEARCH DESIGN AND METHODS: A total of 16 subjects (52 +/- 2 years old [range 36-64], BMI 30.8 +/- 1.9 kg/m2) with newly diagnosed type 2 diabetes had a 2-3 week course of intensive insulin therapy that was then discontinued. RESULTS: Fasting glucose fell from 13.3 +/- 0.7 to 7.0 +/- 0.4 mmol/l, and this improvement was maintained at the 1-year follow-up (6.7 +/- 0.3 mmol/l). The insulin area under the curve for the posttreatment oral glucose tolerance test also improved (8,251 +/- 1,880 before therapy, 18,404 +/- 4,040 directly after insulin therapy, and 42,368 +/- 8,517 pmol.min at the 1-year follow-up). At 1 year, seven of the subjects maintained good glycemic control on diet therapy alone, eight required oral hypoglycemic agent (OHA) therapy, and one required insulin therapy. The distinguishing features of those who did not require OHA or insulin therapy were that they required less insulin during the active insulin therapy phase (0.37 +/- 0.05 vs. 0.73 +/- 0.07 units.kg(-1).day(-1)) and were able to attain a lower fasting serum glucose at the end of the period of insulin therapy (5.9 +/- 0.3 vs. 7.7 +/- 0.4 mmol/l). CONCLUSIONS: These results demonstrate that in newly diagnosed type 2 diabetes with elevated fasting glucose levels, a 2- to 3-week course of intensive insulin therapy can successfully lay a foundation for prolonged good glycemic control. The ease with which normoglycemia is achieved on insulin may predict those patients who can later succeed in controlling glucose levels with attention to diet alone.

Administration, Oral↗
PubMed1993

Type 2 diabetes mellitus. Aspects of complications and treatment.

Non-insulin-dependent or type 2 diabetes is a heterogeneous disorder, characterized by defects in insulin secretion as well as in insulin action; these defects are worsened by the developing hyperglycaemia. Diabetes is an independent risk factor for the development of cardiovascular disease. In addition to hypertension, which is encountered in almost 50% of patients, lipid abnormalities, comprising elevations of both LDL-cholesterol and VLDL-triglycerides, as well as decreases in the levels of HDL-cholesterol, contribute to the high prevalence of vascular disease. Elevated levels of serum lipoprotein(a) may add to this increased risk. Considering the apparent clustering of risk factors such as poor metabolic control, obesity, hypertension and dyslipidaemia, the attainment of optimal blood glucose control forms only one of the aims of treatment to prevent the neurological and vascular complications, which severely affect the quality of life. Dietary advice comprises the adoption of healthy eating habits and reducing the intake of refined sugars and saturated fat. The long-term metabolic effects of intensive dietary therapy, however, have been disappointing. This necessitates early pharmacological treatment in a considerable number of patients. With mild hyperglycaemia, the metabolic effects of sulphonylurea and insulin treatment were comparable, but insulin is superior to sulphonylurea in patients who are more hyperglycaemic (fasting blood glucose > 11 mmol/l). In addition to its effects on blood glucose control, insulin therapy favourably affects dyslipidaemia. Treatment can be safely instituted on an outpatient basis, and hypoglycaemic side-effects are infrequent. Combination therapy of insulin and sulphonylurea results in similar metabolic improvement when compared with insulin treatment alone, but with a lower dose of insulin and the need for only one injection in two-thirds of patients. Drugs such as ACE inhibitors, which have no metabolic side-effects, have become the therapy of choice when treating hypertension in diabetic patients.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2006

Insulin secretion and sensitivity as determinants of HbA1c in type 2 diabetes.

BACKGROUND: Defects in insulin secretion and sensitivity, two major determinants of glycaemic control, can occur and progress or not in parallel. The present study was designed to compare the respective roles of both determinants on HbA1c, in type 2 diabetic patients, according to whether or not residual beta-cell function was stimulated with insulin secretagogues. MATERIALS AND METHODS: Insulin secretion and insulin sensitivity were both estimated using the homeostasis model assessment (HOMA). HbA1c, insulin sensitivity (HOMA2%S) and insulin secretion (HOMA2%B) were determined in 289 noninsulin-using type 2 diabetic patients who were further divided into two groups according to treatment: metformin alone (group I, n = 57) or metformin and glyburide (group II, n = 232). The patients of both groups were further divided into three subsets in order to test the dependence of HbA1c on HOMA2%B and HOMA2%S. RESULTS: In group I mean HbA1c were greater (8.4%) in patients with HOMA2%B < 50% than in the two subsets with HOMA2%B > or = 50%: 7.2 and 6.8% (P = 0.0013). In group II mean values of stimulated-insulin secretion (HOMA2%B) were lesser (40.7 and 30.1%) in the two subsets of patients with HbA1c > or = 8% than in patients with HbA1c < 8%: 55.1% (P < 0.0001). By contrast, we found no differences in both groups with HOMA2%S. A stepwise multiple regression showed that HOMA2%B contributed to HbA1c more than HOMA2%S both in groups I (33.5% vs. 23.4%) and II (22.7% vs. 8%). CONCLUSIONS: Although the role of insulin sensitivity is not negligible, insulin secretion appears to be the major determinant of diabetic control in overt type 2 diabetic patients who are treated with metformin alone or with a two-drug therapy combining metformin and glyburide.

Biomarkers↗
PubMed2007

Functional patterns of HIV-1-specific CD4 T-cell responses in children are influenced by the extent of virus suppression and exposure.

BACKGROUND: Virus-specific CD4 T cells play a critical role in antiviral immunity. HIV-1-specific CD4 T cells in chronically infected adults are mostly composed of IFN-gamma-secreting cells, whereas a selective defect in IL-2-secreting CD4 T cells has been demonstrated. HIV-1-specific IL-2-secreting CD4 T cells are key components of effective immunity. OBJECTIVE: To determine the function of HIV-1-specific CD4 T cells in HIV-1 vertically infected children after antiretroviral treatment (ART). DESIGN: Twenty-three vertically HIV-infected children treated with ART for an extended period (mean 7 years) were retrospectively studied. METHODS: The function of HIV-1-specific CD4 T cells was determined by their ability to secrete IL-2 and IFN-gamma after stimulation with HIV-1 p55 gag protein using polychromatic flow cytometry. RESULTS: : Substantial differences in the patterns of CD4 T-cell responses were associated with different conditions of response to ART. Interestingly, children with suppression of viraemia below 50 HIV-1-RNA copies/ml of plasma for at least 2 years showed dominant IL-2 CD4 T-cell responses; children with viraemia below 50 copies but experiencing transient blips of viraemia showed polyfunctional (IL-2 plus IFN-gamma) CD4 T-cell responses; children with uncontrolled high viraemia levels had dominant IFN-gamma CD4 T-cell responses. Furthermore, the total frequency of HIV-1-specific CD4 T cells including IL-2 and IFN-gamma-secreting cells was significantly higher compared with HIV-infected adults with chronic infection. CONCLUSION: The higher frequency of HIV-1-specific CD4 T cells in children compared with adults and the recovery of IL-2-secreting CD4 T cells after successful ART-mediated suppression of virus replication indicate a greater capacity of immune restoration in children than adults.

Analysis of Variance↗
PubMed2005

Diagnosis and management of pituitary tumours in the elderly: a review based on personal experience and evidence of literature.

An increasing proportion of pituitary adenomas are recognized in the elderly, raising the question of their optimal diagnosis and management. Age-related endocrine changes and associated diseases may significantly modify the clinical presentation and hormonal evaluation of these patients. About 80% of pituitary adenomas in this age group are non-secreting, requiring careful differential diagnosis with non-adenomatous sellar lesions. In this group, visual deterioration and hypopituitarism remain the leading symptoms. Recognized secreting tumours are mainly GH-secreting, most of them intrasellar, followed by prolactinomas, which present as clinically non-secreting and are usually invasive. Cushing's disease appears as a very rare eventuality in the elderly. Optimal therapeutic management should aim to control the disease while preserving or improving patient's quality of life. Transsphenoidal surgery has proved to be an efficient and well-tolerated option for non-secreting adenomas with visual defects and intrasellar GH-secreting adenomas, being able to improve metabolic and cardiovascular complications of acromegaly even in this age group. In contrast, dopamine-agonist drugs can be proposed as a primary therapy for prolactinomas even in the presence of severe neurological complications. Because the use of radiotherapy is hampered by its delay of action and potential neurological side effects, its indications should be better defined in this age group. The clinical importance of hypopituitarism should not be underestimated, and thyroid- and adrenal-replacement therapy are mandatory in the presence of documented hormone deficiency, carefully avoiding overtreatment in order to limit possible side effects on the cardiovascular system and bone mineralization. Indications for GH- and sex steroid-replacement therapy still await age-specific guidelines.

Acromegaly↗
PubMed1994

Isolation of three classes of conditional lethal Chinese hamster ovary cell mutants with temperature-dependent defects in low density lipoprotein receptor stability and intracellular membrane transport.

Fluorescence-activated cell sorting was used to isolate 19 independent, temperature-sensitive, low density lipoprotein (LDL) receptor-deficient Chinese hamster ovary cell mutants that define three recessive complementation groups, ldlE, ldlF, ldlG. LDL receptor activity, essentially normal at the permissive temperature (34 degrees C), was virtually abolished in the mutants after incubation for 8-12 h at the nonpermissive temperature (39-40.5 degrees C). The mutants died after incubation for > 24 h at 39.5 degrees C. These mutants exhibited two striking and unexpected abnormalities that suggest that they define three genes important for general vesicular membrane traffic. First, LDL receptors were degraded abnormally rapidly at the nonpermissive temperature (chloroquine inhibited this degradation in ldlE and ldlG, but not in ldlF). In ldlE cells, the rapid degradation did not require efficient receptor clustering into coated pits and was not observed for all cell surface proteins. This selective degradation may be due to endocytic missorting. Second, the mutants exhibited temperature-sensitive defects in the posttranslational processing and intracellular transport of many membrane-associated and secreted proteins, including the LDL, mannose 6-phosphate/insulin-like growth factor II, and scavenger receptors, the vesicular stomatitis virus G protein and decay accelerating factor. Although the initial synthesis, folding, and processing of precursor forms of these proteins in the endoplasmic reticulum were apparently normal at the nonpermissive temperature, there was either a delay or a block in oligosaccharide processing associated with endoplasmic reticulum to medial Golgi transport at the nonpermissive temperature. This was accompanied by a dramatic inhibition of total soluble protein secretion. The posttranslational processing defects, the instability of cell surface LDL receptors, and the defective protein secretion exhibited by these mutants suggest that the ldlE-G gene products regulate or participate in reactions that are vital for a variety of secretory and endocytic membrane transport processes. This suggestion is strongly supported by our recent observation that a cDNA encoding a component of the coatomer, epsilon-COP, corrects the mutant phenotypes of ldlF cells (Guo, Q., Vasile, E., and Krieger, M. (1994) J. Cell Biol. 125, 1213-1224). Thus, these mutant cells should prove useful for further genetic and biochemical analysis of the mechanisms underlying intracellular membrane traffic.

Animals↗
PubMed2001

Impaired pancreatic ductal bicarbonate secretion in cystic fibrosis.

Patients with cystic fibrosis demonstrate a defect in HCO(3)(-) secretion by their pancreatic duct cells. However, attempts toward understanding or correcting this defect have been hampered by a lack of knowledge regarding the cellular and molecular mechanisms mediating HCO(3)(-) transport in these cells. Recent functional and molecular studies indicate a major role for a basolateral electrogenically-driven Na(+):HCO(3)(-) cotransporter (NBC1) in mediating the transport of HCO(3)(-) into the duct cells. The HCO(3)(-) exits at the lumen predominantly via two recently discovered apical HCO(3)(-) transporters. cAMP, which mediates the stimulatory effect of secretin on pancreatic ductal HCO(3)(-) secretion, potentiates the basolateral Na(+):HCO(3)(-) cotransporter due to generation of a favorable electrogenic gradient as a result of membrane depolarization by Cl(-)-secreting cystic fibrosis transmembrane conductance regulator (CFTR). Two apical HCO(3)(-) transporters drive the secretion of bicarbonate into the pancreatic duct lumen. Molecular and functional studies indicate that CFTR upregulates the expression of these two apical HCO(3)(-) transporters. In addition, CFTR may also upregulate the expression of certain water channels and facilitate the secretion of fluid into the duct lumen. In brief, current research suggests that the defect in pancreatic HCO(3)(-) secretion in patients with cystic fibrosis is multifactorial and involves the alteration in the function/expression of transporters at the basolateral and luminal membrane domains of the duct cells.

Bicarbonates↗
PubMed1998

Dominant-negative suppression of HNF-1alpha function results in defective insulin gene transcription and impaired metabolism-secretion coupling in a pancreatic beta-cell line.

Mutations in the hepatocyte nuclear factor-1alpha (HNF-1alpha) have been linked to subtype 3 of maturity-onset diabetes of the young (MODY3), which is characterized by a primary defect in insulin secretion. The role of HNF-1alpha in the regulation of pancreatic beta-cell function was investigated. Gene manipulation allowed graded overexpression of HNF-1alpha and controlled dominant-negative suppression of HNF-1alpha function in insulinoma INS-1 cells. We show that HNF-1alpha is essential for insulin gene transcription, as demonstrated by a pronounced decrease in insulin mRNA expression and in insulin promoter activity under dominant-negative conditions. The expression of genes involved in glucose transport and metabolism including glucose transporter-2 and L-type pyruvate kinase is also regulated by HNF-1alpha. Loss of HNF-1alpha function leads to severe defects in insulin secretory responses to glucose and leucine, resulting from impaired glucose utilization and mitochondrial oxidation. The nutrient-evoked ATP production and subsequent changes in plasma membrane potential and intracellular Ca2+ were diminished by suppression of HNF-1alpha function. These results suggest that HNF-1alpha function is essential for maintaining insulin storage and nutrient-evoked release. The defective mitochondrial oxidation of metabolic substrates causes impaired insulin secretion, indicating a molecular basis for the diabetic phenotype of MODY3 patients.

Adenosine Triphosphate↗