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PubMed1990

Secretion of human atrial natriuretic peptide in response to atrial pacing and its function in patients with ventricular septal defect.

The capacity to secrete human atrial natriuretic peptide (hANP) in response to atrial pacing and the resulting changes in diuresis and urinary electrolyte excretion were compared in children with and without a ventricular septal defect (VSD). The subjects examined were 9 children with a history of Kawasaki disease (as controls) and 11 patients with a VSD, including 5 patients with congestive heart failure (CHF). Their ages ranged from 6 to 40 months old. Atrial pacing resulted in a significant increase in the plasma hANP level from 40 +/- 19 to 140 +/- 37 pg/ml in the controls and from 757 +/- 762 to 1540 +/- 1160 pg/ml in the VSD patients. In control children, the urinary flow rate increased 2.3-fold, urinary sodium excretion increased 6.2-fold and urinary chloride excretion increased 7.6-fold, but these values increased only slightly in VSD patients, especially in those patients with CHF, in spite of the marked increase in their plasma hANP level. These results indicate that the capacity for hANP secretion was increased in VSD patients who had chronic volume overloading of the left atrium, but that their diuresis and urinary electrolyte excretion in response to hANP were attenuated.

Atrial Natriuretic Factor↗
PubMed2004

Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors.

The role of the gluco-incretin hormones GIP and GLP-1 in the control of beta cell function was studied by analyzing mice with inactivation of each of these hormone receptor genes, or both. Our results demonstrate that glucose intolerance was additively increased during oral glucose absorption when both receptors were inactivated. After intraperitoneal injections, glucose intolerance was more severe in double- as compared to single-receptor KO mice, and euglycemic clamps revealed normal insulin sensitivity, suggesting a defect in insulin secretion. When assessed in vivo or in perfused pancreas, insulin secretion showed a lack of first phase in Glp-1R(-/-) but not in Gipr(-/-) mice. In perifusion experiments, however, first-phase insulin secretion was present in both types of islets. In double-KO islets, kinetics of insulin secretion was normal, but its amplitude was reduced by about 50% because of a defect distal to plasma membrane depolarization. Thus, gluco-incretin hormones control insulin secretion (a) by an acute insulinotropic effect on beta cells after oral glucose absorption (b) through the regulation, by GLP-1, of in vivo first-phase insulin secretion, probably by an action on extra-islet glucose sensors, and (c) by preserving the function of the secretory pathway, as evidenced by a beta cell autonomous secretion defect when both receptors are inactivated.

Animals↗
PubMed2003

Reduced beta-cell mass and altered glucose sensing impair insulin-secretory function in betaIRKO mice.

Pancreatic beta-cell-restricted knockout of the insulin receptor results in hyperglycemia due to impaired insulin secretion, suggesting that this cell is an important target of insulin action. The present studies were undertaken in beta-cell insulin receptor knockout (betaIRKO) mice to define the mechanisms underlying the defect in insulin secretion. On the basis of responses to intraperitoneal glucose, approximately 7-mo-old betaIRKO mice were either diabetic (25%) or normally glucose tolerant (75%). Total insulin content was profoundly reduced in pancreata of mutant mice compared with controls. Both groups also exhibited reduced beta-cell mass and islet number. However, insulin mRNA and protein were similar in islets of diabetic and normoglycemic betaIRKO mice compared with controls. Insulin secretion in response to insulin secretagogues from the isolated perfused pancreas was markedly reduced in the diabetic betaIRKOs and to a lesser degree in the nondiabetic betaIRKO group. Pancreatic islets of nondiabetic betaIRKO animals also exhibited defects in glyceraldehyde- and KCl-stimulated insulin release that were milder than in the diabetic animals. Gene expression analysis of islets revealed a modest reduction of GLUT2 and glucokinase gene expression in both the nondiabetic and diabetic mutants. Taken together, these data indicate that loss of functional receptors for insulin in beta-cells leads primarily to profound defects in postnatal beta-cell growth. In addition, altered glucose sensing may also contribute to defective insulin secretion in mutant animals that develop diabetes.

Animals↗
PubMed1998

Insulin resistance versus insulin deficiency in non-insulin-dependent diabetes mellitus: problems and prospects.

A definitive assessment of the relative roles of insulin resistance and insulin deficiency in the etiology of NIDDM is hampered by several problems. 1) Due to better methodology, data on insulin resistance are generally more accurate and consistent than data on insulin deficiency. 2) In source data, case-control studies are prone to selection bias, while epidemiological associations, whether cross-sectional or longitudinal, are liable to misinterpretation. 3) Insulin secretion and action are physiologically interconnected at multiple levels, so that an initial defect in either is likely to lead with time to a deficit in the companion function. The fact that both insulin resistance and impaired insulin release have been found to precede and predict NIDDM in prospective studies may be in part a reflection of just such relatedness. 4) Direct genetic analysis is effective in rarer forms of glucose intolerance (MODY, mitochondrial mutations, etc.) but encounters serious difficulties with typical late-onset NIDDM. Despite these uncertainties, the weight of current evidence supports the view that insulin resistance is very important in the etiology of typical NIDDM for the following reasons: 1) it is found in the majority of patients with the manifest disease; 2) it is only partially reversible by any form of treatment (117); 3) it can be traced back through earlier stages of IGT and high-risk conditions; and 4) it predicts subsequent development of the disease with remarkable consistency in both prediabetic and normoglycemic states. Of conceptual importance is also the fact that the key cellular mechanisms of skeletal muscle insulin resistance (defective stimulation of glucose transport, phosphorylation, and storage into glycogen) have been confirmed in NIDDM subjects by a variety of in vivo techniques [ranging from catheter balance (118) to multiple tracer kinetics (119) to 13C nuclear magnetic resonance spectroscopy (120)], and have been detected also in normoglycemic NIDDM offspring (121). If insulin resistance is a characteristic finding in many cases of NIDDM, insulin-sensitive NIDDM does exist. On the other hand, given the tight homeostatic control of plasma glucose levels in humans, beta-cell dysfunction, relative or absolute, is a sine qua non for the development of diabetes. If insulin deficiency must be present whereas insulin resistance may be present, is this proof that the former is etiologically primary to the latter? If so, do we have convincing evidence that the primacy of insulin deficiency is genetic in nature? The answer to both questions is negative on several accounts. The defect in insulin secretion in overt NIDDM is functionally severe but anatomically modest: beta-cell mass is reduced by 20-40% in patients with long-standing NIDDM (122). Moreover, the insulin secretory deficit is progressively worse with more severe hyperglycemia (123) and recovers considerably upon improving glycemic control (124). These observations indicate that part of the insulin deficiency is acquired (through glucose toxicity, lipotoxicity, or both). In addition, although insulin deficiency is necessary for diabetes, it may not always be sufficient to cause NIDDM. In fact, subtle defects in the beta-cell response to glucose may be widespread in the population (108, 125) and only cause frank hyperglycemia when obesity/insulin resistance stress the secretory machinery. Conceivably, there could be beta-cell dysfunction without NIDDM just as there is insulin resistance without diabetes. Incidentally, any defect in insulin secretion, whether in normoglycemic or hyperglycemic persons, could be due to other factors than primary beta-cell dysfunction: amyloid deposits in the pancreas (126), changes in insulin secretagogues (amylin, GLP-1, GIP, galanin) (127-130), early intrauterine malnutrition (131). Finally, the predictive power of early changes in insulin secretion for the development of typical NIDDM is generally lower than that of insulin

Diabetes Mellitus, Type 2↗
PubMedDate not supplied

Insulin secretion and insulin action in non-insulin-dependent diabetes mellitus: which defect is primary?

Defects in both insulin secretion and insulin action exist in patients with non-insulin-dependent diabetes mellitus (NIDDM). The loss of the acute plasma insulin response to intravenous glucose is seen in patients with relatively mild degrees of fasting hyperglycemia, but patients with severe fasting hyperglycemia also demonstrate absolute hypoinsulinemia in response to an oral glucose challenge. In contrast, day-long circulating insulin levels are within normal limits even in severely hyperglycemic patients with NIDDM. The relationship between NIDDM and insulin action in NIDDM is less complex, and is a characteristic feature of the syndrome. This metabolic defect is independent of obesity, and the severity of the resistance to insulin-stimulated glucose uptake increases with magnitude of hyperglycemia. Control of hyperglycemia with exogenous insulin ameliorates the degree of insulin resistance, and reduction of insulin resistance with weight loss in obese patients with NIDDM leads to an enhanced insulin response. Since neither therapeutic intervention is capable of restoring all metabolic abnormalities to normal, these observations do not tell us which of these two defects is primarily responsible for the development of NIDDM. Similarly, the observation that most patients with impaired glucose tolerance are hyperinsulinemic and insulin resistant does not prove that insulin resistance is the primary defect in NIDDM. In conclusion, reduction in both insulin secretion and action is seen in patients with NIDDM, and the relationship between these two metabolic abnormalities is very complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Glucose↗
PubMed2001

Growth hormone (GH) secretion in patients with an inactivating defect of the GH-releasing hormone (GHRH) receptor is pulsatile: evidence for a role for non-GHRH inputs into the generation of GH pulses.

GH secretion is regulated by the interaction of GHRH and somatostatin and is released in 10-20 pulses in each 24-h cycle. The exact roles in pulse generation played by somatostatin, GHRH, and the recently isolated GH-releasing peptide, Ghrelin, are not fully elucidated. To investigate the GHRH-mediated GH secretion in human, we investigated pulsatile, entropic, and 24-h rhythmic GH secretion in two young adults (male, 24 yr; female, 23 yr) from a Moroccan family with a novel inactivating defect of the GHRH receptor gene. Data were compared with values in age- and gender-matched controls. Plasma GH concentration were measured by a sensitive immunofluorometric assay, with a detection limit of 0.01 mU/L. All plasma GH concentrations in the female patient were measurable; in the male patient 30 of 145 samples were at or below the detection limit. GH secretion was pulsatile, with 21 and 23 secretory episodes/24 h in the male and female patients, respectively. The fraction of basal to total GH secretion was raised in both patients by 0.18 and 0.15, respectively. The total 24-h GH production rate was greatly diminished; in the male patient it was 6.9 mU/L (normal values for his age, 26--63 mU/L), and in the female patient it was 4.2 mU/L (normal values for her age, 96--390 mU/L). The nyctohemeral plasma GH rhythm was preserved (P < 0.001), with normal acrophases (0430 and 0218 h in the male and female, respectively). Approximate entropy was greatly elevated in both subjects (0.82 in the male and 1.17 in the female; upper normal values for age and gender, 0.24 and 0.59, respectively). Intravenous injection of 50 microg GHRH failed to increase the plasma GH concentration in both patients, but 100 microg GH-releasing peptide-2 elicited a definite increase (male patient, 0.13 to 1.74 mU/L; female patient, 0.29 to 0.87 mU/L). Both patients had a partial empty sella on magnetic resonance imaging scanning. In summary, the present studies in two patients with a profound loss of function mutation of the GHRH receptor favor the view that in the human the timing of GH pulses is primarily supervised by intermittent somatostatin withdrawal, and the amplitude of GH pulses is driven by GHRH. In addition, we infer that effectual GHRH input controls the GH cell mass and the orderliness of the secretory process.

Adult↗
PubMed2003

Mapping protein expression in mouse pancreatic islets by immunolabeling and electron energy loss spectrum-imaging.

A combination of immuno-electron microscopy and electron energy-loss spectrum-imaging was used to map the distributions of endocrine polypeptide hormones and proteins in mouse pancreatic islet of Langerhans. Tissue was analyzed from control animals and from mice that were heterozygous for the Anx7 gene, which defines a Ca2+/GTP-dependent membrane fusion and ion channel protein. The heterozygous Anx7 (+/-) mouse displays defects in IP3 receptor mediated Ca2+ signaling and insulin secretion. Therefore, information was obtained about the distributions of the hormones insulin and glucagon, as well as the proteins ANX7 and the IP3 receptor. Insulin secretion appears to be defective in the mutants. It was found from immunolabeling experiments that expression of the IP3 receptor is reduced in mutant islets compared to control islets. Subcellular distributions of sulfur and nitrogen obtained by electron energy-loss spectrum-imaging showed that the insulin concentrations of beta granules were essentially the same in control and mutant islets. By contrast, immunogold labeling of mutant islets shows more insulin immunoreactivity in the beta granules. It follows that insulin may be packaged differently in mutant islets, making antigenic determinants more available to the labeling antibody. The increased rate of insulin secretion in the hyperplastic mutant islets can be explained by compensatory increases in islet size, rather than by an increased insulin concentration in the beta cells. The results indicate that reduced ANX7 expression leads to defects in the IP3 receptor expression in the endocrine cells of the mutant mouse. Increased size of the islet or of adrenal medulla may be a compensatory mechanism for secretion defect by individual endocrine cells. Defects in IP3 receptor expression, and documented consequences of a Ca2+ signaling defect, lead to other changes in organelles such as the mitochondrial number in islet beta-cells. The effects and consequences of reduced ANX7 expression on mitochondria are evident in ultrastructural observations.

Animals↗
PubMed2006

The complement component C3 plays a critical role in both Th1 and Th2 responses to antigen.

BACKGROUND: Complement component C3 is synthesized by keratinocytes and is activated after skin injury. C3 is also synthesized by peritoneal macrophages, which are activated by the adjuvant alum. OBJECTIVE: We sought to investigate the role of C3 in inciting allergic skin Inflammation and systemic immune responses after epicutaneous sensitization or intraperitoneal sensitization with antigen. METHODS: C3-deficient (C3-/-) mice and wild-type (WT) control animals were subjected to epicutaneous sensitization with the antigen ovalbumin (OVA) on shaved and tape-stripped skin or intraperitoneal immunization with OVA in alum. RESULTS: Skin Infiltration by eosinophils and expression of mRNA encoding the TH2 cytokines IL-4 and IL-5 in OVA-sensitized skin sites was impaired in C3-/- mice. Splenocytes from epicutaneously sensitized C3-/- mice secreted less IL-4, IL-5, IL-13, and IFN-gamma in response to OVA stimulation than splenocytes from WT control animals. The defect in cytokine secretion by splenocytes was also observed after intraperitoneal immunization of C3-/- mice. C3-/- mice had impaired IgG1, IgG2a, and IgE antibody responses after both epicutaneous and intraperitoneal immunization. The defect in cytokine secretion of C3-/- mice was not due to defective proliferation to antigen, was not observed after anti-CD3 stimulation, and was corrected by the addition of purified C3 protein. CONCLUSION: These results suggest that C3 plays an important role in both the TH1 and TH2 response to antigen in vivo. CLINICAL IMPLICATIONS: The complement pathway might be a potential target in the therapy of allergic diseases.

Administration, Cutaneous↗
PubMed2004

Nephrotic livers secrete normal VLDL that acquire structural and functional defects following interaction with HDL.

BACKGROUND: Binding of very low-density lipoprotein (VLDL) isolated from serum of nephrotic rats VLDL to endothelial cells is defective. This defect is conferred on normal VLDL by prior incubation with high-density lipoprotein (HDL) from nephrotic, but not control rats. It is not known whether the defect is present in nascent VLDL (nVLDL) or is acquired after secretion. We test the hypothesis that VLDL is normal at the time of secretion from the liver and the defect in binding to endothelium is conferred following secretion through interaction with HDL. METHODS: nVLDL was synthesized by and collected from isolated perfused livers from either control or nephrotic rats. nVLDL was labeled with 3H-oleate to measure binding and 35S methionine to evaluate apolipoprotein exchange and composition. To test whether HDL conferred a binding defect, nVLDL was incubated with HDL obtained either from control or nephrotic rats prior to measurement of binding. To distinguish the effects of proteinuria from reduced albumin concentration we additionally incubated nVLDL with HDL obtained from rats with hereditary analbuminemia. Both HDL and VLDL were reisolated by centrifugation prior to subsequent binding and lipolysis determination. Exchange of 35S-labeled apolipoprotein E (apoE) among the subsequent VLDL and HDL fractions was determined. To determine the effect of HDL on lipolysis, HDL-treated VLDL was exposed to lipoprotein lipase-coated 96-well plates and 3H-oleate release measured. To establish whether differences in apoE content could explain the differences in binding and lipolysis, apoE was restored to nephrotic VLDL and lipolysis and binding were subsequently measured. RESULTS: Binding of nephrotic nVLDL was greater than control nVLDL (0.58 +/- 0.13 vs. 0.75 +/- 0.07 ng protein bound/mg cell protein) (P= 0.04, N= 6). Lipolysis was similarly elevated (0.091 +/- 0.010 vs 0.064 +/- 0.002 nmol NEFA released/well/hour) (P < 0.05). Prior incubation with nephrotic HDL reduced binding of nVLDL obtained from either nephrotic or control livers (P= 0.02, N= 6). Treatment with nephrotic (vs. control) HDL reduced both binding (control nVLDL + control HDL, 0.64 +/- 0.02; control + nephrotic, 0.43 +/- 0.06; nephrotic + control, 0.69 +/- 0.05; and nephrotic + nephrotic, 0.62 +/- 0.04 mg VLDL protein/mg cell protein) and lipolysis (control nVLDL + control HDL, 0.053 +/- 0.004; control + nephrotic, 0.038 +/- 0.004; nephrotic + control, 0.069 +/- 0.004; and nephrotic + nephrotic, 0.062 +/- 0.004 nmol NEFA/well/hour) (P < 0.05 vs. nVLDL + control HDL) of nVLDL from either source. The apoE content of nVLDL coincubated with control HDL or analbuminemic HDL was increased compared nVLDL incubated with either no HDL or nephrotic HDL (P < 0.05). Similarly, the apoE/apoA-I ratio was reduced in HDL from nephrotic rats but not in HDL from controls (P < 0.05). Reintroduction of apoE to nephrotic VLDL resulted in increased binding. CONCLUSION: Unlike circulating VLDL, binding of nVLDL from isolated livers from nephrotic rats to endothelial cells is greater and its lipolysis is increased compared to control nVLDL. Decreased binding and lipolysis is conferred following incubation with HDL isolated from control, but not nephrotic rats and binding can be restored by reintroduction of apoE. Thus both defects are conferred on VLDL by exposure to HDL obtained from nephrotic animals, possibly a consequence of a failure of nephrotic HDL to enrich VLDL with apoE during clearance.

Animals↗
PubMedDate not supplied

Treatment of type 2 diabetes.

Type 2 diabetes is a heterogeneous disease resulting from a dynamic interaction between defects in insulin secretion and insulin action. As most subjects are overweighted or obese, the initial treatment is optimization of the meal plan and enhancement of physical activity in order to obtain sustained weight reduction. In case of failure of life-style changes, various oral antihyperglycaemic agents may be used. Some are targeting defective insulin secretion (sulphonylureas, glinides) while others are targeting insulin resistance (metformin, thiazolidinediones). Criteria of drug selection should include both patient's characteristics (body weight, age, degree of hyperglycaemia, comorbidities) and pharmacological properties of the compound (mode of action, safety profile, cost). Monotherapy is usually recommended first, but combined therapy using drugs with additive or synergistic effects may be required to obtain appropriate blood glucose control. As the natural history of the disease is characterized by a progressive exhaustion of beta cells, exogenous insulin may be required in the long term, usually in combination with oral agents. Finally, as patients with type 2 diabetes are insulin-resistant and often have a metabolic syndrome, a multifactorial intervention including aggressive treatment of arterial hypertension and dyslipidaemia is recommended in order to reduce the incidence of cardiovascular complications.

Diabetes Mellitus, Type 2↗
PubMed1996

Kinesin mutations cause motor neuron disease phenotypes by disrupting fast axonal transport in Drosophila.

Previous work has shown that mutation of the gene that encodes the microtubule motor subunit kinesin heavy chain (Khc) in Drosophila inhibits neuronal sodium channel activity, action potentials and neurotransmitter secretion. These physiological defects cause progressive distal paralysis in larvae. To identify the cellular defects that cause these phenotypes, larval nerves were studied by light and electron microscopy. The axons of Khc mutants develop dramatic focal swellings along their lengths. The swellings are packed with fast axonal transport cargoes including vesicles, synaptic membrane proteins, mitochondria and prelysosomal organelles, but not with slow axonal transport cargoes such as cytoskeletal elements. Khc mutations also impair the development of larval motor axon terminals, causing dystrophic morphology and marked reductions in synaptic bouton numbers. These observations suggest that as the concentration of maternally provided wild-type KHC decreases, axonal organelles transported by kinesin periodically stall. This causes organelle jams that disrupt retrograde as well as anterograde fast axonal transport, leading to defective action potentials, dystrophic terminals, reduced transmitter secretion and progressive distal paralysis. These phenotypes parallel the pathologies of some vertebrate motor neuron diseases, including some forms of amyotrophic lateral sclerosis (ALS), and suggest that impaired fast axonal transport is a key element in these diseases.

Animals↗
PubMedDate not supplied

Discovery of the 'porosome'; the universal secretory machinery in cells.

The release of neurotransmitters at the nerve terminal for neurotransmission, release of insulin from beta-cells of the endocrine pancreas for regulating blood glucose levels, the release of growth hormone from GH cells of the pituitary gland to regulate body growth, or the expulsion of zymogen from exocrine pancreas to digest food, are only a few examples of key physiological processes made possible by cell secretion. It comes as no surprise that defects in cell secretion are the cause for numerous diseases, and have been under intense investigation for over half century. Only in the last decade, the molecular machinery and mechanism of cell secretion has become clear. Cell secretion involves the docking and transient fusion of membrane-bound secretory vesicles at the base of plasma membrane structures called porosomes, and the regulated expulsion of intravesicular contents to the outside, by vesicle swelling. The discovery of the porosome in live cells, its morphology and dynamics at nanometer resolution and in real time, its isolation, its composition, and its structural and functional reconstitution in lipid membrane, are complete. The molecular mechanism of secretory vesicle fusion at the base of porosomes, and the regulated expulsion of intravesicular contents during cell secretion, are also resolved. In this minireview, the monumental discovery of the porosome, a new cellular structure at the cell plasma membrane, is briefly discussed.

Amino Acid Sequence↗
PubMed2002

DsbA and DsbC are required for secretion of pertussis toxin by Bordetella pertussis.

The Dsb family of enzymes catalyzes disulfide bond formation in the gram-negative periplasm, which is required for folding and assembly of many secreted proteins. Pertussis toxin is arguably the most complex toxin known: it is assembled from six subunits encoded by five genes (for subunits S1 to S5), with 11 intramolecular disulfide bonds. To examine the role of the Dsb enzymes in assembly and secretion of pertussis toxin, we identified and mutated the Bordetella pertussis dsbA, dsbB, and dsbC homologues. Mutations in dsbA or dsbB resulted in decreased levels of S1 (the A subunit) and S2 (a B-subunit protein), demonstrating that DsbA and DsbB are required for toxin assembly. Mutations in dsbC did not impair assembly of periplasmic toxin but resulted in decreased toxin secretion, suggesting a defect in the formation of the Ptl secretion complex.

Animals↗
PubMed2002

YopD and LcrH regulate expression of Yersinia enterocolitica YopQ by a posttranscriptional mechanism and bind to yopQ RNA.

Pathogenic yersiniae secrete 14 Yop proteins via the type III pathway. Synthesis of YopQ occurs when the type III machinery is activated by a low-calcium signal, but not when the calcium concentration is above 100 microM. To characterize the mechanism that regulates the expression of yopQ, mutants that permit synthesis of YopQ in the presence of calcium were isolated. Yersiniae bearing deletion mutations in yopN, tyeA, sycN, or yscB synthesized and secreted YopQ in both the presence and the absence of calcium. In contrast, yersiniae with a deletion in yopD or lcrH synthesized YopQ in the presence of calcium but did not secrete the polypeptide. These variants displayed no defect in YopQ secretion under low-calcium conditions, revealing that yopD and lcrH are required for the regulation of yopQ expression. Experiments with transcriptional and translational fusions to the npt reporter gene suggest that yopD and lcrH regulate yopQ expression at a posttranscriptional step. YopD and LcrH form a complex in the bacterial cytosol and bind yopQ mRNA. Models that can account for posttranscriptional regulatory mechanisms of yop expression are discussed.

Bacterial Outer Membrane Proteins↗
PubMed1990

Decreased secretion due to a Ca2+ influx defect in frog peptic cells isolated with EGTA.

Cells prepared from frog esophageal peptic glands by dispersal in low-Ca2+ medium (peptic acini) or 1 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA)-containing medium ("EGTA cells") were compared. EGTA cells were characterized by decreased secretory responses to agonists [bombesin (BB), acetylcholine, and isoproterenol] and intracellular messenger activators (forskolin, 12-O-tetradecanoyl-phorbol-13-acetate), decreased relative intrinsic efficacies of muscarinic agonists, and somatostatin insensitivity. Decreased BB and muscarinic receptor responses were not associated with changes in receptor number or characteristics. The time course of BB- and acetylcholine-stimulated pepsinogen secretion indicated that the marked reduction was confined largely to the late secretory phase (2-30 min), dependent on extracellular Ca2+, rather than early phase (less than 2 min) secretion, which is related to release of intracellular Ca2+. The defect could be reversed by the Ca2+ ionophore A23187. BB-stimulated intracellular Ca2+ mobilization measured with fura-2/AM was similar in the two cell preparations, whereas BB-stimulated 45Ca2+ uptake was reduced threefold in EGTA cells, and this defect was also reversed by A23187. Somatostatin inhibited both BB-stimulated secretion and 45Ca uptake by peptic acini, but it had no significant effect on these parameters in EGTA cells. Cytochalasin B inhibited BB stimulation in peptic acini but not EGTA cells. These findings suggest that peptic cells isolated with EGTA exhibit decreased secretory responses that are due at least in part to impairment of a mechanism for uptake of extracellular Ca2+.

Acetylcholine↗
PubMed2002

[Treatment of diabetes mellitus: general goals, and clinical practice management].

Diabetes mellitus is associated with a marked increased of cardiovascular events. The treatment strategy of diabetes has to be based on the knowledge of its pathophysiology. Thus, insulin is essential for treatment of type 1 diabetic patients because there is a defect in insulin secretion. However, treatment of type 2 diabetic patients is more complex because a defect in both insulin secretion and insulin action exists. Therefore, the treatment selection will depend on the stage of the disease and the individual characteristics of the patient. This article examines the general goals of the treatment and reviews the management of type 2 diabetes.

Administration, Oral↗
PubMed2004

Decrease in glucose-stimulated insulin secretion with aging is independent of insulin action.

While the incidence of diabetes increases with age, a decrease in beta-cell function independent of age-related insulin resistance has not been conclusively determined. We studied insulin secretion (by hyperglycemic clamp) in 3-, 9-, and 20-month-old chronically catheterized, awake, Sprague Dawley (SD) rats (n = 78). Insulin action was modulated in a group of old rats by caloric restriction (CR) or by surgical removal of visceral fat (VF-). During the first 2 h of the clamp (11 mmol/l glucose), insulin secretion and insulin resistance (S(i hyper clamp)) demonstrated the characteristic hyperbolic relationship. However, after hyperglycemia for an additional 2 h, the ability to maintain insulin secretion, commensurate with the degree of insulin resistance, was decreased in all aging rats (P < 0.05). Increasing plasma glucose levels to 18 mmol/l glucose, after clamp at 11 mmol/l, increased insulin secretion by approximately threefold in young rats, but failed to induce similar magnitude of response in the aging rats ( approximately 50%). However, elevation of plasma free fatty acid (FFA) levels by twofold (by intralipid infusion during 11 mmol/l glucose clamp) resulted in a robust, approximate twofold response in both young and old rats. Thus, prolonged stimulation by hyperglycemia unveiled a functional defect in insulin secretion with aging. This age-related defect is independent of insulin action and is specific to glucose and not FFAs. We suggest that prolonged hyperglycemic stimulation can be a tool to identify functional defects in insulin secretion, particularly in the context of the hyperbolic relationship with insulin action, in elderly subjects or those at risk for type 2 diabetes.

Aged↗
PubMed1995

Absence of vacuolar H(+)-ATPase pump in the collecting duct of a patient with hypokalemic distal renal tubular acidosis and Sjögren's syndrome.

Distal renal tubular acidosis (dRTA) is a common complication of autoimmune connective tissue diseases. The underlying pathophysiology of renal tubular acidosis in these syndromes is frequently characterized by impaired hydrogen ion secretion, i.e., secretory defect dRTA. However, the precise molecular events leading to this disturbance remain poorly understood. An opportunity was recently afforded to examine the ultrastructural features of the collecting duct in a patient with Sjögren's syndrome and secretory defect dRTA. Immunocytochemical analysis of a renal biopsy obtained 12 months after the patient's initial presentation demonstrated a complete absence of vacuolar H(+)-ATPase in the collecting duct. Antibodies to the 31- and 56-kd kidney-specific subunits of the H(+)-ATPase pump were used to characterize pump distribution. Interestingly, although antiserum to the CI-:HCO3- anion exchanger (band-3 protein) reacted strongly with normal human kidney and the patient's red blood cells, no immunoreactivity was observed in the patient's collecting duct epithelium. Importantly, electron microscopy of the patient's renal biopsy specimen disclosed cells that ultrastructurally were indistinguishable from intercalated cells. These results suggest that the functional basis of impaired hydrogen ion secretion in this patient was secondary to the absence of intact H(+)-ATPase pumps rather than defective pump function or distribution. The presence of intercalated cells ultrastructurally, but the absence of discernible staining for band-3 protein and H(+)-ATPase, also suggests that the defect in proton secretion may represent a defect involving the assembly of at least two of the ion transport pumps essential for the normal maintenance of acid-base homeostasis by the intercalated cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Acidosis, Renal Tubular↗