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PubMed2005

Human chorionic gonadotropin therapy in adolescent boys with constitutional delayed puberty vs those with beta-thalassemia major.

We studied 12 adolescent boys with beta-thalassemia major and delayed puberty (age, 15.8 +/- 1 years) with Tanner I sexual development treated with a long-term low-transfusion regimen. Ten nonthalassemic adolescents (> 14 years) with constitutional delay of growth and puberty (CDGP) served as controls. Auxologic parameters and testicular size were measured, and bone age was determined. Measurement of basal gonadotropin (luteinizing hormone [LH] and follicle-stimulating hormone [FSH]) and testosterone (T) levels taken at 8 am revealed prepubertal levels in both groups of patients. Human chorionic gonadotropin (hCG, 2500 U/m(2)) was injected intramuscularly twice weekly for 6 months, and anthropometric data, testicular diameter, and serum T concentrations were remeasured after 1 and 6 months. The testicular diameter after 6 month of hCG therapy was significantly correlated with the testicular diameter and T level after 1 month of therapy (r = 0.93 and 0.39, respectively, P < .01). After 6 months of hCG therapy, the mean growth velocity (GV) increased from 4.1 to 8.6 cm/y in thalassemic patients and from 4.6 to 10.3 cm/y in those with CDGP during hCG therapy. In thalassemic boys, the mean T concentration increased from 0.93 to 2.7 nmol/L (mean increase = 1.8 nmol/L) vs an increase from 0.47 to 4.81 nmol/L (mean increase = 4.32 nmol/L) in those with CDGP. All adolescents with CDGP, but only 7 the 12 thalassemic adolescents, had T secretion above 2 nmol/L after 6 months of hCG therapy and maintained their growth and pubertal development for a year after stopping hCG. The 5 thalassemic patients with defective T secretion after hCG therapy had significantly higher ferritin level (1985 +/- 658 ng/mL) vs the other 7 patients (1100 +/- 425 ng/mL). These findings denoted significant testicular dysfunction in those patients with higher iron overload (testicular siderosis). Statural GV was significantly correlated with insulin-like growth factor 1 (IGF-1) concentrations and testicular diameter after hCG therapy (r = 0.5 and 0.43 respectively, P < .001). In summary, hCG therapy was effective in treating 7 of 12 (58%) of thalassemic adolescents with delayed puberty. In the rest of patients (5/12, 46%) with significantly higher iron overload, hCG therapy failed to stimulate testicular growth and adequate T. Proper iron chelation appears to protect against testicular dysfunction. In the first group of patients, hCG therapy can be used for the treatment of their hypogonadism, whereas T replacement remains the therapy of choice for the second group.

Adolescent↗
PubMedDate not supplied

Neuroendocrine perturbations as a cause of insulin resistance.

Insulin resistance is followed by several prevalent diseases. The most common condition with insulin resistance is obesity, particularly when localized to abdominal, visceral regions. A summary of recent reviews on the pathogenesis of systemic insulin resistance indicates that major factors are decreased insulin effects on muscular glycogen synthase or preceding steps in the insulin signalling cascade, on endogenous glucose production and on circulating free fatty acids (FFA) from adipose tissue lipolysis. Contributions of morphologic changes in muscle and other factors are considered more uncertain. Newly developed methodology has made it possible to determine more precisely the neuroendocrine abnormalities in abdominal obesity including increased cortisol and adrenal androgen secretions. This is probably due to a hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, amplified by inefficient feedback inhibition by central glucocorticoid receptors, associated with molecular genetic defects. Secondly, secretion of gender-specific sex steroid hormones becomes inhibited and the sympathetic nervous system activated. At this stage the HPA axis shows signs of a 'burned-out' condition, and cortisol secretion is no longer elevated. Cortisol counteracts the insulin activation of glycogen synthase in muscle, the insulin inhibition of hepatic glucose production and the insulin inhibition of lipolysis in adipose tissue, leading to the well-established systemic insulin resistance caused by excess cortisol. This is exaggerated by increased free fatty acid mobilization, particularly with a concomitant elevation of the activity of the sympathetic nervous system. Furthermore, capillarization and fiber composition in muscle are changed. These are the identical perturbations responsible for insulin resistance in recent reviews. The diminished sex steroid secretion in abdominal obesity has the same consequences. It is thus clear that insulin resistance may be induced by neuroendocrine abnormalities, such as those seen in abdominal obesity. These endocrine perturbations also direct excess fat to visceral fat depots via mechanisms that are largely known, indicating why abdominal obesity is commonly associated with insulin resistance. This possible background to the most prevalent condition of insulin resistance has been revealed by development of methodology that allows sufficiently sensitive measurements of HPA axis activity. These findings demonstrate the power of neuroendocrine regulations for somatic health.

Animals↗
PubMed2002

Mutations that affect vacuole biogenesis inhibit proliferation of the endoplasmic reticulum in Saccharomyces cerevisiae.

In yeast, increased levels of the sterol biosynthetic enzyme, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase isozyme, Hmg1p, induce assembly of nuclear-associated ER membranes called karmellae. To identify additional genes involved in karmellae assembly, we screened temperature-sensitive mutants for karmellae assembly defects. Two independently isolated, temperature-sensitive strains that were also defective for karmellae biogenesis carried mutations in VPS16, a gene involved in vacuolar protein sorting. Karmellae biogenesis was defective in all 13 other vacuole biogenesis mutants tested, although the severity of the karmellae assembly defect varied depending on the particular mutation. The hypersensitivity of 14 vacuole biogenesis mutants to tunicamycin was well correlated with pronounced defects in karmellae assembly, suggesting that the karmellae assembly defect reflected alteration of ER structure or function. Consistent with this hypothesis, seven of eight mutations causing defects in secretion also affected karmellae assembly. However, the vacuole biogenesis mutants were able to proliferate their ER in response to Hmg2p, indicating that the mutants did not have a global defect in the process of ER biogenesis.

Anti-Bacterial Agents↗
PubMed1998

Disordered growth hormone secretion in fibromyalgia: a review of recent findings and a hypothesized etiology.

Growth hormone (GH) deficiency occurs in about 30% of fibromyalgia patients. Treatment of GH deficient fibromyalgia patients with recombinant growth hormone improves several clinical features, including the tender point count. Defective GH secretion in these patients appears to be due to increased somatostatin tone in the hypothalamus. An hypothesis is presented which relates dysfunctional GH secretion to the effects of intermittent hypercortisolemia on upregulating the density of beta-adrenergic receptors in the hypothalamus. The resulting augmentation of beta-adrenergic tone stimulates the release of somatostatin, thus, impairing GH secretion.

Clinical Trials as Topic↗
PubMed1990

A single amino acid substitution in the variable region of the light chain specifically blocks immunoglobulin secretion.

Although immunoglobulin light chains are usually secreted in association with heavy chains, free light chains can be secreted by lymphocytes. To identify the structural features of light chains that are essential for their secretion, we mutated a conserved sequence in the variable domain of a lambda I light chain. The effects of the mutations on secretion were assayed by transient expression in COS-1 cells. One mutant (AV60), which replaced Ala-60 with Val, was secreted as efficiently as wild-type lambda I by transfected COS-1 cells. This result was not surprising because secreted lambda II chains contain valine in this position. However, a second lambda I mutant (AV60FS62), which replaced Phe-62 with Ser as well as Ala-60 with Val, was not secreted. This mutant was arrested in the endoplasmic reticulum, as judged by immunofluorescence and by its association with a lumenal endoplasmic reticulum protein, immunoglobulin heavy chain binding protein (BiP). The defect in secretion was not due to gross misfolding of the lambda I chain, since cells cotransfected with AV60FS62 and an immunoglobulin heavy chain gene produced functional antigen-binding antibodies. These assembled IgM molecules were still not secreted. Hence, the replacement of Phe-62 with Ser specifically affects a determinant on the lambda I light chain that is necessary for the intracellular transport of this molecule.

Animals↗
PubMed1999

CD40-CD40 ligand interaction is central to cell-mediated immunity against Toxoplasma gondii: patients with hyper IgM syndrome have a defective type 1 immune response that can be restored by soluble CD40 ligand trimer.

Cell-mediated immunity that results in IL-12/IFN-gamma production is essential to control infections by intracellular organisms. Studies in animal models revealed contrasting results in regard to the importance of CD40-CD40 ligand (CD40L) signaling for induction of a type 1 cytokine response against these pathogens. We demonstrate that CD40-CD40L interaction in humans is critical for generation of the IL-12/IFN-gamma immune response against Toxoplasma gondii. Infection of monocytes with T. gondii resulted in up-regulation of CD40. CD40-CD40L signaling was required for optimal T cell production of IFN-gamma in response to T. gondii. Moreover, patients with hyper IgM (HIGM) syndrome exhibited a defect in IFN-gamma secretion in response to the parasite and evidence compatible with impaired in vivo T cell priming after T. gondii infection. Not only was IL-12 production in response to T. gondii dependent on CD40-CD40L signaling, but also, patients with HIGM syndrome exhibited deficient in vitro secretion of this cytokine in response to the parasite. Finally, in vitro incubation with agonistic soluble CD40L trimer enhanced T. gondii-triggered production of IFN-gamma and, through induction of IL-12 secretion, corrected the defect in IFN-gamma production observed in HIGM patients. Our results are likely to explain the susceptibility of patients with HIGM syndrome to infections by opportunistic pathogens.

Adjuvants, Immunologic↗
PubMed1995

Increased secretion of 32,33 split proinsulin after intravenous glucose in glucose-tolerant first-degree relatives of patients with non-insulin dependent diabetes of European, but not Asian, origin.

OBJECTIVE: The aetiology of non-insulin dependent diabetes is unknown, but defective insulin secretion is a feature. The disease also has a strong genetic basis and first-degree relatives of patients have an increased risk of future diabetes. To investigate whether beta-cell dysfunction is an early feature of the disease, we studied insulin secretion in healthy first-degree relatives of patients with non-insulin dependent diabetes. DESIGN: Each subject underwent a 1-hour intravenous glucose tolerance test (0.3 g/kg). PATIENTS: Seventeen first-degree relatives of patients (10 of European and 7 of Asian (Indian subcontinent) origin) with normal glucose tolerance were compared with 17 matched control subjects with no family history of diabetes. MEASUREMENTS: Plasma immunoreactive insulin (IRI) was measured by radioimmunoassay, and specific insulin, intact and 32,33 split proinsulin were measured by specific immunoradiometric assays (IRMA) for the 1st phase (0-10 minutes) and 2nd phase (10-60 minutes) responses. Glucose and intermediary metabolites were measured enzymatically. RESULTS: Fasting concentrations of IRI, IRMA insulin, intact and 32,33 split proinsulin were similar in relatives and controls in each group. Fasting glucose levels were similar in European relatives and controls but lower in Asian relatives compared to their controls (mean +/- SE 4.9 +/- 0.2 vs 5.5 +/- 0.2 mmol/l, P < 0.05). Following intravenous glucose, European relatives had similar IRI and glucose levels to their controls. Secretion of 32,33 split proinsulin was increased in European relatives compared to their controls, significantly so for 2nd phase secretion (1st phase median (range): 71 (7-352) vs 55 (17-118) pmol/l min, NS; 2nd phase: 433 (115-1459) vs 234 (55-745) pmol/l min, P < 0.05). Secretion of IRMA insulin and intact proinsulin were similar in European relatives and controls (IRMA insulin: 1st phase 2757 (700-10,969) vs 2830 (632-4682) pmol/l min; 2nd phase 6387 (3006-15,865) vs 5284 (2060-18,605) pmol/l min; intact proinsulin: 1st phase 31 (13-113) vs 32 (16-72) pmol/l min; 2nd phase: 174 (87-737) vs 159 (97-298) pmol/l min). European relatives had a greater percentage of proinsulin-like molecules (intact + 32,33 split proinsulin) to total insulin (sum of IRMA insulin + intact + 32,33 split proinsulin) during the 2nd phase of secretion (9.1 (5.0-11.8) vs 5.9 (4.3-12.6)%, P < 0.05). In contrast, Asian relatives had similar secretion of IRI, IRMA insulin, intact and 32,33 split proinsulin to their controls. Glucose disappearance (KG) was similar in relatives and controls within each ethnic group (Europeans: relatives 725 +/- 101 vs controls 668 +/- 47/min; Asian: relatives 610 +/- 97 vs controls 783 +/- 936/min). Asian relatives had higher fasting circulating glycerol (65 +/- 7 vs 44 +/- 4 mumol/l, P < 0.05), non-esterified fatty acid (569 +/- 59 vs 375 +/- 64 mumol/l, P < 0.05) and 3-hydroxybutyrate levels (147 (44-187) vs 35 (21-57) mumol/l, P < 0.01) than their controls and this persisted following intravenous glucose. This difference was not observed in the European group. CONCLUSION: First-degree relatives of European patients with NIDDM possess early signs of beta-cell dysfunction, with increased and disproportionate secretion of 32,33 split proinsulin after intravenous glucose, whilst glucose tolerance is still normal.

Adult↗
PubMed1985

Hypothalamic control of GH secretion: pathophysiology and clinical implications.

GH is secreted episodically. Its pattern is regulated by the interplay of a releasing and a release-inhibiting hormone of hypothalamic origin. Modulation occurs by metabolic factors (glucose, free fatty acids, ketone bodies, amino acids). Altered GH secretion has been observed in states of metabolic derangement such as diabetes mellitus, malnutrition and obesity. Further modulation occurs by extrahypothalamic CNS structures. In man--but not in animals, including subhuman primates--sleep has an important effect on GH secretion. A defective GH secretory pattern has been found to occur in several states of sleep disturbance, such as sleep deprivation, narcolepsy, severe psychosocial derangement, the apallic syndrome. Other CNS influences on GH secretion are related to stress, emotional changes and psychiatric disturbances. The exact mechanisms by which most of these influences are relayed to the GH secretory apparatus of the hypothalamus remain yet to be investigated.

Amino Acids↗
PubMed1994

Neutrophil lysosomal dysfunctions in mutant C57 Bl/6J mice: interstrain variations in content of lysosomal elastase, cathepsin G and their inhibitors.

In this paper we report the serum antiprotease screening and the biochemical and functional characteristics of neutrophils in a variety of mouse strains with different susceptibilities for developing a protease-mediated injury. C57Bl/6J mice and their mutants tight-skin and pallid have a lower serum elastase inhibitory capacity (-30, -65 and -70% respectively) than other inbred strains (i.e. NMRI and Balb/c, which both have similar values). We demonstrate that these values are a consequence of a decreased concentration of the alpha 1-protease inhibitor for elastase [PI(E)], which is the major serum inhibitor of elastase and cathepsin G. In addition, neutrophil lysosomal dysfunctions characterized by abnormally high contents of elastase and cathepsin G, or defective lysosomal secretion are observed in tight-skin and pallid mice respectively. Another C57Bl/6J mutant with lysosomal abnormalities is the beige mouse. Negligible amounts of elastase and cathepsin G, as well as defective neutrophil degranulation, have been described previously in this strain. We found, however, discrete amounts of a latent form of neutrophil elastase that undergoes a spontaneous activation by a protease-dependent mechanism. We also report that neutrophil cathepsin G in this mouse is tightly bound to lysosomal membranes, but is released in near normal quantities during exocytosis. Cytosolic elastase and cathepsin G inhibitors, which were previously reported as being specific for the beige neutrophils, have also been detected in all the examined strains. Neutrophil functions, lysosomal enzyme content and serum antiprotease screening may represent key elements in the protease-antiprotease balance and may explain the different interstrain susceptibility to developing lesions in which an elastolytic activity has been implicated.

Amino Acid Sequence↗
PubMed2002

Overexpression of protein-tyrosine phosphatase PTP sigma is linked to impaired glucose-induced insulin secretion in hereditary diabetic Goto-Kakizaki rats.

The impaired glucose-induced insulin release in type 2 diabetes mellitus may be accounted for by reduced B-cell ATP/ADP ratio or decreased phosphorylation of proteins regulating exocytosis of insulin. This, in turn, could be due to enhanced phosphatase activity. Using in situ hybridization techniques to assess the expression of 11 different phosphotyrosine phosphatases (PTPases), known to be present in the B-cells, overexpression by approximately 60% of PTP sigma (also known as LAR-PTP2 or PTP NE-3) was demonstrated in pancreatic islets and liver of spontaneously type 2 diabetic Goto-Kakizaki (GK) rats. In agreement with these findings Western blot of islet lysates, using a polyclonal PTP sigma antiserum, showed increased amounts of the protein in GK relative to control rat islets. Exposure of isolated islets for 20 h to 5 muM antisense to PTP sigma, composed of an antisense PNA sequence of 15 bases linked to the cell penetrating peptide transportan, increased glucose-induced insulin secretion from GK rat islets, but not from control islets. In parallel, the amounts of the phosphatase decreased. In conclusion, increased expression of PTP sigma may be of pathogenetic significance for the defective insulin secretion in GK rat islets.

Animals↗
PubMed1993

Evidence of defective tubular reabsorption and normal secretion of uric acid in the syndrome of inappropriate secretion of antidiuretic hormone.

The mechanisms responsible for the increased renal clearance of uric acid in the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) are not fully clarified. Studies using either pyrazinamide or probenecid, or both drugs but at an interval of several days, could not undoubtedly distinguish the 'hypersecretory theory' from the one favoring a defect in either post- or presecretory reabsorption. We decided to do a combined pyrazinamide and probenecid test in 5 patients with hyponatremia due to SIADH in order to evaluate more clearly the respective importance of these different pathways. Our results allow the conclusion of a diminished presecretory and mainly postsecretory reabsorption (80 +/- 4.6 and 14 +/- 3% of filtered load, respectively). As far as the secretion of uric acid is concerned (17 +/- 10% of filtered load), we may say that this pathway is adapted to the amount of hypouricemia.

Absorption↗
PubMed2003

Hepatic secretion of apoB-100 is impaired in hypobetalipoproteinemic mice with an apoB-38.9-specifying allele.

Apolipoprotein B (apoB) truncation-specifying mutations cause familial hypobetalipoproteinemia (FHBL). Lipoprotein kinetics studies have shown that production rates of apoB-100 are reduced by 70-80% in heterozygous FHBL humans, instead of the expected 50%. To develop suitable mouse models to study the underlying mechanism, apoB-38.9-only (Apob(38.9/38.9)) mice were crossbred with Apobec-1 knockout (Apobec-1(-/-)) mice or apoB-100-only (Apob(100/100)) mice to produce two lines of apoB-38.9 heterozygous mice that produce only apoB-38.9 and apoB-100, namely Apobec-1(-/-)/Apob(38.9/+) and Apob(38.9/100) mice. In vivo rates of apoB-100 secretion were measured using [35S]Met/Cys to label proteins and Triton WR-1339 to block apoB-100 VLDL lipolysis/uptake. Rates of secretion were reduced by 80%, rather than the expected 50%, in both Apobec-1(-/-)/Apob(38.9/+) and Apob(38.9/100) mice compared with those of the respective Apobec-1(-/-)/Apob(+/+) and Apob(100/100) control mice. Continuous labeling and pulse-chase experiments in primary hepatocyte cultures revealed that rates of apoB-100 synthesis by Apobec-1(-/-)/Apob(38.9/+) and Apob(38.9/100) hepatocytes were reduced to the expected 50% of those of the respective controls, but the efficiency of secretion of apoB-100 was significantly lower in apoB-38.9 heterozygous hepatocytes. The greater-than-expected decreases in apoB-100 production rates of FHBL heterozygous humans appear to be attributable to a defect in secretion rather than in the synthesis of apoB-100 from the unaffected apoB allele.

APOBEC-1 Deaminase↗
PubMed1998

The vanadate-tolerant yeast Hansenula polymorpha undergoes cellular reorganization during growth in, and recovery from, the presence of vanadate.

When present at intracellular concentrations above micromolar, vanadate becomes toxic to most organisms. However, the yeast Hansenula polymorpha is able to grow on vanadate concentrations in the millimolar range, showing at the same time modifications in cellular ultrastructure and polyphosphate metabolism. Here, the development of the ultrastructural changes, and of vacuolar and secretory activities, during exponential growth on vanadate and upon a return to vanadate-free conditions was investigated. External invertase secretion was inhibited by vanadate, as shown by a decrease in external invertase activity, an intracellular accumulation of small vesicles and a cytoplasmic accumulation of internal invertase. An aberrant appearance of the cell wall and defects in cellular surface growth, possibly linked to defects in secretion, were also observed. However, inhibition of the secretory pathway was not complete since the activity of another secreted enzyme, exoglucanase, increased in the presence of vanadate. Growth on vanadate was also accompanied by an enhancement of vacuolar proteolysis, as indicated by an increase in carboxypeptidase Y activity. However, these modifications were all reversible upon return to vanadate-free conditions, with the normalization process being complex and involving new and dramatic ultrastructural changes and activation of an autophagic mechanism. This mechanism is involved in the elimination/resorption of the observed vanadate-induced aberrant cell structures and/or sites involved in vanadate accumulation, a necessary prerequisite for restoration of conventional ultrastructure and metabolic functions.

Carboxypeptidases↗
PubMed1992

Evaluation of hypothalamic-pituitary function in patients with thalassemia major.

The increased survival of patients with thalassemia major, made possible by more adequate therapeutic regimens, has emphasized the importance of the endocrine abnormalities often associated with this disease. In twelve thalassemic patients, we evaluated the hypothalamic-pituitary function by measuring plasma levels of anterior pituitary hormones under basal conditions and in the course of provocative tests. An impairment of growth hormone (GH) secretion was demonstrated in a considerable proportion (7/12) of these patients. In some of them failure of GH response to insulin-hypoglycemia and normal hormone rise after growth hormone-releasing hormone indicate a hypothalamic defect. A defective prolactin secretion was observed in the female hypogonadic but not in the male thalassemic patients. This abnormality appears to be dependent on estrogen deficiency rather than on a hypothalamic-pituitary dysfunction. In our series a high prevalence (8/12) of hypogonadism was also noticed. In these cases, the low gonadotropin levels and their unresponsiveness to gonadotropin-releasing hormone are compatible with a hypothalamic and/or pituitary damage. Lastly, the enhanced ACTH responses to the stimuli associated to a reduced cortisol release suggest the existence, in these patients, of a diminished adrenocortical reserve. On the whole, this study has shown several derangements of the hypothalamic-pituitary function in thalassemia. This emphasizes the need for careful endocrine surveillance in this disease.

Adolescent↗
PubMed2005

Qualitative disorders of platelets and megakaryocytes.

Qualitative disorders of platelet function and production form a large group of rare diseases which cover a multitude of genetic defects that by and large have as a common symptom, excessive mucocutaneous bleeding. Glanzmann thrombasthenia, is enabling us to learn much about the pathophysiology of integrins and of how alphaIIb beta3 functions. Bernard-Soulier syndrome, an example of macrothrombocytopenia, combines the production of large platelets with a deficit or non-functioning of the major adhesion receptor of platelets, the GPIb-IX-V complex. Amino acid substitutions in GPIb alpha, may lead to up-regulation and spontaneous binding of von Willebrand factor as in Platelet-type von Willebrand disease. In disorders with defects in the MYH9 gene, macrothrombocytopenias are linked to modifications in kidney, eye or ear, whereas other inherited thrombocytopenias variously link a low platelet count with a propensity to leukemia, skeletal defects, learning impairment, and abnormal red cells. Defects of secretion from platelets include an abnormal alpha-granule formation as in the gray platelet syndrome (with marrow myelofibrosis), and of organelle biogenesis in the Hermansky-Pudlak and Chediak-Higashi syndromes where platelet dense body defects are linked to abnormalities of other lysosomal-like organelles including melanosomes. Finally, defects involving surface receptors (P2Y(12), TPalpha) for activating stimuli, of proteins essential for signaling pathways (including Wiskott-Aldrich syndrome), and of platelet-derived procoagulant activity (Scott syndrome) show how studies on platelet disorders are helping unravel the pathways of primary hemostasis.

Bernard-Soulier Syndrome↗
PubMed2004

Effects of type 2 diabetes on the regulation of hepatic glucose metabolism.

Glucose production is inappropriately increased in people with type 2 diabetes both before and after food ingestion. Excessive postprandial glucose production occurs in the presence of decreased and delayed insulin secretion and lack of suppression of glucagon release. These abnormalities in hormone secretion, coupled with impaired insulin-induced suppression of glucose production and stimulation of splanchnic glucose uptake, likely account in large part for the excessive amounts of glucose that reach the systemic circulation for disposal by peripheral tissues following food ingestion. In contrast, when adequate basal insulin concentrations are present, neither glucagon-induced stimulation of glucose production nor glucose-induced suppression of glucose production differs in diabetic and nondiabetic subjects matched for gender, age, and degree of obesity. However, when insulin secretion is defective, lack of suppression of glucagon can cause substantial hyperglycemia by enhancing rates of glucose production. Therefore, normalization of hepatic glucose metabolism in people with type 2 diabetes mellitus likely will require normalization of insulin and glucagon secretion as well as hepatic insulin action.

Diabetes Mellitus, Type 2↗
PubMedDate not supplied

Beta- and alpha-cell dysfunction in type 2 diabetes.

Insulin resistance is a common pathogenetic feature of type 2 diabetes. However, hyperglycemia would not develop if a concomitant defect in insulin secretion were not present. Impaired insulin secretion results from functional and survival defects of the beta-cell. The functional defects can be demonstrated early in the natural history of diabetes and they are hallmarked by abnormal pulsatility of basal insulin secretion and loss of first-phase insulin release in response to a glucose challenge. Moreover, a significant reduction of the beta-cell mass is apparent at the time of the diagnosis of diabetes. The progressive increase in glucose levels, that seems to characterize the natural history of type 2 diabetes, has been claimed to be largely due to progressive reduction of function and mass of beta-cells. Although a genetic predisposition is likely to account for impaired insulin secretion, chronic exposure to hyperglycemia and high circulating FFA is likely to contribute to both functional and survival defects. The disturbance in the endocrine activity of the pancreas is not limited to insulin, since a concomitant increase in fasting plasma glucagon and impaired suppression after the ingestion of an oral glucose load are often observed. This alteration becomes prominent after the ingestion of a mixed meal, when plasma glucagon remains much higher in the diabetic patient as compared to normal individuals. The disproportionate changes in the plasma concentration of the two pancreatic hormones is clearly evident when the insulin:glucagon molar ratio is considered. It is the latter that mainly affects hepatic glucose production. Because of the reduction of the insulin:glucagon molar ratio basal endogenous glucose concentration will be higher causing fasting hyperglycemia, while the hepatic glucose output will not be efficiently suppressed after the ingestion of a meal, contributing to excessive post-prandial glucose rise. Correcting beta- and alpha-cell dysfunction becomes, therefore, an attractive and rational therapeutic approach, particularly in the light of new treatments that may directly act on these pathogenetic mechanisms of type 2 diabetes.

Diabetes Mellitus, Type 2↗
PubMed2002

Genomic screen for vacuolar protein sorting genes in Saccharomyces cerevisiae.

The biosynthetic sorting of hydrolases to the yeast vacuole involves transport along two distinct routes referred to as the carboxypeptidase Y and alkaline phosphatase pathways. To identify genes involved in sorting to the vacuole, we conducted a genome-wide screen of 4653 homozygous diploid gene deletion strains of Saccharomyces cerevisiae for missorting of carboxypeptidase Y. We identified 146 mutant strains that secreted strong-to-moderate levels of carboxypeptidase Y. Of these, only 53 of the corresponding genes had been previously implicated in vacuolar protein sorting, whereas the remaining 93 had either been identified in screens for other cellular processes or were only known as hypothetical open reading frames. Among these 93 were genes encoding: 1) the Ras-like GTP-binding proteins Arl1p and Arl3p, 2) actin-related proteins such as Arp5p and Arp6p, 3) the monensin and brefeldin A hypersensitivity proteins Mon1p and Mon2p, and 4) 15 novel proteins designated Vps61p-Vps75p. Most of the novel gene products were involved only in the carboxypeptidase Y pathway, whereas a few, including Mon1p, Mon2p, Vps61p, and Vps67p, appeared to be involved in both the carboxypeptidase Y and alkaline phosphatase pathways. Mutants lacking some of the novel gene products, including Arp5p, Arp6p, Vps64p, and Vps67p, were severely defective in secretion of mature alpha-factor. Others, such as Vps61p, Vps64p, and Vps67p, displayed defects in the actin cytoskeleton at 30 degrees C. The identification and phenotypic characterization of these novel mutants provide new insights into the mechanisms of vacuolar protein sorting, most notably the probable involvement of the actin cytoskeleton in this process.

Actins↗