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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A study was made of the capacity of insulinoma to catalyze the splitting of hippuryl-L-arginine (HA) and the contents of proinsulin-like component in the tissues of the tumours and in the blood serum of the patients. As revealed, in the absence of HA splitting by the tumour cytoplasmic fraction in the neutral pH zone there was noted a higher proinsulin-like component both in the tumour tissue and in the blood serum. An increase amount of proinsulin-like component in the blood serum stipulates possibly a more prolonged period of starvation before the occurrence of hypoglycemia, and a less pronounced picture of hypoglycemia in such patients in comparison with the patients whose tumours were capable of splitting HA similarly to the normal islands of Langerhans.
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PMID:[Mechanism of hypoglycemia in insulinoma]. 19 60

In 15 patients with insulinoma, six patients after successful removal of this tumour, two patients with previous pancreas resection because of hypoglycaemia elsewhere, and 10 control subjects, the diagnostic usefulness of euglycaemic clamp procedures (without exogenous insulin) was assessed in comparison with prolonged starvation. Only insulinoma patients developed sustained hypoglycaemia (less than or equal to 2.3 mmol l-1) within 2-44 h without caloric intake, because of inappropriately elevated immunoreactive insulin (IR-insulin) concentrations. IR-proinsulin values were elevated in most (7 out of 10), but not in all insulinoma patients. The steady-state glucose infusion rate necessary to maintain a stable plasma glucose concentration of 4.4-5.0 mmol l-1 was significantly (P less than or equal to 0.001) higher in insulinoma patients (2.5 +/- 0.6 mg kg-1 min-1) than in pancreas resected patients (0.6 +/- 0.2 mg kg-1 min-1), or in control subjects (0.5 +/- 0.1 mg kg-1 min-1). Due to a considerable degree of overlap, sensitivity (0.44) and specificity (0.95) were too low for such a procedure to qualify as a diagnostic test. There was no correlation of glucose infusion rates to IR-insulin values (r = 0.024, P = 0.461). One reason for this was the development of insulin resistance in some, but not in all insulinoma patients. When, in analogy to insulin/glucose ratios, a diagnostic index was derived by multiplying the steady state glucose infusion rate by the steady state IR-insulin concentration, the diagnostic accuracy was greatly increased (sensitivity and specificity 0.94, respectively), but still lower than that of 'amended' insulin/glucose ratios in fasting plasma or at the time of discontinuation of prolonged fasts (1.00). Somatostatin infusions inhibited insulin secretion (IR-C-peptide plasma concentrations) by 52-88% in subjects without insulinoma and in those insulinoma patients whose tumour cells ultrastructurally contained plenty of normal secretory granules, and to a lesser degree when only abnormal or virtually no secretory granules were present, i.e. in more de-differentiated tumours. In contrast to this significant (P = 0.036) association, malignancy, i.e. the presence of metastases, could not be predicted from whether or not insulin secretion was resistant to the inhibitory action of somatostatin. In conclusion, euglycaemic clamp experiments are less reliable for detecting or excluding a functioning insulinoma than the relation of glucose and insulin values during starvation. The inhibition of insulin secretion by somatostatin depends on the presence of normal beta-granules, and does not distinguish adenomas from carcinomas.
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PMID:Evaluation of a euglycaemic clamp procedure as a diagnostic test in insulinoma patients. 196 48

In situ hybridization of proinsulin and proglucagon mRNA was performed in rat pancreas to assess prohormone gene expression during various glucopenic conditions. During a 4-d fast mean blood glucose declined by 48 mg/dl; proinsulin mRNA signal density remained normal while proglucagon mRNA signal density more than doubled. At the end of a continuous 12-d insulin infusion blood glucose averaged 53 +/- 12 mg/dl; proinsulin mRNA signal density declined to 30% of controls while proglucagon mRNA signal density more than doubled. In insulinoma-bearing NEDH rats blood glucose averaged 34 +/- 3.5 mg/dl; the proinsulin mRNA signal was virtually undetectable and proglucagon mRNA signal density was more than twice the controls. There was no detectable change in either beta-cell area or islet number in rats subjected to fasting or insulin infusion, but in insulinoma-bearing rats beta cell area was markedly reduced. Thus compensation during 4 d of starvation involves an increase in glucagon gene expression without change in insulin gene expression or beta cell mass. In moderate insulin-induced hypoglycemia glucagon gene expression is increased and insulin gene expression decreased. In more profound insulinoma-induced hypoglycemia, in addition to the foregoing changes in hormone gene expression, there is a profound reduction in the number of insulin-expressing cells.
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PMID:Effects of hypoglycemia and prolonged fasting on insulin and glucagon gene expression. Studies with in situ hybridization. 276 Feb 7

Calcium influx through L-type voltage-dependent calcium channels (VDCCs) triggers insulin secretion. Until recently, the structure of VDCCs in pancreatic beta-cells and their regulation in altered metabolic states were not known. Study of the VDCC protein in skeletal muscle has shown that the alpha 1 subunit is functionally the most important subunit among the five subunits (alpha 1, alpha 2, beta, gamma and delta), acting as a voltage sensor and an ion-conducting pore. Molecular cloning of a novel alpha 1 subunit (beta-cell/neuroendocrine type, CACN4) of VDCCs from pancreatic islets and insulinoma have made it possible to study the electrophysiological and pharmacogical properties, regulation, and genetics of the VDCCs expressed in beta-cells. The CACN4 is structurally related to other members of the VDCC alpha 1 subunit family, including skeletal muscle, cardiac, and brain types. In situ hybridization experiments reveal that CACN4 mRNAs are expressed in beta-cells in the islets. Heterologous expression studies show that CACN4 in the presence of the beta subunit elicits L-type VDCC currents, although expression of CACN4 alone is not sufficient for VDCC activity. Studies of animal models with chronic hyperglycemia and starvation have indicated that the reduced CACN4 mRNA levels in pancreatic islets are associated with impaired insulin responses to stimuli in both hyperglycemic and fasting states. These studies demonstrate that CACN4 is the major component of VDCCs in pancreatic beta-cells and suggest that it plays a crucial role in the regulation of insulin secretion in normal and altered metabolic states.
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PMID:CACN4, the major alpha 1 subunit isoform of voltage-dependent calcium channels in pancreatic beta-cells: a minireview of current progress. 852 24

Glucose and amino acid starvation of cells in culture generally enhances their sensitivity to oxidative stress. This is explained by compensatory autophagocytosis, which results in increased amounts of lysosomal low-molecular-weight, redox-active iron, due to the degradation of metallo-proteins, with a potential increase in iron-catalyzed, intralysosomal oxidative reactions. Such reactions diminish the stability of lysosomal membranes, with resultant leakage of hydrolytic enzymes into the cytosol and ensuing cellular degeneration, often of apoptotic type. However, starvation of NIT insulinoma cells, which are normally remarkably sensitive to oxidative stress, actually attenuated the sensitivity to such stress. We found that starved NIT cells rapidly synthesized ferritin. Moreover, ferritin was found to be autophagocytosed, and the lysosomes were stabilized, as assayed by the acridine orange relocation test. We hypothesize that compensatory autophagocytosis during starvation increases the cytosolic pool of redox-active iron, as a reflection of enhanced transportation of low-molecular-weight iron from autophagic lysosomes to the cytosol, resulting in ferritin induction. The newly formed ferritin would, in turn, become autophagocytosed and bind redox-active lysosomal iron in a non-redox-active form. We also suggest that the proposed mechanism may be a way for oxidative stress-sensitive cells to compensate partly for their failing capacity to degrade hydrogen peroxide before it leaks into the acidic vacuolar apparatus and induces intralysosomal oxidative stress. The insulin-producing beta cell may belong to this type of cells.
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PMID:Starvation-induced autophagocytosis paradoxically decreases the susceptibility to oxidative stress of the extremely oxidative stress-sensitive NIT insulinoma cells. 975 30

The case of a young female presenting severe mental problems and episodic neurological symptoms is described. Obsessive-compulsive disorder was diagnosed upon psychiatric treatment for eight months. No neurological condition was found. Hypoglycaemia was observed during an episode of long-lasting somnolescence and the patient referred for endocrinological examination. Reactive hypoglycaemia was ruled out in an oral glucose tolerance test. A test of prolonged starvation revealed hypoglycaemia associated with neuropsychiatric symptoms. Glucose abolished this condition, suggesting an insulinoma as the basis of the spontaneous hypoglycaemia. Subsequently, two insulinomas were resected from the tail of the pancreas. The patient has recovered completely after her surgery, with no signs of mental or neurological disease and blood glucose within normal limits. As insulinoma is often associated to the MEN1-syndrome, the patient and her relatives are now being investigated for this condition.
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PMID:[Neuropsychiatric disorders in insulinoma]. 1008 51

To elucidate the molecular mechanisms of cell death, we have cloned a new gene, designated death-upregulated gene (DUG), from rat insulinoma cells. DUG is constitutively expressed at very low levels in normal cells but is dramatically upregulated in apoptotic cells following serum/glucose starvation or death receptor ligation by Fas ligand. The DUG mRNA is present in two splicing forms: a long form that encodes a protein of 469 amino acids and a short form that gives rise to a polypeptide of 432 amino acids. The predicted DUG protein sequence contains two putative nuclear localization signals and multiple phosphorylation sites for protein kinases and two conserved MA3 domains. Importantly, DUG is homologous to eukaryotic translation initiation factor (eIF) 4G and binds to eIF4A presumably through MA3 domains. Upon transfection, DUG inhibits both intrinsic and extrinsic pathways of apoptosis. Thus, DUG is a novel homologue of eIF4G that regulates apoptosis.
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PMID:DUG is a novel homologue of translation initiation factor 4G that binds eIF4A. 1222 May 11

Insulinoma tumors are often difficult to detect, as the symptoms largely precede occurrence of a visualized tumor. We report the case of an insulinoma patient with long delayed diagnosis and marked adaptation to extreme hypoglycemia. The patient with a 7-yr history of seizures was found to have plasma glucose concentration during a starvation test as low as 16 mg/dl, with no clinically significant symptoms and concomitant normal plasma insulin levels: 10-30 microIU/ml. All attempts to localize a tumor with repeated abdominal ultrasound examinations or computed tomography scanning were unsuccessful. The patient did not tolerate the introduced oral treatment with diazoxide. Once it had become technically available, endoscopic ultrasonography of the pancreas was performed. It revealed a 10 mm tumor in the pancreatic head. The tumor was subsequently removed surgically. During the operation plasma insulin concentration rose almost 15-fold, which confirmed the insulin-secreting character of the growth. Microscopic examination revealed benign insulinoma, with partially trabecular structure. One month after the operation the patient had normal plasma glucose values of 60-120 mg/dl, but she constantly complained of excessive thirst, which occurred soon after the operation and slowly subsided in the following weeks. In conclusion, the present report demonstrates that insulinoma should be considered and searched for in every case of hypoglycemia associated with normal insulin levels. It also confirms the essential role of endoscopic ultrasonography in the diagnosis of insulin-secreting tumors.
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PMID:Diagnostic difficulties in long-standing insulinoma with near-normal plasma insulin levels. 1588 65

Glucose controls islet beta-cell mass and function at least in part through the phosphatidylinositol 3-kinase (PI3K)/Akt pathway downstream of insulin signaling. The Foxo proteins, transcription factors known in other tissues to be negatively regulated by Akt activation, affect proliferation and metabolism. In this study, we tested the hypothesis that glucose regulates Foxo1 activity in the beta-cell via an autocrine/paracrine effect of released insulin on its receptor. Mouse insulinoma cells (MIN6) were starved overnight for glucose (5 mmol/l) then refed with glucose (25 mmol/l), resulting in rapid Foxo1 phosphorylation (30 min, P < 0.05 vs. untreated). This glucose response was demonstrated to be time (0.5-2 h) and dose (5-30 mmol/l) dependent. The use of inhibitors demonstrated that glucose-induced Foxo1 phosphorylation was dependent upon depolarization, calcium influx, and PI3K signaling. Additionally, increases in glucose concentration over a physiological range (2.5-20 mmol/l) resulted in nuclear to cytoplasmic translocation of Foxo1. Phosphorylation and translocation of Foxo1 following glucose refeeding were eliminated in an insulin receptor knockdown cell line, indicating that the glucose effects are mediated primarily through the insulin receptor. Activity of Foxo1 was observed to increase with decreased glucose concentrations, assessed by an IGF binding protein-1 promoter luciferase assay. Starvation of MIN6 cells identified a putative Foxo1 target, Chop, and a Chop-promoter luciferase assay in the presence of cotransfected Foxo1 supported this hypothesis. The importance of these observations was that nutritional alterations in the beta-cell are associated with changes in Foxo1 transcriptional activity and that these changes are predominantly mediated through glucose-stimulated insulin secretion acting through its own receptor.
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PMID:Glucose regulates Foxo1 through insulin receptor signaling in the pancreatic islet beta-cell. 1673 20

There are three types of cell death; apoptosis, necrosis, and autophagy. The possibility that activation of the macroautophagy (autophagy) pathway may increase beta cell death is addressed in this study. Increased autophagy was present in pancreatic islets from Pdx1(+/-) mice with reduced insulin secretion and beta cell mass. Pdx1 expression was reduced in mouse insulinoma 6 (MIN6) cells by delivering small hairpin RNAs using a lentiviral vector. The MIN6 cells died after 7 days of Pdx1 deficiency, and autophagy was evident prior to the onset of cell death. Inhibition of autophagy prolonged cell survival and delayed cell death. Nutrient deprivation increased autophagy in MIN6 cells and mouse and human islets after starvation. Autophagy inhibition partly prevented amino acid starvation-induced MIN6 cell death. The in vivo effects of reduced autophagy were studied by crossing Pdx1(+/-) mice to Becn1(+/-) mice. After 1 week on a high fat diet, 4-week-old Pdx1(+/-) Becn1(+/-) mice showed normal glucose tolerance, preserved beta cell function, and increased beta cell mass compared with Pdx1(+/-) mice. This protective effect of reduced autophagy had worn off after 7 weeks on a high fat diet. Increased autophagy contributes to pancreatic beta cell death in Pdx1 deficiency and following nutrient deprivation. The role of autophagy should be considered in studies of pancreatic beta cell death and diabetes and as a target for novel therapeutic intervention.
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PMID:Autophagy regulates pancreatic beta cell death in response to Pdx1 deficiency and nutrient deprivation. 1965 19


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