Noc2 is essential in normal regulation of exocytosis in endocrine and exocrine cells

Rab3 is a subfamily of the small GTP-binding protein Rab family and plays an important role in exocytosis. Several potential effectors of Rab3, including rabphilin3 and Rims (Rim1 and Rim2), have been isolated and characterized. Noc2 was identified originally in endocrine pancreas as a molecule homologous to rabphilin3, but its role in exocytosis is unclear. To clarify the physiological function of Noc2 directly, we have generated Noc2 knockout (Noc2(-/-)) mice. Glucose intolerance with impaired insulin secretion was induced in vivo by acute stress in Noc2(-/-) mice, but not in wild-type (Noc2(+/+)) mice. Ca(2+)-triggered insulin secretion from pancreatic isles of Noc2(-/-) mice was markedly impaired, but was completely restored by treatment with pertussis toxin, which inhibits inhibitory G protein Gi/o signaling. In addition, the inhibitory effect of clonidine, an alpha(2)-adrenoreceptor agonist, on insulin secretion was significantly greater in Noc2(-/-) islets than in Noc2(+/+) islets. Impaired Ca(2+)-triggered insulin secretion was rescued by adenovirus gene transfer of wild-type Noc2 but not by that of mutant Noc2, which does not bind to Rab3. Accordingly, Noc2 positively regulates insulin secretion from endocrine pancreas by inhibiting Gi/o signaling, and the interaction of Noc2 and Rab3 is required for the effect. Interestingly, we also found a marked accumulation of secretory granules in various exocrine cells of Noc2(-/-) mice, especially in exocrine pancreas with no amylase response to stimuli. Thus, Noc2, a critical effector of Rab3, is essential in normal regulation of exocytosis in both endocrine and exocrine cells.     

A mutation in the B chain coding region is associated with impaired proinsulin conversion in a family with hyperproinsulinemia.

Gruppuso et al. [Gruppuso, P.A., Gordon, P., Kahn, C. R., Cornblath, M., Zeller, W. P. & Schwartz, R. (1984) N. Engl. J. Med. 311, 629-634] have recently described a family in which hyperproinsulinemia is inherited in an autosomal dominant pattern, suggesting a structural abnormality in the proinsulin molecule as the basis for this disorder. However, unlike two previous kindreds with a similar syndrome, the serum proinsulin-like material in this family did not appear to be an intermediate conversion product but instead behaved like normal human proinsulin by several criteria. To further characterize this disorder we isolated and sequenced the insulin gene of the propositus. Leukocyte DNA was cloned into lambda-WES and recombinants containing the two insulin alleles, lambda MD41 and lambda MD51, were isolated by plaque hybridization. DNA sequencing of lambda MD51 showed that it contained the normal coding sequence for human preproinsulin. Sequence analysis of lambda MD41, however, revealed a single nucleotide substitution in the codon for residue 10 of proinsulin (CAC----GAC) that predicts the exchange of aspartic acid for histidine in the insulin B chain region. This mutation was also found in an insulin allele cloned from a second affected family member (propositus's father). These results, along with the linkage analysis of Elbein et al. [Elbein, S.C., Gruppuso, P., Schwartz, R., Skolnick, M. & Permutt, M.A. (1985) Diabetes 34, 821-824], strongly implicate this mutation as the cause of the hyperproinsulinemia in this family. Inhibition of the conversion of proinsulin to insulin may be related to altered folding and/or self-association properties of the [Asp10]proinsulin.     

Effects of streptozotocin-induced diabetes on circulating levels of vitamin D metabolites

In order to investigate vitamin D metabolism in insulin-deficient diabetic rats, plasma vitamin D metabolites were measured at various periods after induction of diabetes by iv administration of 60 mg/kg streptozotocin (STZ). After STZ injection, plasma insulin was significantly decreased and plasma urea nitrogen increased with the duration of diabetes, while plasma creatinine remained unchanged. Plasma calcium, 25-dihydroxyvitamin D (25(OH)D), and 24,25-dihydroxyvitamin D (24,25(OH)2D) progressively decreased. On the other hand, plasma 1,25-dihydroxyvitamin D (1,25(OH)2D) did not change at any period, but the ratio of 1,25(OH)2D to 25(OH)D became high in proportion to the severity of hypocalcaemia. Since significantly lower 25(OH)D and 24,25(OH)2D levels were observed at the later stage of diabetes, it is suggested that the altered vitamin D metabolism in diabetes is secondary to the disturbances in metabolic homeostasis derived form the insulin deficiency.     

Sequence of an intestinal cDNA encoding human gastric inhibitory polypeptide precursor.

Gastric inhibitory polypeptide (GIP) is a 42-amino acid hormone that stimulates insulin secretion in the presence of glucose. Complementary DNA clones encoding human GIP were isolated from a library prepared with RNA from duodenum. The predicted amino acid sequence indicates that GIP is derived by proteolytic processing of a 153-residue precursor, preproGIP. The GIP moiety is flanked by polypeptide segments of 51 and 60 amino acids at its NH2 and COOH termini, respectively. The former includes a signal peptide of about 21 residues and an NH2-terminal propeptide of 30 amino acids. GIP is released from the precursor by processing at single arginine residues. There is a region of nine amino acids in the COOH-terminal propeptide of the GIP precursor that has partial homology with a portion of chromogranin A as well as pancreastatin.     

Nestin-positive cells in adult pancreas express amylase and endocrine precursor Cells

The neural precursor cell-specific marker nestin is expressed in fetal and adult pancreas, but its role is not fully understood. Using nestin-enhanced green fluorescent protein (EGFP) transgenic mice and fluorescence activated cell sorter, we characterized nestin-positive cells in adult mice pancreas. EGFP mRNA- and protein-positive cells expressed amylase, a pancreatic exocrine marker. Interestingly, EGFP mRNA-negative and protein-positive cells expressed insulin, glucagon, somatostatin and pancreatic polypeptide, pancreatic endocrine markers. These findings demonstrate that nestin-positive cells comprise a portion of pancreatic exocrine cells and suggest that they can be differentiated into pancreatic endocrine cells.     

Hepatic resection for metastatic tumors from noncolorectal carcinoma

BACKGROUND/AIMS: The role of liver resection for hepatic metastases from noncolorectal carcinomas has yet to be clarified. The present study examines a single institutional experience of hepatic resection for noncolorectal metastases. METHODOLOGY: From January 1987 to March 1999, 14 patients underwent curative resection for liver metastases from noncolorectal carcinomas. Records of these patients were reviewed. RESULTS: Resections were performed for liver metastases from gastric cancers (n = 8), pancreatic cancers (n = 2), and cancers of bile duct, the papilla of Vater, kidney, and breast (n = 1, each). Six patients (5 with gastric cancers and 1 with pancreas cancer) presented with synchronous disease and 8 with metachronous disease. In the gastric cancer patients, there are 2 disease-free survivors (26 and 53 months) in the metachronous group, though all of the 5 patients with synchronous disease died within 29 months. All of the 4 patients with pancreatobiliary carcinomas died within 2 years. One case of breast cancer and another of renal cell cancer are alive without disease at 49 and 9 months, respectively. CONCLUSIONS: For metastases from gastric cancers, better survival after hepatic resection is expected in metachronous cases than in synchronous cases. Hepatic resection may afford little benefit for patients with liver metastases from pancretobiliary cancers.     

Difference in elevation of N-terminal pro-BNP and conventional cardiac markers between patients with ST elevation vs non-ST elevation acute coronary syndrome.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is elevated in patients with acute coronary syndrome (ACS), and is a powerful predictor of long-term mortality. Differences in the clinical utility and pathophysiological implication of NT-proBNP and conventional cardiac markers in patients with ST elevation (STE) vs non-STE (NSTE) ACS were investigated in the present study. METHODS AND RESULTS: Ninety consecutive patients admitted with acute chest pain and a diagnosis of unstable angina or acute myocardial infarction were analyzed. Patients with >or=Killip class II were excluded to focus on the effect of myocardial ischemia on the release of cardiac markers. The markers were measured on admission and analyzed according to the time from onset. Conventional cytosolic marker (creatine kinase-MB) and myofibril marker (troponin T: TnT) were both significantly higher in STE-ACS patients compared with NSTE-ACS patients. Conversely, NT-proBNP was significantly higher in NSTE-ACS patients than STE-ACS especially within 3 h of onset, suggesting a larger ischemic insult despite the smaller extent of myocardial necrosis compared with STE-ACS patients. There was no significant correlation between NT-proBNP level and left ventricular ejection fraction (LVEF) obtained at acute-phase echocardiography in either NSTE-ACS patients (LVEF 57.7+/-11.2%) or STE-ACS patients (LVEF 55.1+/-12.7%). Comparison between NT-proBNP and TnT levels revealed a marked difference of elevations, with significantly augmented elevation of NT-proBNP (p<0.001) in NSTE-ACS patients as compared with prominent elevation of TnT in STE-ACS patients. CONCLUSIONS: NT-proBNP is an early sensitive marker of myocardial ischemia that rises much higher in the earlier phase as compared with conventional markers of myocardial damage, especially in NSTE-ACS patients.