Tjin-Shing Jap

Intra-arterial calcium stimulation test for detection of insulinomas: Detection rate, responses of pancreatic peptides, and its relationship to differentiation of tumor cells

The selective intra-arterial calcium stimulation test has greatly facilitated the precise regionalization of insulinomas smaller than 2 cm, which noninvasive techniques (ultrasound [US], computed tomography [CT], magnetic resonance imaging [MRI]) often fail to localize. This study examined not only the role of the test in the localization of insulinomas, but also the responsiveness of 3 beta-cell peptides (insulin, C peptide, and proinsulin) and their relationship to the degree of differentiation of the tumor cells, using percentage decrease of both proinsulin/insulin (P/I) and proinsulin/C peptide (P/C) ratios after stimulation as indices. Ten consecutive surgically proven insulinoma patients each received an injection of calcium into the arteries supplying the pancreas after standard selective angiography and beta-cell peptide levels were measured in samples taken from the right hepatic vein before and 30, 60, 90, 120, and 180 seconds after each injection prior to operation. After surgery, the expressions of the calcium sensing receptor (CaSR) on the resected tumors were assessed by immunohistochemistry. Intra-arterial calcium stimulation with sampling either for insulin or for C peptide correctly predicted the site of insulinoma in 8 of 9 patients or in 7 of 8 patients if the 2 big malignant insulinomas were excluded; thus, the detection rate of this test was 89% and 88%, respectively. Calcium administration stimulated a marked and prompt release of insulin and C peptide simultaneously. Both peaked within 30 to 60 seconds, then declined gradually thereafter, remaining above the baseline at 180 seconds. The magnitude of increase correlated well with the corresponding percentage decrease of P/I and P/C ratios. The response of proinsulin was much less. Immunohistochemistry demonstrated variable membraneous staining for CaSR in normal pancreatic islets and in about 9% of the total normal beta cells, whereas staining in tumor cells was only minimally detectable. We conclude that selective intra-arterial calcium stimulation with hepatic venous sampling either for insulin or for C peptide is a highly sensitive method for the preoperative localization of small insulinomas. Calcium injection stimulates a brisk response of insulin, C peptide, and proinsulin simultaneously and the magnitude of increase of both insulin and C peptide appears to be correlated well with the degree of differentiation of the tumor cells. The exact mechanism by which calcium provokes the release of beta-cell peptides is less clear and whether the CaSR is involved in the mechanism of its action requires further study.

Mutations in the lipoprotein lipase gene as a cause of hypertriglyceridemia and pancreatitis in Taiwan.

Introduction Familial lipoprotein lipase (LPL) deficiency is inherited as an autosomal recessive trait and is characterized by chylomicronemia, eruptive xanthoma, hepatosplenomegaly, and recurrent pancreatitis. Aims and Methodology Two unrelated Chinese of Han descent with hypertriglyceridemia were enrolled in this study, and another six Han Chinese with no family history of hypertriglyceridemia and diabetes were recruited as normal controls. LPL activity was determined with use of an artificial substrate of 14C-trioleine and Arabic gum, and release of 14C free fatty acid was determined by the liquid-liquid partitioning system. LPL mass was measured by enzyme immunoassay. Genomic DNA was extracted from EDTA-preserved whole blood, and PCR was used to amplify the nine coding exons and the minimal promoter of the LPL gene. Results DNA sequence analysis revealed that mutations were identified in both patients; one patient had compound heterozygous mutations in codon 252 [CTG(Leu) → GTG(Val)] and in codon 264 [TGC(Cys) → TGa(Ter)] of exon 6, and the other patient had homozygous L252V mutation. These subjects had ≥90% reduction in LPL mass and ≥60% reduction in LPL activity. Conclusion The mutated and truncated LPLs caused hypertriglyceridemia in these patients in Taiwan with hypertriglyceridemia and pancreatitis.

Novel mutations in the MEN1 gene in subjects with multiple endocrine neoplasia‐1

Objectiveu2002 To identify MEN1 gene mutations and characterize clinical manifestations in Chinese kindred with multiple endocrine neoplasia type 1 (MEN1) in Taiwan.

Evidence for a delayed, integral, and proportional phase of glucocorticoid feedback on ACTH secretion in normal human volunteers

To investigate the mechanisms responsible for glucocorticoid feedback on nonstress-induced ACTH secretion in normal subjects, 24 volunteer subjects (14 males and 10 females, 21 to 43 years) were divided into six groups in a randomized fashion and studied. Each subject received a single midnight dose of 30 mg/kg per body weight of metyrapone and then cortisol was administered according to different protocols in the next morning to provide extreme variations of the input signal. It was found that no obvious inhibition in plasma ACTH levels was shown during the first 15 min despite the fact that cortisol was given at rather larger doses and short time intervals. However, a significant suppression in plasma ACTH levels began to manifest approximately 30 min after cortisol administration in each study group and it became apparent that the degree of inhibition of ACTH level at 75 min correlated with the plasma cortisol concentrations at the same moment (r = 0.97, P less than 0.01) as well as with the dosage of cortisol during this time, whatever administered (r = 0.99, P less than 0.01). In summary, our data provided evidence for a delayed, proportional, and integral phase of glucocorticoid feedback on nonstress-induced ACTH secretion in normal human volunteers.

A novel mutation in the hepatocyte nuclear factor-1α/MODY3 gene in Chinese subjects with early-onset Type 2 diabetes mellitus in Taiwan

Aims The goal of this study was to determine the frequency of mutation in hepatic nuclear factor (HNF)‐1α, a gene recently implicated as causing maturity‐onset diabetes of the young (MODY) and to analyse the respective clinical presentations in an ethnically Chinese population.

Insulin-like growth factor-I receptor increases in aortic endothelial cells from diabetic rats

Endothelial cells are likely to play an important role in the development of diabetic vascular diseases, since they are exposed directly to the abnormal circulating metabolites of diabetes and may be easily damaged early in the natural course of vascular complications. In this study, aortic endothelial cells were cultured from diabetic BB rats. Their binding and internalization of insulin-like growth factor-I (IGF-I) were measured. IGF-I binding was higher in cells of diabetic rats than of control rats at both 37 degrees C (4.5% +/- 1.6% v 2.74% +/- 0.9% per mg protein, P < .05) and 4 degrees C (20.6% +/- 5.6% v 13.7% +/- 4.6% per mg protein, P < .01). Internalization of IGF-I also increased (1.62% +/- 0.2% v 0.74% +/- 0.15% of total count at 37 degrees C after 60 minutes, P < .05). Cross-linking studies showed that in cells from diabetic rats, the major band of 140 kd corresponding to the alpha-subunit of the IGF-I receptor increased in density by 50% compared with those from control rats. The IGF-I-stimulated tyrosine kinase activity (TKA) of partially purified receptor from cells of diabetic rats, measured using poly-glu-tyr as substrate, was normal. Since the biological effects of IGF-I are initiated by its binding to the IGF-I receptor, which is able to transduce mitogenic and metabolic signals, our results support the hypothesis that the IGF-I receptor is involved in the development of diabetic vascular complications.

Serum procarboxypeptidase B, amylase and lipase in chronic renal failure

Procarboxypeptidase B (human pancreas‐specific protein) has been reported to be a good serum marker for the diagnosis of acute pancreatitis. The current study was conducted in order to evaluate the frequency and degree of elevated serum levels of procarboxypeptidase B in chronic renal failure and their correlations with serum levels of amylase, lipase and renal function tests. Blood samples were taken from 84 asymptomatic patients with chronic renal failure, including 34 patients with periodical haemodialysis and 50 patients without haemodialysis. Serum levels of procarboxypeptidase B, amylase, lipase, creatinine and blood urea nitrogen were measured. Serum levels of procarboxypeptidase B in 84 patients were 63.4±5.5 μg/L significantly greater than the figure of 29.6±1.6 μg/L in healthy adults in our previous report (P< 0.0001). There was a significant difference in serum levels of PCPB between patients with and without haemodialysis (78.0±9.4 vs 53.6±6.3 μg/L; P< 0.01). The frequencies of elevated serum levels of procarboxypeptidase B, amylase and lipase greater than upper normal limits were 27.4, 35.7 and 26.2%, respectively. The frequencies of elevated PCPB in patients with and without haemodialysis were 38.2 and 20%, respectively. Only one patient had a serum procarboxypeptidase B level greater than three‐fold the upper normal limit. A significant correlation was found between procarboxypeptidase B and lipase (r = 0.785; P< 0.0001). No significant correlation was noted between procarboxypeptidase B vs amylase or renal function tests. In conclusion, in patients with chronic renal failure, the elevation of serum procarboxypeptidase B is as common as the elevations of other pancreatic enzymes.

Modulatory effects of corticotropin-releasing factor on the delayed corticosteroid feedback in humans: Implications of feedback sites☆

We recently demonstrated the presence of a delayed phase of glucocorticoid feedback on nonstress-induced ACTH secretion in normal volunteers. In this study, we investigate the effects of corticotropin-releasing factor (CRF) on that delayed feedback pathway with an attempt to determine the sites on which glucocorticoid exerts its delayed feedback effects. Thirty normal subjects were subjected to study and each subject received a single midnight dosage of 30 mg/kg BW metyrapone before each test. The whole experiment was divided into two studies. In study I, we found that ovine CRF (oCRF) 1 microgram/kg BW alone as an IV bolus injection caused an increase in the plasma ACTH level, which persisted for at least 120 minutes. Continuous infusion of cortisol 25 mg/h alone for two hours produced a significant decrease in the plasma ACTH level; this fall of ACTH began 30 minutes after the onset of cortisol administration. When IV bolus injection of oCRF 1 microgram/kg BW and the continuous infusion of cortisol 25 mg/h for two hours were both given, the plasma ACTH level increased firstly and then decreased 60 minutes after the onset of cortisol administration, progressing thereafter to the end of the study. Study II showed in those who received the IV bolus injection of human CRF (hCRF) 100 micrograms and the continuous infusion of cortisol 25 mg/h for two hours, the plasma ACTH level increased firstly and began to decline 45 minutes after the onset of cortisol administration, progressing thereafter to the end of the test.(ABSTRACT TRUNCATED AT 250 WORDS)

A Novel Mutation in the Hepatocyte Nuclear Factor-lα/MODY3 Gene in Han Chinese Subjects with Early-Onset NIDDM in Taiwan

Aims: The goal of this study was to determine the frequency of mutation in HNF-1α a gene recently implicated as causing MODY and to analyze the respective clinical presentations in an ethnically Chinese population. nMethods: We analyzed 20 unrelated subjects (12 females and 8 males) aged less than 40 who had early onset diabetes to test the possibility that mutation of the HNF-1α gene was responsible for this disorder, In addition, 20 normal Chinese subjects served as controls. Genomic DNA was extracted from EDTA-preserved whole blood and the 10 coding exons and the minimal promoter of the HNF-lα gene were amplified by the PCR. PCR products were sequenced directly by the dideoxynucleotide-cycle-sequencing technique. nResults: We identified four previously described polymorphisms in the HNF-1α gene in our normal Chinese subjects, including neutral polymorphism in codon17 (exon 1, CTC(Leu) CTG (Leu), C=0.60, G=0.40) and in codon 459 (exon7, CTG (Leu) TTG (Leu), C=0.55, T=0.45) and 2 polymorphism that resulted in neutral aminoacid changes in codon 27 (exon 1; ATC (Ile) CTC (Leu), A=0.45, C=0.55) and codon 487(AGC(Ser) AAC (Asn), A =0.48, G=0.52) of exon7. These polymorphisms did not increase susceptibility to MODY or early onset diabetes. One patient with MODY had a novel missense mutation in exon 3 of the HNF-lα gene (Y218C) in a region of the protein that corresponds to a predicted DNA binding domain. . nConclusion: the prevalence of mutations of the HNF-lα gene is very low in early onset type 2 diabetes of Han Chinese in Taiwan.