[Show abstract][Hide abstract] ABSTRACT: Most patients with Cushing's disease (CD) respond to corticotrophin-releasing hormone (CRH) or desmopressin with increased corticotrophin (ACTH) and cortisol levels. Although the vasopressin receptor subtype located on normal corticotrophs is the V3 receptor (V3R), desmopressin is a selective V2 receptor (V2R) agonist and it is unclear whether corticotrophinomas exhibit aberrant V2R expression. Furthermore, no studies have determined the relationship between the in vivo response of CD patients to desmopressin and vasopressin receptor expression, or between the response to CRH and CRH receptor (CRHR) expression. Therefore, the aim of this study was to investigate the expression of vasopressin receptors (V1R, V2R, and V3R) and CRHR on corticotroph tumours and its possible relation to the in vivo response.
A prospective study of 29 patients with CD.
Patients underwent desmopressin and CRH stimulation tests before surgery. The expression of vasopressin receptors and CRHR on corticotrophinomas was determined by immunocytochemistry.
Most of the corticotrophinomas exhibited abundant expression of V1R, V3R, and CRHR, whereas the expression of V2R varied greatly and was lower in macroadenomas than in microadenomas. Both the percentage increment of ACTH and net area under the curve (AUC) of ACTH in the desmopressin stimulation test were found to be correlated with tumour volume. After adjustment for tumour volume, a positive correlation was found between the percentage increment of ACTH and the degree of V2R expression, but not between that of V1R or V3R. No relationship between the level of expression of CRHR on tumour tissues and the percentage increment or netAUC of ACTH to CRH was observed in CD patients.
We concluded that V2R was expressed on corticotrophinomas and that the level of its expression correlated well with the ACTH response to desmopressin in CD patients, although abundant expression of V1R and V3R was also found in almost all corticotroph tumours. Further studies are needed to elucidate the role of these receptors in the pathogenesis of CD.
[Show abstract][Hide abstract] ABSTRACT: To determine the relationships between cardiovascular autonomic neuropathy (CAN) and autonomic symptoms, clinical parameters and diabetic complications in type 2 diabetes (T2DM).
The results of autonomic symptoms, clinical parameters, diabetes complications and cardiovascular reflex (CVR) tests of 674 T2DM were analyzed.
Significant correlations were found between CAN risk and age (p=0.019), duration of diabetes (p=0.008), HbA1c (p<0.001), systolic blood pressure (p=0.006), nephropathy (p<0.001), retinopathy (p<0.001), and QTc interval (p<0.001), but not BMI and hyperlipidemia. Patients with retinopathy or proteinuria had increase risk of CAN, and proliferative diabetic retinopathy (PDR) was the most significant risk factor (odds ratio: 6.85; 95% CI: 2.32-20.20) for CAN. Eighty-three percent of patients complained of autonomic symptoms; and the more symptoms complained, the higher the prevalence of CAN. Impotence was the only single symptom associated with CAN risk. Additional CAN risks were also observed when patients with multiple symptoms and/or complications in combinations.
Our results implied that patients with multiple symptoms and/or complications in combinations have increased CAN risk, and this may provide additional information for clinicians to identify T2DM at risk of having CAN.
Diabetes research and clinical practice 10/2008; 82(2):282-90. · 2.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The differential diagnosis of adrenocorticotropin (ACTH)-dependent Cushing's syndrome (CS) remains a challenging issue for clinical endocrinologists. In this respect, bilateral inferior petrosal sinus sampling (BIPSS) appears to be the most sensitive and specific test. Here, we report our 15-year experience of analyzing the performance of BIPSS, both in the correct diagnosis and in the precise lateralization of tumors in patients with Cushing's disease (CD).
Between 1992 and 2006, 18 patients with CD (16 females, 2 males; age range, 14-56 years) were admitted to Taipei Veterans General Hospital and subjected to BIPSS plus ovine corticotropin-releasing hormone (oCRH) stimulation. Four of them had previously undergone transsphenoidal hypophysectomy (TSH) and had a recurrence thereafter. BIPSS was performed by inserting a catheter in the right and left inferior petrosal sinus for ACTH assay via a femoral vein puncture. An inferior petrosal sinus/peripheral ACTH ratio (C/P ratio) > or = 2 at baseline > or = 3 after oCRH injection indicated a pituitary origin of ACTH secretion, and an interpetrosal ACTH gradient (IPS ratio) > or = 1.4 at baseline or after oCRH indicated evidence of lateralization.
Positive BIPSS results were found in 16 patients at baseline and in 17 patients after oCRH injection. In 17 out of 18 patients, TSH was subsequently carried out and a pituitary source was confirmed on histopathologic examination. The only 1 false-negative test result was noted in a patient who had undergone previous TSH. Thus, the sensitivities of BIPSS for the diagnosis of CD before and after oCRH stimulation were 89% and 94%, respectively. Moreover, using an IPS ratio > or = 1.4 as a criterion, BIPSS correctly lateralized the tumor in 9 of 17 and 10 of 17 patients at baseline and after oCRH stimulation, respectively, including in 2 patients who had a centrally located tumor and who had an IPS ratio < 1.4. Thus, the sensitivities of lateralization of BIPSS were 53% and 59%, respectively. None of the 4 patients who had previous TSH were precisely localized by BIPSS. If these 4 patients were excluded, the sensitivities of BIPSS for localizing in the patients who had not undergone previous operation increased to 70% (9/13) at baseline and 77% (10/13) after oCRH stimulation, respectively.
BIPSS combined with oCRH stimulation is a safe and reliable examination both in the differential diagnosis of CD and in the correct lateralization of pituitary microadenoma in patients without previous pituitary surgery. Nevertheless, this procedure may provide misleading results in patients who have received previous pituitary surgery.
Journal of the Chinese Medical Association 01/2007; 70(1):4-10. · 0.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Noninsulinoma pancreatogenous hypoglycaemia syndrome (NIPHS), characterized by postprandial neuroglycopaenia, negative prolonged fasts and negative perioperative localization studies for insulinoma, but positive selective arterial calcium stimulation tests and nesidioblastosis in the gradient-guided resected pancreas, is a rare hypoglycaemic disorder of undetermined aetiology. We analysed the clinical, morphological and immunohistological features to further clarify the aetiology and pathogenesis of this rare disease.
Ten consecutive patients with NIPHS (nine men and one woman, aged 29-78 years) were included in the study. Six of the 10 received a gradient-guided subtotal (70%) or distal (50%) pancreatectomy. In the remaining four patients, diazoxide treatment was initiated and the precise mechanism of its action was assessed by meal tests.
All of the patients showed a combination of postprandial neuroglycopaenia, negative prolonged fasts (except one patient) and negative localization studies for insulinoma, but positive calcium stimulation tests and nesidioblastosis in the gradient-guided resected pancreas. Immunohistological studies of the resected pancreatic tissues revealed neither an increased rate of proliferation of beta-cells nor an abnormal synthesis and/or processing of either proinsulin or amylin. Evidence of overexpression of the two pancreatic differentiation factors, PDX-1 and Nkx-6.1, as well as the calcium sensing receptor (CaSR) was absent. Nevertheless, abnormal expression of islet neogenesis-associated protein (INGAP), a human cytokine expressed only in the presence of islet neogenesis, in ducts and/or islets, was identified in three of the five patients studied. All of the six patients who received a surgical operation were relieved of further neuroglycopaenic attacks, but one patient who received a subtotal pancreatectomy developed diabetes. In the remaining four patients who received diazoxide treatment, hypoglycaemic episodes were satisfactorily controlled with an attenuated response of beta-cell peptides to meal stimulation.
Our results strengthen the existence of this unique clinical hypoglycaemic syndrome from beta-cell hyperfunction as well as the value of the selective arterial calcium stimulation test in its correct diagnosis and localization. The mechanisms underlying beta-cell hyperfunction and release of insulin to calcium, however, remain poorly characterized. Nevertheless, in a subset of patients with NIPHS, there exists some, as yet undefined, pancreatic humoral/paracrine factor(s) other than proinsulin, amylin, PDX-1, Nkx-6.1 and possibly glucagon-like peptide-1 (GLP-1) that are capable of inducing the INGAP gene and, if activated, will initiate ductal proliferation and islet neogenesis. As for the treatment, we recommend that diazoxide be tried first in each patient and, should it fail, a gradient-guided subtotal or distal pancreatectomy be attempted.
[Show abstract][Hide abstract] ABSTRACT: Insulin autoimmune syndrome, characterized by the presence of insulin-binding autoantibodies and fasting or late postprandial hypoglycemia, is a rare cause of hypoglycemia. We report a patient with pulmonary tuberculosis who developed recurrent spontaneously post-absorptive hyperinsulinemic hypoglycemia after treatment with anti-tuberculous drugs. Imaging studies of the pancreas were unremarkable, and selective intra-arterial calcium stimulation with hepatic venous sampling for insulin failed to show a gradient, thus almost completely excluding the possibility of occult insulinoma or nesidioblastosis. Examinations of sera, however, disclosed a high titer of polyclonal insulin-binding autoantibodies containing at least 2 classes of binding sites, 1 with high affinity but low capacity, and the other with low affinity but high capacity. An oral glucose tolerance test revealed high serum levels of total insulin associated with relatively low levels of free insulin, but not of C-peptide, suggesting binding of the released insulin to autoantibodies. Regretfully, shortly after the withdrawal of isoniazid, the patient died of respiratory failure unrelated to hypoglycemia, and whether these antibodies were induced by isoniazid remains unknown. We recommend that insulin autoimmune syndrome be one of the differential diagnoses in patients with hyperinsulinemic hypoglycemia.
Journal of the Chinese Medical Association 03/2005; 68(2):82-6. · 0.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Adequate surgical treatment of hypoglycemia caused by benign diffuse islet cell disease (BDICD) is not associated with predictable results. Arterial stimulation and venous sampling (ASVS) has been reported to establish the diagnosis of BDICD, as well as serve as a guide to resection. The purpose of this study is to determine the efficacy of this method for the treatment of benign diffuse islet cell disease.
We retrospectively reviewed 38 adults with symptomatic hyperinsulinemic hypoglycemia treated by a single surgeon from 1982 to 1998. Nine of them had pathologic evidence of BDICD. We demonstrated the clinical presentations, serum level of fasting blood sugar, insulin and C-peptide before and after operations, pathological results, and outcomes of distal pancreatectomy in 5 patients and ASVS-guided pancreatectomies in 4 patients with BDICD.
Five patients (4 females and 1 male) who received distal pancreatectomy (Group 1) were aged from 19 to 75, and were culled from a group of 30 patients with spontaneous hyperinsulinemic hypoglycemia. Two had the multiple endocrine neoplasia (MEN) 1 syndrome. The follow-up was from 7 to 16 years. Three patients (including 1 MEN 1 patient) became diabetic. Another 1 is euglycemic, and the other MEN 1 patient developed recurrent disease. Four patients (2 males and 2 females, Group 2), found in a group of 8 patients with hyperinsulinemic hypoglycemia, had ASVS-guided pancreatectomies. Their ages ranged from 29 to 69 years. The area of the pancreas supplied by the splenic artery was removed in all patients. Follow-up from half to 2 years showed that all the patients had normal fasting levels of glucose, normal levels of insulin and C-peptide, and no more hypoglycemic attacks.
Arterial stimulation venous sampling is a useful guide for pancreatectomy to treat adult patients with BDICD. Data from this small sample of patients suggest that the results may be superior to those obtained by "blind" distal pancreatectomy.
Zhonghua yi xue za zhi = Chinese medical journal; Free China ed 04/2002; 65(3):111-8.
[Show abstract][Hide abstract] ABSTRACT: A 69-year-old man with recurrent hypoglycaemia had inappropriately elevated plasma insulin level during a symptomatic hypoglycaemia, but had a negative prolonged fast. Computerized tomography (CT) of the abdomen revealed a nodular lesion over the body of pancreas, whereas pancreatic arteriography failed to show tumour blush. Hence, arterial stimulation (with calcium) and venous sampling (ASVS) was performed and a brisk response of plasma insulin level was found when calcium was injected both into the splenic and the superior mesenteric arteries. Since no tumour was found during the operation, the patient received subtotal distal pancreatectomy. Pathological examination of the resected tissue disclosed a typical finding of nesidioblastosis. We suggest that selective intra-arterial calcium injection with hepatic venous sampling for insulin gradients is useful for the diagnosis of adult nesidioblastosis.
Diabetic Medicine 12/1997; 14(11):985-8. · 3.24 Impact Factor