Endocrine function after hetero- and ortho-topic segmental pancreatic transplantation in primates

This study assessed the early postoperative pancreatic endocrine function after intraperitoneal segmental hetero- and ortho-topic pancreatic allotransplantation in hemipancreatectomized, nonimmunesuppressed chacma baboons. Hemipancreatectomized animals remained normoglycaemic but rendered significantly reduced K values and insulin release during IVGTT, findings consistent with major pancreatic resection. Segmental hetero- or ortho-topic pancreatic transplantation did not improve reduced K values and hypoinsulinaemia following hemipancreatectomy although orthotopically sited grafts rendered the best glucose tolerance test curves. Glucagon output during IVGTT remained the same in both transplant models. It is concluded that the postoperative hormonal response was similar in both orthotopic and heterotopic transplant recipients, which indicates that drainage of graft venous effluent into the portal circulation has no advantage over systemic insulin drainage as reflected in this "diabetic" model.     

Early postoperative pancreatic endocrine function after segmental and pancreaticoduodenal allotransplantation in nonimmunosuppressed primates

In this study we evaluated the short-term hormonal effects of segmental and whole pancreatic allotransplantation on the glucose intolerance produced by hemipancreatectomy in the primate. In hemipancreatectomized animals without grafts the K-values were reduced to 0.6 +/- 0.05, plasma insulin increased from 27.5 +/- 2.5 to 63.5 +/- 6.3 microU/ml, and glucagon levels declined from 252 +/- 29.9 to 216.5 +/- 33.0 pg/ml. Hemipancreatectomized segmental allograft recipients rendered K-values of 0.79 +/- 0.05, plasma insulin increased from 19.98 +/- 3.43 to 66.0 +/- 17.03 microU/ml, and glucagon release declined from 395.6 +/- 63.0 to 226.2 +/- 37.6 pg/ml during IVGTT postoperatively. Hemipancreatectomized, pancreaticoduodenal allograft recipients rendered K-values of 0.82 +/- 0.1, results not significantly different from hemipancreatectomized or segmental allograft recipients. Plasma insulin increased from 29.5 +/- 4.0 to 186.0 +/- 25.0 microU/ml, and glucagon release declined from 1,087.0 +/- 31.6 to 656.0 +/- 12.7 pg/ml. In summary, segmental pancreatic allotransplantation could not, in the short-term, restore the reduced K-values and hypoinsulinaemia in hemipancreatectomized primates to that of normal, unstressed controls. Although K-values of hemipancreatectomized recipients were not significantly improved, whole pancreas transplantation resulted in improved insulin release and hyperglucagonaemia during IVGTT when compared to segmental allograft recipients. The unexpected findings of hypoinsulinaemia and hyperglucagonaemia in both transplant groups may only reflect a function of the stressed state of the animals in the immediate postoperative phase.     

Islet cell function in long-term surviving primates after segmental pancreatic allotransplantation

Islet cell function was studied in pancreatectomized primates with functioning segmental pancreatic allografts more than 100 days after transplantation. Segmental allograft recipients were immunosuppressed with total lymphoid irradiation (TL1) and cyclosporine (CSA). After 100 days, islet function was assessed, at which stage immunosuppression was terminated. Glucose, insulin, glucagon, and C-peptide response was assessed during intravenous glucose tolerance test (IVGTT) and during arginine and tolbutamide stimulation. In eight normoglycaemic primates in which immunosuppressive treatment had been stopped and with mean graft survival of 145 days, islet stimulation was associated with moderate glucose intolerance, reduced K-values, hypoinsulinaemia, and low C-peptide values. Postmortem findings in all animals intentionally killed revealed severe graft atrophy in the absence of significant rejection. Severe graft atrophy in normoglycaemic primates, together with significantly impaired graft function after segmental pancreatic transplantation compared to normal animals, suggest that transplantation of the whole pancreas may be mandatory if normal or near-normal function is to be achieved.     

Glucose intolerance in sarcoma patients

Twenty-seven otherwise healthy patients with localized sarcoma were examined to determine if glucose intolerance can be detected before the appearance of clinical signs of cachexia. No patient had lost weight or demonstrated severe malnutrition. Fasting plasma samples for glucose, insulin, glucagon, and free fatty acids (FFA) were obtained, and a standard intravenous glucose tolerance test performed. Glucose disappearance rate (K) was calculated between 5 and 60 minutes. K levels were compared to those of normal controls and to those of patients with more extensive cancer (statistics obtained from the literature). Levels for K were compared to tumor volume measurements following surgery. Fasting glucose, insulin, and glucagon levels were normal. Fasting FFA levels were slightly elevated. K levels for sarcoma patients were significantly lower than in control patients (P = 0.04), and higher than in patients with advanced cancer (P less than 0.0001). The subset of patients who weighed less than the ideal had a significantly lower K level than did the rest of the sarcoma population. K levels correlated inversely with tumor volume (r = -0.34; P = 0.04). These data indicate that mild glucose intolerance (reduction in clearance of a glucose load) occurs early in untreated sarcoma patients, is most prevalent in patients who maintain less than the ideal weight, correlates with tumor burden, and occurs before other signs of cachexia appear.     

A specific and sensitive radioimmunoassay for rat C-peptide

A sensitive and specific radioimmunoassay for rat serum C-peptide (RCP) has been developed and validated using a guinea pig anti-rat C-peptide antibody to synthetic rat C-peptide. Negligible crossreactivity (<0.01%) to human proinsulin was observed, whereas human insulin, human pancreatic polypeptide (hPP), porcine insulin, porcine C-peptide, bovine insulin, rat insulin, porcine-PP, and glucagon, respectively, did not produce measurable displacement of RCP tracer. Human C-peptide even in a supraphysiological concentration range crossreacted poorly (<0.1%). The sensitivity limit of the assay calculated at ±3 standard deviations was 24.2pM (0.07 ng/mL). RCP standard concentrations ranged from 25–1600pM. The intraassay-and between assay-coefficient of variations (CV) were 3.5–6.1% and 4.1–9.5%, respectively. The mean percentage recovery of RCP added to rat serum samples was 100.8±2%. Serum volume dilution from 25 to 100 μL did not significantly alter the expected RCP level. Migration of rat serum C-peptide and that of synthetic RCP were identical in a Sephadex G-50 chromatographic analysis. The mean fasting and postprandial plasma RCP levels in normal rats were 102±15pM and 485±75pM, respectively. RCP levels following intravenous glucose tolerance test in diabetic and nondiabetic rats were consistent with expected patterns. In conclusion, we have developed and validated a rat C-peptide assay that is sensitive, simple, and specific for RCP in serum. The assay provides a reliable tool for studies of diabetes using rodent animal models.     

Postprandial hypoglycemia in islet beta cell hyperplasia with adenomatosis of the pancreas.

Organic hyperinsulinism causing hypoglycemia in adults is caused by insulinoma, islet hyperplasia, or a combination of adenomata and hyperplasia. We present a patient with long-standing symptoms of postprandial hypoglycemia occurring within 15 minutes of meals in the absence of fasting hypoglycemic symptoms. An intravenous glucagon stimulation test resulted in a rise of plasma insulin from 194 to 21,883 pmol/L at 7.5 minutes. Blood glucose simultaneously rose from 4.9 to 5.9 mmol/L. A glucose tolerance test revealed an exuberant insulin response. A euglycemic hyperinsulinemic clamp demonstrated incomplete suppression of plasma C-peptide. At surgery, three nodules were found and a 50-60% distal pancreatectomy was performed. The pancreas revealed a combination of multiple beta-cell islet adenomata and islet hyperplasia with no evidence of nesidioblastosis. The coexistence of islet adenomata with hyperplasia must be considered in the differential diagnosis of postprandial hypoglycemia.     

Effects of transplantation and resection of a radiation-induced rat insulinoma on glucose homeostasis and the endocrine pancreas

Twenty-one days after s.c. subscapular transplantation of a radiation-induced insulinoma, male NEDH rats exhibited hyperinsulinaemia and hypoglycaemia. These features were associated with islet atrophy, degenerative changes in pancreatic A and B cells, and decreases in the pancreatic contents of insulin, glucagon and somatostatin. The immunoreactive glucagon and somatostatin contents of extrapancreatic tissues of insulinoma-bearing rats were unchanged. Surgical resection of the tumour resulted in an immediate fall of plasma insulin, attaining concentrations similar to those of anaesthetised control rats by 10 min. The estimated half-life of insulin was 3.5 min. Hypoglycaemia persisted until 60 min after resection, followed by hyperglycaemia of 1-2 days duration. Glucose tolerance was impaired 1 day after tumour resection despite the coexistence of raised insulin concentrations. Evidence for abnormal pancreatic B cell function was gained by injection of arginine which failed to evoke a plasma insulin response in the resected rats. Two days after resection, plasma glucose and insulin concentrations were similar to those of control rats. Plasma glucose and insulin responses to glucose and arginine were suggestive of tumour recurrence by 12 days. A single large encapsulated tumour was eventually observed in each rat, with resection giving a 17-56 day prolongation of life.     

Medical Treatment for Inoperable Insulinoma: Clinical Usefulness of Diphenylhydantoin and Diltiazem

This report describes a 78-year-old woman with insulinoma, treatedwith a combination of diphenylhydantoin and a calcium antagonist.The effectiveness of 200 mg of diphenylhydantoin and 180 mgof diltiazem was evaluated by measuring the levels of plasmaglucose, immunoreactive insulin and immunoreactive insulin/plasmaglucose after fasting or by the oral glucose tolerance test,and by the appearance of hypoglycemic symptoms. The mean concentrationof fasting plasma glucose increased significantly during thetreatment. The levels of immunoreactive insulin/plasma glucoseand C-peptide imniunoreactivity/plasma glucose significantlydecreased. Symptomatically. no episode of hypoglycemia was notedduring the combined treatment.     

Gastrointestinal hormones in the blood serum of patients with chronic renal failure

Content of gastrointestinal hormones (gastrin, insulin, glucagon, C-peptide), beta2-microglobulin, glomerular filtration rate (GFR) were studied in 65 patients with nephrolithiasis (NL) and in 73 patients with chronic renal failure (CRF). It was found that NL with GFR under 80 ml/min runs with elevated insulin, glucagon and C-peptide while CRF with CRF under 30 ml/min is characterized by aggravated disorders of hormonal homeostasis (gastrin, insulin, glucagons, C-peptide elevation). As gastrointestinal hormones in patients with CRF are high, it is recommended to combine medication with diet containing low amount of carbohydrates easy for digestion which is important in the treatment of CRF.     

Diabetes in pancreatectomized baboons: a model for pancreatic transplantation studies

This study was designed to assess plasma glucose levels (PLG) and insulin release in totally pancreatectomized baboons when challenged with intravenous glucose administration (IVGTT). Ten animals (Papio ursinus) were used and duodenectomy was intentionally avoided. The PLG at death was 18.0 +/- mmol/L, and the mean K-value within 3 days after pancreatectomy was 0.4% +/- 0.2%, indicating a significant impairment of glucose disappearance from the blood when compared to the control animals (P less than 0.01). Plasma insulin levels before and after stimulation with glucose were below the lowest level of insulin assay sensitivity. We conclude that in the primate, as in the dog, surgical pancreatectomy produced a reliable diabetic model, which is uniformly lethal if left untreated.     

Significance of glucose intolerance and SHIP2 expression in hepatocellular carcinoma patients with HCV infection

Glucose intolerance frequently is found in hepatocellular carcinoma (HCC) patients with hepatitis C virus (HCV) infection; however, the significance of glucose intolerance remains unclear. In addition, SH2 domain-containing inositol phosphatase (SHIP) 2 is a negative regulator of intracellular insulin signaling; however, changes in SHIP2 expression have not been investigated in HCC. To assess the significance of glucose intolerance, we analyzed 118 HCC patients with HCV infection. Twenty HCC specimens were used for immunoblotting and immunostaining for SHIP2. Patients were classified into two groups: a glucose intolerance group (n=39) and a normal glucose tolerance group (n=79). There was no significant difference in the disease-free survival (P=0.838) or long-term survival (P=0.091) between the groups. However, for males, the cumulative survival rate was significantly lower in the glucose intolerance group (n=22) than that in the normal glucose tolerance group (n=52) (P=0.036). In multivariate analysis, Child-Pugh class (P=0.0003) and glucose intolerance (P=0.036) were identified as statistically significant and independent prognostic factors in males. SHIP2 expression level decreased in HCC compared to that in nontumor tissues. In conclusion, this study is the first to demonstrate the significance of glucose intolerance in prognosis of male HCC patients and down-regulation of SHIP2 expression in HCC.     

肝癌的糖代谢、胰岛素和C肽变化的研究

 目的　探讨肝癌糖代谢异常的特点 ,外周血胰岛素(INS)、C肽(C-P)水平的变化及胰岛β细胞的功能状态。方法　对21例原发性肝癌和20例正常人进行葡萄糖耐量(OGTT)、胰岛素释放和C肽释放试验, 分别比较空腹及服糖后2小时的血糖(BG)、INS和C-P水平。结果　肝癌组2 小时的BG、INS和C-P水平较对照组同期显著增加(P＜0.05),肝癌组2小时/空腹INS 比值、2小时/空腹C-P比值显著高于对照组(P＜0.05)。结论　肝癌 患者糖代谢异常表现为糖耐量减低,餐后高胰岛素血症和高C肽血症可能是由于β细胞代偿 性分泌增多。     

Defective regulation of insulin release and transmembrane Ca2+ fluxes by human islet cell tumours

Regulation of insulin release and transmembrane Ca2+ fluxes was examined using pieces of 3 benign medullary-type insulinomas removed from the pancreas of female patients at surgery. Immunocytochemical staining confirmed the presence of insulin-containing cells with no demonstrable glucagon, somatostatin or pancreatic polypeptide. After 3 days of culture in RPMI-1640, tumour pieces released 11-158 mg insulin kg-1 dry wt during acute 60 min incubations with the concomitant uptake of 2-47 mmol 45Ca kg-1 into the intracellular lanthanum-nondisplaceable pool. At 2.56 mM Ca2+, glucose alone or in combination with glyceraldehyde, mannoheptulose or diazoxide did not modify insulin release or 45Ca uptake. Theophylline significantly increased insulin release from 2 tumours with a small stimulatory effect on the third. A depolarising concentration of K+ enhanced insulin release from one tumour but this was not associated with an increase of 45Ca uptake. Calcium antagonists, (verapamil, D-600 and trifluoroperazine) and calcium ionophores (A23187 and Br-X537A) failed to modify insulin release or 45Ca uptake by each of the two tumours tested. Evaluation of 45Ca efflux from one tumour confirmed the unresponsiveness to glucose, K+, verapamil and A23187. Prolonged culture of 2 tumours for up to 16 days was associated with the gradual decline of insulin release to a steady output of 2-15 ng 24 h-1. Addition of verapamil to the cultures inhibited insulin output from one tumour, but mannoheptulose or diazoxide were without effect. The results indicate that inappropriate insulin release from these 3 benign medullary-type insulinomas is associated with disturbances in the regulation of transmembrane Ca2+ fluxes.     

药物疗法对恶性肿瘤患者糖化血红蛋白和空腹血糖的影响

目的探讨药物疗法对恶性肿瘤患者糖化血红蛋白(Hb A1c)和空腹血糖(FBG)的影响。方法将2012年2月至2014年2月收治的63例恶性肿瘤行化疗患者作为研究对象,观察患者单次化疗前后、多次化疗前后的Hb A1c和FBG水平,同时分析血糖、胰岛素水平及胰岛功能与疗程的相关性。结果单次化疗后患者的FBG、空腹C-肽及胰岛素水平均明显高于化疗前(P<0.05),但单次化疗前后Hb A1c水平的差异无统计学意义(P>0.05)。多次化疗后患者的FBG、空腹C-肽、Hb A1c及空腹胰岛素水平均高于化疗前,差异有统计学意义(P<0.05)。不同疗程胰岛素抵抗指数(HOMA-IR)、Hb A1c及胰岛素水平与化疗次数呈正相关(P<0.05),而C-肽、FBG及胰岛素分泌指数(HOMA-β)与化疗次数无相关性(P>0.05)。结论化疗会影响恶性肿瘤患者的血糖代谢指标及胰岛功能,长期化疗则会降低胰岛功能并诱发糖尿病。     

Correlation between mammary tumor and blood glucose, serum insulin, and free fatty acids in mice

The blood glucose level and serum levels of insulin, glucagon, and free fatty acids were examined in 7- to 8-mo-old female SHN mice with or without spontaneous mammary tumors (MT). Blood glucose levels in the females with MT were significantly higher than in those without MT, rising in proportion to the increase in size of MT up to 30 mm in diameter. In 4-mo-old male SHN and 11-mo-old female C57BL mice bearing mammary tumor grafts (MTg), the blood glucose level was significantly higher than in mice without MTg. Serum insulin and free fatty acids in female SHN mice with MT rose to higher levels than in mice without MT, whereas serum glucagon levels were unaltered. In 50% of mice with MT, pancreatic islets contained a large number of pyknotic cells. Livers of mice with MT or MTg were significantly heavier than those of mice without MT or MTg. In both female SHN mice with spontaneous MT and male SHN and female C57BL mice with MTg, the total number of hepatocytes and the total amount of liver DNA increased significantly compared with values from corresponding controls without MT or MTg. These findings suggest that MT or MTg induce a hyperglycemic state and an enhanced production of free fatty acids and insulin, which may in turn stimulate the growth of mammary tumors and the liver.     

Mechanism of impaired glucose tolerance in patients with neoplasia.

The disappearance rate (k) of i.v. glucose was measured in cachectic and non-cachectic cancer patients and tumour-free controls. The respective k values were found to be 1.06 +/- 0.27 (mean +/- s.d.), 1.64 +/- 0.34 and 1.63 +/- 0.23. Of the other parameters measured, only plasma albumin level was found to vary significantly amongst the 3 categories, the mean level being the lowest in cachectic cancer patients. The means of total plasma protein, fasting blood glucose and plasma liver enzyme concentrations were similar in the 3 groups. Glucagon, a potent insulin secretogogue, failed to augment the fasting insulin level in cachectic but did so in non-cachectic cancer patients. Taken together, the findings suggest that the reduced glucose tolerance in patients with neoplasia is due to impairment of insulin release exhibited predominantly by ill-nourished advanced cancer patients having a moderate to sever degree of hypoalbuminemia.     

Insulin resistance and breast-cancer risk.

Life-style has a major influence on the incidence of breast cancer. To evaluate the effects of life-style related metabolic-endocrine factors on breast cancer risk we conducted a case-control study comparing 223 women aged 38 to 75 years presenting with operable (stage I or II) breast cancer and 441 women of the same age having no breast cancer, who participated in a population-based breast cancer screening program. Women reporting diabetes mellitus were excluded. Sera from 110 women of the same age group presenting with early stage melanoma, lymphoma or cervical cancer were used as a second 'other-cancer control group'. Serum levels of C-peptide were significantly higher in early breast cancer cases compared to controls. The same was found for the ratios C-peptide to glucose or C-peptide to fructosamine, indicating insulin resistance. Sex hormone binding globulin was inversely, triglycerides and available estradiol were positively related to C-peptide. Serum C-peptide levels were related to body mass index (BMI), and to waist/hip ratio (WHR), in particular in controls. However, the relative increase of C-peptide, C-peptide to glucose or C-peptide to fructosamine in cases was independent of BMI or WHR. The log relative risk was linearly related to the log C-peptide levels. Relative risk according to quintiles, and adjusted for age, family history, BMI and WHR, for women at the 80% level was 2.9 as compared with those at the 20% level for C-peptide. Elevated C-peptide or C-peptide to fructosamine values were not observed in the sera from women belonging to the 'other-cancer control group'. This study suggests that hyperinsulinemia with insulin resistance is a significant risk factor for breast cancer independent of general adiposity or body fat distribution.     

Changes in plasma hormone profiles after tumor transplantation into syngeneic and allogeneic rats

Transplantation of 2 chemically (DMBA, MCA)-induced tumors into syngeneic female or male DA strain rats elicited hormonal changes during tumor growth. Plasma levels of 7 different hormones were studied. Tumor cells in syngeneic recipients produced a biphasic decrease in insulin, an early increase in prolactin, and a late-phase decrease in thyroxine. Corticosterone decreased in female tumor bearers but increased in males. This difference may reflect differences in the tumors transplanted. Male rats had a decrease in testosterone during the late phase of tumor growth, while females had a biphasic decrease in progesterone and a late-phase increase in growth hormone. The tumors used were moderately immunogenic in syngeneic recipients. However, tumor transplantation to allogeneic recipients produced an early decrease in growth hormone and no change in insulin, corticosterone or thyroxine. Further, transplantation of normal liver cells to syngeneic or allogeneic recipients produced no hormonal abnormalities. This study demonstrates that hormonal changes which are not observed with normal cells or allogeneic tumor transplantation can occur within 2 days of syngeneic tumor transplantation. Progressive tumor growth is characterized by a worsening endocrine imbalance which involves multiple hormone systems.     

Conversion from low grade to high grade of rat urinary bladder carcinomas

The present study was conducted to test if low-grade carcinomas induced by a single dose of N-methyl-Nitrosourea (MNU) can be converted to high-grade carcinomas by a second identical dose of the carcinogen. The heterotopically transplanted rat urinary bladder system was used. Four wk after heterotopic bladder transplantation, the recipient male Fischer 344 rats were divided into 2 groups. The first group received 0.25 mg of MNU into heterotopically transplanted rat urinary bladder; the second group (controls) received 0.9% NaCl solution. At week 29 of the experiment, 1/3 of the animals from each group were killed for histological examination of the heterotopically transplanted rat urinary bladders. The remaining animals from each group were divided into 2 subgroups, the first receiving 0.25 mg MNU and the second, 0.9% NaCl solution. All animals were killed at 50 wk of the experiment. MNU-induced carcinomas at week 29 were all of low histological grade and were noninvasive. Longer follow-up without a second carcinogen administration resulted in both an increase in tumor incidence (P less than 0.005) and more tumors per bladder (P less than 0.001), but high-grade invasive carcinomas were rare. The second dose of MNU administered at the stage when low-grade carcinomas were prevalent (week 29) resulted in a significant increase in invasive high-grade carcinomas (P less than 0.01). Our data are consistent with the view that the second carcinogen administration induces a new mutation(s) within low-grade carcinomas which leads to invasive carcinomas.     

Long-term risk of malignant neoplasm associated with gestational glucose intolerance

BACKGROUND: Previous studies have demonstrated an association between diabetes mellitus and cancer risk. However to the author's knowledge, no data regarding the risk of cancer associated with subclinical impaired glucose tolerance have been published to date. An association between various types of cancer and any continuum of risk across the spectrum of glucose tolerance may be important in determining the nature of the association between diabetes mellitus and the risk of malignancy. METHODS: The current study was conducted to examine the long-term risk of malignant neoplasms associated with maternal glucose intolerance. A 20-year follow-up study of a cohort of women who had previously taken part in a study in 1980 that investigated maternal glucose metabolism and fetal outcome was performed. Gestational glucose metabolism, smoking behavior, and weight and height measured at the time of index pregnancy, as well as weight, height, and smoking behavior assessed by questionnaire in 1999, were examined. The main endpoint of the study was hospital admission with a diagnosis of malignant neoplasm as ascertained by linkage data. RESULTS: Thirty-four of the 753 women living in Grampian (4.5%) were admitted to the hospital with a diagnosis of malignant neoplasm; of these, 18 cases were malignant neoplasms of the breast. After adjustment for known risk factors, both malignant neoplasm and malignant neoplasm of the breast were found to be significantly associated with gestational glucose intolerance. CONCLUSIONS: Subclinical glucose intolerance during pregnancy was found to be associated with a dose-related increase in the risk of malignant neoplasm, particularly malignant neoplasm of the breast.