Glucagon secretion from pancreatic α-cells

Type 2 diabetes involves a ménage à trois of impaired glucose regulation of pancreatic hormone release: in addition to impaired glucose-induced insulin secretion, the release of the hyperglycaemic hormone glucagon becomes dysregulated; these last-mentioned defects exacerbate the metabolic consequences of hypoinsulinaemia and are compounded further by hypersecretion of somatostatin (which inhibits both insulin and glucagon secretion). Glucagon secretion has been proposed to be regulated by either intrinsic or paracrine mechanisms, but their relative significance and the conditions under which they operate are debated. Importantly, the paracrine and intrinsic modes of regulation are not mutually exclusive; they could operate in parallel to control glucagon secretion. Here we have applied mathematical modelling of α-cell electrical activity as a novel means of dissecting the processes that underlie metabolic regulation of glucagon secretion. Our analyses indicate that basal hypersecretion of somatostatin and/or increased activity of somatostatin receptors may explain the loss of adequate counter-regulation under hypoglycaemic conditions, as well as the physiologically inappropriate stimulation of glucagon secretion during hyperglycaemia seen in diabetic patients. We therefore advocate studying the interaction of the paracrine and intrinsic mechanisms; unifying these processes may give a more complete picture of the regulation of glucagon secretion from α-cells than studying the individual parts.     

Somatostatin receptor expression and biological functions in endocrine pancreatic cells: review based on a doctoral thesis

Type 1 diabetes is resulting from the selective destruction of insulin-producing betacells within the pancreatic islets. Somatostatin acts as an inhibitor of hormone secretion through specific receptors (sst1-5). All ssts were expressed in normal rat and mouse pancreatic islets, although the expression intensity and the co-expression pattern varied between ssts as well as between species. This may reflect a difference in response to somatostatin in islet cells of the two species. The Non-Obese Diabetic (NOD) mouse model is an experimental model of type 1 diabetes, with insulitis accompanied by spontaneous hyperglycaemia. Pancreatic specimens from NOD mice at different age and stage of disease were stained for ssts. The islet cells of diabetic NOD mice showed increased islet expression of sst2-5 compared to normoglycemic NOD mice. The increase in sst2-5 expression in the islets cells may suggest either a contributing factor in the process leading to diabetes, or a defense response against ongoing beta-cell destruction. Somatostatin analogues were tested on a human endocrine pancreatic tumour cell line and cultured pancreatic islets. Somatostatin analogues had an effect on cAMP accumulation, chromogranin A secretion and MAP kinase activity in the cell line. Treatment of rat pancreatic islets with somatostatin analogues with selective receptor affinity was not sufficient to induce an inhibition of insulin and glucagon secretion. However, a combination of selective analogues or non-selective analogues via costimulation of receptors can cause inhibition of hormone production. For insulin and glucagon, combinations of sst2 + sst5 and sst1 + sst2, respectively, showed a biological effect. In summary, knowledge of islet cell ssts expression and the effect of somatostatin analogues with high affinity to ssts may be valuable in the future attempts to influence beta-cell function in type 1 diabetes mellitus, since down-regulation of beta-cell function may promote survival of these cells during the autoimmune attack.     

胰腺局部肾素-血管紧张素系统的生理作用

全身肾素-血管紧张素系统(RAS)在调节血压及水、电解质平衡方面起重要作用。而最近发现多种组织、器官中存在局部独立的RAS,在局部自分泌、旁分泌等生理功能方面起不同程度的作用。目前发现在胰腺组织内,包括胰腺腺泡、导管、胰岛、上皮细胞以及星形细胞中存在局部RAS,在生理和包括低氧、胰腺炎、胰岛移植、糖尿病等病理刺激条件下,其表达发生相应改变。RAS在胰腺内、外分泌功能中起重要作用:调节局部血流、导管细胞分泌碳酸氢钠、腺泡细胞分泌消化酶、胰岛β细胞合成及释放胰岛素、δ细胞分泌生长抑素、胰腺细胞增殖和分化。此外,还可能介导氧化应激诱导的细胞炎症、凋亡和纤维化。通过上述影响,胰腺局部RAS在胰腺炎、糖尿病、囊性纤维化及胰腺肿瘤的形成中可能起一定的作用,本文就胰腺局部RAS的生理功能及临床意义进行综述。     

生长抑制素在治疗胰瘘和预防胰腺手术后并发症中的作用

应用生长抑制素治疗５例胰瘘和１８例壶腹周围癌行胰十二指肠切除术患者。结果表明生长抑制素具有明显抑制胰液、胆汁、胃液等消化液分泌的作用。对促进手术后胰瘘的愈合具有十分满意的疗效。对少数高危的胰头癌患者，于围手术期预防性应用生长抑制素，术后病程平稳，未发生消化道瘘并发症。提示生长抑制素有助于治疗胰瘘和预防胰腺手术后并发症。     

Somatostatin analogue treatment of neuroendocrine tumours.

The long-acting analogues of somatostatin have an established place in the medical treatment of patients with neuroendocrine tumours. They act through binding with specific, high-affinity membrane receptors. Somatostatin analogue therapy is an effective and safe treatment for most growth hormone and thyrothropin-secreting pituitary adenomas. The potential therapeutic consequences of the presence of somatostatin receptors on clinically ''nonfunctioning'' pituitary tumours are still uncertain. Somatostatin analogues are not useful in the treatment of patients with prolactinomas, or adrenocorticotropin (ACTH)-secreting adenomas. However, the somatostatin analogue octreotide suppressed pathological ACTH release in some patients with Nelson''s syndrome and ACTH and cortisol secretion in several patients with Cushing''s syndrome caused by ectopic ACTH secretion. Somatostatin analogues are effective in the sympatomatic treatment of most (metastatic) pancreatic islet cell tumours and most (metastatic) carcinoids. In some of these patients, they also induce tumour stabilisation or reduction. In some patients with (metastatic) medullary thyroid carcinomas, continuous treatment with very high doses of octreotide can be of temporary relief. The clinical effectiveness of somatostatin analogues in patients with small cell lung cancer is currently under investigation. Long-term therapy with somatostatin analogues of catecholamine-secreting (malignant) paragangliomas and phaeochromocytomas has not shown clinical benefits.     

生长抑素和头孢噻甲羧肟对急性出血坏死性胰腺炎早期细菌移位的影响

为探讨急性出血坏死性胰腺炎（ＡＨＮＰ） 感染的防治, 我们观察了头孢噻甲羧肟和生长抑素对ＡＨＮＰ早期细菌移位的影响。结果提示生长抑素具有肠粘膜屏障保护作用, 可能与其清除肠道氧自由基有关。我们还发现ＡＨＮＰ早期应用抗生素可减轻血行的细菌移位。     

生长抑素联合生长激素对重症急性胰腺炎胰腺细胞凋亡的影响

目的研究生长抑素联合生长激素对重症急性胰腺炎（SAP）胰腺细胞凋亡的影响。方法选用30只Wistar大鼠,随机分为对照组、生长抑素组、生长抑素联合生长激素治疗组（简称联合组）,每组10只,胆胰管逆行注射牛黄胆酸钠制备大鼠重症急性胰腺炎模型。测血清淀粉酶值,免疫组化分析Caspase-3的表达,TUNEL技术检测胰腺细胞的凋亡,并对胰腺组织进行病理学评分。结果与对照组比较,生长抑素组的血清淀粉酶、Caspase-3的平均灰度值和病理学评分较低（P〈0.05）,胰腺细胞的凋亡指数较高（P〈0.05）;与生长抑素组比较,联合组的血清淀粉酶、Caspase-3的平均灰度值和病理学评分较低（P〈0.05）,胰腺细胞的凋亡指数较高（P〈0.05）;凋亡指数与病理学评分呈负相关（r=-0.812,P〈0.001）。结论生长抑素联合生长激素可能通过上调Caspase-3的表达来促进胰腺细胞凋亡,减轻胰腺组织病理损伤,且优于单一应用生长抑素。     

生长抑素在重症急性胰腺炎治疗中的临床观察

目的：探讨生长抑素在重症急性胰腺炎临床治疗中的作用。方法：将102例重症急性胰腺炎病人分为生长抑素治疗组(n=52)和对照组（n＝50），对两组之间胰腺囊肿，胰腺脓肿，胰瘘，肠瘘，腹腔内出血的发生率，病死率，死亡原因及住院天数进行了对比分析。结果：生长抑素治疗组的并发症明显低于对照组，生长抑素可降低重症急性胰腺炎病人的病死率，缩短住院时间，而且生长抑素使用的早晚对重症急性胰腺炎病人的治疗也有重要的影响。结论：生长抑素对重症急性胰腺炎的治疗有重要的价值。越早使用效果趣好。     

持续腹腔冲洗加生长抑素治疗胰十二指肠切除术后胰瘘

目的探讨持续腹腔冲洗及生长抑素在治疗胰十二指肠切除术后胰瘘中的效果。方法 2007年1月～2012年1月期间,对16例胰十二指肠切除术后发生胰瘘患者行双套管持续腹腔冲洗,并予生长抑素静脉使用。结果全组病人的胰瘘均治愈,未出现腹腔脓肿、腹壁外瘘、脓毒血症及出血等明显并发症。结论持续腹腔冲洗及生长抑素静脉使用,是治疗胰瘘的有效方法。     

重症急性胰腺炎的介入治疗

目的 评价经胰血管留置导管持续区域灌注生长抑素和抗生素治疗重症急性胰腺炎(SAP)的疗效。方法 24例SAP患者采用seldinger技术经右侧股动脉超选择插管至胰腺坏死的供血动脉留置导管，用微泵持续24h灌注生长抑素及抗生素症状消失后拔管。结果灌注治疗后24～48h腹部体征明显改善，7～11d后症状全部消失。结论 经胰血管留置导管持续区域灌注生长抑素及抗生素治疗SAP疗效好、病程短、并发症少，值得推广应用。     

Glucose control of glucagon secretion—‘There’s a brand-new gimmick every year’

Glucagon from the pancreatic α-cells is a major blood glucose-regulating hormone whose most important role is to prevent hypoglycaemia that can be life-threatening due to the brain’s strong dependence on glucose as energy source. Lack of blood glucose-lowering insulin after malfunction or autoimmune destruction of the pancreatic β-cells is the recognized cause of diabetes, but recent evidence indicates that diabetic hyperglycaemia would not develop unless lack of insulin was accompanied by hypersecretion of glucagon. Glucagon release has therefore become an increasingly important target in diabetes management. Despite decades of research, an understanding of how glucagon secretion is regulated remains elusive, and fundamentally different mechanisms continue to be proposed. The autonomous nervous system is an important determinant of glucagon release, but it is clear that secretion is also directly regulated within the pancreatic islets. The present review focuses on pancreatic islet mechanisms involved in glucose regulation of glucagon release. It will be argued that α-cell-intrinsic processes are most important for regulation of glucagon release during recovery from hypoglycaemia and that paracrine inhibition by somatostatin from the δ-cells shapes pulsatile glucagon release in hyperglycaemia. The electrically coupled β-cells ultimately determine islet hormone pulsatility by releasing synchronizing factors that affect the α- and δ-cells.     

海洛因依赖大鼠胰岛D细胞免疫组织化学研究

目的:探讨海洛因依赖对大鼠胰岛生长抑素(somatostatin,SS)免疫反应(IR)细胞(D细胞)的影响.方法:用免疫组织化学SABC单染法、形态计量法,观察海洛因依赖大鼠胰岛SS-IR细胞免疫组织化学反应及平均灰度值的变化.结果:与正常组和盐水对照组比较,海洛因依赖大鼠胰岛SS-IR细胞免疫染色增强,平均灰度值降低,差异有显著性.结论:胰岛SS-IR细胞参与了海洛因依赖期间机体的调节过程.     

ISLET FORMATION AND REGENERATION

INSULIN DEPENDENTdiabetesmellitus(ID DM)occurredinhumanwhenamajorityofβcellsaredestroyed.Itisreportedthatpancreaticstemcellsofpancreaticductintheadultareabletodiffer entiatetoisletcellsafterlong termculture.Pancreaticstem cells,agroupofpluripotentcells,h…     

The Effect of GHRH, GHRP-2 and Somatostatin on GH Secretion by fetal pituitary

Growthhormonereleasehormone(GHRH)andsomatostatin(SMS)secretedbyhypothalamusplayaprimaryroleincon-trolofGHsecretion.Growthhormonere-leasing-peptide(GHRP-2)isasynthetichexapeptide,whichspecificallystimulatesGH-secretionby`humanpituitarysoma-totrophs-ManyevidencesshowedthatGHRP-2mediateditseffectsmainlyviahy-drolysisofmembranephosphatidylinositol(PI)andthesubsequentactivationofpro-teinkinaseC(PKC).Inthisstudywein-vestigatedtheeffectsofGHRH,GHRP-2andSMSonregulationofGHsecretionbyfet…     

Remission of symptoms during long term treatment of metastatic pancreatic endocrine tumours with long acting somatostatin analogue

Five patients with metastatic pancreatic endocrine tumours injected a long acting somatostatin analogue (SMS 201-995) 50 micrograms subcutaneously every 12 hours and were followed up for three to six months. Treatment aimed at controlling excess secretion of hormone by the tumours thereby bringing symptomatic relief. Four patients showed a significant reduction in tumour related hormone concentrations but in none did values return to normal. All five patients, however, noted definite symptomatic improvement and in one this was dramatic (disappearance of life threatening diarrhoea and correction of metabolic acidosis and hypokalaemia within 48 hours). Mild worsening of symptoms and increasing fasting tumour related hormone concentrations after three to six months of treatment were reversed by doubling the 12 hourly dose. The treatment was well tolerated and had no deleterious effect on fasting blood glucose concentrations. This somatostatin analogue seems a promising non-invasive treatment for metastatic pancreatic endocrine tumours.     

生长抑素对重症胰腺炎胰腺细胞凋亡的影响

目的　探讨生长抑素治疗大鼠急性坏死性胰腺炎时对胰腺细胞凋亡和调控基因bax及bcl- 2的影响。方法　以牛胆酸钠诱导SD大鼠急性坏死性胰腺炎模型 ,并应用TUNEL法染色和免疫组化SABC法检测胰腺组织中基因bax及bcl- 2蛋白表达及生长抑素治疗后对胰腺细胞凋亡及凋亡调控基因bax及bcl- 2蛋白表达的影响。结果　TUNEL法染色显示生理盐水治疗组胰腺细胞凋亡指数显著低于生长抑素治疗组 ,免疫组化SABC法检测生长抑素治疗组胰腺细胞bax染色阳性率高于生理盐水治疗组 ,但无统计学意义 ;生理盐水治疗组胰腺细胞bcl- 2染色阳性率明显高于生长抑素治疗组。结论　生长抑素治疗急性坏死性胰腺炎的机制之一可能是诱导损伤的胰腺细胞凋亡以减轻胰腺炎症反应 ,细胞凋亡机制可能与生长抑素抑制bcl- 2的表达有关而与促进bax的表达无关。     

生长抑素及其功能性受体表达与胰腺腺泡细胞外分泌的关系

目的 探讨SD大鼠胰腺腺泡细胞上的生长抑素受体(SSTR)各亚型的分布及生长抑素具体与哪种亚型的SSTR结合发挥作用.方法 急性分离大鼠胰腺腺泡细胞,取得胰腺腺泡细胞悬液.用Trizol法提取各时间段胰腺腺泡细胞的mRNA并在PCR扩增仪上得到产物,使用Labimage图像分析系统对电泳结果 进行量化分析.结果 SSTR1～5在SD大鼠胰腺腺泡细胞上有表达,其表达分别为0.980±0.085;0.766±0.064;0.850±0.078;0;2.010±0.225.生长抑素作用15、30 min后SSTR1～5的表达分别为0.908±0.059;1.142±0.078;0.798±0.030;0;1.852±0.132和0.891±0.049;1.347±0.063;0.764±0.071;0;1.791±0.102.SSTR2表达较对照组明显增高(P＜0.05).结论 SD大鼠胰腺腺泡细胞上存在SSTR1～3、5亚型.生长抑素与SSTR2受体结合后,发挥其抑制胰腺腺泡细胞外分泌的作用.     

Pancreatic somatostatinoma characterized by extreme hypoglycemia

Somatostatinomas are very rare endocrine tumors, accounting for less than 1% of all gastrointestinal endocrine tumors. It usually arises within the pancreas and some from extrapancreafic sites, including the duodenum, ampulla, jejunum, or cystic duct,with an annual incidence of 1 in 40 million. Since the first case of pancreatic somatostafinoma was reported in 1977 by Larsson et al,4 less than 200 cases of somatostatinoma have been reported in literature, and only a few cases have been reported in China. The most described features of patients with somatostatinoma induced by excessive somatostatin secretion are characterized by cholelithiasis, steatorrbea, achlorhydria, hypochlorhydria and mild hyperglycemia, As somatostafin inhibits the secretion of insulin from pancreatic islets,     

Somatostatin analogue SMS 201-995 long term therapy for vipoma

The definitive treatment of a pancreatic tumour secreting vasoactive intestinal polypeptide is surgical removal of the tumour, but when curative resection is not possible symptomatic treatment of the endocrine hyperfunction is important. Streptozotocin, although effective for palliation, can involve unpleasant side effects. We report the long term use of subcutaneous somatostatin analogue SMS 201-995 in an elderly man presenting with severe watery diarrhoea and anaemia due to a pancreatic vipoma. Good symptomatic improvement has been achieved with no side effects over a period of 24 months. We suggest there is a use for subcutaneous SMS 201-995 in elderly patients with inoperable pancreatic gut hormone producing tumours with metastases and in those where surgery would carry a high operative risk.     

DYNAMIC OBSERVATION ON THE CHANGES OF PLASMA SOMATOSTATIN AND GLUCAGON DURING THE DEVELOPMENT OF CIRRHOSIS AND AFTER PORTACAVAL SHUNTING IN THE CIRRHOTIC RATS

In the present study we observed dynamically and systemically the changes of plasma somatostatin and glucagon in the peripheral and portal vein, and the changes of pancreatic immunopathology in the course of development of cirrhosis induced by CCl_4 and after portacaval shunt (PCS) in the cirrhotic rats as well as investigated their causes and correlationship. The results showed that hyperglucagonemia was caused by spontaneous portosystemic shunting and surgically induced portacaval anastomosis. Moreover, there was much higher level of glucagon in the portal vein with corresponding increase of A cells in PCS rats than those in the controls, indicating that another cause for elevation of glucagon was hypersecretion of pancreatic A cells. Our data demonstrated that both deterioration of liver function and portosystemic shunting might not be responsible for the elevated level of somatostatin in the cirrhotic rats with PCS. However, there was a closed positive correlation between plasma glucagon and somatostatin. Thus it was concluded that hyperglucagonemia stimulated the release of somatostatin. In view of the fact the elevated level of glucagon was much higher than that of somatostatin, there was probably a relative lack of somatostatin in cirrhosis with portal hypertension.