松果菊苷对db/db糖尿病小鼠心肌的保护作用

糖尿病心肌病（diabetic cardiomyopathy, DCM）是指发生于糖尿病患者,不能用冠心病、高血压性心脏病及其他心脏病变来解释的心肌疾病。目前,DCM的病因和发病机制尚未完全阐明,且缺乏特异性治疗手段。中药管花肉苁蓉提取物松果菊苷（echinacoside, ECH）对心肌细胞具有保护作用。以db/m小鼠为正常对照组（db/m组）,db/db小鼠分为模型组（db/db组）和ECH干预组（db/db+ECH组）,探讨了ECH对糖尿病db/db小鼠心肌的影响及机制。db/db+ECH组小鼠给予松果菊苷灌胃,db/m组和db/db组小鼠给予0.9%氯化钠溶液灌胃。心脏超声观察心脏功能,Masson染色观察组织胶原纤维含量,逆转录聚合酶链式反应检测Ⅰ型胶原和Ⅲ型胶原mRNA的表达,蛋白质免疫印迹技术检测转化生长因子-β1（transforming growth factor-β1, TGF-β1）、phospho-Smad2（p-Smad2）和phospho-Smad3（p-Smad3）的表达。结果显示,ECH能够改善db/db小鼠左心室肥大和心脏功能,降低胶原沉积（P<0.05）。ECH能够降低Ⅰ型和Ⅲ型胶原mRNA的表达（P<0.01）,下调TGF-β1、p-Smad2和p-Smad3蛋白的表达（P<0.05）。ECH对糖尿病心肌的保护作用可能与负反馈调节TGF-β1/Smads信号通路相关,研究结果为DCM的早期干预提供了新思路。     

黄葵素抑制巨噬细胞浸润和活化改善db/db小鼠肾纤维化实验研究

为探讨黄葵素对糖尿病肾病肾纤维化治疗作用及机制,采用SPF级C57BLKS/J db/db雄性小鼠20只,随机分为黄葵素低、中、高剂量(97.5、195、390 mg/kg/d)给药组和模型组4组,以同背景的5只db/m小鼠为空白对照组,分别用黄葵素混悬液及等体积的0.5%羧甲基纤维素钠溶液灌胃,连续16周,第24周处死,收集血和肾脏。检测尿ACR、血肌酐、血尿素氮,HE和Masson染色观察肾脏形态学改变和纤维化程度,免疫组化染色检测肾组织巨噬细胞标记F4/80表达情况,Western blot法检测肾组织F4/80蛋白、胶原蛋白III、波形蛋白表达情况,qPCR法检测肾组织TNF-α、IL-1β和iNOS的mRNA水平。结果显示:与模型组相比,黄葵素可以降低db/db小鼠尿ACR、血肌酐、血尿素氮水平,减轻肾脏病理损伤及胶原纤维的沉积,降低肾组织胶原蛋白III、波形蛋白及F4/80蛋白表达,减少肾组织F4/80标记巨噬细胞浸润;并下调了肾组织TNF-α、IL-1β、iNOS的mRNA水平。综上表明黄葵素可有效缓解db/db小鼠肾脏炎症反应,改善肾功能及肾纤维化,发挥肾保护作用,其机制与减少肾组织内巨噬细胞浸润及抑制促炎的M1型巨噬细胞极化相关。     

过敏毒素受体(C3aR)在db/db糖尿病肾病小鼠肾脏中的表达及病理意义分析

利用半定量RT-PCR、免疫组化和Western blotting的方法,同时从mRNA水平和蛋白质水平对过敏毒素受体(C3aR)在不同病理阶段的2型糖尿病肾病模型小鼠——db/db小鼠肾脏中的表达情况进行了较为系统的分析．结果发现：a．在糖尿病前的db/db小鼠(4周龄的db/db小鼠),C3aR与作为正常对照的db/m小鼠相比没有明显差异．随着肥胖的加剧,高血糖、蛋白尿的发生和发展,C3aR在db/db小鼠肾脏中的表达显著升高．b．免疫组化分析显示,C3aR广泛地表达于db/m和db/db小鼠肾脏的皮质和髓质,分布于肾脏的上皮细胞中(包括肾小管上皮细胞、肾小球中的脏层上皮细胞(足细胞)和壁层上皮细胞)．从部位来看,皮髓交界处的肾小管中C3aR表达量明显要比其他部位的多．在肾小球,C3aR特异地存在于足细胞部位．在db/m小鼠,不同周龄小鼠肾脏中C3aR的表达量并没有明显变化,但在db/db小鼠,从8周龄开始,分布在db/db小鼠肾小管上皮细胞和小球足细胞中的C3aR均随小鼠周龄的增加而增加,至少在时间上,与小鼠糖尿病肾病的发生发展相关,其中尤以足细胞中和皮髓交界处肾小管上皮细胞中的变化最为明显． c．在糖尿病肾病小鼠中高表达C3aR的肾小管上皮细胞常有空泡变性的情况．上述工作印证了先前对2型糖尿病肾病患者肾小球基因表达谱的分析结果,更加明确了C3aR与糖尿病肾病的相关性,同时揭示了C3aR在正常小鼠和糖尿病肾病小鼠肾脏中的表达、分布和变化规律,有利于进一步揭示C3aR的功能及其在糖尿病肾病发生、发展过程中的可能作用,探讨糖尿病肾病的分子机制．     

葡萄籽原花青素对db/db小鼠肾组织脂质沉积的影响

该文观察了葡萄籽原花青素(grape seed proanthocyanidin extract,GSPE)对db/db小鼠肾组织脂质沉积的影响。16只雄性db/db小鼠随机分为糖尿病肾病模型组(db/db,n=8)和葡萄籽原花青素治疗组(db/db+GSPE,n=8);16只雄性db/m小鼠随机分为正常对照组(db/m,n=8)和葡萄籽原花青素治疗对照组(db/m+GSPE,n=8)。治疗8周后,血尿半自动生化仪检测小鼠空腹血糖(fasting blood-glucose,FBG)、血尿素氮(blood urea nitrogen,BUN)、血肌酐(serum creatinine,Scr)、总甘油三酯(total triglycerides,TG)、总胆固醇(total cholesterol,TC)及尿白蛋白(urinary albumin excretion,UAE)的变化;Western blot及Real-time PCR检测固醇调节元件结合蛋白-1(sterol regulatory element binding protein-1,SREBP-1)、脂肪酸合成酶(fatty acid synthase,FASN)、乙酰Co A羧化酶(acetylCo A carboxylase,ACC)、过氧化物酶体增殖物激活受体α(peroxisome proliferator-activated receptorα,PPARα)、肉毒碱棕榈酰转移酶1(carnitine palmitoyltransferase 1,CPT1)及脂酰辅酶A氧化酶1(acylcoenzyme aoxidase 1,ACOX1)蛋白及m RNA的表达水平;电镜及油红O染色观察小鼠肾组织脂滴形成情况。结果显示,GSPE干预能够降低db/db小鼠FBG、BUN、Scr、TG、TC及UAE的水平,抑制肾小管上皮细胞内的脂滴形成及脂肪酸合成,同时促进脂肪酸的β氧化。GSPE能抑制db/db小鼠肾组织脂质沉积,主要通过抑制脂肪酸合成及增加脂肪酸β氧化实现的。     

吡格列酮对db/db小鼠骨骼肌蛋白酪氨酸磷酸酶1B表达的影响

目的探讨吡格列酮对db/db小鼠骨骼肌蛋白酪氨酸磷酸酶1B（protein tyrosine phosphatase 1B,PTP1B）表达水平的影响。方法将20只4周龄db/db小鼠随机分为两组（吡格列酮组和db/db对照组）,每组10只,分别给予吡格列酮10mg/kg.d和安慰剂灌胃。另设10只同周龄db/m小鼠,给予安慰剂灌胃作为非糖尿病对照（db/m对照组）。每周监测体重、血糖,4周后用蛋白印迹法检测各组小鼠骨骼肌组织中PTP1B蛋白含量。结果db/db组小鼠骨骼肌PTP1B表达显著高于db/m组,给予吡格列酮干预,血糖、胰岛素抵抗指数显著低于db/db组（P〈0.05）,骨骼肌PTP1B表达水平亦显著降低（P〈0.05）。结论吡格列酮改善胰岛素抵抗,可能与降低骨骼肌PTP1B蛋白表达有关。     

db/db小鼠糖尿病肾病相关基因的分析和克隆

用GM-U74A基因芯片分别检测了正常对照组（db/m小鼠）、糖尿病肾病组（db/db小鼠）、大黄酸治疗组（大黄酸150 mg/kg治疗12周）肾脏基因表达谱.发现在12 437个基因（包括表达序列标签）中,与正常对照组相比,糖尿病肾病组有1 085个基因表达下调,37个基因表达上调,其中变化幅度大于2倍,表达下调的有166个和表达上调的有29个.与糖尿病肾病组相比,大黄酸治疗组有384个基因表达下调,155个表达上调,其中变化幅度大于2倍,表达下调的有47个和表达上调的有30个.在此基础上,对其中的一个差异表达的表达序列标签(EST)进行了详细的生物信息学分析,发现它是一个未知功能基因——“REKEN cDNA 0610006H10”基因的一部分.在用RT-PCR进一步验证了其与糖尿病肾病的相关性后,对“REKEN cDNA 0610006H10”基因进行了克隆.     

Notch1对糖尿病肾小管间质细胞外基质沉积的影响

本文旨在明确糖尿病肾小管间质中Notch1和自噬水平的变化对细胞外基质沉积的影响,并探讨其机制。取db/m小鼠(正常对照组)和db/db小鼠(糖尿病组)各8只,饲养12周后测定相应的生化指标;同时,体外在正常糖(normal glucose, NG)和高糖(high glucose, HG)条件下培养大鼠肾小管导管上皮细胞(NRK52E细胞),用Western blotting检测各组细胞中Notch1和LC3蛋白表达变化;在NG和HG条件下过表达和敲低Notch1,用共聚焦显微镜观察自噬流变化,用细胞免疫荧光化学法观察肾小管上皮细胞中Notch1、I型和III型胶原蛋白(Collagen-I和III)变化。结果显示,与db/m小鼠比较,db/db小鼠肾组织中Notch1和Collagen-III表达增加(P <0.01),而LC3表达降低(P <0.05);体外实验结果显示,HG组与NG组比较,NRK52E细胞Notch1蛋白表达增加(P <0.01),LC3表达明显降低(P <0.01),高渗组与NG组比较,以上蛋白表达无明显变化;高糖条件下敲低Notch1...     

跑台运动通过依赖p38MAPK信号通路上调FNDC5改善db/db小鼠非酒精性脂肪性肝病

该文旨在探讨8周跑台运动改善Ⅱ型糖尿病小鼠非酒精性脂肪性肝病(nonalcoholic fatty liver disease, NAFLD)的作用及分子机制。将SPF级别的8周龄的雄性m/m小鼠作为阴性对照组(Con组), 8周龄的雄性db/db小鼠随机分为4组:Ⅱ型糖尿病模型组(db组)、Ⅱ型糖尿病跑台运动组(db+EX组)、Ⅱ型糖尿病跑台运动联合p38MAPK抑制剂组(db+EX+SB203580组)、单纯p38MAPK抑制剂组(db+SB203580组),每组各10只。腹腔注射p38MAPK抑制剂2 h后进行跑台运动干预,每天运动干预40 min,每周5天,连续8周。通过小鼠体质量、血糖、肝体比、血脂以及HE、油红和Masson染色评价运动干预对NAFLD的干预效果。通过Western blot和qRT-PCR测定相关蛋白和mRNA表达水平。结果显示, 8周跑台运动可以明显减轻db/db小鼠体质量、血糖、肝体比值的增加,降低小鼠血脂水平。运动干预减少了小鼠肝脏脂肪变性、胶原蛋白沉积及ACC1、SREBF1脂肪从头合成酶的表达水平。单纯p38MAPK抑制剂干预加重了肝脏脂肪变性和...     

核桃低聚肽对db/db小鼠血糖的影响作用研究

目的：研究核桃低聚肽（walnut oligopeptides,WOPs）干预对db/db糖尿病模型小鼠血糖的影响作用。方法：选择db/db糖尿病小鼠模型,将其随机分为3个核桃低聚肽组（220、440、880mg/kg·BW）、糖尿病模型对照组、二甲双胍对照组、乳清蛋白对照组;并选用db/m小鼠作为非糖尿病小鼠空白对照。经过为期6周的干预,检测小鼠空腹血糖、餐后血糖以及糖耐量实验血糖曲线下面积。结果：核桃低聚肽（880mg/kg·BW）可降低db/db糖尿病小鼠空腹血糖水平和餐后血糖水平,同时能有效改善糖耐量（P＜0.05）。结论：核桃低聚肽干预可有效降低糖尿病小鼠的血糖水平,改善糖耐量,具有辅助降血糖功能。     

硫辛酸合成酶在Lepr~(db/db)小鼠肝肾中的表达

目的检测瘦素受体缺陷的Lepr~(db/db)小鼠体内肝、肾中硫辛酸合成酶(LIAS)的表达。方法分别选取10周龄Lepr~(db/+)与Lepr~(db/db)雄性小鼠各8只,禁食8 h后,测量两组小鼠体重及空腹血糖(FPG);用乙醚麻醉动物,经腹主动脉采血,处死动物,取肝、肾并称重。取肝右叶和左肾经4%多聚甲醛固定,进行肝、肾组织病理学检查。分离血清,用试剂盒检测血清中CHO、TG、HDL、LDL含量。应用线粒体分离试剂盒分离肝、肾组织线粒体,提取总蛋白,采用western blot方法检测LIAS蛋白的表达。结果组织病理观察,发现Lepr~(db/+)小鼠肝肾结构完整,而Lepr~(db/db)小鼠肝细胞出现脂肪变性,肾小球肥大,基底膜增厚,系膜区增宽;与Lepr~(db/+)小鼠比较,Lepr~(db/db)小鼠体重、GLU、CHO、TG、LDL及AST明显增高,差异有显著性(P0.05);与Lepr~(db/+)小鼠比较,Lepr~(db/db)小鼠肝肾线粒体内LIAS蛋白表达量均增高,差异有显著性(P0.05)。结论瘦素受体缺陷的Lepr~(db/db)小鼠存在糖脂代谢紊乱、肝肾细胞损伤、肝肾组织线粒体LIAS蛋白的表达增高。     

Dehydroepiandrosterone decreases elevated hepatic glucose production in C57BL/KsJ-db/db mice

Dehydroepiandrosterone (DHEA) is known to improve hyperglycemia in diabetic db/db mice that are obese and insulin resistant. In a previous study, we reported that DHEA suppresses the elevated hepatic gluconeogenic glucose-6-phosphatase (G6Pase) activity and gene expression in C57BL/KsJ-db/db mice. In the present study, we evaluated the total amount of gluconeogenesis using NaH[(14)C]CO(3) and hepatic glucose production using fructose as a substrate in primary cultured hepatocytes. Despite hyperinsulinemia, the glucose production of db/db mice in the total body and hepatocytes was elevated as compared to their heterozygote littermate C57BL/KsJ-db/+m mice. Administration of DHEA significantly decreased the blood glucose level and increased the plasma insulin level in db/db mice. Administration of DHEA decreased the elevated total body and hepatic glucose production in db/db mice. In addition, the glucose production in the primary cultured hepatocytes of db/db mice was decreased significantly by the direct addition of DHEA or DHEA-S to the medium. These results suggest that administration of DHEA suppresses the elevated total body and hepatic glucose production in db/db mice, and this effect on the liver is considered to result from increased plasma insulin and DHEA or DHEA-S itself.     

Hepatic glycogen metabolism in the db/db mouse

Summary Knowledge of the metabolic changes that occur in insulin-resistant type 2 diabetes is relatively lacking compared to insulin-deficient type 1 diabetes. This paper summarizes the importance of the C57BL/KsJ-db/db mouse as a model of type 2 diabetes, and illustrates the effects that insulin-deficient and insulin-resistant states have on hepatic glycogen metabolism. A longitudinal study of db/db mice of ages 2–15 weeks revealed that significant changes in certain parameters of hepatic glycogen metabolism occur during this period. The liver glycogen levels were similar between diabetic and control mice. However, glycogen particles from db/db mice were on average smaller in mass and had shorter exterior and interior chain lengths. Total phosphorylase and phosphorylase a activities were elevated in the genetically diabetic mice. This was primarily due to an increase in the amount of enzymic protein apparently the result of a decreased rate of degradation. It was not possible to find a consistent alteration in glycogen synthase activity in the db/db mice. Glycogen synthase and phosphorylase from diabetic liver revealed some changes in kinetic properties in the form of a decrease in V_max, and altered sensitivity to inhibitors like ATP. The altered glycogen structure in db/db mice may have contributed to changes in the activities and properties of glycogen synthase and phosphorylase. The exact role played by hormones (insulin and glucagon) in these changes is not clear but further studies should reveal their contributions. The db/db mouse provides a good model for type 2 diabetes and for fluctuating insulin and glucagon ratios. Its use should clarify the regulation of hepatic glycogen metabolism and other metabolic processes known to be controlled by these hormones. The other animal models of type 2 diabetes, ob/ob mouse and fatty Zucker (fa/fa) rat, show similar impairment of hepatic glycogen metabolism. The concentrations of glycogen metabolizing enzymes are high and in vitro studies indicate enhanced rate of glycogen synthesis and breakdown. However, streptozotocin-induced diabetic animals and BB rats which resemble insulin-deficient type 1 diabetes are characterized by decreased glycogen turnover as a result of reduction in the levels of glycogen metabolizing enzymes.     

Alterations of the Ca2+ signaling pathway in pancreatic beta-cells isolated from db/db mice

Upon glucose elevation, pancreatic beta-cells secrete insulin in a Ca²⁺-dependent manner. In diabetic animal models, different aspects of the calcium signaling pathway in beta-cells are altered, but there is no consensus regarding their relative contributions to the development of beta-cell dysfunction. In this study, we compared the increase in cytosolic Ca²⁺ ([Ca²⁺]_i) via Ca²⁺ influx, Ca²⁺ mobilization from endoplasmic reticulum (ER) calcium stores, and the removal of Ca²⁺ via multiple mechanisms in beta-cells from both diabetic db/db mice and nondiabetic C57BL/6J mice. We refined our previous quantitative model to describe the slow [Ca²⁺]_i recovery after depolarization in beta-cells from db/db mice. According to the model, the activity levels of the two subtypes of the sarco-endoplasmic reticulum Ca²⁺-ATPase (SERCA) pump, SERCA2 and SERCA3, were severely down-regulated in diabetic cells to 65% and 0% of the levels in normal cells. This down-regulation may lead to a reduction in the Ca²⁺ concentration in the ER, a compensatory up-regulation of the plasma membrane Na⁺/Ca²⁺ exchanger (NCX) and a reduction in depolarizationevoked Ca²⁺ influx. As a result, the patterns of glucosestimulated calcium oscillations were significantly different in db/db diabetic beta-cells compared with normal cells. Overall, quantifying the changes in the calcium signaling pathway in db/db diabetic beta-cells will aid in the development of a disease model that could provide insight into the adaptive transformations of beta-cell function during diabetes development.     

Expression of the db (diabetes) gene in mice with hereditary load by generalized autoimmune pathology]

A model of genetically determinate diabetes mellitus in hybrid db/db mice with hereditary load by generalized autoimmune pathology has been described. The data on the character of hormonal-metabolic disturbances permit a conclusion on more serious course of diabetes mellitus in mice (C57Bl/Ks x NZB)F2 db/db as against (C57BL/Ks x NZW)F2 db/db, that is correlated with expression of autoimmune pathology in parent lines of New Zealand mice NZB and NZW. It is stated that diabetic syndrome in males proceeds in more serious form than in females.     

Establishment of an Inflamed Animal Model of Diabetic Nephropathy

Aims Inflammatory stress plays a crucial role in the progression of diabetic nephropathy (DN). This study aimed to establish a novel inflamed animal model of DN and to evaluate its significance in DN.Methods Nondiabetic db/m mice and diabetic db/db mice were randomly divided into four groups: db/m, db/m+casein, db/db, and db/db+casein for eight weeks. Casein was subcutaneously injected to induce chronic inflammation. Body weight and albumin to creatinine ratio (ACR) in the urine were measured every week. The plasma levels of serum amyloid protein A (SAA) and tumour necrotic factor-α (TNF-α) were determined with the enzyme-linked immunosorbent assay. The morphological changes to the renal pathology and ultra-microstructures were checked by pathological staining and electron microscopy. Immunofluorescent staining and Western blotting were used to determine the protein expression of podocyte-specific molecules and inflammatory cytokines in kidneys.Results ACR, plasma levels of SAA and TNF-α, protein expression of inflammatory cytokines, mesangial expansion, collagen accumulation, and foot process effacement in kidneys of casein-injected db/db mice were significantly increased compared with the db/db mice. Casein injection markedly decreased the protein expression of Wilms'' tumor-1 and nephrin in kidneys of db/db mice, which are specific podocyte biomarkers, suggesting that chronic inflammation accelerates podocyte injuries in db/db mice. Interestingly, no obvious urinary protein, inflammatory cytokine expression, or histological changes in the kidneys of casein-injected db/m mice were found compared with the db/m mice.Conclusion An inflamed animal model of DN was successfully established and may provide a useful tool for investigating the pathogenesis of DN under inflammatory stress.     

Effect of mutant genes db(diabetes) and m(misty) on the severity of high-dose streptozotocin diabetes in C57bl/KsJY mice]

It is stated that high-dose streptozotocin diabetes is more serious in gene db-homozygous mice of mutant line C57BL/KsJY than in heterozygotes db +/+ m and mice M+/+m. Manifestation of spontaneous insulin-independent diabetes mellitus in homozygotes db decreases the level of hyperglycemic streptozotocin-induced reactions.     

Metabolic responses to leptin in obese db/db mice are strain dependent

Obese, diabetic C57BL/Ks db/db mice that lack the long-form leptin receptor exhibit no decrease in body weight or food intake when treated with leptin. Here we compared responses to leptin in two strains of db/db mice: C57BL/6J mice that are hyperglycemic and hyperinsulinemic and C57BL/Ks that are hyperglycemic and normo- or hypoinsulinemic. Chronic intraperitoneal infusion of 10 microgram leptin/day partially reversed hyperglycemia in C57BL/6J male mice but exaggerated the diabetic state of female mice. Bolus intraperitoneal injections of 40 microgram leptin/day did not effect glucose in either strain of male db/db mice, whereas chronic intraperitoneal infusion of 20 microgram leptin/day significantly reduced fasting blood glucose in male mice from both strains, especially C57BL/6J mice. Food intake, body weight, rectal temperature, and body fat did not change. Chronic intraperitoneal infusion of 10 microgram leptin/day significantly reduced body fat in lean db/+ C57BL/6J but not in C57BL/Ks mice. Thus peripherally administered leptin is active in mice that have only short-form leptin receptors, and the response is dependent on the method of leptin administration and the background strain.     

Endocrine pancreatic cells of postnatal "diabetes" (db) mice in cell culture.

Ultrastructural characteristics as well as secretory and biosynthetic behavior of monolayer pancreatic cell cultures established from 4-day-old C57BL/KsJ misty diabetic (m db/m db) mice have been studied in comparison to normal littermate controls. Hypersecretion of glucagon by alpha-cells from BL/Ks misty diabetic mice after 2 days in vitro was found to precede any hyperfunction of the insulin-secreting beta-cells. The increased level of glucagon-release in BL/Ks cell cultures from diabetic mice was accompanied by a greatly enhanced level of incorporation of [3H]tryptophan into glucagon-like molecules whose specific radioactivity was up to 15-fold higher than that observed in cultures from genetic controls. The finding of an alpha-cell dysfunction in cultures established from preweaning diabetic BL/Ks mice suggests that glucagon could play an early role in shaping the events that culminate in the expression of frank diabetes in this inbred strain.     

Substance P, neurokinin A, vasoactive intestinal polypeptide and gastrin releasing peptide in the intestine and pancreas of spontaneously obese-diabetic mice

The concentrations and contents of immunoreactive substance P (SP), neurokinin A (NKA), vasoactive intestinal polypeptide (VIP) and gastrin releasing peptide (GRP) were measured in acid-ethanol extracts of intestine (duodenum-jejunum-ileum) and pancreas of C57BL/KsJ diabetes-obese (db/db) mice, Aston obese-hyperglycaemic (ob/ob) mice, and their respective lean controls. The intestinal concentration of GRP and pancreatic concentrations of VIP and GRP were 36-57% lower in lean Aston mice than lean C57BL/KsJ mice, indicating the influence of genetic background in control mice. Intestinal concentrations of SP and NKA were reduced by 19-33% in the db/db and ob/ob mutants compared with their lean controls, but the intestinal contents of these peptides were normal or greater than normal due to intestinal hypertrophy of the mutant mice. The intestinal VIP concentration was not altered, but the content was increased by 87% and 25% respectively in db/db and ob/ob mice, whereas the intestinal GRP concentration was reduced by 51% in ob/ob mice. Pancreatic concentrations and contents of NKA, VIP and GRP were similar in lean and db/db C57BL/KsJ mice. However, pancreatic concentrations and contents of VIP and GRP were reduced by 51-55% in ob/ob mice compared with their lean controls. The sensitivity of the present assay did not permit accurate determination of the low pancreatic concentrations of SP. The results suggest that the spontaneous ob/ob and db/db syndromes of obesity and diabetes in mice are associated with reduced intestinal concentrations of SP and NKA. The ob/ob mouse also exhibited reductions of intestinal GRP and pancreatic GRP and VIP concentrations. These changes in regulatory peptides may relate to abnormalities of intestinal and possibly pancreatic function in obese and diabetic mutant mice.