父代糖尿病对子代糖代谢的长期影响

探讨父代糖尿病对子代老年期糖代谢的潜在影响。健康雄性SD大鼠经腹腔注射链脲佐菌素(35 mg/kg)建立雄性大鼠糖尿病模型,并与健康SD雌鼠交配所得子代为处理组(STZ-O组);健康雄鼠与健康雌鼠交配所得子代为正常对照组(CON-O组)。两组动物出生后记录出生体重,标准饲料喂养至18月龄,测定随机血糖含量、血清胰岛素含量;进行葡萄糖耐量试验(glucose tolerance test,GTT)、胰岛素耐量试验(insulin tolerance test,ITT)检测胰岛素抵抗情况;丙酮酸耐量试验(pyruvic acid tolerance test,PTT)检测肝脏糖异生情况;经糖原染色观察肝脏糖原沉积情况;以Real-time PCR检测肝脏组织糖异生途径关键酶磷酸烯醇式丙酮酸羧激酶(PEPCK)、葡萄糖-6-磷酸酶(G-6-P)、果糖-1,6-磷酸酶(FBP)mRNA表达水平。结果表明:父代糖尿病可导致子代在老年期出现胰岛素抵抗,同时伴有肝脏糖异生作用增强。其具体作用机制仍有待进一步研究。     

人前胰岛素原基因裸质粒DNA肌肉注射可显著降低链脲佐菌素诱发糖尿病小鼠的血糖水平

通过基因治疗的方法补充胰岛素已用于实验性治疗胰岛素依赖型糖尿病(IDDM)。本研究构建了含有重组人前胰岛素原基因的棵质粒DNA载体(pCMV—IN),将其肌肉注射入链脲佐菌素(STZ)诱发的糖尿病C57小鼠体内,并辅以电穿孔方法,以获得在体胰岛素转基因治疗。该质粒载体表达的胰岛素mRNA,可通过RT—PCR方法在转基因局部的骨骼肌组织中检测到。在接受pCMV—IN注射的糖尿病小鼠中,血浆胰岛素水平显著升高,达到了未注射STZ的正常对照小鼠的水平,且胰岛素的表达可持续至少35d。pCMV—IN质粒注射转基因治疗显著降低了糖尿病小鼠在第7至35d的血糖水平,其下降幅度约6mmol／L;转基因治疗也显著降低了严重糖尿病小鼠的死亡率,其第6周时的死亡率由100％降为37％。结果表明,直接肌肉注射含人前胰岛素原基因裸质粒可获得胰岛素的有效表达,显著降低糖尿病小鼠的血糖水平并降低严重糖尿病小鼠的死亡率。裸质粒注射胰岛素转基因治疗有望成为IDDM的一种有效治疗手段。     

沉默长链非编码RNA Meg3损伤小鼠胰岛细胞的胰岛素分泌功能

MEG3是一种长链非编码RNA。已有研究证明,鼠源Meg3参与小鼠诱导多能干细胞、神经元和视网膜的分化过程。最新报道,MEG3在人胰岛β细胞中高表达,但其对维持成年胰岛β细胞的功能尚不清楚。本研究旨在探讨Meg3在小鼠胰岛细胞胰岛素分泌功能中的作用。实时定量PCR揭示,与Balb/c小鼠心、肝、脾、肺、肌、肾等组织/器官比较,Meg3在胰腺组织中高表达。在非糖尿病小鼠发生自发性糖尿病的第8、12周,Meg3在胰岛中的表达水平分别下调24%±8%和29%±9% (P<0.01);而当血糖升高20 mmol/L,小鼠胰岛中Meg3表达下调72%±16%(P<0.01)。在MIN6细胞中采用RNA干扰敲减Meg3的表达,在高糖浓度（20 mmol/L）刺激条件下,胰岛素分泌显著减少。小鼠静脉注射siRNA,结合血糖测定或葡萄糖耐受试验（IPGTT）显示,si-Meg3小鼠血清胰岛素水平显著下降。注射葡萄糖前血糖升高,注射葡萄糖后耐受能力降低;免疫组化分析显示,si-Meg3小鼠胰岛素阳性细胞的面积减少。实验结果提示,Meg3通过参与胰岛素的合成和分泌维持成年小鼠胰岛功能。Meg3表达失调可能参与I型糖尿病（T1DM）发病过程。     

木犀草素预防高脂膳食诱导的小鼠胰岛素抵抗的实验研究

目的:探讨黄酮类成分木犀草素对高脂饮食诱导的肥胖小鼠模型的胰岛素抵抗的影响。方法:30只C57BL/6J小鼠分正常饮食对照组(10只),高脂膳食组(对照组,10只)和高脂膳食加2%木犀草素组(木犀草素组,10只),干预16周,观察体重、血脂水平、血糖、胰岛素敏感性及胰岛素水平的变化。结果:小鼠在给予高脂膳食16周后,体重水平、血脂水平、血糖水平、胰岛素水平显著高于木犀草素组,胰岛素敏感性显著下降,与木犀草素组比较,P<0.05或P<0.01。而木犀草素组则可显著抑制体重、血脂、血糖及胰岛素水平的升高,与胰岛素敏感性未见明显下降,与正常对照组比较,P>0.05。结论:木犀草素可预防高脂膳食诱导的胰岛素抵抗。     

人血小板生成素cDNA转导促进小鼠生长与胰岛素样生长因子相关

人血小板生成素 ( TPO)基因转导能刺激小鼠生长 .将编码人 TPO的真核表达质粒pc DNA3 h TPO、野生型 pc DNA3 或生理盐水注射小鼠后肢肌肉 ,称量小鼠的体重、器官重 .用半定量 ELISA检测 TPO转导小鼠血清中胰岛素样生长因子 ( IGF) - 、 和血小板源生长因子( PDGF)水平 .结果发现 ,TPO基因转导能促进小鼠的生长 .这种促生长作用与年龄和性别有关 ,但与动物的种系无关 .8～ 1 2周龄雌鼠在基因转导后 1周生长开始加快 .在第 1、2、3和 4周的升高幅度分别为 4.3%、5.3%、4.1 %和 4.38% ( P分别 <0 .0 0 5、0 .0 0 2、0 .0 1和 0 .0 1 ) .小于 4周龄的幼鼠、大于 1 6周的老龄鼠 ,以及雄性鼠在基因转导后体重无明显改变 .半定量 ELISA分析发现 ,体重增加的成年雌性鼠 ,其血清中 IGFs和 PDGF均升高 .基因转导鼠血液中葡萄糖、甘油三酯及碱性磷酸酶水平升高 .结果表明 ,一些生长因子 ,特别是 IGF- ,介导着 TPO对转基因动物的生长刺激作用 .     

多次小剂量STZ诱导的成年鼠糖尿病指标的自发恢复

多次小剂量链脲佐菌素(streptozotocin,STZ)诱导的迟发型1型糖尿病成年小鼠(MLD-STZ成年鼠)血糖水平可自发恢复正常。该文试图对该现象及发生该现象的MLD-STZ成年鼠糖尿病指标进行综合分析。造模后,以放射免疫分析法、免疫荧光和HE染色等技术研究MLD-STZ鼠糖尿病各指标的变化。结果发现,糖尿病发生后,MLD-STZ鼠的摄食、饮水、体重、血糖和血清胰岛素水平等均随患病时间延长而逐渐加重,在糖尿病第20周时最为严重,此后,上述指标、胰岛β细胞量及胰岛炎症等逐渐改善。在糖尿病第36周时,尽管血糖水平正常的MLD-STZ鼠体重尚不及正常对照,但其摄食、饮水、血糖和血清胰岛素水平等尽皆恢复正常,且其胰岛内未见淋巴细胞浸润。上述结果说明MLD-STZ成年鼠糖尿病各指标可自发恢复至正常水平。     

高脂饮食诱导的C57BL/6J肥胖小鼠脂肪组织RIP140基因表达水平的研究(英文)

目的:探讨高脂饮食致肥胖小鼠脂肪组织RIP140mRNA表达水平的变化及其与胰岛素抵抗的关系。方法:将C57BL/6J雄性小鼠随机分为正常饮食(NFD)组、高脂饮食(HFD)组分别喂养14周后,测量两组小鼠体重,以NFD组小鼠体重作为对照,选取HFD组中体重大于对照组小鼠平均体重20%的小鼠作为肥胖组小鼠。对照组和肥胖组小鼠取血测甘油三酯(TG)、总胆固醇(TC)、空腹血糖(FBG)、空腹胰岛素水平(FIns),计算稳态模型胰岛素抵抗指数(HOMA-IR);采用RT-PCR技术检测两组小鼠附睾脂肪组织RIP140 mRNA的表达水平,并进行统计学分析。结果:HDF组小鼠中有12只符合标准计入肥胖组。肥胖组小鼠TG、TC、FBG、FIns(P0.05),HOMA-IR(P0.01)均明显高于对照组;肥胖组小鼠脂肪组织RIP140 mRNA的表达高于对照组,差异具有统计学意义(P0.05);相关分析显示小鼠脂肪组织RIP140 mRNA表达水平与TG水平呈正相关(r=0.536,P0.05),与胰岛素抵抗指数呈正相关(r=0.465,P0.05),而与TC、FBG、FIns水平相关分析无统计学意义(P0.05)。结论:高脂饮食诱导的肥胖小鼠脂肪组织RIP140 mRNA表达增加,并与胰岛素抵抗程度呈正相关。     

妊娠期糖尿病小鼠胎盘EGFR的表达与其发病关系的研究

目的:研究妊娠期糖尿病小鼠胎盘表皮生长因子受体(EGFR)的表达,探讨EGFR表达与妊娠期糖尿病发病的关系。方法:采用链脲佐菌素建立妊娠期糖尿病(gestational diabetes mellitus,GDM)小鼠模型,对照组为正常妊娠小鼠,腹腔注射等量缓冲溶液。测定母鼠体重、血糖;计算胎鼠的存活率;测定胎鼠、胎盘重量,计算胎盘效率;RT-PCR、免疫组化分别测定GDM组和对照组胎盘EGFR m RNA和EGFR蛋白的表达。Pearson相关性分析用于母鼠血糖与EGFR表达的相关性分析。结果:GDM组母鼠体重和血糖均高于对照组(P0.01);GDM组胎鼠、胎盘重量及胎盘效率均高于对照组(P0.01);RT-PCR和免疫组化结果显示GDM组胎盘EGFR m RNA和EGFR蛋白的表达与对照组相比差异有统计学意义(P0.01)。GDM组小鼠血糖值与其胎盘EGFR的表达具有相关性(r=0.582,P0.05)。结论:GDM导致胎盘EGFR表达升高,EGFR并不是GDM的发病因素,EGFR是预防GDM的潜在靶点。     

黄连素降糖调脂机制的研究

目的 旨在研究黄连素对KKAy小鼠体重、血糖、血脂、胰岛素等相关代谢指标的影响,且应用基因芯片探讨黄连素降血糖、调血脂的机制.方法 选用KKAy小鼠16只,随机分为黄连素组(给予每日250 mg/kg的黄连素粉末悬浊液)和对照组(给予等体积生理盐水),均连续灌胃4周.每周末测定小鼠空腹血糖(FBG)和体重.3周末进行口服糖耐量(OGTT)实验.4周末测定小鼠FBG、血脂和空腹胰岛素(FINS)水平.取小鼠骨骼肌组织进行RT-PCR基因芯片实验.结果黄连素组小鼠FBG、OGTT曲线下面积(AUC)、TC、TG、FINS和HOMA-IR值均比对照组显著降低(P<0.05或P<0.01).基因芯片显示黄连素组GLUT4、MAPK8、MAPK14、PPARα、UCP2上调,PPARγ、PGC、CEBP、resistin、HNF4α下调.结论 黄连素不仅能有效降低KKAy小鼠FBG,改善胰岛素敏感性,还能调节脂代谢.黄连素可能是通过AMPK-p38 MAPK-GLUT4通路调节KKAy小鼠血糖.PPARα上调参与黄连素对KKAy小鼠血脂的调节.     

人参、刺五加提取物对链脲佐菌素诱导糖尿病小鼠的降糖作用研究

本实验通过观察高血糖小鼠空腹血糖(Fasting blood glucose,FBG)、糖耐量、血清胰岛素敏感指数(Insulin sensitivity index,ISI)、血清超氧化物歧化酶(Superoxide dismutase,SOD)和丙二醛(Malondialdehyde,MDA)含量变化,探讨人参与刺五加配伍药物降糖的初步机制。采用腹腔注射链脲佐菌素(Streptozotocin,STZ)的方法建立小鼠糖尿病模型,根据随机分组对照法,对各组小鼠进行不同干预处理。结果表明,给药组小鼠空腹血糖和糖耐量均显著降低(P0.01或P0.05),血清胰岛素敏感性及SOD活性显著回升(P0.01或P0.05),血清MDA含量明显下降(P0.01或P0.05)。这表明人参与刺五加配伍可有效改善糖尿病小鼠空腹血糖水平并增强其抗氧化能力,同时提示其降糖机制可能与增强胰岛素敏感性,提高抗氧化能力等有关。     

Effect of adipocyte beta3-adrenergic receptor activation on the type 2 diabetic MKR mice

The antiobesity and antidiabetic effects of the beta3-adrenergic agonists were investigated on nonobese type 2 diabetic MKR mice after injection with a beta3-adrenergic agonist, CL-316243. An intact response to acute CL-316243 treatment was observed in MKR mice. Chronic intraperitoneal CL-316243 treatment of MKR mice reduced blood glucose and serum insulin levels. Hyperinsulinemic euglycemic clamps exhibited improvement of the whole body insulin sensitivity and glucose homeostasis concurrently with enhanced insulin action in liver and adipose tissue. Treating MKR mice with CL-316243 significantly lowered serum and hepatic lipid levels, in part due to increased whole body triglyceride clearance and fatty acid oxidation in adipocytes. A significant reduction in total body fat content and epididymal fat weight was observed along with enhanced metabolic rate in both wild-type and MKR mice after treatment. These data demonstrate that beta3-adrenergic activation improves the diabetic state of nonobese diabetic MKR mice by potentiation of free fatty acid oxidation by adipose tissue, suggesting a potential therapeutic role for beta3-adrenergic agonists in nonobese diabetic subjects.     

Diabetic peculiarity of the ALS-Ay and ALR-Ay strains

ALS and ALR mice were developed as mouse models of alloxan-induced diabetes. These strains do not show spontaneous onset of diabetes. When an obesity gene (Ay) was introduced to these two strains, severe diabetic conditions occurred spontaneously in the produced ALS-Ay and ALR-Ay strains. These strains were examined body weight gain, food consumption, water consumption, urinary sugar content, ketone body level and blood sugar level, and subjected to glucose tolerance test. As a result, in comparison with ALS mice, male ALS-Ay mice showed no obesity and very low tolerance to the glucose tolerance test performed 24 weeks after birth. The level of insulin secretion was 5.0 microU/ml or less, showing hardly any secretory reaction. On the other hand, female ALS-Ay mice were obese and showed no marked decrease in glucose tolerance. The level of insulin secretion was high, and the secretory reaction was strong. In ALR-Ay strain, both male and female mice were obese and showed diabetic conditions similar to those of ALS-Ay mice, though the severity tended to be lower. The characteristic features of diabetic conditions in these mice suggest that these strains, particularly ALS-Ay, may serve as useful new-type models of diabetes.     

MK-626, a dipeptidyl peptidase-4 inhibitor, does not improve the hyperglycemia or hyperinsulinemia of nonobese diabetic MKR mice

Dipeptidyl peptidase-4 (DPP-4) inhibitors increase circulating levels of incretin hormones, which can enhance insulin secretion and β cell function. The aim of this study was to evaluate the effectiveness of MK-626 (a novel DPP-4 inhibitor) to reduce the hyperglycemia and hyperinsulinemia of nonobese type 2 diabetic MKR mice. Twelve to 14-week-old hyperglycemic MKR mice were gavaged daily with MK-626 (3 mg/kg body weight) or vehicle (0.5% methyl cellulose (MC)) for 2 weeks. MK-626-treated mice displayed no change in body weight or adverse reactions, suggesting good tolerance of the drug. Fed blood glucose was significantly reduced over the 2-week experiment; however, it was also reduced in the MC group, suggesting an effect of gavage alone. Fed plasma insulin and glucagon levels and glucose tolerance of MK-626-treated mice were similar to those of MC mice. Therefore, treatment with MK-626 did not correct the prolonged hyperglycemia and impaired glucose tolerance of MKR mice.     

Intracerebroventricular leptin infusion improves glucose homeostasis in lean type 2 diabetic MKR mice via hepatic vagal and non-vagal mechanisms

MKR mice, lacking insulin-like growth factor 1 receptor (IGF-1R) signaling in skeletal muscle, are lean yet hyperlipidemic, hyperinsulinemic, and hyperglycemic, with severe insulin resistance and elevated hepatic and skeletal muscle levels of triglycerides. We have previously shown that chronic peripheral administration of the adipokine leptin improves hepatic insulin sensitivity in these mice independently of its effects on food intake. As central leptin signaling has been implicated in the control of peripheral glucose homeostasis, here we examined the ability of central intracerebroventricular leptin administration to affect energy balance and peripheral glucose homeostasis in non-obese diabetic male MKR mice. Central leptin significantly reduced food intake, body weight gain and adiposity, as well as serum glucose, insulin, leptin, free fatty acid and triglyceride levels relative to ACSF treated controls. These reductions were accompanied by increased fat oxidation as measured by indirect calorimetry, as well as increased oxygen consumption. Central leptin also improved glucose tolerance and hepatic insulin sensitivity determined using the euglycemic-hyperinsulinemic clamps relative to pair fed vehicle treated controls, as well as increasing the rate of glucose disappearance. Hepatic vagotomy only partially reversed the ability of central leptin to improve glucose tolerance. These results demonstrate that central leptin dramatically improves insulin sensitivity independently of its effects on food intake, in a lean mouse model of type 2 diabetes. The findings also suggest that: 1) both hepatic vagal and non-vagal pathways contribute to this improvement, and 2) central leptin alters glucose disposal in skeletal muscle in this model.     

MKR mice are resistant to the metabolic actions of both insulin and adiponectin: discordance between insulin resistance and adiponectin responsiveness

Most rodent models of insulin resistance are accompanied by decreased circulating adiponectin levels. Adiponectin treatment improves the metabolic phenotype by increasing fatty acid oxidation in skeletal muscle and suppressing hepatic glucose production. Muscle IGF-I receptor (IGF-IR)-lysine-arginine (MKR) mice expressing dominant-negative mutant IGF-IRs in skeletal muscle are diabetic with insulin resistance in muscle, liver, and adipose tissue. Adiponectin levels are elevated in MKR mice, suggesting an unusual discordance between insulin resistance and adiponectin responsiveness. Therefore, we investigated the metabolic actions of adiponectin in MKR mice. MKR and ob/ob mice were treated both acutely (28 microg/g) and chronically (for 2 wk) with full-length adiponectin. Acute hypoglycemic effects of adiponectin were evident only in ob/ob mice but not in MKR mice. Chronic adiponectin treatment significantly improved both insulin sensitivity and glucose tolerance in ob/ob but not in MKR mice. Adiponectin receptor mRNA levels and adiponectin-stimulated phosphorylation of AMPK in skeletal muscle and liver were similar among MKR, wild-type, and ob/ob mice. Thus MKR mice are adiponectin resistant despite normal expression of adiponectin receptors and normal AMPK phosphorylation in muscle and liver. MKR mice may be a useful model for dissecting relationships between insulin resistance and adiponectin action in regulation of glucose homeostasis.     

Type 2 diabetes mellitus in obese mouse model induced by monosodium glutamate.

The number of diabetic patients is increasing every year, and new model animals are required to study the diverse aspects of this disease. An experimental obese animal model has reportedly been obtained by injecting monosodium glutamate (MSG) to a mouse. We found that ICR-MSG mice on which the same method was used developed glycosuria. Both female and male mice were observed to be obese but had no polyphagia, and were glycosuric by 29 weeks of age, with males having an especially high rate of incidence (70.0%). Their blood concentrations of glucose, insulin, total cholesterol, and triglycerides were higher than in the control mice at 29 weeks. These high concentrations appeared in younger males more often than in females, and were severe in adult males. Also, the mice at 54 weeks of age showed obvious obesity and increased concentrations of glucose, insulin, and total cholesterol in the blood. The pathological study of ICR-MSG female and male mice at 29 weeks of age showed hypertrophy of the pancreatic islet. This was also observed in most of these mice at 54 weeks. It was recognized as a continuation of the condition of diabetes mellitus. From the above results, these mice are considered to be useful as new experimental model animals developing a high rate of obese type 2 (non-insulin dependent) diabetes mellitus without polyphagia.     

A new mouse model of spontaneous diabetes derived from ddY strain.

By the selective breeding of obese male mice of the ddY strain and using indices of the heavy body weight and appearance of urinary glucose, we established two inbred strains in 1992: one with obesity and urinary glucose (Tsumura, Suzuki, Obese Diabetes: TSOD) and the other without them (Tsumura, Suzuki, Non Obesity: TSNO). The male TSOD mice constantly showed signs of obesity and urinary glucose with increases in food and water intake, body weight and some fat weight. The body mass index (BMI) clearly showed moderate obesity. Increases in the levels of diabetic blood parameters (glucose, insulin and lipids) were also found in males, in which the levels of blood glucose and insulin were high to the ages past the growth peak. In the histological studies, pancreatic islets of the TSOD males were found hypertrophic without any signs of insulitis or fibrous formation. Among these diabetic characteristics, some of which were similar to the reported models of non-insulin-dependent diabetes mellitus (NIDDM), the stable appearances of the hyperglycemia, the hyperinsulinemia and the hypertrophy of pancreatic islets to the ages past the growth peak were the prominent features. In these respect the TSOD mouse may be a useful model for researching the mechanisms of human diabetes and its complications.     

Developing a new model for non-insulin dependent diabetes mellitus (NIDDM) by using the Philippine wild mouse, Mus musculus castaneus.

The Philippine wild-caught castaneus mouse (Mus musculus castaneus) and laboratory mouse (C57BL/6J: B6) were used to develop a new non-insulin dependent diabetes mellitus (NIDDM) model. Offspring from the cross between a wild male and B6 female were backcrossed to the sire. One male which exhibited highest fasting hyperglycemia (190 mg/dl) among eighty-seven backcross offspring was selected at 10 weeks of age, and crossed with a B6 female to comprise the fundamental stock (F0). Thereafter, full-sib mating was performed to develop a new inbred strain named CBD (Castaneus-B6 diabetic) mouse. Mice with relatively higher fasting hyperglycemia among F0 and F1 generations were selected for breeding. From the F2 generation, mice were defined as diabetic when blood glucose levels exceeded 200 mg/dl at 120 min in intraperitoneal glucose tolerance test (IPGTT) at 10 weeks of age, and have been selectively bred. The incidence of diabetic males from the F3-F6 generation fluctuated 45-75% at 10 weeks of age and 59-72% at 20 weeks of age. Diabetic males had about two-fold higher fasting glucose and insulin levels than B6 males. Glucose-stimulated insulin secretion was impaired in diabetic CBD mice compared to B6 males at 20 weeks. Moreover, diabetic mice had slight obesity compared to B6 mice. These facts indicated that diabetic features of CBD mice resemble NIDDM in humans. The CBD strain, characterized by high incidence and early onset of diabetes with mild obesity would be of value as a new NIDDM model. The method, utilizing wild castaneus mouse of different origin from laboratory mice, maybe useful in the development of other animal models.     

Functionalized gadofullerene ameliorates impaired glycolipid metabolism in type 2 diabetic mice

The soaring global prevalence of diabetes makes it urgent to explore new drugs with high efficacy and safety. Nanomaterial-derived bioactive agents are emerging as one of the most promising candidates for biomedical application. In the present study, we investigated the anti-diabetic effects of a functionalized gadofullerene (GF) using obese db/db and non-obese mouse model of type 2 diabete mellitus (MKR) mouse type 2 diabetes mellitus (T2DM) models. In both mouse models, the diabetic phenotypes, including hyperglycemia, impaired glucose tolerance, and insulin sensitivity, were ameliorated after two or four weeks of intraperitoneal administration of GF. GF lowered blood glucose levels in a dose-dependent manner. Importantly, the restored blood glucose levels could persist ten days after withdrawal of GF treatment. The hepatic AKT/GSK3β/FoxO1 pathway is shown to be the main target of GF for rebalancing gluconeogenesis and glycogen synthesis in vivo and in vitro. Furthermore, GF treatment significantly reduced weight gain of db/db mice with reduced hepatic fat storage by the inhibition of de novo lipogenesis through mTOR/S6K/SREBP1 pathway. Our data provide compelling evidence to support the promising application of GF for the treatment of T2DM.     

Protein-tyrosine phosphatase 1B deficiency reduces insulin resistance and the diabetic phenotype in mice with polygenic insulin resistance

Mice heterozygous for insulin receptor (IR) and IR substrate (IRS)-1 deficiency provide a model of polygenic type 2 diabetes in which early-onset, genetically programmed insulin resistance leads to diabetes. Protein-tyrosine phosphatase 1B (PTP1B) dephosphorylates tyrosine residues in IR and possibly IRS proteins, thereby inhibiting insulin signaling. Mice lacking PTP1B are lean and have increased insulin sensitivity. To determine whether PTP1B can modify polygenic insulin resistance, we crossed PTP1B-/- mice with mice with a double heterozygous deficiency of IR and IRS-1 alleles (DHet). DHet mice weighed slightly less than wild-type mice and exhibited severe insulin resistance and hyperglycemia, with approximately 35% of DHet males developing diabetes by 9-10 weeks of age. Body weight in DHet mice with PTP1B deficiency was similar to that in DHet mice. However, absence of PTP1B in DHet mice markedly improved glucose tolerance and insulin sensitivity at 10-11 weeks of age and reduced the incidence of diabetes and hyperplastic pancreatic islets at 6 months of age. Insulin-stimulated phosphorylation of IR, IRS proteins, Akt/protein kinase B, glycogen synthase kinase 3beta, and p70(S6K) was impaired in DHet mouse muscle and liver and was differentially improved by PTP1B deficiency. In addition, increased phosphoenolpyruvate carboxykinase expression in DHet mouse liver was reversed by PTP1B deficiency. In summary, PTP1B deficiency reduces insulin resistance and hyperglycemia without altering body weight in a model of polygenic type 2 diabetes. Thus, even in the setting of high genetic risk for diabetes, reducing PTP1B is partially protective, further demonstrating its attractiveness as a target for prevention and treatment of type 2 diabetes.