Role of the intestinal acyl-CoA:cholesterol acyltransferase activity in the hyperresponse of diabetic rats to dietary cholesterol.

Contrary to normal rats, diabetic rats are known to develop marked hypercholesterolemia when fed a cholesterol-enriched diet. The triggering factor involved in this hyperresponse has not been identified. With the aim of clarifying the role of the intestinal acyl-CoA:cholesterol acyltransferase (ACAT), we studied the effects of a high fat diet and the changes of intestinal ACAT activity during the early development of streptozotocin-diabetes in rats. Feeding diabetic rats with a diet enriched in cholesterol and saturated fat produced an increase in plasma and in tissue cholesterol as early as 3 days after streptozotocin injection in the absence of hyperphagia. Under these experimental conditions, treatment with insulin or with the ACAT inhibitor CL-277082 significantly reduced the plasma cholesterol to levels measured in nondiabetic rats fed the same high fat diet. An increase in [14C]cholesterol in plasma very low density lipoprotein was observed after oral administration of labeled cholesterol to 3-day diabetic rats. In parallel experiments, the direct measurement of small intestine microsomal ACAT activity revealed an increase, averaging 288% in diabetic rats 3 days after diabetes induction. This change in ACAT activity occurred simultaneously with an increase in plasma glucagon and was normalized by insulin treatment. The induction of intestinal ACAT activity in diabetic rats, its modulation by insulin, and the hypocholesterolemic effects of insulin or CL-277082 treatment clearly indicate that ACAT activity plays a major role in the initiation of diabetes-associated hypercholesterolemia.     

Effects of vanadate on glucose production in cultured hepatocytes isolated from rats on high saturated fat diet

Insulin resistance is a common phenomenon in obesity and Type 2 diabetes. Common factor important for development of diabetes and insulin resistance is intake of saturated fat. Vanadate treatment improves glucose homeostasis in vivo. The aim of this study was to find out changing of hepatic glucose output in dependence of saturated fat diet and possible direct action of vanadate in cultured hepatocytes. Hepatocytes were isolated by a collagenase perfusion technique and cultured for 24 h in M 199 serum-free medium. The glucose production in hepatocytes isolated from rats on high saturated fat diet was significantly 139% higher comparable to standard controls. Glucagon 100% increased glucose production in hepatocytes from rats on standard diet and 200% in hepatocytes on saturated high fat diet. The addition vanadate significantly decreased basic glucose production and did not influence glucagon stimulated glucose production. Presence of insulin did not influence either glucagon or vanadate effect. High saturated fat diet not only increases insulin resistance but also decreases chances of successful therapy of diabetes.     

Effect of probucol on recovery from streptozotocin diabetes in rats.

The present study was conducted to see the effect of probucol on streptozotocin diabetes in rats. After 2 weeks of a 1% probucol diet, 35 or 50 mg/kg of streptozotocin were intravenously injected into male Wistar rats. All the rats became diabetic 2 days after treatment. Thereafter, in order to see the effect of probucol on spontaneous recovery from streptozotocin diabetes, 25 mg/kg of streptozotocin was injected into rats after two weeks of probucol diet and the diet was continued for additional two weeks. All the rats with a standard diet (group CS, n = 13) and 12 of 13 rats with probucol diet (group PS) became diabetic 2 days after streptozotocin injection. One rate from group PS did not develop diabetes. Two weeks after injection, only 4 of 13 rats in groups CS showed recovery, while 11 of 12 rats in group PS showed recovery from streptozotocin diabetes (p less than 0.05). The average blood glucose levels in group PS were significantly lower than group CS (10.5 +/- 4.6 vs 18.5 +/- 0.6 mM, p less than 0.05). In addition, the pancreatic insulin content of group PS was 8 times greater than that of group CS (0.75 +/- 0.24 vs 0.09 +/- 0.03 mmol/pancreas, p less than 0.01). Thus, the in vivo diabetogenic action of streptozotocin could not be reduced by pretreatment with probucol. However, recovery from streptozotocin diabetes was induced by subsequent treatment with probucol. The precise mechanisms for this phenomenon were not known; but the present findings suggest the protective effect of probucol on beta-cell damage induced by small dose of streptozotocin.     

The rat model of type 2 diabetic mellitus and its glycometabolism characters.

To develop a rat model of type 2 diabetic mellitus that simulated the common manifestation of the metabolic abnormalities and resembled the natural history of a certain type 2 diabetes in human population, male Sprague-Dawley rats (4 months old) were injected with low-dose (15 mg/kg) STZ after high fat diet (30% of calories as fat) for two months (L-STZ/2HF). The functional and histochemical changes in the pancreatic islets were examined. Insulin-glucose tolerance test, islet immunohistochemistry and other corresponding tests were performed and the data in L-STZ/2HF group were compared with that of other groups, such as the model of type 1 diabetes (given 50 mg/kg STZ) and the model of obesity (high fat diet). The body weight of rats in the group of rats given 15 mg/kg STZ after high fat diet for two months increased significantly more than that of rats in the group of rats given 50 mg/kg STZ (the model of type 1 diabetes) (595 +/- 33 g vs. 352 +/- 32 g, p<0.05). Fast blood glucose levels for L-STZ/2HF group were 16.92 +/- 1.68 mmol/l, versus 5.17 +/- 0.55 mmol/l in normal control and 5.59 +/- 0.61 mmol/l in rats given high fat diet only. Corresponding values for fast serum insulin were 0.66 +/- 0.15 ng/ml, 0.52 +/- 0.13 ng/ml, 0.29 +/- 0.11 ng/ml, respectively. Rats of type 2 diabetes (L-STZ/2HF) had elevated levels of triglyceride (TG, 3.82 +/- 0.88 mmol/l), and cholesterol(Ch, 2.38 +/- 0.55 mmol/l) compared with control (0.95 +/- 0.15 mmol/l and 1.31 +/- 0.3 mmol/l, respectively) (p<0.05). The islet morphology as examined by immunocytochemistry using insulin antibodies in the L-STZ/2HF group was affected and quantitative analysis showed the islet insulin content was higher than that of rats with type 1 diabetes (P<0.05). We concluded that the new rat model of type 2 diabetes established with conjunctive treatment of low dose of STZ and high fat diet was characterized by hyperglycemia and light impaired insulin secretion function accompanied by insulin resistance, which resembles the clinical manifestation of type 2 diabetes. Such a model, easily attainable and inexpensive, would help further elucidation of the underlying mechanisms of diabetes and its complications.     

The effect of dietary n-3 long-chain polyunsaturated fatty acids on femur mineral density and biomarkers of bone metabolism in healthy, diabetic and dietary-restricted growing rats

INTRODUCTION: Dietary fish oil promotes bone formation in healthy states, but its effect during insulin deficiency or nutrient restriction is unclear. METHODS: Eighty weanling male rats were randomized to receive an injection of streptozotocin to induce insulin deficiency (diabetes) or saline (control) and a diet containing soy oil or corn + fish oil for 35 days. Half of the saline-injected rats were randomized to 20% dietary restriction. Measurements were growth, biomarkers of bone metabolism and femur bone mass. RESULTS: Density of femur was elevated in the corn + fish group and reduced in the diabetes group. Plasma osteocalcin and bone prostaglandin E2 (PGE2) were reduced by the corn + fish diet. N-telopeptide, IGF-1, bone PGE2 and urinary Ca were highest and calcitriol lowest in the diabetes group. CONCLUSIONS: These data suggest that the benefit of a diet high in n-3 long-chain polyunsaturated fatty acid is most advantageous to long bone density in healthy states.     

Effect of β-Caryophyllene on insulin resistance in skeletal muscle of high fat diet and fructose-induced type-2 diabetic rats

High fat diet feeding results in hyperglycemia and insulin resistance, which is a major pathological feature of type-2 diabetes mellitus. The use of oral hypoglycaemic drugs is limited due to its deleterious side effects and there is a need to find more efficacious agents for diabetes management. Hence, it is of interest to show the mechanism of action of β-Caryophyllene on insulin signalling molecules in gastrocnemius muscle of high fat diet - induced type-2 diabetic rats. An oral effective dose of with β-Caryophyllene (200 mg/kg b.wt) was given for 30 days to high fat diet (comprising 2% cholesterol, 1% cholic acid, 30% coconut oil, 67% conventional rat feed) and fructose fed type-2 diabetic rats to find out whether β-Caryophyllene regulates IRS-1/Akt pathway of insulin signalling. The data shows that, β-Caryophyllene treatment significantly increased the mRNA and protein expression of insulin receptor (IR) in diabetic rats whereas there is no significant difference in mRNA expression of insulin receptor-substrate-1 (IRS-1) was observed among groups. The Akt mRNAand GLUT-4mRNA and protein level were also improved in gastrocnemius muscle of type-2 diabetic rats. Thus, we concluded that β-Caryophyllene could be used as potential phyto medicine for type-2 diabetes management.     

急、慢性运动对2型糖尿病大鼠脂肪PI3K/AKT/GLUT4通路的影响

目的:探讨急性和慢性运动对2型糖尿病(T2DM)大鼠脂肪组织明磷脂酰肌醇3激酶(PI3K)/蛋白激酶B(AKT)/葡萄糖运载体4(GLUT4)信号通路的影响。方法:15月龄SD雄性大鼠52只随机分为正常对照组(n=13)和高脂组(n=39),分别喂养普通和高脂饲料。8周后,高脂组体重＞正常对照组20％,注射小剂量STZ后,血糖＞16.7 mmol/l,造模成功。将糖尿病模型组随机分为糖尿病对照组(DC,n=13),糖尿病慢性运动组(DCE,n=13),糖尿病急性运动组(DAE,n=13)。DCE组进行8周的游泳运动,DAE组进行一次性游泳运动。测定血脂,血糖和血清胰岛素,Western blot法测定脂肪PI3K、AKT和GLUT4蛋白含量。结果:糖尿病组体重、血脂、血糖、胰岛素显著高于正常对照组(P均＜0.01);高密度脂蛋白胆固醇(HDL-C)水平降低(P＜0.05),脂肪组织中PI3K、AKT和GLUT4蛋白表达下降(P均＜0.01)。糖尿病慢性运动组体重、血脂、血糖、胰岛素均出现显著性下降(P均＜0.01);HDL-C升高(P＜0.05),脂肪PI3K、AKT和GLUT4蛋白表达上升(P＜0.01)。糖尿病急性运动组血脂、血糖、胰岛素下降(P均＜0.05);HDL-C升高(P＜0.05),脂肪PI3K、AKT和GLUT4含量显著上升(P均＜0.05)。结论:①高脂饮食结合小剂量STZ诱导的T2DM大鼠脂肪组织PI3K/AKT通路受损,降低了胰岛素的敏感性。②急性、慢性有氧运动,均可以通过PI3K/AKT通路,改善糖脂代谢紊乱,慢性运动略优于急性运动。     

Essential fatty acid deficiency in mice impairs lactose digestion

Essential fatty acid (EFA) deficiency in mice induces fat malabsorption. We previously reported indications that the underlying mechanism is located at the level of the intestinal mucosa. We have investigated the effects of EFA deficiency on small intestinal morphology and function. Mice were fed an EFA-deficient or control diet for 8 wk. A 72-h fat balance, the EFA status, and small intestinal histology were determined. Carbohydrate absorptive and digestive capacities were assessed by stable isotope methodology after administration of [U-(13)C]glucose and [1-(13)C]lactose. The mRNA expression and enzyme activity of lactase, and concentrations of the EFA linoleic acid (LA) were measured in small intestinal mucosa. Mice fed the EFA-deficient diet were markedly EFA-deficient with a profound fat malabsorption. EFA deficiency did not affect the histology or proliferative capacity of the small intestine. Blood [13C6]glucose appearance and disappearance were similar in both groups, indicating unaffected monosaccharide absorption. In contrast, blood appearance of [13C]glucose, originating from [1-(13)C]lactose, was delayed in EFA-deficient mice. EFA deficiency profoundly reduced lactase activity (-58%, P<0.01) and mRNA expression (-55%, P<0.01) in mid-small intestine. Both lactase activity and its mRNA expression strongly correlated with mucosal LA concentrations (r=0.77 and 0.79, respectively, P<0.01). EFA deficiency in mice inhibits the capacity to digest lactose but does not affect small intestinal histology. These data underscore the observation that EFA deficiency functionally impairs the small intestine, which in part may be mediated by low LA levels in the enterocytes.     

Trifolium pratense (Red Clover) Improve SIRT1 Expression and Glycogen Content in High Fat Diet‐Streptozotocin Induced Type 2 Diabetes in Rats

Flowering tops of Trifolium pratense L. (Fabaceae) are known for its traditional medicinal values. In present study, our aim was to investigate effect of standardized aqueous extract of flowering tops of Trifolium pratense L. on insulin resistance and SIRT1 expression in type 2 diabetic rats. Type 2 diabetes was induced by feeding high fat diet and administering low dose of streptozotocin. Diabetic animals were treated with standardized aqueous extract at three different doses. Parameters such as blood glucose, lipid profile, glycohemoglobin, insulin sensitivity, HOMA‐IR and liver glycogen content were measured. Changes in morphology and expression of SIRT1 in pancreatic tissue were measured in histopathological and immunohistological studies. Aqueous extract treatment showed reduction in hyperglycemia and improved insulin sensitivity. Extract treatment also showed reduction in formation of glycated hemoglobin and improved liver glycogen level. Histopathological study revealed protecting effect of extract in pancreatic tissue against hyperglycemia induced damage. Treatment increased expression of SIRT1 in rat pancreatic tissue. Results indicate that the aqueous extract of Trifolium pratense had beneficial role in improving insulin sensitivity and SIRT1 expression.     

GABA in the endocrine pancreas: cellular localization and function in normal and diabetic rats

Gamma amino butyric acid (GABA) and its related enzymes have been demonstrated in pancreatic beta cells of normal rat. Antibodies against GABA-synthesizing enzymes have been implicated in the pathogenesis of Type I diabetes. In spite of the importance of GABA in the aetiology of diabetes mellitus, detailed morphological data on the pattern of distribution of GABA in the pancreas of normal and diabetic rats are lacking. Diabetes mellitus (DM) was induced by a single dose of streptozotocin (STZ) given intraperitoneally (60 mg kg body weight(-1)). Four weeks after the induction of DM, normal (n = 6) and diabetic (n = 6) rats were anesthetized with chloral hydrate and their pancreata were removed and processed for the localization and effect of GABA on insulin secretion using immunohistochemistry and radioimmunoassay techniques. The number of GABA-like immunoreactive (GABA-LIR) cells in the pancreatic islets of STZ-diabetic rats decreased significantly (P<0.0001) when compared to non-diabetic control rats. The pattern and percentage distribution of GABA in the islet of Langerhans of normal and diabetic rat was similar to that of insulin. GABA induced a significant (P<0.0007) increase in insulin secretion from the pancreas of normal rats. In diabetic pancreas, GABA evoked a higher but not significant (P<0.1) increase in insulin secretion. These findings showed that the number of GABA-LIR cells is reduced significantly in diabetes. Moreover, GABA is a strong secretagogue of insulin from the pancreas of normal rat.     

Reduced serum dipeptidyl peptidase-IV after metformin and pioglitazone treatments

Dipeptidyl peptidase-IV (DPP-IV) regulates metabolism by degrading incretins involved in nutritional regulation. Metformin and pioglitazone improve insulin sensitivity whereas glyburide promotes insulin secretion. Zucker diabetic rats were treated with these antidiabetic agents for 2 weeks and DPP-IV activity and expression were determined. Serum DPP-IV activity increased whereas tissue activity decreased as the rats aged. Treatment of rats with metformin, pioglitazone, and glyburide did not alter DPP-IV mRNA expression in liver or kidney. Metformin and pioglitazone significantly (P<0.05) reduced serum DPP-IV activity and glycosylated hemoglobin. Glyburide did not lower DPP-IV activity or glycosylated hemoglobin. Regression analysis showed serum DPP-IV activity correlated with glycosylated hemoglobin (r=0.92) and glucagon-like peptide-1 levels (r=-0.49). Metformin, pioglitazone, and glyburide had no effect on serum DPP-IV activity in vitro, indicating these are not competitive DPP-IV inhibitors. We propose the in vivo inhibitory effects observed with metformin and pioglitazone on serum DPP-IV activity results from reduced DPP-IV secretion.     

Myostatin信号通路在4周离心耐力运动改善2型糖尿病大鼠骨骼肌萎缩中的作用

目的：观察4周离心耐力运动对2型糖尿病大鼠代谢障碍及肌萎缩的影响,探讨myostatin/Smad3/atrogin-1信号通路在肌萎缩中的作用。方法：9周高脂饲养联合STZ注射建立2型糖尿病大鼠模型。将普通饲料组大鼠随机分为对照组（C,n=6）和运动组（E,n=9;将2型糖尿病模型组大鼠随机分为糖尿病对照组（D,n=8）和糖尿病运动组（DE,n=12）。运动方案：坡度-5°,跑速16 m/min,每次60 min、每日一次,每周训练5 d,连续4周。最后一次运动后禁食12 h,测定空腹血糖（FBG）、空腹胰岛素（FINS）,计算稳态模式胰岛素抵抗指数（HOMA-IR）和胰岛素敏感指数（ISI）,进行葡萄糖耐量试验。取比目鱼肌观察肌萎缩现象并检测myostatin、Smad3、p-Smad3和atrogin-1表达情况。结果：①与对照组相比,糖尿病组大鼠体重、比目鱼肌质量/胫骨长和肌纤维平均横截面积、FINS和ISI显著降低（P<0.01）,FBG、HOMA-IR和血糖曲线下面积（AUC_BG）以及myostatin、Smad3、p-Smad3、atrogin-1表达均显著升高（P<0.01）。②4周离心运动后,与糖尿病组相比,糖尿病运动组大鼠肌纤维平均横截面积显著升高（P<0.01）,AUC_BG、HOMA-IR及myostatin、p-Smad3、atrogin-1表达显著降低（P<0.05,P<0.01）。结论：myostatin/Smad3/atrogin-1信号通路上调是导致2型糖尿病肌萎缩的重要原因,4周离心耐力运动可能通过下调myostatin、p-Smad3和atrogin-1表达抑制肌萎缩,进而改善2型糖尿病代谢障碍,提高胰岛素敏感性。     

Deficiency of the mitochondrial electron transport chain in muscle does not cause insulin resistance

Background

It has been proposed that muscle insulin resistance in type 2 diabetes is due to a selective decrease in the components of the mitochondrial electron transport chain and results from accumulation of toxic products of incomplete fat oxidation. The purpose of the present study was to test this hypothesis.

Methodology/Principal Findings

Rats were made severely iron deficient, by means of an iron-deficient diet. Iron deficiency results in decreases of the iron containing mitochondrial respiratory chain proteins without affecting the enzymes of the fatty acid oxidation pathway. Insulin resistance was induced by feeding iron-deficient and control rats a high fat diet. Skeletal muscle insulin resistance was evaluated by measuring glucose transport activity in soleus muscle strips. Mitochondrial proteins were measured by Western blot. Iron deficiency resulted in a decrease in expression of iron containing proteins of the mitochondrial respiratory chain in muscle. Citrate synthase, a non-iron containing citrate cycle enzyme, and long chain acyl-CoA dehydrogenase (LCAD), used as a marker for the fatty acid oxidation pathway, were unaffected by the iron deficiency. Oleate oxidation by muscle homogenates was increased by high fat feeding and decreased by iron deficiency despite high fat feeding. The high fat diet caused severe insulin resistance of muscle glucose transport. Iron deficiency completely protected against the high fat diet-induced muscle insulin resistance.

Conclusions/Significance

The results of the study argue against the hypothesis that a deficiency of the electron transport chain (ETC), and imbalance between the ETC and β-oxidation pathways, causes muscle insulin resistance.     

Bone‐marrow mesenchymal stem cell transplantation to treat diabetic nephropathy in tree shrews

Diabetic nephropathy (DN) is a common microvascular complication of diabetes. We used a new DN model in tree shrews to validate the use of bone‐marrow mesenchymal stem cell (BM‐MSC) transplantation to treat DN. The DN tree shrew model was established by a high‐sugar and high‐fat diet and four injections of streptozotocin. 4',6‐Diamidino‐2‐phenylindole labelled BM‐MSCs were injected into tree shrews. The DN tree shrew model was successfully established. Blood glucose was significantly increased ( p < 0.01) during the entire experiment. DN tree shrews showed dyslipidemia, insulin resistance and increased 24‐h proteinuria. At 21 days after BM‐MSC transplantation, glucose and levels of triglycerides, total cholesterol and 24‐h urine volume were lower than in tree shrews with DN alone ( p < 0.01) but were still higher than control values ( p < 0.01). Levels of creatinine and urea nitrogen as well as 24‐h proteinuria were lower for DN tree shrews with BM‐MSCs transplantation than DN alone ( p < 0.05). High‐sugar and high‐fat diet combined with STZ injection can induce a tree shrew model of DN. BM‐MSCs injection can home to damaged kidneys and pancreas, for reduced 24‐h proteinuria and improved insulin resistance. Copyright © 2014 John Wiley & Sons, Ltd.     

链脲佐菌素制备糖尿病大鼠模型探讨

目的探讨链脲佐菌素(STZ)配合不同饮食建立糖尿病模型的方法,并对模型大鼠学习记忆能力进行考察,为糖尿病的深入研究及药物开发提供可靠的模型。方法雄性SD大鼠70只,随机分为7组,分别为空白对照组(Ⅰ);高糖高脂膳食组(Ⅱ);0周STZ(30 mg/kg)+高糖高脂膳食组(Ⅲ);0周STZ(30 mg/kg)+常规膳食组(Ⅳ);6周STZ(20 mg/kg)+高糖高脂膳食组(Ⅴ);6周STZ(25 mg/kg)+高糖高脂膳食组(Ⅵ);6周STZ(30 mg/kg)+高糖高脂膳食组(Ⅶ)。采用尾静脉注射STZ配合不同饮食制备糖尿病模型,动态监测模型大鼠血糖的变化,生化方法检测大鼠血脂的改变,放免法检测模型大鼠血清胰岛素、胰高血糖素。Morris水迷宫检测不同造模型条件对大鼠空间学习记忆能力的影响。结果与对照组比较,Ⅲ组大鼠于注射72 h后血糖升高明显(P<0.01),至注射第2周血糖升高达顶点(P<0.01),以后逐渐降低,至观察第10周,血糖维持在15 mmol/L(P<0.05)。IV组大鼠于注射72 h后血糖升高,以后迅速降低,至观察第10周,血糖降低至正常水平。Ⅴ、Ⅵ、Ⅶ组大鼠于注射72 h后显著升高,此后呈波浪式变化;随着注射剂量增加,降低程度减慢。高糖高脂饲料喂养10周后,各组大鼠CHO,TG,LDL-C均增加;Ⅲ、Ⅳ、Ⅴ组大鼠血清INS水平较对照组增高,除IV外,各组胰高血糖素均高于对照组。水迷宫试验结果显示,Ⅶ组潜伏期延长,与对照组比较,具有统计学意义。结论 STZ(30 mg/kg)配合高糖高脂膳食能够快速、稳定的建立糖尿病大鼠模型,高糖高脂膳食组6周后尾静脉注射STZ(30 mg/kg)制备模型,血糖升高显著,血清胰岛素水平降低明显,倾向于1型糖尿病模型。     

Formononetin Ameliorates Diabetic Neuropathy by Increasing Expression of SIRT1 and NGF

Diabetic neuropathy is commonly observed complication in more than 50 % of type 2 diabetic patients. Histone deacetylases including SIRT1 have significant role to protect neuron from hyperglycemia induced damage. Formononetin (FMNT) is known for its effect to control hyperglycemia and also activate SIRT1. In present study, we evaluated effect of FMNT as SIRT1 activator in type 2 diabetic neuropathy. Type 2 diabetic neuropathy was induced in rats by modification of diet for 15 days using high fat diet and administration of streptozotocin (35 mg/kg/day, i. p.). FMNT treatment was initiated after confirmation of type 2 diabetes. Treatment was given for 16 weeks at 10, 20 and 40 mg/kg/day dose orally. FMNT treatment‐controlled hypoglycemia and reduced insulin resistance significantly in diabetic animals. FMNT treatment reduced oxidative stress in sciatic nerve tissue. FMNT treatment also reduced thermal hyperalgesia and mechanical allodynia significantly. It improved conduction velocity in nerve and unregulated SIRT1 and NGF expression in sciatic nerve tissue. Results of present study indicate that continuous administration of FMNT protected diabetic animals from hyperglycemia induced neuronal damage by controlling hyperglycemia and increasing SIRT1 and NGF expression in nerve tissue. Thus, FMNT can be an effective candidate for treatment of type 2 diabetic neuropathy.     

Dietary carbohydrate dictates development of Type 2 diabetes in the Nile rat

Amount and type of dietary carbohydrate (CHO), as well as the CHO:fat ratio, are thought to be critical for both the rate of development and severity of Type 2 diabetes mellitus. Thus, these nutritional considerations were examined in the previously described “spontaneous” model of diabetes and metabolic syndrome, the Nile rat. Weanling male Nile rats (n=92) were fed semipurified diets, modifying glycemic index and load by changing the amount of fiber or altering the CHO:fat ratio. Random and fasting blood glucose and body weight were assessed, and diabetes was characterized in terms of blood glucose, relevant plasma and liver parameters, food and water intake and terminal organ weights. Nile rats fed with hiCHO became more hyperglycemic than rats fed with modCHO (P<.05), while loCHO and hiCHO+hiFiber rats remained essentially normoglycemic. Liver lipid and glycogen accumulation was associated with severe hyperlipemia in diabetic rats, analogous to metabolic syndrome in humans. Advanced diabetes was linked to liver and kidney damage and elevated blood urea nitrogen with weight loss. Dispersing dietary CHO by fiber or replacing it by moderate fat (reducing the glycemic index and load) delayed the onset of diabetes but did not prevent signs of insulin resistance. A very low content of dietary CHO (high fat) seemed to prevent even these early indicators of insulin resistance. Thus, the Nile rat represents a novel CHO-sensitive model for study of Type 2 diabetes that reliably follows the course of disease in humans.     

A high-selenium diet induces insulin resistance in gestating rats and their offspring

Although supranutrition of selenium (Se) is considered a promising anti-cancer strategy, recent human studies have shown an intriguing association between high body Se status and diabetic risk. This study was done to determine if a prolonged high intake of dietary Se actually induced gestational diabetes in rat dams and insulin resistance in their offspring. Forty-five 67-day-old female Wistar rats (n=15/diet) were fed a Se-deficient (0.01 mg/kg) corn-soy basal diet (BD) or BD+Se (as Se-yeast) at 0.3 or 3.0mg/kg from 5 weeks before breeding to day 14 postpartum. Offspring (n=8/diet) of the 0.3 and 3.0mg Se/kg dams were fed with the same respective diet until age 112 days. Compared with the 0.3mg Se/kg diet, the 3.0mg/kg diet induced hyperinsulinemia (P<0.01), insulin resistance (P<0.01), and glucose intolerance (P<0.01) in the dams at late gestation and/or day 14 postpartum and in the offspring at age 112 days. These impairments concurred with decreased (P<0.05) mRNA and/or protein levels of six insulin signal proteins in liver and muscle of dams and/or pups. Dietary Se produced dose-dependent increases in Gpx1 mRNA or GPX1 activity in pancreas, liver, and erythrocytes of dams. The 3.0mg Se/kg diet decreased Selh (P<0.01), Sepp1 (P=0.06), and Sepw1 (P<0.01), but increased Sels (P<0.05) mRNA levels in the liver of the offspring, compared with the 0.3mg Se/kg diet. In conclusion, supranutrition of Se as a Se-enriched yeast in rats induced gestational diabetes and insulin resistance. Expression of six selenoprotein genes, in particular Gpx1, was linked to this metabolic disorder.     

Diet and diabetic state modify glycogen synthase activity and expression in rat hepatocytes

Glycogen synthase (GS), a key regulatory enzyme in glycogen synthesis, is controlled by multisite phosphorylation and allosteric regulation and is activated by insulin. This study investigated changes in GS activity and expression in hepatocytes isolated from rats under altered nutritional and diabetic conditions. Experiments were carried out in healthy rats fed a chow diet, rats on high simple sugar (60% of energy from fructose and sucrose) or high fat (46% of energy from fat) diet, and in rats with streptozotocin induced diabetes. In the presence of insulin, activated GS activity (GS(I) form) was increased by 89% in hepatocytes isolated from healthy rats. The stimulatory effect of insulin on GS activity and expression was blunted by cycloheximide and actinomycin treatment. In rats fed a high simple sugar or high fat diet, insulin stimulation of GS(I) in isolated hepatocytes was impaired and GS expression was significantly lower in rats fed the high fat diet in comparison to controls. GLUT-2 protein expression was significantly lowered by both the high fat and high simple sugar diets. In hepatocytes isolated from diabetic rats, total GS activity (GS(T)) was lower than in hepatocytes from healthy animals. Insulin added to the incubation medium did not stimulate GS activity, demonstrating impaired sensitivity to insulin in diabetic rats. However, insulin administration significantly increased GS expression indicating that a defect in synthase phosphorylation may be responsible for impaired GS activity in the diabetic state. The results presented in this study further confirm that GS activity is affected by both dietary and hormonal factors which can be measured in a rat hepatocyte model.     

不同性别大鼠在2型糖尿病造模过程中的稳定性

目的研究不同性别大鼠在2型糖尿病造模过程中的成功率及模型的稳定性。方法高糖高脂饮食联合腹腔注射小剂量链脲佐菌素诱导建立雄、雌性大鼠2型糖尿病模型。成模后所有大鼠每周固定时间测血糖和体重。观察24周后,心脏穿刺取血,测定空腹血糖（FPG）、血清胰岛素（FINS）、HbA1c、甘油三脂（TG）、胆固醇（TC）、高密度脂蛋白-胆固醇（HDL-C）、低密度脂蛋白-胆固醇（LDL-C）。结果单纯高糖高脂饮食喂养,雄、雌性大鼠血糖与正常组无显著差异;STZ注射后,雄性大鼠血糖升高并逐渐平稳,而雌性需两次STZ注射,模型才比较稳定。实验结束时,雄、雌性糖尿病大鼠FPG、FINS、HOMA-IR以及TG、TC、LDL-C均显著升高,说明模型存在胰岛素抵抗和脂代谢紊乱。结论高糖高脂饲料加一次性小剂量链脲佐菌素腹腔注射,可成功建立雄性大鼠2型糖尿病模型,而同等剂量,雌性模型需两次STZ。雄、雌性糖尿病大鼠模型具有高血糖、脂质代谢紊乱和胰岛素抵抗特点。造模成功率及稳定性与性别有关,雄性大鼠较雌性大鼠成模率高,稳定性好,且耗时更短。