The development of diabetes mellitus in Wistar rats kept on a high-fat/low-carbohydrate diet for long periods

The present study was performed to determine the effect of long-term feeding with a high-fat/low-carbohydrate (HF/LC) diet on the onset of type-2 diabetes mellitus in normal rats. Male Wistar Imamichi rats were kept on a Control (carbohydrate 60%, fat 15%) or HF/LC (carbohydrate 10%, fat 65%) diet for 16 mo. An intraperitoneal glucose tolerance test was performed once every 2 mo. Glucose tolerance was impaired 2 mo after the start of HF/LC diet feeding, accompanied by a decrease in the insulinogenic index. Along with time of HF/LC diet feeding, the glucose tolerance was further deteriorated with more serious impairment of insulin secretion and sensitivity. At the end of the experiment, 15 of 18 rats in the HF/LC group were diabetic, whereas only 4 of 17 rats in the Control group were diabetic. The present results demonstrate that long-term feeding with a HF/LC diet decreases the secretion and sensitivity of insulin, and induces diabetes mellitus in rats. Furthermore, long-term feeding with such a diet may produce adverse effects on the blood plasma lipid profile, with elevated levels of trigly cerides, non-esterified fatty acids, total cholesterol, and reduced levels of high density protein cholesterol in the plasma.     

A low-carbohydrate/high-fat diet improves glucoregulation in type 2 diabetes mellitus by reducing postabsorptive glycogenolysis

The aim of this study was to examine the mechanisms by which dietary carbohydrate and fat modulate fasting glycemia. We compared the effects of an eucaloric high-carbohydrate (89% carbohydrate) and high-fat (89% fat) diet on fasting glucose metabolism and insulin sensitivity in seven obese patients with type 2 diabetes using stable isotopes and euglycemic hyperinsulinemic clamps. At basal insulin levels glucose concentrations were 148 +/- 11 and 123 +/- 11 mg/dl (8.2 +/- 0.6 and 6.8 +/- 0.6 mmol/liter) on the high-carbohydrate and high-fat diet, respectively (P < 0.001), with insulin concentrations of 12 +/- 2 and 10 +/- 1 microIU/ml (82 +/- 11 and 66 +/- 10 pmol/liter) (P = 0.08). Glucose production was higher on the high-carbohydrate diet (1.88 +/- 0.06 vs. 1.55 +/- 0.05 mg/kg.min (10.44 +/- 0.33 vs. 8.61 +/- 0.28 micromol/kg.min) (P < 0.001) because of higher glycogenolysis. Gluconeogenic rates were not different between the diets. During the use of hyperinsulinemic euglycemic clamps, insulin-mediated suppression of glucose production and stimulation of glucose disposal were not different between the diets. Free fatty concentrations were suppressed by 89 and 62% (P < 0.0001) on the high-carbohydrate and high-fat diet, respectively. We conclude that short-term variations in dietary carbohydrate to fat ratios affect basal glucose metabolism in people with type 2 diabetes merely through modulation of the rate of glycogenolysis, without affecting insulin sensitivity of glucose metabolism.     

Effect of short-term consumption of a high-fat, low-carbohydrate diet on metabolic control in insulin-deficient diabetic rats

This study examined the effect of changing the proportion of dietary fat on metabolic control in rats rendered mildly diabetic with streptozotocin (STZ). The high-fat (HF) diet contained 66% energy as fat and 12% as carbohydrate while the low-fat (LF) diet contained 12% energy as fat and 66% as carbohydrate. Both diets had a P/S ratio of 1:3. Young male rats weighing 100 g were treated with STZ (60 mg/kg IV) and randomly allocated to either the LF of HF diet. After 2 weeks, the fasting plasma glucose concentrations were significantly higher in the HF-STZ rats than in the LF-STZ rats (13.2 +/- 1.2 mmol/L v 7.1 +/- 0.8 mmol/L, respectively, P less than 0.001). The increase in plasma glucose above the basal level following the intravenous glucose load (0.5 g/kg body wt) was similar in both groups of STZ-treated rats and glucose clearance was similarly impaired. The fall in glucose concentrations in the 30 minutes following the IV insulin (0.5 U Actrapid insulin/kg body wt) was greater in the LF-STZ rats (delta AUC = -1.60 +/- 0.20 mmol/L 0.5h) than in the HF-STZ group (delta AUC = -0.97 +/- 0.20 mmol/L 0.5 h, P less than 0.05) and either of the control groups (delta AUC = -0.94 +/- 0.37, -0.83 +/- 0.09 mmol/L 0.5 h for LF and HF rats, respectively, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Glucose intolerance induced by a high-fat/low-carbohydrate diet in rats effects of nonesterified fatty acids

We examined the time course of effects of a high-fat/low-carbohydrate (HF/LC) diet on the impairment of glucose tolerance in rats, clarified whether insulin secretion and sensitivity were impaired by the HF/LC diet, and investigated the relationship between the increased nonesterified fatty acids (NEFA) after HF/LC diet feeding and insulin secretion and sensitivity. We found that glucose tolerance and the postglucose-loading insulin secretion were impaired after 3 and 7 d on the HF/LC diet. The glucose intolerance was accompanied by a rise in the fasting plasma NEFA level. When stimulated with 15 mmol/L of glucose, the insulin secretion was impaired in pancreatic islets from rats fed the HF/LC diet. Rats fed the HF/LC diet showed insulin resistance in vivo. The glucose-stimulated insulin secretion was inhibited in the islets following 24-h culture with palmitic acid. The 24-h infusion of palmitic acid decreased whole-body insulin sensitivity. In summary, at least 3 d on a HF/LC diet is needed to induce glucose intolerance in rats, and the impairment may be induced by decreased insulin secretion and sensitivity, which is related to the increase in the plasma NEFA level.     

限蛋白质摄入对2型糖尿病早期肾病的影响

目的 评估限蛋白质摄入对２型糖尿病肾病在肾功能和营养状况方面的影响。方法 门诊６７例早期肾病病人,按就诊顺序分为限蛋白治疗组和正常蛋白组,试验期为１年。结果 两组病人体重指数、血常规及血液生化、血糖指标、血液肾功能治疗后无显著性差异。治疗组两组间血清白蛋白有显著性差异。实验组尿白蛋白排泄率明显下降。结论 限蛋白膳食可以显著减少２型糖尿病早期肾病病人尿白蛋白排泄率,从而改善营养状况,保护肾功能。     

Endothelial dysfunction and the development of renal injury in spontaneously hypertensive rats fed a high-fat diet

Obesity and hypertension have been identified as cardiovascular risk factors that contribute to the progression of end-stage renal disease. To examine the mechanisms by which a high-fat diet and hypertension contribute to endothelial dysfunction and renal injury, 8-week-old male spontaneously hypertensive rats and Wistar rats were fed a high-fat (36% fat) or a normal-fat (7% fat) diet for 10 weeks. The high-fat diet increased body weight in Wistar and hypertensive rats by 25 and 31 g, respectively. Systolic blood pressure was higher in the hypertensive rats compared with Wistar rats; however, blood pressure was unaltered by the high-fat diet. Afferent arteriole response to acetylcholine was impaired in the high-fat groups after just 3 weeks. Renal macrophage infiltration was increased in the hypertensive high-fat group compared with others, and monocyte chemoattractant protein-1 excretion was increased in both of the high-fat-fed groups. Renal PCR arrays displayed significant increases in 2 inflammatory genes in hypertensive rats fed a normal diet, 1 gene was increased in high-fat-fed Wistar rats, whereas 12 genes were increased in high-fat-fed hypertensive rats. Urinary albumin excretion was increased in the hypertensive rats compared with the Wistar rats, which was further exacerbated by the high-fat diet. Glomerular nephrin expression was reduced and desmin was increased by the high-fat diet in the hypertensive rats. Our results indicate that endothelial dysfunction precedes renal injury in normotensive and spontaneously hypertensive rats fed a high-fat diet, and hypertension with obesity induces a powerful inflammatory response and disruption of the renal filtration barrier.     

阻断肾素-血管紧张素系统对长期高脂喂养大鼠肝脂肪变性的影响

目的 观察长期高脂喂养诱导胰岛素抵抗状态大鼠肝脏脂肪变性与肝内血管紧张素原(AGT)、解偶联蛋白2(UCP-2)和转化生长因子β1(TGFβ1)表达的关系,并通过阻断肾素-血管紧张素系统(RAS)观察是否改善肝脂肪变性,探讨其作用机制.方法 40只大鼠分正常对照组、高脂组、血管紧张素转换酶抑制剂(ACEI)干预高脂组、血管紧张素Ⅱ受体阻滞剂(ARB)干预高脂组.正常血糖高胰岛素钳夹试验评价胰岛素敏感性,免疫组化和RT-PCR检测肝脏内AGT、UCP-2和TGFβ1蛋白及mRNA的表达,并检测血清脂质水平和肝内脂肪含量.结果 正常对照组、高脂组、ACEI干预高脂组、ARB干预高脂组稳态第2小时葡萄糖输注率分别为(11.22±1.45)、(6.22±1.02)、(8.08±1.13)、(8.16±1.26)mg·kg-1·min-1.高脂组血清学指标和肝内脂肪含量均高于正常对照组(P＜0.05),ACEI干预高脂组、ARB干预高脂组与高脂组比较,肝内脂肪含量降低(P＜0.01),脂肪变和纤维化减轻,肝内UCP-2和TGFβ1表达减少(P＜0.05).结论 阻断RAS可改善胰岛素抵抗,并可能通过下调肝内UCP-2和TGFβ1的表达,对长期高脂喂养大鼠肝脏有保护作用.     

The metabolic response to a high-protein, low-carbohydrate diet in men with type 2 diabetes mellitus

We recently reported that in subjects with untreated type 2 diabetes mellitus, a 5-week diet of 20:30:50 carbohydrate-protein-fat ratio resulted in a dramatic decrease in 24-hour integrated glucose and total glycohemoglobin compared with a control diet of 55:15:30. Body weight, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and serum ketones were unchanged; insulin and nonesterified fatty acids were decreased. We now present data on other hormones and metabolites considered to be affected by dietary macronutrient changes. The test diet resulted in an elevated fasting plasma total insulin-like growth factor 1, but not growth hormone. Urinary aldosterone was unchanged; free cortisol was increased, although not statistically. Urinary pH and calcium were unchanged. Blood pressure, creatinine clearance, serum vitamin B12, folate, homocysteine, thyroid hormones, and uric acid were unchanged. Serum creatinine was modestly increased. Plasma alpha-amino nitrogen and urea nitrogen were increased. Urea production rate was increased such that a new steady state was present. The calculated urea production rate accounted for 87% of protein ingested on the control diet, but only 67% on the test diet, suggesting net nitrogen retention on the latter. The lack of negative effects, improved glucose control, and a positive nitrogen balance suggest beneficial effects for subjects with type 2 diabetes mellitus at risk for loss of lean body mass.     

Phosphate depletion with phosphate binder arrests the development of nephropathy in spontaneously hypertensive rats with non-insulin-dependent diabetes mellitus fed a high-protein diet

The protective effect of phosphate binder (PB) on nephropathy was examined in spontaneously hypertensive rats with non-insulin-dependent diabetes mellitus (NIDDM) fed a high-protein diet. The rats were treated with vehicle or streptozocin neonatally. After 14 weeks, all rats were fed a high-protein diet (50% protein content), and in half of the diabetic rats the diets were supplemented with PB. At 24 weeks, the urinary excretion rate of albumin and kidney weight increased in diabetic rats, but decreased or tended to decrease in diabetic rats treated with PB. The elevation of urinary excretion rate of N-acetyl-β-d-glucosaminidase, probably due to protein load, was also abolished with PB.     

A high-monounsaturated-fat/low-carbohydrate diet improves peripheral insulin sensitivity in non-insulin-dependent diabetic patients

It is commonly believed that high-carbohydrate (CHO) diets improve peripheral insulin sensitivity; however, this concept is based on anecdotal evidence. Furthermore, it has been demonstrated that in non-insulin-dependent diabetic patients treated with insulin, a high-monounsaturated-fat (MUFA) diet is more effective than a high-complex-CHO diet in reducing blood glucose levels. The aim of our study was to compare the effect of a high-MUFA diet and a high-CHO diet on peripheral insulin sensitivity and metabolic control in non-insulin-dependent diabetic patients. Ten non-insulin-dependent diabetic patients aged 52 +/- 8 years with a body mass index (BMI) of 26.7 +/- 3.5 kg/m2 who were being treated with diet alone (n = 5) or with diet plus glibenclamide (n = 5) were randomly assigned to a 15-day period of either a high-MUFA/low-CHO diet (CHO, 40%; fat, 40%; protein, 20%; fiber, 24g) or a low-MUFA/high-CHO diet (CHO, 60%; fat, 20%; protein, 20%; fiber, 24g) and were then crossed-over to the other diet. Diets were similar in their content of monosaccharides, disaccharides, and saturated fats, and were administered to the patients in a metabolic ward. The dosage of hypoglycemic drugs was maintained at a constant level throughout the study. With the high-MUFA/low-CHO diet, a decrease in both postprandial glucose (8.76 +/- 2.12 v 10.08 +/- 2.76 mmol/L; P < .05) and plasma insulin (195.0 +/- 86.4 v 224.4 +/- 75.6 pmol/L; P < .02) levels was observed. Furthermore, fasting plasma triglyceride levels were reduced after the high-MUFA fat/low-CHO diet (1.16 +/- 0.59 v 1.37 +/- 0.59 mmol/L; P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of a high protein diet on the evolution of diabetes in streptozotocin-induced and spontaneously diabetic “BB” wistar rats

Summary Recently, we demonstrated a reduction in the diabetogenic action of streptozotocin (STZ) in rats previously adapted to a high protein (HP) diet. These data suggested that amelioration of diabetes resulted from the combination of two effects of the HP diet: initial protection against the diabetogenic action of the drug at the time of exposure and subsequent improvement of the induced diabetic condition. The present study evaluated the effects of a HP diet on the evolution of the metabolic condition in rats with STZ-induced or spontaneous diabetes (BB Wistar rats). Two days after STZ injection, the animals were given isocaloric HP (70% protein, 8% fat) or control (66% carbohydrate, 16% protein, 8% fat) diets for 15 days. After 13 days, the STZ-treated rats fed HP diet showed an impressive decrease in severity of diabetes, as judged by rate of body weight change, plasma glucose, urine volume and glycosuria, serum and pancreatic insulin. The BB Wistar rats, already diabetic for 5 weeks before being transferred to the HP or control diet, were treated with daily injections of insulin. After 31 days on the HP diet, the BB rats showed reduced insulin requirement, reduced blood and urinary glucose levels, but no difference in body weight gain or pancreatic insulin content. The data show that short-term use of HP diets can greatly improve the diabetic condition in STZ-treated animals, but that the beneficial effects of the diet are much less marked in rats with chronic spontaneous diabetes. These data suggest that the ameliorating effect of HP diet is fully manifested only when the diabetic rats have a sufficient number of residual functioning B-cells.     

The vascular response of spontaneously hypertensive and normotensive rats with diabetes mellitus

Streptozotocin-induced diabetes caused an increase in AP and reactivity to noradrenaline in perfused caudal artery of normotensive rats (WKY). In spontaneously hypertensive rats (SHR) diabetes led to an increase in reactivity not only to noradrenaline but also to alpha 1-agonist phenylephrine; a response to endothelium-dependent agent acetylcholine was decreased. Alterations in function of the vascular endothelium may be one of the factors causing elevation of vasoconstriction in diabetes mellitus.     

高脂高糖饮食诱导建立2型糖尿病小型猪模型

目的建立2型糖尿病小型猪模型,观察其血清中胰高血糖素样肽-1（GLP-1）的变化及其与血糖、胰岛素、C肽的关系。方法将20头4月龄中国实验用小型猪[雌雄各半,体重（16．9±1．1）kg]按数字表法随机分为两组：基础饲料组（CD组）和高脂高糖组（HFSD组）,每组10头,雌雄各半。其中CD组喂食基础饲料,HFSD组喂食高脂高糖饲料,用于制作2型糖尿病小型猪模型,以空腹血糖值≥7．0mmol／L为模型制作成功。分别于实验起始起第0、3、6个月末取2组动物隔夜空腹血,测定血糖、胰岛素、C肽以及血脂;取餐后2h血,测定GLP-1。两组间数据比较采用t检验,GLP-1与其他变量的关系检验用Pearson相关分析法。结果在第6个月末HFSD组体重为（74±11）kg,CD组为（44±4）kg,组问差异有统计学意义（t=7．93,P〈0．01）;在第6个月末HFSD组空腹血糖为（7．6±1．8）mmol／L,CD组为（4．4±0．7）mmol／L,2组差异有统计学意义（t：4．32,P〈0．01）,证实糖尿病动物模型成功建立。与CD组相比,在第6个月末HFSD组TG、TC均显著升高,差异均有统计学意义[分别为（0．83±0．29）、（0．56±0．18）mmol／L和（4．0±1．0）、（2．8±0．5）mmol／L,t=2．05、7．11,均P〈0．05]。HFSD组GLP一1降低趋势明显,其水平与空腹血糖呈负相关（r=-0．81,P〈0．01）,与c肽呈正相关（r=0．73,P〈0．01）,与胰岛素无明显相关趋势（r=0．19,P〉0．01）。结论高脂高糖6个月饲养可建立较为理想的2型糖尿病小型猪模型,其表现为体重增加、血糖升高并且血清TG、TC水平升高,GLP-1水平显著下降。     

The effect of thymectomy on the development of hypertension in spontaneously hypertensive rats

We studied the effect of thymectomy on the development of hypertension in spontaneously hypertensive rats (SHR). There were no significant differences between thymectomized and sham thymectomized SHR during either the initial or chronic phase of spontaneous hypertension. Similarly, administration of anti-Thyl. 1 or anti-T sera did not influence the blood pressure in SHR during the chronic phase. The results suggest that the thymus does not play a direct role in the development and maintenance of blood pressure in SHR.     

罗格列酮对高糖高脂饮食诱导糖尿病大鼠脂肪肝的治疗作用

目的探讨罗格列酮（RSG）对2型糖尿病（T2DM）大鼠合并脂肪肝的治疗作用。方法建立T2DM合并脂肪肝的大鼠模型，以RSG进行干预治疗。18周末留取肝组织及血清，检测比较各组血糖、血脂、胰岛素、谷丙转氨酶、TNF-α、瘦素等指标及肝脏病理变化和TNF-α在肝脏的表达。结果RSG治疗组大鼠肝脏结构较糖尿病对照组明显好转，TNF-α在肝脏的表达水平降低（P〈0.05），TG、TC、瘦素水平均明显下降（P〈0.05，P〈0.01，P〈0.05）。结论RSG对实验性糖尿病大鼠合并脂肪肝具有一定的治疗作用。     

Genetics and diet as factors in development of diabetes mellitus

Diabetes mellitus developed in selected albino rats fed a high-sucrose diet. The interaction between gentic factor(s) and sucrose feeding in the rat and the application of this interaction to the problem of diabetes in the human population is discussed.     

The choriocapillaris in spontaneously diabetic rats.

During diabetes in rats, the choroid of the eye shows increased permeability to albumin, basement membrane thickening, and decreased anionic charge sites on the abluminal surfaces of the choriocapillary microvessels. In other microvascular beds, permeability differences are correlated with differences in luminal membrane microdomains as indicated by the distribution of luminal membrane anionic charge. To see whether luminal surface charge distribution or other structural features of the choroidal microvasculature become altered during diabetes, we studied spontaneously diabetic and control rats using ultrastructural tracers and morphometric techniques. Rats were injected with horseradish peroxidase and perfused with aldehydes, and then retina-choroid tissue sections were incubated with cationized ferritin, reacted to visualize peroxidase, and prepared for electron microscopic study. The most striking alterations in the diabetic rats were vascular debris and migrating cells resembling vascular cells in the choriocapillaris stroma, suggesting an increase in capillary turnover. In addition, extracellular matrix material was increased, and peroxidase uptake and ferritin binding were low in some vessels of the diabetic rats compared with the controls. Variability was large in the diabetic animals, however, and other vessels remained apparently normal.     

艾塞那肽对糖尿病大鼠肝脏组织胰岛素抵抗的影响

目的 研究胰高糖素样肽1受体激动剂艾塞那肽对高脂喂养联合小剂量链脲佐菌素诱导的糖尿病大鼠肝脏组织胰岛素抵抗的影响及其机制.方法 健康雄性6周龄SD大鼠采用随机数字法分为正常对照组（C组,n=6）、正常对照＋艾塞那肽处理组（C＋E组,n=6）、糖尿病组（D组,n=5）以及糖尿病＋艾塞那肽处理组（D＋E组,n=5）,由高脂饮食加小剂量STZ诱导成2型糖尿病后,D＋E组以及C＋E组大鼠予艾塞那肽,5μg腹部皮下注射,每天1次干预;8周后,分别测定空腹葡萄糖出现率、肝糖输出率、甘油出现率、甘油糖异生相关参数;测定外源性胰岛素持续输注状态下的肝糖输出和葡萄糖输注率.同时行透射电子显微镜观察大鼠肝脏组织超微结构改变.多组间数据比较采用单因素方差分析.结果 D＋E组大鼠空腹血糖、血浆甘油三酯、总胆固醇、低密度脂蛋白、稳态模型胰岛素抵抗指数（HOMA-IR）水平均显著低于D组,但显著高于C组及C＋E组,差异均有统计学意义（F=82.827、81.648、27.613、26.300、105.234,均P＜0.05）,ISI则显著高于D组大鼠,但仍显著低于C组及C＋E组（F=17.566,P＜0.05）.空腹状态下,D＋E组大鼠的葡萄糖出现率、甘油出现率、肝糖输出率、甘油糖异生相关参数（甘油转化为葡萄糖的百分率、来源于甘油的葡萄糖百分比、甘油糖异生速率）均显著低于D组大鼠,但仍显著高于C组及C＋E组（F=68.424、41.543、68.424、40.223、17.491、86.465,均P＜0.05）.胰岛素钳夹稳态时,D＋E组大鼠内源性肝糖输出较D组大鼠显著抑制,但仍显著高于C组及C＋E组（F=85.403,P＜0.05）;其外源性葡萄糖输注率则显著高于D组大鼠,仍显著低于C组及C＋E组（F=49.954,P＜0.05）.超微结构研究显示D＋E组大鼠的肝细胞超微结构损伤显著减轻.结论 胰高糖素样肽1受体激动剂艾塞那肽显著改善糖尿病大鼠肝脏组织超微结构损伤,进而改?