Ⅱ型糖尿病神经病理性痛大鼠模型的建立

目的:建立Ⅱ型糖尿病神经病理性痛大鼠模型。方法:60只SD大鼠随机分为:A组(对照组,即普通饲料组,n=10),B组(实验组,即高脂高糖组,n=50)。A组以普通饲料喂养,8周后单次空腹腹腔注射柠檬酸缓冲液。B组高脂高糖喂养8周诱发胰岛素抵抗,继以不同剂量链脲佐菌素(streptozotocin,STZ,30 mg/kg、35 mg/kg、40 mg/kg)腹腔注射1次,于不同时间点分别测体重、血糖、胰岛素,计算胰岛素敏感性、机械缩足阈值和热缩足潜伏期的变化。结果:高脂高糖饮食8周,模型组大鼠体重明显增加,空腹胰岛素浓度升高,胰岛素敏感性下降,机械缩足阈值和热缩足潜伏期无变化,血糖未升高。注射STZ后,30 mg/kg剂量组血糖升高但不能长期维持;40 mg/kg剂量组血糖较高,死亡率高;35 mg/kg剂量组血糖中度升高且相对稳定,胰岛素浓度和胰岛素敏感性均降低,其机械缩足阈值和热缩足潜伏期均低于基础值和对照组(P<0.05)。结论:高脂高糖饲料喂养8周后联合腹腔注射STZ 35 mg/kg可以建立理想的Ⅱ型糖尿病神经病理性痛大鼠模型。     

Bromocriptine: a novel approach to the treatment of type 2 diabetes

OBJECTIVE: In vertebrates, body fat stores and insulin action are controlled by the temporal interaction of circadian neuroendocrine oscillations. Bromocriptine modulates neurotransmitter action in the brain and has been shown to improve glucose tolerance and insulin resistance in animal models of obesity and diabetes. We studied the effect of a quick-release bromocriptine formulation on glucose homeostasis and insulin sensitivity in obese type 2 diabetic subjects. RESEARCH DESIGN AND METHODS: There were 22 obese subjects with type 2 diabetes randomized to receive a quick-release formulation of bromocriptine (n = 15) or placebo (n = 7) in a 16-week double-blind study. Subjects were prescribed a weight-maintaining diet to exclude any effect of changes in body weight on the primary outcome measurements. Fasting plasma glucose concentration and HbA(1c) were measured at 2- to 4-week intervals during treatment. Body composition (underwater weighing), body fat distribution (magnetic resonance imaging), oral glucose tolerance (oral glucose tolerance test [OGTT]), insulin-mediated glucose disposal, and endogenous glucose production (2-step euglycemic insulin clamp, 40 and 160 mU x min(-1) x m(-2)) were measured before and after treatment. RESULTS: No changes in body weight or body composition occurred during the study in either placebo- or bromocriptine-treated subjects. Bromocriptine significantly reduced HbA(1c) (from 8.7 to 8.1%, P = 0.009) and fasting plasma glucose (from 190 to 172 mg/dl, P = 0.02) levels, whereas these variables increased during placebo treatment (from 8.5 to 9.1%, NS, and from 187 to 223 mg/dl, P = 0.02, respectively). The differences in HbA(1c) (delta = 1.2%, P = 0.01) and fasting glucose (delta = 54 mg/dl, P < 0.001) levels between the bromocriptine and placebo group at 16 weeks were highly significant. The mean plasma glucose concentration during OGTT was significantly reduced by bromocriptine (from 294 to 272 mg/dl, P = 0.005), whereas it increased in the placebo group. No change in glucose disposal occurred during the first step of the insulin clamp in either the bromocriptine- or placebo-treated group. During the second insulin clamp step, bromocriptine improved total glucose disposal from 6.8 to 8.4 mg x min(-1) kg(-1) fat-free mass (FFM) (P = 0.01) and nonoxidative glucose disposal from 3.3 to 4.3 mg min(-1) x kg(-1) FFM (P < 0.05), whereas both of these variables deteriorated significantly (P < or = 0.02) in the placebo group. CONCLUSIONS: Bromocriptine improves glycemic control and glucose tolerance in obese type 2 diabetic patients. Both reductions in fasting and postprandial plasma glucose levels appear to contribute to the improvement in glucose tolerance. The bromocriptine-induced improvement in glycemic control is associated with enhanced maximally stimulated insulin-mediated glucose disposal.     

Modeling disease progression and rosiglitazone intervention in type 2 diabetic Goto-Kakizaki rats

The pharmacokinetics (PK) and pharmacodynamics (PD) of rosiglitazone were studied in type 2 diabetic (T2D) Goto-Kakizaki (GK) rats that received daily doses of 0, 5, or 10 mg/kg for 23 days followed by 60 days of washout. Blood glucose, plasma insulin, and hemoglobin A1c were determined over time. Oral glucose tolerance tests were performed before and at the end of treatment and after 20 days of washout to determine insulin sensitivity and β-cell function. Rosiglitazone effectively lowered glucose by inhibiting hepatic glucose production and enhancing insulin sensitivity. The glucose-insulin inter-regulation was characterized by a feedback model: glucose and insulin have their own production (k(in)) and elimination (k(out)) rate constants, whereas glucose stimulates insulin production (k(inI)) and insulin, in turn, promotes glucose utilization (k(outG)). Animal handling and placebo treatment affected glucose turnover with k(pl) = 0.388 kg/mg/day. The PK of rosiglitazone was fitted with a one-compartment model with first-order absorption. The effect of rosiglitazone was described as inhibition of k(inG) with I(max) = 0.296 and IC(50) = 1.97 μg/ml. Rosiglitazone also stimulated glucose utilization by improving insulin sensitivity with a linear factor S(R) = 0.0796 kg/mg. In GK rats, 23 days of treatment increased body weight but did not cause hemodilution. Weight gain was characterized with body weight input (k(s)(w)) and output (k(d)(w)), and rosiglitazone inhibited k(d)(w) with ID(50) = 96.8 mg/kg. The mechanistic PK/PD model quantitatively described the glucose-insulin system and body weights under chronic rosiglitazone treatment in T2D rats.     

实验性2型糖尿病肾病大鼠模型研究

目的建立2型糖尿病肾病大鼠模型。方法雄性Wistar大鼠高糖高脂喂养8周后,腹腔注射链脲佐菌素（STZ,30mg／kg）诱导糖尿病大鼠。通过葡萄糖耐量试验和胰岛素抵抗指数判断胰岛素抵抗情况。结果在注射STZ之前,高糖高脂喂养大鼠和对照组血糖基本相似,而血清胰岛素水平明显高于对照组。在注射STZ之后,高糖高脂大鼠血糖明显增高,血清胰岛素降至对照组水平。在第10周末,2型糖尿病大鼠体重、血压、胆固醇、甘油三酯、24小时尿蛋白定量和肾重指数较对照组存在差异而肾功无明显差异。。肾脏病理显示2型糖尿病大鼠具有典型2型糖尿病肾病的病理改变。结论联合高糖高脂饮食和小剂量STZ方法建立的动物模型可以用于2型糖尿病肾病的研究。     

Effects of multiple daily insulin injections on peripheral glucose disposal in Latin Americans with type 2 diabetes mellitus.

OBJECTIVE: To evaluate the effects of insulin in multiple daily injections (MDI) on peripheral glucose disposal in Latin American patients with type 2 diabetes. METHODS AND RESULTS: Ten Latin American patients (four men and six women) with type 2 diabetes between the ages of 32 and 45 years were evaluated. All women were premenopausal and had regular menstrual periods. A hyperinsulinemic-euglycemic clamp procedure was performed at baseline and was repeated approximately 2 years after insulin monotherapy on MDI was initiated. Both genders had comparable baseline anthropometric and laboratory features, including a mean body mass index > 30 kg/m2 and percent body fat > 30%. Baseline percent hemoglobin A1c (HbA1c%) was 9.5 +/- 1.5%, and post-intervention HbA1c% was 7.0 +/- 1.2%. The peripheral glucose disposal rate at baseline was 4.5 +/- 2.2 mg/kg/min fat-free mass and at postintervention was 3.6 +/- 2.3 mg/kg/min fat-free mass. CONCLUSIONS: Despite a significant improvement in glycemic control, MDI did not seem to increase the insulin-mediated glucose disposal rate. Underlying obesity and increased percent body fat may have been the most counteracting factors on the potential improvement in insulin sensitivity expected with insulin monotherapy.     

Orally administered octacosanol improves some features of high fructose-induced metabolic syndrome in rats

We examined whether orally administered octacosanol, a long-chain aliphatic saturated alcohol, improves the features of high fructose-induced metabolic syndrome in rats. Five-week-old rats were fed a high fructose diet containing 60% fructose for 3 weeks. Then, the high fructose fed rats received a daily single oral administration of octacosanol (10 or 100 mg/kg body weight) with high fructose feeding for one week. Three- or four-week high fructose feeding increased insulin resistance, serum insulin, triglyceride, total cholesterol, free fatty acids, uric acid, and lipid peroxide concentrations, and hepatic triglyceride and cholesterol contents significantly and decreased serum high-density lipoprotein cholesterol and adiponectin concentrations significantly but did not affect blood pressure and hepatic lipid peroxide and reduced glutathione contents. Four-week high fructose feeding decreased hepatic ascorbic acid content significantly. Oral administration of octacosanol (10 or 50 mg/kg body weight) to high fructose-fed rats for the last 1-week fructose diet feeding attenuated these changes except serum insulin level and insulin resistance significantly and increased hepatic reduced glutathione content significantly. The higher dose of Oct decreased hepatic lipid peroxide content significantly. These results indicate that orally administered octacosanol improves dyslipidemia, hyperuricemia, hypoadiponectinemia, and oxidative stress associated with the features of high fructose-induced metabolic syndrome rats.     

Short-term moderate weight loss and resistance training do not affect insulin-stimulated glucose disposal in postmenopausal women.

OBJECTIVES: Moderate weight loss and exercise have been proposed as important tools in the treatment and prevention of type 2 diabetes. Therefore, we tested the hypothesis that short-term (4 weeks) moderate energy restriction (-750 kcal/day) would result in a significant increase in insulin-stimulated glucose disposal (40 mU x m(-2) x min(-1) hyperinsulinemic-euglycemic clamp) in moderately overweight postmenopausal women and that when combined with resistance training (RT) an even greater effect would be seen. RESEARCH DESIGN AND METHODS: Older women were randomly assigned to energy restriction (WLoss group; n = 9) or energy restriction plus RT (RT + WLoss group; n = 10). RESULTS: For the WLoss versus the RT + WLoss groups, changes in body weight (-3.0 +/- 0.2 kg vs. -3.2 +/- 0.3 kg), fat mass (FM) (-3.0 +/- 0.3 kg vs. -3.2 +/- 0.3 kg), and percent body fat (BF) (-2.1 +/- 0.4 vs. -2.4 +/- 0.3%) were not different between groups. Muscle mass (group-by-time interaction, P = 0.04) was preserved in RT + WLoss (0.40 +/- 0.40 kg) and reduced in WLoss (-0.64 +/- 0.18 kg). There were no changes in fat-free mass (FFM) and waist-to-hip ratio in either group. Whole body glucose disposal (WLoss 6.14 +/- 0.57 vs. 6.03 +/- 0.53, RT + WLoss 5.85 +/- 0.60 vs. 6.09 +/- 0.56 mg/kg of FFM/min) did not change in either group. CONCLUSIONS: The results of this study demonstrate that short-term energy restriction resulting in moderate decreases in body weight (4.0 +/- 0.3%) and FM (8.2 +/- 0.7%) did not improve insulin-stimulated glucose disposal. The addition of RT to the hypoenergetic diet preserved muscle mass but provided no synergistic effect on insulin action. These results suggest that a greater change in body weight or FM may be necessary to observe a significant improvement in insulin action.     

Comparative influence of propranolol and verapamil on glycemic control and histamine sensitivity associated with L-thyroxine-induced hyperthyroidism - an experimental study

The present investigation was undertaken to study the comparative effectiveness of beta-adrenergic antagonist propranolol and calcium channel blocker verapamil on L-thyroxine-induced alteration on glycemic control and histamine sensitivity on rats and guinea pigs, respectively. Injection of L-thyroxine sodium every alternate day for 3 weeks in guinea pigs (75 microg/kg, i.p.) and rats (75 mg/kg, s.c.) produced a condition similar to thyrotoxicosis. Verapamil and propranolol administered daily in the third week along with L-thyroxine to two separate groups of hyperthyroid animals reversed thyroxine-induced loss in body weight, reduction in serum TSH levels, and rise in body temperature. Effect on glucose metabolism and insulin sensitivity was studied on rats. Compared to normal rats, L-thyroxine-treated animals showed a state of hyperglycemia, hyperinsulinemia, impaired glucose tolerance, and insulin resistance. Propranolol (10 mg/kg, i.p.) treatment significantly decreased fasting serum glucose levels without affecting serum insulin levels, AUC glucose, and K(ITT) values. Treatment with verapamil (5 mg/kg, i.p.) significantly reduced fasting serum glucose and insulin levels, AUC glucose, and significantly increased K(ITT) values. Effect of propranolol (15 mg/kg, orally) and verapamil (20 mg/kg, orally) treatment on histamine sensitivity was studied on L-thyroxine-treated guinea pigs. Compared to normal guinea pigs, L-thyroxine-treated guinea pigs showed an increased sensitivity to histamine-induced asphyxia. Verapamil treatment reversed this increased histamine sensitivity while propranolol aggravated it. In conclusion, compared to propranolol, verapamil has advantageous effects on glucose metabolism, insulin and histamine sensitivity and could therefore be a valuable addition as an adjunctive therapy option currently available for thyrotoxicosis associated with diabetes and/or anaphylaxis.     

Effects of pioglitazone versus diet and exercise on metabolic health and fat distribution in upper body obesity

OBJECTIVE: Insulin resistance is associated with visceral adiposity, and interventions that reduce this depot, e.g., diet and exercise, improve insulin resistance. Thiazolidinediones (TZDs) also improve insulin action but paradoxically increase total fat mass, perhaps through remodeling (recruitment of smaller fat cells) and redistribution of adipose tissue. We assessed the effects of pioglitazone versus diet and exercise on fat distribution and the relationship between fat distribution and insulin sensitivity in upper body obesity. RESEARCH DESIGN AND METHODS: Thirty-nine upper body obese, insulin-resistant, nondiabetic men and premenopausal women were randomly assigned to receive either 30 mg/day pioglitazone or a diet and exercise program for 20 weeks. Before and after the intervention, insulin sensitivity, body composition, body fat distribution (waist-to-hip ratio [WHR], computed tomography abdomen, and dual-energy X-ray absorptiometry), and abdominal and femoral fat cell size were assessed. RESULTS: Diet and exercise resulted in an 11.8 +/- 1.1 kg weight loss. Both diet and exercise and pioglitazone improved insulin sensitivity, but only the former was associated with loss of intra-abdominal fat. Pioglitazone increased total body fat, which preferentially accumulated in the lower body depot in both men and women. WHRs decreased in both groups. Abdominal fat cell size decreased (P = 0.06) after diet and exercise. No statistically significant changes in fat cell size were observed in pioglitazone-treated volunteers. CONCLUSIONS: In nondiabetic upper body obese subjects, increasing insulin sensitivity via diet and exercise accompanies reductions in visceral fat. Pioglitazone treatment also improves insulin sensitivity and lowers WHR, but this is due to a selective increase in lower body fat. This confirms a site-specific responsiveness of adipose tissue to TZD and suggests that improvements in insulin sensitivity by pioglitazone are achieved independent of changes in intra-abdominal fat.     

Altered aortic prostaglandin synthesis in a mild form of diabetes and the influence of dietary cholesterol

Extreme hyperglycemia (350 mg/dl) in rats results from streptozocin injection (50 mg/kg) and leads to a reduced aortic capacity for prostacyclin synthesis. Other complications such as hyperlipemia and alterations in body weight gain (loss or no gain) that might be responsible for the altered aortic prostacyclin synthesis occur concurrently. We injected neonatal rats (2 days of age) with intraperitoneal streptozocin to induce chronic mild diabetes (mean plasma glucose, 241 mg/dl) characterized in adult rats by normal body weight gain, normolipemia, and a physical appearance virtually indistinguishable from controls. Plasma insulin levels were reduced in rats with mild diabetes rats to 66% of control levels. A group of control and diabetic rats were given a 0.5% cholesterol diet for 7 weeks to induce hyperlipemia. Rats with diabetes and control rats given the cholesterol diet had elevated plasma insulin levels of 32% and 51%, respectively, and no alteration in plasma glucose levels (compared with respective controls), suggesting a state of insulin resistance. Aortic synthesis of 6-keto-PGF1 alpha from endogenous arachidonic acid was reduced in rats with mild diabetes and normolipemia or hyperlipemia. In contrast, the aortic conversion of exogenous arachidonic acid to 6-keto-PGF1 alpha was reduced only in rats with mild diabetes and hyperlipemia. Our results demonstrate that: (1) aortic prostacyclin synthesis is reduced in mild diabetes in the absence of alteration in plasma lipid levels and body weight gain; (2) aortic prostacyclin synthesis from endogenous arachidonic acid is more sensitive to diabetes than synthesis from exogenous arachidonic acid; (3) dietary cholesterol induces a state similar to insulin resistance and interacts with mild diabetes, resulting in reduced aortic prostacyclin synthesis from exogenous arachidonic acid.     

非诺贝特对高脂饮食诱导的胰岛素抵抗大鼠的影响

目的观察非诺贝特对胰岛素抵抗大鼠（insulin resistance,IR）糖脂代谢和血压的影响,探讨非诺贝特改善IR的机制。方法高脂饮食喂养Wistar大鼠6周后再给予非诺贝特4周,测定体重、附睾脂肪重量、FPG、FINS、FFA和血脂;高胰岛素．正常葡萄糖钳夹技术评价胰岛素敏感性;经颈动脉测量血压。结果非诺贝特治疗后IR大鼠的体重、附睾脂肪重量、FINS、TG、FFA降低（P〈0．01或P〈0．05）,HDL-C和胰岛素敏感性显著增加（P〈0．01）,血压水平也下降明显（SBP和DBP分别下降了19mmHg和21mmHg）,但与HF组比较无统计学差异（P〉0．05）。结论非诺贝特可以明显减轻体重和内脏脂肪重量,改善脂代谢紊乱,提高胰岛素敏感性,并可能降低血压。     

Effects of bis(alpha-furancarboxylato)oxovanadium(IV) on non-diabetic and streptozotocin-diabetic rats

BACKGROUND: Bis(alpha-furancarboxylato)oxovanadium(IV) (BFOV), a new orally active anti-diabetic vanadium complex with organic agent, has been synthesized and characterized. The current study examined the stability in aqueous solution and effects of the complex on carbohydrate and lipid metabolism in non-diabetic and streptozotocin-induced diabetic rats. METHODS: Diabetic rats were induced by a single dose injection of streptozotocin (STZ, 50 mg/kg body weight, i.p.). The rats were randomly divided into non-diabetic (control, CON), diabetic (DM) and BFOV (0.2 mmol/kg body weight)-treated, diabetic-BFOV (0.1, 0.2 and 0.4 mmol/kg body weight) groups. All substances were given intragastrically to non-diabetic and STZ-induced diabetic rats for 4 weeks. Blood glucose concentration was monitored during administration and, at the end of experiment glycosylated hemoglobin, serum insulin, lipid concentrations and glycogen content were observed. RESULTS: Administration of BFOV to STZ-diabetic rats dose-dependently reduced blood glucose concentration when compared to diabetic rats (P<0.01), but it did not influence blood glucose in non-diabetic rats. Serum insulin concentrations were not increased in the BFOV-treated diabetic groups and, in contrast, significantly lowered in the 0.2 mmol/kg body weight BFOV-treated non-diabetic group at the end of experiment. Moreover, BFOV markedly reduced glycosylated hemoglobin concentration and improved dyslipidemia in STZ-diabetic rats, in a dose-dependent manner (P<0.05, P<0.01), but had no significant effect on non-diabetic rats. CONCLUSION: The organic vanadium complex was found to effectively attenuate diabetic alterations in STZ-diabetic rats.     

Experimental diabetes treated with trigonelline: effect on β cell and pancreatic oxidative parameters

Oxidative stress in diabetes coexists with a reduction in the antioxidant status, which can further increase the deleterious effects of free radicals. Trigonelline is the major component of Mirabilis jalapa L., which has been used to treat diabetes in China. The present study was designed to evaluate the beneficial effects of trigonelline against hyperglycemia, hyperlipidemia, β cell damage and antioxidant of pancreas in diabetic rats. Diabetic rats were induced by intraperitoneal injection 35 mg/kg streptozotocin and a high‐carbohydrate/high‐fat diet. Rats were divided into four groups: normal control, diabetic control, trigonelline‐treated diabetic, and glibenclamide‐treated diabetic. After 4‐week treatment, blood glucose, serum insulin, total cholesterol (TC), and triglyceride (TG) levels, insulin content in pancreas, and oxidative stress parameters in pancreatic homogenate were assayed. Pancreas was examined by hematoxylin/eosin staining. Trigonelline significantly decreased blood glucose, TC, and TG levels of diabetic rats. Pancreas‐to‐body weight ratio, insulin level, insulin sensitivity index, insulin content in pancreas, malonaldehyde and nitric oxide contents, and superoxide dismutase, catalase, glutathione and inducible nitric oxide synthase activities were altered in diabetic rats, and were near control levels treated with trigonelline. These findings suggest that trigonelline has beneficial effect for diabetes through decreasing blood glucose and lipid levels, increasing insulin sensitivity index and insulin content, up‐regulating antioxidant enzyme activity and decreasing lipid peroxidation.     

Acute and chronic effects of the incretin enhancer vildagliptin in insulin-resistant rats

The enzyme dipeptidyl peptidase-IV (DPP-4) inactivates the incretin hormone glucagon-like peptide-1 (GLP-1). Because GLP-1 has therapeutic effects in patients with type 2 diabetes, but its potential is limited by a short half-life, DPP-4 inhibition is a promising approach to diabetes treatment. This study examined acute (single dose) and chronic (once-a-day dosing for 21 days) effects of the DPP-4 inhibitor vildagliptin (0.03-10 mg/kg) on plasma DPP-4 activity, intact GLP-1, glucose, and insulin after an oral glucose load in insulin-resistant Zucker fatty rats and acute effects in mildly insulin-resistant high-fat-fed normal rats. A single oral dose of vildagliptin in Zucker rats produced a rapid and dose-related inhibition of DPP-4: the minimum effective dose (MED) was 0.3 mg/kg. Glucose-induced increases of intact GLP-1 were greatly but similarly enhanced by vildagliptin at doses > or =0.3 mg/kg. Postload glucose excursions decreased, and the insulinogenic index (Deltainsulin/Deltaglucose at 10 min) increased, with an MED of 0.3 mg/kg and a maximally effective dose of 3 mg/kg. The effects of vildagliptin after chronic treatment were nearly identical to those of acute administration, and vildagliptin had no effect on body weight. In fat-fed normal rats, vildagliptin (3 mg/kg) also decreased postload glucose excursions and increased the insulinogenic index, but these effects were smaller than those in Zucker rats. Thus, vildagliptin is an orally effective incretin enhancer with antihyperglycemic activity in insulin-resistant rats and exhibits no tachyphylaxis. GLP-1-mediated augmentation of glucose-induced insulin release seems to make the major contribution to the antidiabetic properties of vildagliptin.     

Improvement of insulin-induced glucose disposal in obese patients with NIDDM after 1-wk treatment with d-fenfluramine

OBJECTIVE: To study the short-term effects of the serotoninergic anorectic drug d-fenfluramine on insulin-induced glucose disposal. RESEARCH DESIGN AND METHODS: A randomized double-blind placebo-controlled crossover trial with 1-wk treatment periods (2 x 15 mg/day d-fenfluramine) was conducted. Twenty obese subjects, 10 with normal oral glucose tolerance and 10 with non-insulin-dependent diabetes mellitus (NIDDM), were all treated with a weight-maintaining diet. Euglycemic-hyperinsulinemic glucose clamps with measurement of glucose kinetics with D-[3-3H]glucose were performed at either two (patients without NIDDM, 0.05 and 0.10 U.kg-1.h-1) or three (patients with NIDDM, 0.05, 0.10, and 0.50 U.kg-1.h-1) insulin delivery rates. RESULTS: In the nondiabetic subjects, no significant changes in any metabolic or hormonal parameter were measured in the basal state or during the clamp despite a slight reduction in body weight (-1.2 +/- 0.5 kg, P less than 0.05). In the diabetic patients, no significant changes in body weight or basal plasma insulin levels were observed, but fasting blood glucose levels (8.0 +/- 0.8 vs. 9.4 +/- 1.1 mM, P less than 0.005) and plasma free fatty acid concentrations (1150 +/- 227 vs. 1640 +/- 184 microM, P less than 0.05) were significantly reduced after d-fenfluramine compared with placebo. During the clamp, insulin metabolic clearance rate (MCR) was similar after both placebo and d-fenfluramine; endogenous (hepatic) glucose production was similarly and almost completely suppressed, whereas glucose disposal was remarkably enhanced after d-fenfluramine (average increase of glucose MCR 35 +/- 12%, P less than 0.02). CONCLUSIONS: Whatever the mechanism(s) involved, a 1-wk treatment with d-fenfluramine induces better blood glucose control and improves insulin sensitivity in obese patients with NIDDM independent of significant weight reduction; this last effect is not present in obese subjects with normal oral glucose tolerance.     

Magnesium deficiency induces joint cartilage lesions in juvenile rats which are identical to quinolone-induced arthropathy.

Quinolones accumulate in cartilage, and because they form chelate complexes with divalent cations, they possess the potential to induce a deficiency of functionally available magnesium. To test the hypothesis that quinolone-induced arthropathy is caused (or aggravated) by magnesium deficiency in cartilage, we induced magnesium deficiency by feeding juvenile rats a magnesium-deficient diet for 9 days and treated the rats with single oral doses of ofloxacin (0, 100, 300, 600, or 1,200 mg/kg of body weight) during this period. Additional groups of juvenile rats on a normal diet were treated with ofloxacin correspondingly. Typical cartilage lesions (e.g., swollen matrix, cleft formation) were found in knee joints of all magnesium-deficient rats, including those without ofloxacin treatment. Lesions in these groups were not distinguishable from lesions induced by a single dose of 600 mg of ofloxacin per kg of body weight or higher in rats on a normal diet. Ofloxacin levels in plasma after 600 mg/kg of body weight were approximately 10-fold higher than those in humans during therapy with this quinolone. Lesions in rats treated with ofloxacin plus magnesium deficiency were more pronounced than those in rats with normal magnesium concentrations. After intake of a magnesium-deficient diet for 9 days, the magnesium concentration in serum (mean +/- standard deviation) was 0.18 +/- 0.05 mmol/liter (control on normal diet, 0.82 +/- 0.10 mmol/liter). Magnesium concentrations in bone (femur) and cartilage (processus xiphoideus) samples were 64.7 +/- 10.5 and 14.3 +/- 3.9 mmol/kg of dry weight, respectively, which corresponded to approximately 50% of the concentrations measured in controls on a normal diet. It was concluded that quinolone-induced arthropathy is probably caused by a deficit of available magnesium in joint cartilage due to the formation of quinolone-magnesium chelate complexes. If juvenile patients must be treated with quinolones for serious infections, it seems prudent to ensure that these patients do not have a disturbed magnesium balance.     

Patterns of glucose and lipid abnormalities in black NIDDM subjects.

OBJECTIVE: We had previously shown two variants among black non-insulin-dependent diabetic (NIDDM) subjects in a normoglycemic remission: one with insulin resistance and the other with normal insulin sensitivity. This study examined whether these two variants exist in the ordinary hyperglycemic black NIDDM population. Research Design and Methods: Fifty-two black NIDDM subjects were assessed for insulin-stimulated glucose disposal (euglycemic clamp), glycemic control (fasting plasma glucose and HbA1c), and fasting lipid profiles. RESULTS: The distribution of glucose disposal in 30 black NIDDM subjects (body mass index; BMI less than 30 kg/m2) was bimodal, which indicated two populations. Eighteen of 30 subjects (BMI 26.4 +/- 0.5 kg/m2) had insulin resistance (glucose disposal 3.21 +/- 0.24 mg.kg-1.min-1). Twelve of 30 subjects (BMI 24.83 +/- 1.1 kg/m2) had normal insulin sensitivity (glucose disposal 7.19 +/- 0.46 mg.kg-1.min-1). Twenty-one of the remaining 22 subjects (BMI 33.4 +/- 0.7 kg/m2) were insulin resistant (glucose disposal 2.88 +/- 0.21 mg.kg-1.min-1). Fasting serum triglyceride levels were lowest in the insulin-sensitive population (0.91 +/- 0.07 mM) and different from the insulin-resistant population, BMI less than 30 and greater than 30 kg/m2, (1.20 +/- 0.10 mM, P less than 0.05 and 1.42 +/- 0.17 mM, P less than 0.025, respectively). Fasting serum low-density lipoprotein cholesterol levels were not significantly different among the groups, although it did increase with insulin resistance and increasing obesity. Total serum cholesterol levels and glycemic control were similar for all three groups. Serum high-density lipoprotein cholesterol levels were higher in women compared with men. CONCLUSIONS: In the hyperglycemic black NIDDM population, two variants exist: one with insulin resistance and one with normal insulin sensitivity. This insulin-sensitive variant represents 40% of subjects with a BMI less than 30 kg/m2. Moreover, the insulin-sensitive group has a lower risk profile for cardiovascular disease.     

一日三餐高脂低碳水化合物摄入对健康成人糖耐量的影响

目的观察葡萄糖耐量（OGTT）前1天高脂低碳水化合物撮入（热量相同但碳水化合物撮入减少,脂肪撮入增加）对健康成人糖耐量的影响,从而进一步确定是否OGTT前1天高脂低碳水化合物（HF）撮入导致糖耐量减低（IGT）的误诊。方法30例男性健康成人随机分为两组（HF组和对照组）进行交叉试验;分别于OGTT前1天早、中、晚餐时撮入热量相同的HF或对照配餐;次日清晨行75g OGTT;分别测定血糖、胰岛素、游离脂肪酸、甘油三酯厦胆固醇浓度;2次OGTT间隔1周。结果OGTT前1天HF使糖负荷后30、60、120分钟血糖分别升高33％、51％厦42％,胰岛素分泌指数（△I／△G）降低50％,空腹血浆游离脂肪酸（FFA）浓度上升100％,使30％健康成人被误诊为IGT。结论即使总热量撮入相同,OGTT前1天HF引起健康成人空腹血浆游离脂肪酸水平升高,抑制早期胰岛素分泌,引起糖负荷后血糖的升高,导致IGT的误诊。     

Antihyperglycemic effect of diosmin on hepatic key enzymes of carbohydrate metabolism in streptozotocin-nicotinamide-induced diabetic rats

The purpose of this study was to investigate the effect of diosmin on hepatic key enzymes of carbohydrate metabolism in streptozotocin-nicotinamide-induced diabetic rats. Diosmin was administered to streptozotocin-induced (45 mg/kg b.w) diabetic rats at different doses (25, 50, 100 mg/kg b.w) for 45 days to assess its effect on fasting plasma glucose, insulin, glycosylated hemoglobin, hemoglobin and carbohydrate metabolic enzymes, it was found that plasma glucose was significantly reduced in a dose-dependent manner when compared to the diabetic control. In addition, oral administration of diosmin (100 mg/kg b.w) significantly decreased glycosylated hemoglobin and increased hemoglobin and plasma insulin. The activities of the hepatic key enzymes such as hexokinase and glucose-6-phosphate dehydrogenase were significantly increased whereas, glucose-6-phosphatase and fructose-1,6-bisphosphatase were significantly decreased. Furthermore, protection against body weight loss of diabetic animals was also observed. These results showed that diosmin has potential antihyperglycemic activity in streptozotocin-nicotinamide-induced diabetic rats.