ARA290 Improves Insulin Release and Glucose Tolerance in Type 2 Diabetic Goto-Kakizaki Rats

Effects of ARA290 on glucose homeostasis were studied in type 2 diabetic Goto-Kakizaki (GK) rats. In GK rats receiving ARA290 daily for up to 4 wks, plasma glucose concentrations were lower after 3 and 4 wks, and hemoglobin A_1c (Hb A_1c) was reduced by ~20% without changes in whole body and hepatic insulin sensitivity. Glucose-stimulated insulin secretion was increased in islets from ARA290-treated rats. Additionally, in response to glucose, carbachol and KCl, islet cytoplasmic free Ca²⁺ concentrations, [Ca²⁺]_i, were higher and the frequency of [Ca²⁺]_i oscillations enhanced compared with placebo. ARA290 also improved stimulus–secretion coupling for glucose in GK rat islets, as shown by an improved glucose oxidation rate, ATP production and acutely enhanced glucose-stimulated insulin secretion. ARA290 also exerted an effect distal to the ATP-sensitive potassium (K_ATP) channel on the insulin exocytotic pathway, since the insulin response was improved following islet depolarization by KCl when K_ATP channels were kept open by diazoxide. Finally, inhibition of protein kinase A completely abolished effects of ARA290 on insulin secretion. In conclusion, ARA290 improved glucose tolerance without affecting hematocrit in diabetic GK rats. This effect appears to be due to improved β-cell glucose metabolism and [Ca²⁺]_i handling, and thereby enhanced glucose-induced insulin release.     

Effects of Dietary D-Psicose on Diurnal Variation in Plasma Glucose and Insulin Concentrations of Rats

The effects of supplemental D-psicose in the diet on diurnal variation in plasma glucose and insulin concentrations were investigated in rats. Forty-eight male Wistar rats were divided into four groups. Each group except for the control group was fed a diet of 5% D-fructose, D-psicose, or psico-rare sugar (3:1 mixture of D-fructose and D-psicose) for 8 weeks. Plasma glucose levels were lower and plasma insulin levels were higher at all times of day in the psicose and psico-rare sugar groups than in the control and fructose groups. Weight gain was significantly lower in the psicose group than in the control and fructose groups. Liver glycogen content, both before and after meals was higher in the psicose group than in the control and fructose groups. These results suggest that supplemental D-psicose can lower plasma glucose levels and reduce body fat accumulation. Hence, D-psicose might be useful in preventing postprandial hyperglycemia in diabetic patients.     

栀子水提取物对实验性2型糖尿病大鼠血糖及同型半胱氨酸水平的影响

观察栀子提取物对实验性2型糖尿病大鼠血糖、血脂及同型半胱氨酸水平的影响.采用Wistar雄性大鼠70只,随机抽取10只作为正常对照组,喂以普通维持饲料,其余60只高糖高脂饲料喂养4周后,ip链脲佐菌素(STZ)30 mg/kg建立2型糖尿病模型,7d后选取成模大鼠50只随机分为模型对照组(生理盐水)、盐酸二甲双胍对照组、栀子提取物低、中、高剂量组(0.2、0.4、0.6 g/kg),每组10只.连续ig给药4周后,观察各组大鼠血糖、血脂及同型半胱氨酸水平等变化.栀子提取物ig能降低糖尿病大鼠的血糖、甘油三酯(TG)、胆固醇(TC)、低密度脂蛋白(LDLC),同时能升高高密度脂蛋白(HDLC),降低同型半胱氨酸水平.     

Placental Transfer of Lactate,Glucose and 2-deoxyglucose in Control and Diabetic Wistar Rats

Placental transfer of lactate, glucose and 2-deoxyglucose was examined employing the in situ perfused placenta. Control and streptozotocin induced diabetic Wistar rats were infused with [U¹⁴C]-glucose and [³H]-2-deoxyglucose (2DG). The fetal side of the placenta was perfuseci with a cell free medium and glucose uptake was calculated in the adjacent fetuses. Despite the 5-fold higher maternal plasma glucose concentration in the diabetic dams the calculated fetal glucose metabolic index was not significantly different between the 2 groups. Placental blood flow was reduced in the diabetic animals compared with controls but reduction of transfer of [U¹⁴C]-glucose and [³H]-2-deoxyglucose and endogenously derived [¹⁴C]-Lactate to the fetal compartment, could not be accounted for by reduced placental blood flow alone. There was no significant net production or uptake of lactate into the perfusion medium that had perfused the fetal side of the placenta in either group. The plasma lactate levels in the fetuses adjacent to the perfused placenta were found to be higher than in the maternal plasma and significantly higher in the fetuses of the diabetic group compared with control group. In this model the in situ perfused placenta does not secrete significant quantities of lactate into the fetal compartment in either the control or diabetic group.     

Use of Glycated Hemoglobin to Assess Glycemic Control in Wistar Diabetic Fatty Rats and Zucker Fatty Rats

The Wistar Diabetic Fatty rat (WDF fafa) is a con-genic strain of the Wistar Kyoto rat. Studies using blood glucose reveal that only fatty male (not female) WDF rats spontaneously develop hyperglycemia when fed a stock diet Blood glucose values have not provided consistent results for evaluation of glycemic status in fatty male WDF rats. Zucker fatty (fafa) rats, while sharing the fa gene and the development of hyperinsulinemia and hyperlipemia, do not spontaneously become hyperglycemic. In order to examine strain differences and the effects of age on long-term average glycemic status in WDF and Zucker rats, glycated hemoglobin (GHb) was analyzed. Glycated hemoglobin was measured in male lean and obese WDF and Zucker rats at 2,3,6, and 12 months of age. Nonfasted plasma glucose was measured in male lean and obese WDF rats at 2, 3, 6, and 12 months of age and in lean and obese Zucker rats at 3, 6, and 12 months of age. Plasma insulin was measured in lean and obese WDF and Zucker rats at 3, 6, and 12 months of age. Obese WDF rats had significantly elevated GHb compared to lean controls at 3, 6, and 12 months of age. Glycated hemoglobin was substantially above the normal range (3.8-6.5%) at 3 months of age (14.1%). Glycated hemoglobin significantly declined in the obese WDF rats between 6 and 12 months of age. Nonfasted plasma glucose was significantly elevated in the obese WDF rats at 3 months (14.1 ± 2.1 mM/L) and 6 months of age (16.2 ± 2.3 mM/L) compared to lean controls. At 12 months of age there was no difference in plasma glucose between obese and lean WDF rats. Obese and lean Zucker rats had similar levels of GHb and plasma glucose at all ages. In conclusion, GHb provides more integrated data for classifying disease status of WDF rats and evaluation of potential long-term complications associated with hyperglycemia.     

Circadian and Ultradian Rhythms in Blood Glucose and Plasma Insulin of Healthy Adults

The circadian and ultradian variations of blood glucose and plasma insulin have been characterized individually and as a group phenomenon in five healthy young adults studied while adhering as closely as possible to their usual routine of sleep, activity, meal content and timing. Three complementary methods were used to analyze the data: displaying raw data as a function of time; cosinor method according to Nelson and Halberg; and time series analyses as proposed by De Prins and Malbecq. The subjects were studied in the laboratory and their life routine were controlled, but very close to that of their habitual routine. They had mainly ultradian rhythms of blood glucose (mainly about 6 hr) and circadian rhythms of immunoreactive insulin (I.R.I.). Blood glucose ultradian rhythms seem to be mainly but not exclusively mealtime dependent, while I.R.I, circadian rhythms appear to be primarily endogenous in origin. Therefore, the role played by insulin in the control of blood glucose levels seems to be programmed on a circadian basis rather than by a time independent feedback phenomenon as postulated by the conventional homeostatic hypothesis. The advantage of this chronophysiologic approach is to consider circadian rhythms of both I.R.I. and insulin effectiveness as an adaptive phenomenon able to maintain blood sugar changes in the ultradian domain of rhythms.     

Effects of Syzygium aromaticum-Derived Triterpenes on Postprandial Blood Glucose in Streptozotocin-Induced Diabetic Rats Following Carbohydrate Challenge

Purpose

Recent reports suggest that the hypoglycaemic effects of the triterpenes involve inhibition of glucose transport in the small intestine. Therefore, the effects of Syzygium spp-derived triterpenes oleanolic acid (OA) and maslinic acid (MA) were evaluated on carbohydrate hydrolyzing enzymes in STZ-induced diabetic rats and consequences on postprandial hyperglycaemia after carbohydrate loading.

Methods

We determined using Western blot analysis the expressions of α-amylase and α-glucosidase and glucose transporters SGLT1 and GLUT2 in the small intestine intestines isolated from diabetic rats treated with OA/MA for 5 weeks. In vitro assays were used to assess the inhibitory activities of OA and MA against α-amylase, α-glucosidase and sucrase.

Results

OA and MA ameliorated postprandial hyperglycemia in carbohydrate loaded diabetic rats as indicated by the significantly small glucose area under the curve (AUC) in treated diabetic animals compared with that in untreated diabetic rats. Western blotting showed that OA and MA treatment not only down-regulated the increase of SGLT1 and GLUT2 expressions in the small intestine of STZ-induced diabetic rats, but also inhibited small intestine α-amylase, sucrase and α-glucosidase activity. IC₅₀ values of OA against α-amylase (3.60 ± 0.18 mmol/L), α-glucosidase (12.40 ± 0.11 mmol/L) and sucrase (11.50 ± 0.13 mmol/L) did not significantly differ from those of OA and acarbose.

Conclusions

The results of suggest that OA and MA may be used as potential supplements for treating postprandial hyperglycemia.

Novelty of the Work

The present observations indicate that besides improving glucose homeostasis in diabetes, OA and MA suppress postprandial hyperglycaemia mediated in part via inhibition of carbohydrate hydrolysis and reduction of glucose transporters in the gastrointestinal tract. Inhibition of α-glucosidase and α-amylase can significantly decrease the postprandial hyperglycaemia after a mixed carbohydrate diet and therefore can be an important strategy in the management of postprandial blood glucose levels in NIDDM patients.     

Effects of Dietary Korean Proso-Millet Protein on Plasma Adiponectin,HDL Cholesterol,Insulin Levels,and Gene Expression in Obese Type 2 Diabetic Mice

We investigated the effect of dietary Korean proso-millet protein concentrate (PMP) on glycemic responses, plasma lipid levels, and the plasma level and gene expression of adiponectin in obese type 2 diabetic mice under normal and high-fat feeding conditions. The findings were that the feeding of PMP clearly elevated plasma high-density lipoprotein cholesterol (HDL cholesterol) and adiponectin levels and brought about effective reduction in the levels of glucose and insulin in mice under high-fat diet conditions as compared with a control diet. Gene expression study revealed that the diet up-regulated expression of adiponectin and down-regulated tumor necrosis factor-α (TNF-α). Considering the central role of adiponectin and HDL cholesterol in improving and ameliorating type 2 diabetes, obesity, and cardiovascular disease, our findings imply that PMP may have potential for therapeutic intervention in type 2 diabetes.     

Effects of Dietary Nasunin on the Serum Cholesterol Level in Rats

The effects of nasunin, a major anthocyanin in eggplant, and its aglycone, delphinidin, on the serum cholesterol conpentration were determined in rats fed with a cholesterol-enriched diet. The serum total cholesterol and HDL-cholesterol concentrations tended to be decreased and increased, respectively, by feeding nasunin and delphinidin, while the fecal excretion of both cholesterol and bile acids tended to be increased by feeding with the anthocyanins. There was no difference between the nasunin and delphinidin activity to decrease serum total cholesterol, nor to increase serum HDL-cholesterol or the fecal excretion of cholesterol and bile acids. These results suggest that the slightly lower serum total cholesterol concentration in rats fed with nasunin and delphinidin may in part be due to inhibition of the intestinal absorption of both cholesterol and bile acids by these anthocyanins, and that the delphinidin moiety of nasunin mainly contributes to this activity.     

血糖波动对2 型糖尿病大鼠心肌组织形态的影响及机制研究

目的:观察血糖波动对2型糖尿病大鼠心肌组织形态的影响并探讨其可能机制。方法:选取45只雄性Sprague-Dawley(SD)大鼠,按随机数字法分成正常对照组(CON组)和糖尿病组(DM组)。DM组给予4周高糖高脂饲料喂养后,予小剂量链脲佐菌素35 mg/Kg腹腔注射建立2型糖尿病大鼠模型。将成模大鼠按随机数字法分成糖尿病对照组(CDM组)和波动血糖组(FDM组)。FDM组大鼠每天定时皮下注射短效胰岛素并错时给予葡萄糖,建立糖尿病血糖波动模型,CON组、CDM组予等量生理盐水皮下注射。每周测血糖值2天,4次/天,动态观测各组大鼠外形、进食量、饮水量等变化。造模成功12周后取腹主动脉血测定糖化血红蛋白(Hb Alc),取大鼠心脏组织行Masson染色观察心肌纤维化水平,免疫印记法分别检测心肌组织AKT、p-AKT蛋白的表达,免疫组织化学法分析各组大鼠心肌细胞中Caspase-3蛋白的表达。结果:(1)与CON组相比,FDM组、CDM组大鼠Hb A1c、血糖变异系数(CV)水平升高,差异具有统计学意义(P0.05);与CDM组相比,FDM组Hb A1c水平差异无统计学意义(P0.05),CV值进一步升高,差异具有统计学意义(P0.05)。(2)与CON组相比,CDM组、FDM组大鼠心肌组织形心肌纤维化水平升高,差异具有统计学意义(P0.05);与CDM组相比,FDM组心肌组织心肌纤维化水平进一步升高,差异具有统计学意义(P0.05)。(3)与CON组相比,FDM组、CDM组大鼠心肌p-AKT蛋白表达水平均减少,差异具有统计学意义(P0.05);与CDM组相比,FDM组p-AKT蛋白表达水平均进一步减少,差异具有统计学意义(P0.05)。而三组大鼠心肌组织AKT蛋白表达水平差异无统计学意义(P0.05)。(4)与CON组相比,FDM组、CDM组大鼠心肌Caspase-3蛋白表达水平均升高,差异具有统计学意义(P0.05);与CDM组相比,FDM组Caspase-3蛋白表达水平进一步升高,差异具有统计学意义(P0.05)。结论:血糖波动可加重2型糖尿病大鼠的心肌纤维化,其机制可能与抑制AKT活化有关。     

蝇蛆壳聚糖对实验性糖尿病大鼠脂代谢的影响

目的测定实验糖尿病大鼠血脂,探讨蝇蛆壳聚糖改善脂代谢以降低血糖的机制。方法用全自动生化分析仪测定各组大鼠血清总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白(HDL)、低密度脂蛋白(LDL)的含量。结果经蝇蛆壳聚糖治疗后,高剂量组TC,TG含量明显低于模型对照组(P<0.01),其中TG含量与拜糖平组相比有明显差异(P<0.05)。中剂量组TC含量明显低于模型对照组(P<0.01),TG含量低于模型对照组(P<0.05)。低剂量组HDL含量最高,与模型对照组相比有显著差异(P<0.01)。结论蝇蛆壳聚糖有改善实验糖尿病大鼠血脂的作用。     

Effects of Dietary Oxidized Cholesterol on Lipid Metabolism in Differently Aged Rats

Male Sprague-Dawley rats, 4 weeks (young) or 8 months (adult) of age, were fed one of three purified diets free of or containing either 0.5% cholesterol or 0.5% oxidized cholesterol (92% oxidized cholesterol) for 3 weeks. Feeding of oxidized cholesterol caused a significant reduction of food intake, body weight gain, and relative liver weight in rats of both ages. The activity of the HMG-CoA reductase and cholesterol 7α-hydroxylase of liver microsomes, the key enzymes in cholesterol synthesis and catabolism, respectively, was lowered by oxidized cholesterol compared to the diet free of cholesterol in both ages, and the difference was significantly in the adult. On the other hand, the activity of Δ6-desaturase of liver microsomes, a key enzyme in linoleic acid metabolism to arachidonic acid, was significantly increased by oxidized cholesterol in adult rats, leading to the increase in linoleic acid desaturation index [(20:3n-6 + 20:4n-6)/18:2n-6] in liver phospholipids. Oxidized cholesterol reduced the concentration of cholesterol in serum and liver. Also, the fecal excretion of acidic steroids was lower in rats fed the oxidized cholesterol diet than in those fed the cholesterol-free diet. Thus, oxidized cholesterol significantly influenced cholesterol and fatty acid metabolism in particular in adult rats.     

Effects of Relaxation Training on Glucose Tolerance and Diabetic Control in Type II Diabetes

The present study examined the effects of progressive relaxation training and EMG biofeedback on acute glucose disposal in diabetic subjects, as measured by glucose tolerance and three other measures of diabetic metabolic control. Twenty subjects with non-insulin-using Type II diabetes took part in progressive relaxation training and EMG biofeedback in a pre-post treatment versus wait-list experimental design. Treatment effects were assessed on glucose tolerance along with three measures of diabetic control: fasting blood glucose, two-hour postprandial blood glucose, and fructosamine. Stress reduction and relaxation was assessed with two physiological measures and two subjective questionnaires. The training program produced significant reductions in stress, as measured by State Anxiety, and significant changes in physiological measures of muscle activity and skin conductance compared to the control condition. However, no changes were found in glucose tolerance (while practicing relaxation) nor in any of the three measures of general diabetic metabolic control. The major implication of this study is that relaxation training does not appear to directly improve diabetic control in mildly stressed non-insulin-using Type II diabetic patients.     

Diurnal Variation in Oral Glucose Tolerance: Blood Sugar and Plasma Insulin Levels Morning,Afternoon, and Evening

Twenty-four subjects received three oral glucose tolerance tests, in the morning, afternoon, and evening of separate days. The mean blood sugar levels in the afternoon and evening tests were similar, and they were both significantly higher than those in the morning test. Plasma immunoreactive insulin levels, however, were highest in the morning test. The pattern of insulin levels during the afternoon and evening tests resembled that described as typical of maturity-onset diabetes.     

Effects of Insulin Administration in Diabetic Rats on Food and Drink Rhythmic Schedules

In normal rats food and water intakes are associated in terms of time and quantity and their diurnal rhythms are synchronized. Intake behavior in streptozotocin-induced diabetic rats (ID) with marked polyphagia and polydipsia and in diabetic rats with continuous insulin administration (IT) has been studied. The daily percentages of food and water intakes during the dark phase were lower in IT than in control rats (C), being even lower in ID rats. However, all three groups showed circadian rhythmicity in food intake, although with less amplitude in the ID and IT animals compared to the C ones. A loss of the normal circadian rhythm of water intake was observed in the ID rats and although the insulin administration recovered circadian rhythmicity, it did not restore the temporal relations between food and water intakes. These results may indicate that the circadian pattern of water intake is more influenced by insulin than food intake. The daily pattern of this hormone may play an important role in the circadian modulation of the homeostatic mechanisms integrating both intake behaviors.     

Effects of Various Polyunsaturated Fatty Acids on Blood Cholesterol and Eicosanoids in Rats

The hypocholesterolemic efficacy of various polyunsaturated fatty acids was compared in rats given cholesterol-enriched diets with (0.004%) or without indomethacin, the cyclooxygenase inhibitor. Evening primrose oil (EPO, linoleic+ γ-linolenic), safflower oil (SFO, linoleic) or soybean oil (SBO, linoleic + α-linolenic) were added to diets at the 10% level. The serum cholesterol level of the EPO group was consistently lower than the other groups and after 3 weeks, it was significantly different from the SFO group without indomethacin and the SBO group with indomethacin. In rats fed EPO, the aorta tended to produce more prostacyclin whereas the concentration of plasma thromboxane B₂ was much lower than in rats fed SFO or SBO. The effects of indomethacin on these eicosanoids were less evident in rats fed EPO. Thus, in addition to the hypocholesterolemic action of β-linolenic acid (GLA) in preference to linoleic and possibly α-linolenic acid, GLA appears to cultivate an environment suitable for the prevention of carbiovascular disease even in the presence of excess cholesterol in the diet.     

A Comparison of the Effects of Tolazamide and Tolbutamide Upon Blood Glucose and Serum Insulin and Lipid Levels in Diabetic Subjects

The effects of tolazamide (300 mg. daily), a new oral hypoglycemic sulfonylurea, and tolbutamide on the blood glucose, serum insulin, cholesterol and triglyceride levels were compared in 14 subjects with maturity-onset diabetes of varying severity. The mean effects of the two drugs in the pharmacologically equivalent doses were the same. In particular, the mean reduction of the blood glucose level was 19% and of the serum triglyceride level was 17% with both agents. However, an individual subject might respond to one agent and not to the other; neither the blood glucose nor the serum lipid response could be predicted from the pretreatment blood glucose level or the per cent of ideal body weight.     

The Effects of Estrogen and Progesterone on the Blood Levels of Glucose,Non-Esterified Fatty Acids and Cholesterol in Ovariectomized Sheep

The effects of estrogen and progesterone on the blood levels of glucose, non-esterified fatty acids and cholesterol in ovariectomized sheep. The effects of estradiol benzoate and progesterone on blood glucose, NEFA and cholesterol were studied in ovariectomized sheep. Intramuscular injection of 2.5 mg estradiol benzoate gave biphasic changes in NEFA. After 2 hrs. NEFA was decreased, but thereafter an increase occurred and maximum levels were reached after 24 hrs. Blood glucose was significantly increased from 12 to 48 hrs. after the injection. Serum cholesterol was lowered after 24 hrs., but thereafter the level increased. Maximum values were obtained after 120 hrs. Progesterone at the same dose did not change any of the measured parameters. Simultaneous administration of estradiol benzoate and progesterone gave similar responses as estradiol benzoate alone. Blood glucose and NEFA were followed during heat in a lactating cow. Both parameters increased after ovulation. Since NEFA was increased during so long time after the injection of estradiol benzoate, the mechanism behind this effect was discussed. No lipolytic hormone has been reported to give a response of this duration. Estrogen is known to increase plasma GH, and since GH is strongly lipolytic in sheep it seemed possible that the elevated NEFA levels were caused by increased GH secretion. There is now evidence that also estrogen-induced changes in serum cholesterol are pituitary dependant. It was therefore considered possible that all the noted metabolic changes were mediated by the pituitary.     

Effect of Dexamethasone on Oral Glucose Tolerance in Healthy Adults

ObjectiveTo determine the dose-response and time course of action of a single dose of dexamethasone on plasma glucose and insulin dynamics in healthy adults.MethodsParticipants included healthy adults who met the following inclusion criteria: 18 to 65 years of age, body mass index of 18 to 25 kg/m2, no family history of diabetes mellitus, not taking any medication known to affect glucose tolerance, and nonpregnant state for female participants. Each participant underwent 3 sequential blocks of 75-g oral glucose tolerance tests (OGTTs) on days 1, 2, and 3; this sequence was repeated on 3 different occasions separated by more than 2 weeks. On the first day of each block, participants reported to the research center after a 10- to 12-hour overnight fast, and fasting baseline blood samples for glucose, insulin, and C-peptide were obtained. Baseline (0 mg) OGTT was then performed with a 75-g glucose load, and blood samples were collected at 30, 60, 90, and 120 minutes for measurements of glucose, insulin, and C-peptide. After the baseline OGTT on day 1, a single dose of either 2-, 4- or 8-mg of dexamethasone was administered orally. Twenty-four and 48 hours later, participants returned for additional OGTTs.ResultsTen healthy volunteers (4 male and 6 female) were enrolled. The effect of dexamethasone was maximal 24 hours after 8-mg dexamethasone compared with the effect observed after no dexamethasone administration. At 60 minutes during the OGTT (following 8-mg dexamethasone), blood glucose increased from 127 ± 7.1 mg/dL (6.35 ± 0.36 mmol/L) to 176 ± 19 mg/dL (8.8 ± 0.95 mmol/L), insulin increased from 49.3 ± 3.2 μIU/mL (342 ± 22 pmol/L) to 119.7 ± 10.1 μIU/mL (831 ± 70 pmol/L), and C-peptide increased from 6376 ± 510 pg/L (1913 ± 153 pmol/L) to 10 143 ± 1016 pg/L (3043 ± 305 pmol/L); the 60-minute levels returned towards baseline at 48 hours. Smaller changes were observed with 2- and 4-mg dexamethasone. Twenty-four hours after 8-mg dexamethasone, there was a 2.2- and 1.5-fold increase in homeostasis model assessment of insulin resistance and homeostasis model assessment of β cell, respectively, and a 2.5-fold decrease in the Matsuda sensitivity index.ConclusionsA single oral dose of 8-mg dexamethasone increases blood glucose, insulin, and C-peptide levels maximally at 24 hours, 1 hour following 75-g OGTT. A dexamethasone stress test might identify persons at increased risk for type 2 diabetes. (Endocr Pract. 2010:16:770-777)