Metabolism of oral glucose in pancreas transplant recipients with normal and impaired glucose tolerance

To gain insight into the pathophysiology of impaired glucose tolerance in pancreas transplantation, glucose kinetics and insulin secretion were assessed after an oral glucose load in four combined pancreas-kidney recipients with impaired glucose tolerance (IPx), in five combined pancreas-kidney recipients with normal glucose tolerance, in six nondiabetic kidney transplant recipients, and in eight normal subjects employing a dual isotope technique, beta-Cell function was evaluated by calculating prehepatic insulin secretion rates, which subsequently were correlated to the ambient glucose concentrations to obtain an index of beta-cell responsiveness. Oxidative and nonoxidative glucose metabolism were assessed by indirect calorimetry. Basal insulin secretion rates, the glucose-stimulated early insulin secretion rates, as well as beta-cell responsiveness were markedly reduced in IPx than in the glucose-tolerant transplant subjects. Total systemic glucose appearance was similar in the groups with apparently comparable inhibition of systemic glucose release and increase in exogenous glucose appearance. The hyperglycemic response in IPx was due to a significant reduction in the glucose disappearance rates during the first 2 h after glucose ingestion. Nonoxidative glucose metabolism increased significantly less in IPx than in glucose-tolerant groups. Glucagon secretion was less suppressed in the early part of the study in IPx, which may have contributed to the excessive hyperglycemia. In conclusion, IPx after pancreas transplantation was characterized by 1) impaired early insulin secretion, 2) reduced beta-cell responsiveness, 3) reduced glucose uptake, 4) impaired nonoxidative glucose metabolism, and 5) impaired early inhibition of glucagon secretion.     

Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor isoleucine thiazolidide

The hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP)-1 act on the pancreas to potentiate glucose-induced insulin secretion (enteroinsular axis). These hormones (incretins) are rapidly hydrolyzed by the circulating enzyme dipeptidyl peptidase IV (DP IV) into biologically inactive NH2-terminally truncated fragments. This study describes the effect of inhibiting endogenous DP IV with a specific DP IV inhibitor, isoleucine thiazolidide (Ile-thiazolidide), on glucose tolerance and insulin secretion in the obese Zucker rat. In initial studies, the specificity of Ile-thiazolidide as an inhibitor of incretin degradation was determined using matrix-assisted laser desorption/ionization-time of flight mass spectrometry. These results showed that inhibiting DP IV activity with Ile-thiazolidide blocked the formation of NH2-terminally truncated GIP and GLP-1. Oral administration of Ile-thiazolidide resulted in rapid inhibition of circulating DP IV levels by 65% in obese and lean Zucker rats. Suppression of DP IV levels enhanced insulin secretion in both phenotypes with the most dramatic effect occurring in obese animals (150% increase in integrated insulin response vs. 27% increase in lean animals). Ile-thiazolidide treatment improved glucose tolerance in both phenotypes and restored glucose tolerance to near-normal levels in obese animals. This was attributed to the glucose-lowering actions of increasing the circulating half-lives of the endogenously released incretins GIP and, particularly, GLP-1. This study suggests that drug manipulation of plasma incretin activity by inhibiting the enzyme DP IV is a valid therapeutic approach for lowering glucose levels in NIDDM and other disorders involving glucose intolerance.     

Treatment with the oral antidiabetic agent troglitazone improves beta cell responses to glucose in subjects with impaired glucose tolerance

Impaired glucose tolerance (IGT) is associated with defects in both insulin secretion and action and carries a high risk for conversion to non-insulin-dependent diabetes mellitus (NIDDM). Troglitazone, an insulin sensitizing agent, reduces glucose concentrations in subjects with NIDDM and IGT but is not known to affect insulin secretion. We sought to determine the role of beta cell function in mediating improved glucose tolerance. Obese subjects with IGT received 12 wk of either 400 mg daily of troglitazone (n = 14) or placebo (n = 7) in a randomized, double-blind design. Study measures at baseline and after treatment were glucose and insulin responses to a 75-g oral glucose tolerance test, insulin sensitivity index (SI) assessed by a frequently sampled intravenous glucose tolerance test, insulin secretion rates during a graded glucose infusion, and beta cell glucose-sensing ability during an oscillatory glucose infusion. Troglitazone reduced integrated glucose and insulin responses to oral glucose by 10% (P = 0.03) and 39% (P = 0.003), respectively. SI increased from 1.3+/-0.3 to 2.6+/-0.4 x 10(-)5min-1pM-1 (P = 0.005). Average insulin secretion rates adjusted for SI over the glucose interval 5-11 mmol/liter were increased by 52% (P = 0.02), and the ability of the beta cell to entrain to an exogenous oscillatory glucose infusion, as evaluated by analysis of spectral power, was improved by 49% (P = 0.04). No significant changes in these parameters were demonstrated in the placebo group. In addition to increasing insulin sensitivity, we demonstrate that troglitazone improves the reduced beta cell response to glucose characteristic of subjects with IGT. This appears to be an important factor in the observed improvement in glucose tolerance.     

Prevalence of retinopathy in people with diabetes, impaired glucose tolerance, and normal glucose tolerance

OBJECTIVE: Recently, an international expert committee published new revised criteria for diagnosing diabetes. According to the new criteria, the 2-h glucose level for diabetes in the oral glucose tolerance test (OGTT) is the same as in the previous World Health Organization criteria, but the cut point for the fasting blood glucose level has been lowered to be equivalent to the 2-h OGTT level. Measurement of the fasting blood glucose level is preferred to the 2-h OGTT glucose level. The ability of the new cut point for fasting blood glucose to discriminate between those at a high and a low risk for retinopathy was tested in a population-based study RESEARCH DESIGN AND METHODS: The population consisted of all the 1,008 subjects (456 men) born in 1935 and living in a Finnish city A screening for type 2 diabetes was carried out in the first phase. All participants who were not on antidiabetic medication were invited for an OGTT in the second phase. A fasting blood glucose value was measured from the diabetic subjects on antidiabetic medication. In addition, measurements of serum cholesterol, HDL cholesterol, and triglycerides were made, and fundus photographs were taken. Altogether, 831 subjects (368 men) (82%) participated and constitute the eligible study population for the present analyses. Fundus photographs were available for 790 subjects (347 men) (95%). RESULTS: There were 28 subjects (3.5%) who had mild retinopathic changes in the fundus photographs. Retinopathic changes were associated with higher fasting blood glucose levels, but not with any of the other background factors. The prevalence of retinopathy was 10.2% (95% CI 4.8-18.5) in subjects with a fasting blood glucose of > or =6.1 mmol/l, while it was 2.6% (1.5-4.0) in those with a lower fasting blood glucose level. In the former group, a majority (seven of nine) of the subjects with retinopathy were previously diagnosed diabetic patients. Some cases of retinopathy were found regardless the level of glycemia, and measurement of the 2-h OGTT glucose levels did not increase information. CONCLUSIONS: The results of this population study give support to the use of fasting blood glucose levels in diagnosing type 2 diabetes. The lower limit of the highest decile of the fasting glucose level was 6.1 mmol/l, and it discriminated subjects at a high risk for retinopathy from those at a low risk. Because of the limited number of subjects with retinopathy in this study, the level of hyperglycemia associated with retinopathy cannot be estimated accurately.     

Modulation of renal kallikrein production by dietary protein in streptozotocin-induced diabetic rats

Renal kallikrein levels and excretion rates are increased in insulin-treated diabetic rats with hyperfiltration, and inhibition of kallikrein or blockade of kinin receptors reduces GFR and RPF. In contrast, insulin-deprived severely (SD) diabetic rats that display renal vasoconstriction show reduced levels and excretion rates of renal kallikrein. In these two models, dietary protein manipulation was utilized to study further the relationships between renal kallikrein and renal hemodynamic regulation. Insulin-deprived SD and insulin-treated moderately diabetic (MD) rats were fed a low (9%), normal (25%), and a high (50%) protein diet. In SD rats fed the 50% protein diet, GFR, RPF, and kallikrein excretion rate were increased compared with SD rats fed the 25% protein diet (GFR, 2.66 +/- 0.16 versus 1.74 +/- 0.30 mL/min; RPF, 7.78 +/- 0.58 versus 5.14 +/- 1.03 mL/min; total kallikrein, 248 +/- 24 versus 120 +/- 30 micrograms/24 h, SD 50% versus SD 25%, respectively; P < 0.005). In MD rats fed the 9% protein diet, GFR, RPF, and kallikrein excretion rate were significantly reduced compared with MD 25% protein-fed rats (GFR, 1.54 +/- 0.07 versus 1.95 +/- 0.09 mL/min; RPF, 5.58 +/- 0.35 versus 7.81 +/- 0.35 mL/min; total kallikrein, 119 +/- 8.3 versus 219 +/- 15 micrograms/24 h, MD 9% versus MD 25%, respectively; P < 0.005). Protein restriction in normal nondiabetic rats resulted in a twofold decrease in kallikrein mRNA levels. These findings suggest that the renal hemodynamic response to dietary protein manipulation in diabetic rats could be mediated via changes in renal kallikrein-kinin system activity.     

Incidence of diabetes mellitus in women following impaired glucose tolerance in pregnancy is lower than following impaired glucose tolerance in the non-pregnant state

Impaired glucose tolerance (IGT), which is asymptomatic and requires a glucose tolerance test for detection, is a well-known risk factor for diabetes mellitus. Outside the research setting it is rarely identified in people who lack specific risk factors for diabetes except during pregnancy, at which time screening with an oral glucose challenge is a routine procedure. A 75-g oral glucose tolerance test was performed during the latter part of pregnancy or during a routine epidemiology survey in 15-39-year-old Pima Indian women with no history of abnormal glucose tolerance. Those with IGT by World Health Organization criteria were included in this study. Diabetes incidence in women was compared between those whose IGT was first detected during pregnancy and those who were not pregnant when IGT was first recognized. Seventeen of 73 pregnant women and 114 of 244 non-pregnant women developed diabetes within 10 years. When controlled for plasma glucose concentration, age, body mass index, parity and duration of follow-up, those who were not pregnant were at higher risk of developing diabetes than those who were pregnant (hazard rate ratio = 1.71, 95% confidence interval = 1.01-2.91). Previous studies had reported that women with IGT during pregnancy are at higher risk of diabetes than women with normal glucose tolerance. This study suggests that women with IGT during pregnancy are at lower risk than non-pregnant women with a similar plasma glucose concentration who, in the clinical setting, are likely to remain unrecognized.     

Dietary conjugated linoleic acid normalizes impaired glucose tolerance in the Zucker diabetic fatty fa/fa rat

Conjugated linoleic acid (CLA) is a naturally occurring fatty acid which has anti-carcinogenic and anti-atherogenic properties. CLA activates PPAR alpha in liver, and shares functional similarities to ligands of PPAR gamma, the thiazolidinediones, which are potent insulin sensitizers. We provide the first evidence that CLA is able to normalize impaired glucose tolerance and improve hyperinsulinemia in the pre-diabetic ZDF rat. Additionally, dietary CLA increased steady state levels of aP2 mRNA in adipose tissue of fatty ZDF rats compared to controls, consistent with activation of PPAR gamma. The insulin sensitizing effects of CLA are due, at least in part, to activation of PPAR gamma since increasing levels of CLA induced a dose-dependent transactivation of PPAR gamma in CV-1 cells cotransfected with PPAR gamma and PPRE X 3-luciferase reporter construct. CLA effects on glucose tolerance and glucose homeostasis indicate that dietary CLA may prove to be an important therapy for the prevention and treatment of NIDDM.     

Endothelial dysfunction and metabolic control in streptozotocin-induced diabetic rats

1. The aim of this work was to study the influence of the metabolic control, estimated by the levels of glycosylated haemoglobin in total blood samples (HbA1c), in developing vascular endothelial dysfunction in streptozotocin-induced diabetic rats. Four groups of animals with different levels of insulin treatment were established, by determining HbA1c values in 5.5 to 7.4%, 7.5 to 9.4%, 9.5 to 12% and > 12%, respectively. 2. The parameters analysed were: (1) the endothelium-dependent relaxations to acetylcholine (ACh) in isolated aorta and mesenteric microvessels; (2) the vasodilator responses to exogenous nitric oxide (NO) in aorta: and (3) the existence of oxidative stress by studying the influence of the free radical scavenger superoxide dismutase (SOD) on the vasodilator responses to both ACh and NO. 3. In both isolated aortic segments and mesenteric microvessels, the endothelium-mediated concentration-dependent relaxant responses elicited by ACh were significantly decreased when the vessels were obtained from diabetic animals but only with HbA1c values higher than 7.5%. There was a high correlation between HbA1c levels and the impairment of ACh-induced relaxations, measured by pD2 values. 4. The concentration-dependent vasorelaxant responses to NO in endothelium-denuded aortic segments were significantly reduced only in vessels from diabetic animals with HbA1c values higher than 7.5%. Again, a very high correlation was found between the HbA1c values and pD2 for NO-evoked responses. 5. In the presence of SOD, the responses to ACh or NO were only increased in the segments from diabetic rats with HbA1c levels higher than 7.5%, but not in those from non-diabetic or diabetic rats with a good metabolic control (HbA1c levels <7.5%). 6. These results suggest the existence of: (1) a close relation between the degree of endothelial dysfunction and the metabolic control of diabetes, estimated by the levels of HbA1c; and (2) an increased production of superoxide anions in the vascular wall of the diabetic rats, which is also related to the metabolic control of the disease.     

Spontaneous glucose intolerance in the progeny of low dose streptozotocin-induced diabetic mice

Multiple low doses of streptozotocin (LDS) induce low-incidence diabetes mellitus in Balb/cHan and high-incidence diabetes in CD-1 mice. We studied offspring of diabetic parents in both strains. Group 1 consisted of litters from control mice with no streptozotocin treatment. Group 2 litters had an LDS diabetic mother and a control father, group 3 litters had control mother with LDS diabetic father, and group 4 litters had both, LDS diabetic mother and father. Diabetes was induced by 5 x 40 mg streptozotocin per kg on five consecutive days. Progeny of diabetic mothers showed a state of reduced glucose tolerance associated with reduced glucose disappearance during intravenous glucose tolerance test and increased insulin secretion of isolated islets of Langerhans. These metabolic abnormalities predominated in the male litters of both strains of mice. Amniotic insulin was increased in diabetic mothers during pregnancy. No histologic abnormalities were observed in group 2 progeny. Pancreases in male offspring of LDS diabetic CD-1 fathers (group 3) were studied for insulitis. Insulitis was found in 40% of mice with normal glucose tolerance. A single subdiabetogenic dose of streptozotocin (40 mg/kg) induced insulitis in 90% of pancreases accompanied by reduced insulin release of isolated islets. By contrast, male Balb/cHan progeny of diabetic fathers failed to develop insulitis. In conclusion, we found (1) parental LDS diabetes was transmitted more often to male offspring, (2) maternal LDS diabetes was associated with hyperinsulin secretion and glucose intolerance in the offspring and (3) paternal LDS diabetes was accompanied by insulitis and insulin secretion deficiency in CD-1 progeny.     

The 75 g oral glucose tolerance in pregnancy

The first case of the human immunodeficiency virus (HIV) infection was detected in Singapore in 1985 and the first case of the acquired immunodeficiency syndrome (AIDS) in 1986. Since then, the number of infections had increased. By the end of 1993, there were 222 residents with HIV infection, including 75 cases of AIDS. In view of the rapidly increasing magnitude of HIV infection, a microcomputer-based surveillance system was designed and developed in 1992 to better monitor epidemiological trends of HIV infection in Singapore. OBJECTIVE--The objective was to define a composite model of a successful HIV and AIDS registry that included: (a) patient data forms, (b) patient's contact data forms, (c) data analysis, and (d) report generation. METHODOLOGY--An IBM-compatible desk-top microcomputer was used for the project. The main software used for computer programming and data analysis were DBase IV (Version 1.5) and Epi Info (Version 5.0), respectively. Security features were incorporated into the programme to ensure confidentiality of information and that only authorized personnel could gain access to the programme. MAIN FINDINGS--The system functioned as the National HIV Notification Registry and was able to track notifications, analyse data and enabled prompt dissemination of information. The system was also linked to another database system for tuberculosis to enhance surveillance of both HIV infection and tuberculosis. CONCLUSION--The authors believe that this system would enhance surveillance and provide timely information for national AIDS control programmes. However, the effectiveness of this computer-based surveillance system is dependent on an established notification structure with notifications of sufficient completeness for both HIV infection and AIDS.     

Impairment of nitric oxide-mediated relaxations in anaesthetized autoperfused streptozotocin-induced diabetic rats

This work was designed to determine in vivo the influence of the metabolic control of streptozotocin-induced diabetic rats, measured by the levels of haemoglobin glycosylation in blood (HbA1c), on developing vascular endothelial dysfunction. For this, the vasoactive responses to basal and stimulated endothelial nitric oxide (NO) were studied using the technique of the anaesthetized autoperfused rat, analyzing the responses to acetylcholine (ACh) and N(G)-nitro-L-arginine methyl ester (L-NAME) in non-diabetic and diabetic rats with different degrees of metabolic control (four groups with HbA1c levels of 5.5-7.4%, 7.5-9.4%, 9.5-12%, and >12%, respectively). When administered over a noradrenaline-induced vasopressor tone, ACh (0.25, 0.75, 2.5, 7.5 and 25 microg kg(-1)) induced dose-dependent vasodilatatory responses in all rat groups, reducing both mean arterial pressure and perfusion pressure of the left hindlimb. These responses were similar in non-diabetic and in diabetic rats with good metabolic control (HbA1c 5.5-7.4%), while diabetic rats with levels of HbA1c higher than 7.5% showed significantly lower vasodilatatory responses to ACh. In untreated diabetic rats, the relaxant responses evoked by the NO donor sodium nitroprusside were also impaired. On the other hand, increasing doses of L-NAME (0.1 to 10 mg kg(-1)) enhanced both mean arterial pressure and left hindlimb perfusion pressure in diabetic and non-diabetic rats. As with ACh, the responses to L-NAME were significantly reduced in diabetic rats with HbA1c levels higher than 7.5%. To determine the mechanism underlying the NO-mediated endothelial dysfunction, the responses to ACh in untreated diabetic rats (HbA1c >12%) were studied in the presence of the NO substrate L-arginine, in the presence of the oxygen-derived free radical scavenger superoxide dismutase (SOD), or in the presence of both compounds. Both L-arginine and SOD produced a partial improvement of the ACh-induced vasodilatatory responses, but the effects of these agents were not additive. In this group of animals, SOD also induced a partial recovery of the L-NAME-evoked vasoconstrictions. In non-diabetic and untreated diabetic rats, the plasma levels of NO derivatives and arginine were measured. No significant differences were obtained in the amount of nitrites plus nitrates, while plasma levels of arginine were markedly reduced in the untreated diabetic animals. The results indicate that the endothelial dysfunction associated to diabetes is closely related to the level of metabolic control of the disease. Therefore, it is possible to establish a threshold for developing endothelium impairment from percentages of HbA1c higher than 7.5%. As the responses to the NO synthase blocker L-NAME were analogously impaired, it is reasonable to suggest that diabetic endothelial dysfunction is related to the interference with mechanisms linked both to stimulated and basal production of NO. We suggest that this interference is partially due to a deficit in the substrate availability for NO and to an increased generation of superoxide anions.     

Insulin and glucose response following oral glucose administration in well-conditioned ponies

Twenty-three well-conditioned ponies were evaluated for insulin and glucose response following oral glucose administration (1 g/kg bodyweight [bwt] as a 20 per cent solution). Ponies were defined as normal if total insulin secretion (TIS) was less than 149 mu iu/ml h and the glucose concentration was below 11.1 +/- 0.11 mmol/litre (200 +/- 2 mg/dl) at all times following oral glucose administration. When glucose concentrations were maintained below 11.1 +/- 0.11 mmol/litre, the area under the glucose curve (TG) was less than 17.4 mmol/litre/h (314 mg/dl/h). The ponies were assigned to four groups based on insulin and glucose response: Group 1 (n = 7), normal; Group 2 (n = 5), high insulin, normal glucose; Group 3 (n = 8), high insulin, high glucose and Group 4 (n = 3), high glucose, normal insulin. This classification is an initial attempt to define normal insulin and glucose response in ponies. Additional data need to be accumulated to define further insulin resistance and diabetes in ponies.     

Treatment with protease inhibitors associated with peripheral insulin resistance and impaired oral glucose tolerance in HIV-1-infected patients

BACKGROUND: The use of protease inhibitors in the treatment of HIV-1 infection is associated with the new onset of diabetes mellitus, hyperlipidaemia and lipodystrophy. It is unclear whether these findings are coincidental or whether they reflect a causative effect of protease inhibitors. OBJECTIVE: To evaluate the effect of treatment with protease inhibitors on insulin sensitivity, oral glucose tolerance and serum lipids in HIV-infected patients in order to determine whether treatment with protease inhibitors can cause peripheral insulin resistance. DESIGN: Cross-sectional controlled study in HIV-infected patients treated with protease inhibitors to assess insulin sensitivity, oral glucose tolerance and changes in serum lipids. METHODS: Sixty-seven patients treated with protease inhibitors, 13 therapy-naive patients and 18 HIV-negative control subjects were tested for insulin sensitivity (intravenous insulin tolerance test). In a subgroup of 24 treated patients, oral glucose tolerance was determined. Serum lipids prior to and under treatment with protease inhibitors were compared. RESULTS: Patients on protease inhibitors had a significantly decreased insulin sensitivity when compared with therapy-naive patients (median, 75 and 156 micromol/l/min, respectively; P < 0.001). All treated patients with impaired (n=4) or diabetic (n=9) oral glucose tolerance, and four out of 11 patients with normal glucose tolerance showed peripheral insulin resistance; all therapy-naive patients had normal insulin sensitivity. Treatment with protease inhibitors led to a significant increase in total triglycerides and cholesterol in the 67 treated patients (median increase, 113 and 37 mg/ml, respectively). CONCLUSION: Treatment with protease inhibitors is associated with peripheral insulin resistance, leading to impaired or diabetic oral glucose tolerance in some of the patients, and with hyperlipidaemia. Overall, there is a large variation in the severity and clinical presentation of protease inhibitor-associated metabolic side-effects.     

Upregulation of osteopontin expression in renal cortex of streptozotocin-induced diabetic rats is mediated by bradykinin

The model of streptozotocin (STZ)-induced diabetes in Wistar rats was used to study the expression of osteopontin during development of diabetic nephropathy. Diabetes was confirmed by serum glucose levels exceeding 16 mmol/l during the experimental period of 12 weeks. During this period of time, diabetic nephropathy developed, as characterized by a reduced glomerular filtration rate (2.7 +/- 0.3 ml/min in controls vs. 1.7 +/- 0.1 ml/min in diabetic rats) and proteinuria (8.3 +/- 1.7 mg/24 h in controls vs. 22.0 +/- 4 mg/24 h in diabetic rats). Northern blot analysis revealed a time-dependent upregulation of renal cortical osteopontin expression reaching 138 +/- 6% of control levels after 2 weeks and 290 +/- 30% (mean +/- SE, n = 6-9) after 12 weeks. By immunostaining, the increased osteopontin expression could be located to the tubular epithelium of the renal cortex. Chronic treatment of animals with ramipril (3 mg/kg) during the 12-week experimental period led to a further increase in osteopontin mRNA expression in diabetic animals, amounting to 570 +/- 73% (mean +/- SE, n = 6) of controls. Increased levels of osteopontin were not associated with accumulation of monocyte/macrophages that were identified by the cell type specific monoclonal antibody ED-1. The increased osteopontin expression in ramipril-pretreated rats was abolished by application of the bradykinin B2-receptor antagonist, icatibant (0.5 mg/kg). In addition, increased osteopontin expression in diabetic rats, which did not receive any treatment after STZ injection, could as well be reduced by icatibant given for the final 2 weeks of the experimental period. These data suggest that a strong bradykinin B2-receptor-mediated upregulation of osteopontin occurs during the pathogenesis of experimental diabetic nephropathy in rats.     

The effect of gestational impaired glucose tolerance on fetus and newborns

OBJECTIVE: To study the effect of gestational impaired glucose tolerance (GIGT) on fetus and newborns. METHODS: 52 GIGT mothers and 34 gestational diabetes mothers (GDM) were subjected to systematic monitoring prospectively, other 44 normal mothers served as controls. The perinatal outcomes were compared in the three groups. RESULTS: The incidence of macrosmia in the GIGT group was higher than that of the control group (P < 0.025). Neonatal blood glucose level in the GIGT group at 2 hours of age was the lowest in the three groups (P < 0.05). The incidence of hypoglycemia, polycythemia and wet lung in the GIGT group was higher than that of the control group. CONCLUSION: GIGT and GDM are important factors for poor perinatal outcome. Obstetricians and pediatricians must pay more attention to it.     

Studies on pyrazinoylguanidine. 2. Comparative drug and dose effects on glucose and lipid metabolism in streptozotocin-induced diabetic rats

In streptozotocin (STZ)-induced diabetic rats, pyrazinoylguanidine (PZG) markedly reduced elevated fasting concentrations of plasma glucose, triglycerides, and cholesterol. In contrast, these parameters were unaffected by a sulfonylurea, glyburide, or by a biguanide, metformin. PZG's glucose- and lipid-lowering effects were dose-dependent. These metabolic effects were also investigated after: (a) pyrazinoic acid (PZA), a metabolite of PZG; (b) 3-amino-PZG, an analog of PZG, and (c) 3-amino-PZA, a hydrolytic product of 3-amino-PZG. PZA moderately reduced elevated fasting glucose and lipid concentrations in STZ-diabetic rats, suggesting partial medication of PZG's antidiabetic actions by PZA. Neither 3-amino-PZG nor 3-amino-PZA exerted any glucose- or lipid-lowering effect in STZ-diabetic rats.     

A high biotin diet improves the impaired glucose tolerance of long-term spontaneously hyperglycemic rats with non-insulin-dependent diabetes mellitus

Event-related potentials (ERPs) were recorded in a continuous memory recognition task. Readable non-words and abstract geometric figures were presented in an alternating manner with an inter-stimulus interval of 2.1 s. Probability of item repetition was 0.25, a lag of one item lay between initial presentation and repetition. OLD/NEW distinction was indicated by the subject's motor response. Using linked-mastoid electrodes for reference, material-specific hemispheric asymmetries of ERPs started 150 ms after stimulus onset in temporo-lateral and parietal recordings with ERPs elicited by non-words being lateralized to the left and those by figures to the right. Clear OLD/NEW ERP effects were found with non-words: Starting about 200-250 ms after stimulus presentation, ERPs of formerly presented (OLD) items were more positive-going in recordings over the midline than ERPs of items that were new and to be repeated (NEW). In contrast, no local OLD/NEW ERP-difference was found with figures. In some brain regions, OLD/NEW ERP-differences were larger over the left hemisphere compared to the right. This finding, however, did not differ between non-words and figures.     

Effects of thyroid hormone on the sorbitol pathway in streptozotocin-induced diabetic rats

Sorbitol accumulation plays an important role in diabetic complications involving the kidney, nerves, retina, lens and cardiac muscle. To investigate the influence of thyroid hormone on the sorbitol pathway, we studied the effects of thyroid hormone on polyol metabolism in normal and diabetic rats. Rats were divided into three groups: controls, streptozotocin (STZ)-induced diabetic euthyroid rats (DM) and STZ-induced diabetic hyperthyroid (thyroxine-injected) rats (DM+HT). The sorbitol (Sor) concentrations in the kidney, liver and sciatic nerve (2.53+/-0.74, 0.97+/-0.16 and 24.0+/-5.1 nmol/mg protein, respectively) of the DM rats were significantly higher than those (1.48+/-0.31, 0.58+/-0.13 and 3. 1+/-0.6 nmol/mg protein) of the control rats. The Sor concentrations in the kidney and sciatic nerve of the DM+HT rats (1.26+/-0.29 and 9. 40+/-1.2 nmol/mg protein) were significantly lower than those in the DM rats. These values were reduced in the liver, unchanged in the kidney, and increased in the sciatic nerve from the hyperthyroid rats without diabetes. Thyroid hormone reduced the aldose reductase (AR) activities in the kidney, liver and sciatic nerve of the DM rats, and similarly reduced AR in the kidney and liver, but not in the sciatic nerve, of the non-diabetic rats. The sorbitol dehydrogenase (SDH) activities were decreased by thyroid hormone in the kidney and liver but not the sciatic nerve of DM rats. In the non-diabetic rats, this enzyme activity was decreased in liver, but not in kidney or sciatic nerve. A positive correlation between the Sor concentration and AR activity was observed in the kidney and liver but not in the sciatic nerve from control, DM and DM+HT rats. A negative correlation was observed between the Sor concentration and SDH activities in the same organs. These data suggest that thyroid hormone affects the sorbitol pathway, but the detailed mechanism whereby this hormone reduces the sorbitol content (especially in diabetic rats) remains to be clarified.     

Alterations in urinary bladder synaptosomal neurotransmitter concentrations in two-week streptozotocin-induced diabetic rats

Three-month-old male Wistar rats were rendered diabetic with a single intravenous injection of streptozotocin (60 mg/kg body weight). Two weeks after induction of diabetes, synaptosome-rich fractions were prepared from urinary bladder tissue homogenate of the diabetic rats and control rats by differential centrifugation (1000 x g, 17,000 x g and 100,000 x g) with discontinuous sucrose gradient. Synaptosomal acetylcholine, norepinephrine, epinephrine and dopamine were measured by the method of high-performance liquid chromatography. The respective neurotransmitter concentrations for the diabetic rats were 1537.8 +/- 65.3, 4757.7 +/- 361.9, 3720.7 +/- 276.1, and 2447.8 +/- 196.8 pmol/mg synaptosomal protein, respectively; those for the control rats were 338.1 +/- 25.0, 1009.0 +/- 54.6, 645.3 +/- 52.2, and 1426.1 +/- 123.9 pmol/mg protein, respectively. Thus, the synaptosomal concentrations for all the measured neurotransmitters were significantly higher in the diabetic rats (P < 0.05 for each comparison). In conclusion, it has been demonstrated that the vesicle-bound acetylcholine and catecholamines in the synaptosome-rich fraction of the urinary bladder were significantly increased in 2-week diabetic rats. This finding would suggest impaired neurotransmitter release from both the bladder sympathetic and parasympathetic efferent nerve endings in early streptozotocin-induced diabetes.