Oral anti-diabetic pharmacological therapies for the treatment of women with gestational diabetes.

BACKGROUND: Gestational diabetes mellitus (GDM) is a major public health issue with rates increasing globally. Gestational diabetes, glucose intolerance first recognised during pregnancy, usually resolves after birth and is associated with short- and long-term complications for the mother and her infant. Treatment options can include oral anti-diabetic pharmacological therapies. OBJECTIVES: To evaluate the effects of oral anti-diabetic pharmacological therapies for treating women with GDM. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (14 May 2016), ClinicalTrials.gov, WHO ICTRP (14 May 2016) and reference lists of retrieved studies. SELECTION CRITERIA: We included published and unpublished randomised controlled trials assessing the effects of oral anti-diabetic pharmacological therapies for treating pregnant women with GDM. We included studies comparing oral anti-diabetic pharmacological therapies with 1) placebo/standard care, 2) another oral anti-diabetic pharmacological therapy, 3) combined oral anti-diabetic pharmacological therapies. Trials using insulin as the comparator were excluded as they are the subject of a separate Cochrane systematic review.Women with pre-existing type 1 or type 2 diabetes were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and trial quality. Two review authors independently extracted data and data were checked for accuracy. MAIN RESULTS: We included 11 studies (19 publications) (1487 women and their babies). Eight studies had data that could be included in meta-analyses. Studies were conducted in Brazil, India, Israel, UK, South Africa and USA. The studies varied in diagnostic criteria and treatment targets for glycaemic control for GDM. The overall risk of bias was 'unclear' due to inadequate reporting of methodology. Using GRADE the quality of the evidence ranged from moderate to very low quality. Evidence was downgraded for risk of bias (reporting bias, lack of blinding), inconsistency, indirectness, imprecision and for oral anti-diabetic therapy versus placebo for generalisability. Oral anti-diabetic pharmacological therapies versus placebo/standard careThere was no evidence of a difference between glibenclamide and placebo groups for hypertensive disorders of pregnancy (risk ratio (RR) 1.24, 95% confidence interval (CI) 0.81 to 1.90; one study, 375 women, very low-quality evidence), birth by caesarean section (RR 1.03, 95% CI 0.79 to 1.34; one study, 375 women, very low-quality evidence), perineal trauma (RR 0.98, 95% CI 0.06 to 15.62; one study, 375 women, very low-quality evidence) or induction of labour (RR 1.18, 95% CI 0.79 to 1.76; one study, 375 women; very low-quality evidence). No data were reported for development of type 2 diabetes or other pre-specified GRADE maternal outcomes (return to pre-pregnancy weight, postnatal depression). For the infant, there was no evidence of a difference in the risk of being born large-for-gestational age (LGA) between infants whose mothers had been treated with glibenclamide and those in the placebo group (RR 0.89, 95% CI 0.51 to 1.58; one study, 375, low-quality evidence). No data were reported for other infant primary or GRADE outcomes (perinatal mortality, death or serious morbidity composite, neurosensory disability in later childhood, neonatal hypoglycaemia, adiposity, diabetes). Metformin versus glibenclamideThere was no evidence of a difference between metformin- and glibenclamide-treated groups for the risk of hypertensive disorders of pregnancy (RR 0.70, 95% CI 0.38 to 1.30; three studies, 508 women, moderate-quality evidence), birth by caesarean section (average RR 1.20, 95% CI 1.20; 95% CI 0.83 to 1.72, four studies, 554 women, I2 = 61%, Tau2 = 0.07 low-quality evidence), induction of labour (0.81, 95% CI 0.61 to 1.07; one study, 159 women; low-quality evidence) or perineal trauma (RR 1.67, 95% CI 0.22 to 12.52; two studies, 158 women; low-quality evidence). No data were reported for development of type 2 diabetes or other pre-specified GRADE maternal outcomes (return to pre-pregnancy weight, postnatal depression). For the infant there was no evidence of a difference between the metformin- and glibenclamide-exposed groups for the risk of being born LGA (average RR 0.67, 95% CI 0.24 to 1.83; two studies, 246 infants, I2 = 54%, Tau2 = 0.30 low-quality evidence). Metformin was associated with a decrease in a death or serious morbidity composite (RR 0.54, 95% CI 0.31 to 0.94; one study, 159 infants, low-quality evidence). There was no clear difference between groups for neonatal hypoglycaemia (RR 0.86, 95% CI 0.42 to 1.77; four studies, 554 infants, low-quality evidence) or perinatal mortality (RR 0.92, 95% CI 0.06 to 14.55, two studies, 359 infants). No data were reported for neurosensory disability in later childhood or for adiposity or diabetes. Glibenclamide versus acarboseThere was no evidence of a difference between glibenclamide and acarbose from one study (43 women) for any of their maternal or infant primary outcomes (caesarean section, RR 0.95, 95% CI 0.53 to 1.70; low-quality evidence; perinatal mortality - no events; low-quality evidence; LGA , RR 2.38, 95% CI 0.54 to 10.46; low-quality evidence). There was no evidence of a difference between glibenclamide and acarbose for neonatal hypoglycaemia (RR 6.33, 95% CI 0.87 to 46.32; low-quality evidence). There were no data reported for other pre-specified GRADE or primary maternal outcomes (hypertensive disorders of pregnancy, development of type 2 diabetes, perineal trauma, return to pre-pregnancy weight, postnatal depression, induction of labour) or neonatal outcomes (death or serious morbidity composite, adiposity or diabetes). AUTHORS' CONCLUSIONS: There were insufficient data comparing oral anti-diabetic pharmacological therapies with placebo/standard care (lifestyle advice) to inform clinical practice. There was insufficient high-quality evidence to be able to draw any meaningful conclusions as to the benefits of one oral anti-diabetic pharmacological therapy over another due to limited reporting of data for the primary and secondary outcomes in this review. Short- and long-term clinical outcomes for this review were inadequately reported or not reported. Current choice of oral anti-diabetic pharmacological therapy appears to be based on clinical preference, availability and national clinical practice guidelines.The benefits and potential harms of one oral anti-diabetic pharmacological therapy compared with another, or compared with placebo/standard care remains unclear and requires further research. Future trials should attempt to report on the core outcomes suggested in this review, in particular long-term outcomes for the woman and the infant that have been poorly reported to date, women's experiences and cost benefit.

Robust and versatile pectin-based drug delivery systems.

Pectin-based resistant, interactive and versatile hydrogel vehicles for oral administration have been prepared. These systems are thought to be versatile enough to allow the inclusion of substances (such as the surfactants tested: Pluronic, Tween, Na Lauryl sulphate) that may contribute to tailor the drug release patterns. Tolbutamide, that shows a discrete and pH-dependent solubility in water, has been employed as a model drug to test the capability of these matrices to overcome such drug-imposed restraints. The incorporation of different surfactants produced pectin-based hydrogels of difficult manipulation. In order to improve this drawback, two different strategies have been developed: blending with agarose or freeze-drying. The presence of agarose yields robust systems that can be handled and tested as prepared, in the fresh state. Freeze-drying not only allows to shape pure pectin and blend systems, but also generates a porous structure whose microstructure, determined by the different components included, influences on the drug release behavior. Tolbutamide release kinetics from freshly prepared matrices can be fitted to the Higuchi model while the freeze-dried ones adjust to the Korsmeyer-Peppas model; hence the hydrogel chains rearrangement processes rule the release during the rehydration process.

Evaluation of the impact of Polygonum capitatum, a traditional Chinese herbal medicine, on rat hepatic cytochrome P450 enzymes by using a cocktail of probe drugs.

ETHNOPHARMACOLOGICAL RELEVANCE: Polygonum capitatum is a well-known Miao medicinal plant that has been used for many years for its unique therapeutic effects on various urological disorders, including urinary calculus and urinary tract infections. To investigate the effect of Polygonum capitatum on cytochrome P450 (CYP) isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2E1, and CYP3A4) in vivo using a "cocktail" approach by administering five probe drugs to rats. This study assessed the potential of Polygonum capitatum to interact with co-administered drugs. MATERIALS AND METHODS: An aqueous extract of dried whole Polygonum capitatum was prepared and administered orally to rats at a dose of 0.58g/kg or 1.74g/kg twice daily for 7 or 14 consecutive days. A cocktail of caffeine (1.0mg/kg), tolbutamide (1.0mg/kg), omeprazole (2.0mg/kg), chlorzoxazone (4.0mg/kg) and midazolam (4.0mg/kg) was then administered on the eighth or fifteenth day to evaluate the effects of Polygonum capitatum on CYP1A2, 2C9, 2C19, 2E1, and 3A4, respectively. Blood samples were collected at a range of time-points and the plasma concentrations of the probe drugs were simultaneously quantified using ultra high-performance liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated to evaluate the effects of Polygonum capitatum on the activities of these CYP enzymes in rats. RESULTS: Polygonum capitatum pre-treatment had no significant effect on the pharmacokinetic parameters of caffeine, omeprazole or chlorzoxazone. However, the pharmacokinetics of tolbutamide and midazolam were affected significantly (P<0.05) by Polygonum capitatum, which induced more rapid metabolism of these probe compounds. CONCLUSIONS: These results suggested that Polygonum capitatum could induce CYP2C9 and CYP3A4, and did not influence CYP1A2, CYP2C19 or CYP2E1. Therefore, the clinical dose of drugs metabolized by human CYP2C9 or CYP3A4 may need to be adjusted in patients taking Polygonum capitatum, as this herbal medication may result in reduced effective concentrations of these drugs.

Effects of Panax notoginseng saponins on the activities of CYP1A2, CYP2C9, CYP2D6 and CYP3A4 in rats in vivo.

The aim of this study was to assess the influence of the Panax notoginseng saponins (PNS) on the activities of the drug-metabolizing enzymes cytochrome P450 (CYP450) 1A2, 2 C9, 2D6 and 3A4 in rats. The activities of CYP1A2, 2 C9, 2D6 and 3A4 were measured using specific probe drugs. After pretreatment for 1 week with PNS or physiological saline (control group), probe drugs caffeine (10 mg/kg; CYP1A2 activity), tolbutamide (15 mg/kg; CYP2C9 activity), metoprolol (20 mg/kg; CYP2D6 activity) and dapsone (10 mg/kg; CYP3A4 activity) were administered to rats by intraperitoneal injection. The blood was then collected at different times for ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) analysis. The data showed that PNS exhibited an induction effect on CYP1A2 by decreasing caffeine C(max) (36.3%, p < 0.01) and AUC(0-∞) (22.77%, p < 0.05) and increasing CL/F (27.03%, p < 0.05) compared with those of the control group. Western blot analysis was used to detect the effect of PNS on the protein level of CYP1A2, and the results showed that PNS could upregulate the protein expression of CYP1A2. However, no significant changes in CYP2C9, 2D6 or 3A4 activities were observed. In conclusion, the results indicate that PNS could induce CYP1A2, which may affect the disposition of medicines primarily dependent on the CYP1A2 pathway. Our work may be the basis of related herb-drug interactions in the clinic.

A role for ATP-sensitive potassium channels in male sexual behavior.

ATP-sensitive potassium (K(+)(ATP)) channels regulate cell excitability and are expressed in steroid-responsive brain regions involved in sexual behavior, such as the preoptic area (POA) and medial basal hypothalamus (MBH). We hypothesized that K(+)(ATP) channels serve as a mechanism by which testosterone can control the electrical activity of neurons and consequently elicit male sexual responsiveness. RT-PCR analysis indicated that castration induces, while testosterone inhibits, mRNA expression of the K(+)(ATP) channel subunit Kir6.2 in both the POA and MBH of adult male rats. Intracerebral infusion of the pharmacological K(+)(ATP) channel inhibitor tolbutamide increased the proportion of long-term castrates displaying sexual behavior and restored mount frequency, intromission frequency, and copulatory efficacy to values observed in testes-intact animals. Infusions of tolbutamide, but not vehicle, also decreased latencies to mount and intromit in castrated males. Unilateral tolbutamide infusion directly into the POA significantly reduced mount latency of castrates; however, it did not affect other copulatory measures, suggesting that blockade of K(+)(ATP) channels in additional brain regions may be necessary to recover the full range of sexual behavior. These data indicate that blockade of K(+)(ATP) channels is sufficient to elicit the male sexual response in the absence of testosterone. Our observations are consistent with the hypothesis that testosterone modulates male sexual behavior by regulating K(+)(ATP) channels in the brain. Decreased channel expression or channel blockade may increase the excitability of androgen-target neurons, rendering them more sensitive to the hormonal, chemical, and somatosensory inputs they receive, and potentially increase secretion of neurotransmitters that facilitate sexual behavior.

Influence of chalcone analogues on serum glucose levels in hyperglycemic rats.

A series of chalcone derivatives from 3,4-methylenedioxybenzaldehyde and substituted acetophenones have been synthesized and investigated as antihyperglycemic agents in a glucose loaded animal model. Chalcones with biological activity were compared with lispro, regular insulin and tolbutamide effects on serum glucose levels. Compound 01, without substituent in the A-ring was not able to change glycemic levels. On the other hand, compounds 03, 04, 05, 09 and 10 with substitutions at position 3' and/or 4' in the A-ring caused significant reduction in serum glucose levels. Concerning the antihyperglycemic effect, compounds 03 and 05 (methoxy substituent) inhibited the hyperglycemia induced by glucose around 96% similar to that demonstrated for lispro insulin and tolbutamide at 60 min. A rapid and lasting antihyperglycemic effect was found with compound 09 and 10 (nitro substituent). In conclusion, besides the nature of the functional groups electron-donor substituent, as methoxy and hydroxyl or electron-acceptor, as nitro groups, the position of the group may be mandatory for biological activity.

Long-term effects of Terminalia chebula Retz. on hyperglycemia and associated hyperlipidemia, tissue glycogen content and in vitro release of insulin in streptozotocin induced diabetic rats.

The aqueous extract of the fruits of Terminalia chebula Retz. has been evaluated for its antidiabetic activity in streptozotocin (STZ) induced mild diabetic rats and compared with a known drug, tolbutamide. The oral effective dose (ED) of the extract was observed to be 200 mg/kg body weight, which produced a fall of 55.6% (p<0.01) in the oral glucose tolerance test. Oral administration of ED of aqueous extract of T.chebula (AETC) daily once for two months reduced the elevated blood glucose by 43.2% (p<0.01) and significantly reduced the increase in glycosylated hemoglobin (HbA1c) (p<0.01). The same dose also showed a marked improvement in controlling the elevated blood lipids as well as decreased serum insulin levels in contrast to the untreated diabetic animals. Hepatic and skeletal muscle glycogen content decreased by 75% and 62.9% respectively in diabetic controls, these alterations were partly prevented (34.9% and 21.17%) in AETC treated group when compared to the healthy controls. The in vitro studies with pancreatic islets showed that the insulin release was nearly two times more than that in untreated diabetic animals. The treatment did not have any unfavorable effect on other blood parameters of liver and kidney function tests. LD 50 was found to be above 3 g/kg bw i.e. 15 times of ED, because there were no deaths of animals even at this dose indicating high margin of safety. These findings suggest further investigations for the possible use of the aqueous extract of fruits of T.chebula for the treatment of diabetes.

Dioscorea as the principal herb of Die-Huang-Wan, a widely used herbal mixture in China, for improvement of insulin resistance in fructose-rich chow-fed rats.

The present study was designed to clarify the principal herb responsible for the improvement of insulin resistance produced by Die-Huang-Wan, a mixture of six herbs, in rats fed with fructose-rich chow for 4 weeks. A decrease in plasma glucose was observed in fructose-rich chow-fed rats received an oral administration of Die-Huang-Wan at 26 mg/kg for 60 min but it disappeared with the deletion of dioscorea (Dioscoreae rhizoma) while this action was not modified by the deletion of other five herbs. The decrease of plasma glucose in fructose-rich chow-fed rats produced by dioscorea was similar to that treated with Die-Huang-Wan at same dosing; while the other five herbs failed to produce same influence. Similar to the effect of Die-Huang-Wan, dioscorea improved the fructose-induced decrement of insulin-stimulated glucose disposal rate after 3 days of treatment. Also, oral administration of dioscorea at effective dose (4.2 mg/kg per administration, three times daily) into streptozotocin-induced diabetic rats for 10 days increased the response to exogenous insulin, approaching to that induced by Die-Huang-Wan in same treatment. However, these effects failed to induce in the dioscorea-deleted formula of Die-Huang-Wan or other five herbs of this mixture. These results suggest that dioscorea is the major herb for the improvement of insulin sensitivity produced by Die-Huang-Wan. This can be applied to use as an adjuvant for subjects who need to increase insulin sensitivity.

Improvement of insulin resistance by miracle fruit (Synsepalum dulcificum) in fructose-rich chow-fed rats.

In an attempt to probe a new target to improve insulin resistance, miracle fruit (Synsepalum dulcificum) was employed to investigate the effect on insulin resistance induced by fructose-rich chow in rats. Single oral administration of the powder of this miracle fruit decreased the plasma glucose in a dose-dependent manner for 150 min in rats fed fructose-rich chow for 4 weeks. Insulin action on the glucose disposal rate was measured using the glucose-insulin index, the value of the areas under the curve of glucose and insulin during the intraperitoneal glucose tolerance test. Oral administration of miracle fruit (0.2 mg/kg) to fructose-rich chow fed rats, three times daily for 3 days, reversed the raised value of the glucose-insulin index, indicating that miracle fruit has the ability to improve insulin sensitivity. The plasma glucose lowering action of tolbutamide, induced by secretion of endogenous insulin, is widely used to characterize the formation of insulin resistance. The time for the loss of the plasma glucose lowering response to tolbutamide (10.0 mg/kg, i.p.) in fructose-rich chow fed rats was markedly delayed after treatment with miracle fruit compared with the vehicle-treated group. Thus providing supportive data that oral administration of miracle fruit could delay the development of insulin resistance in rats. Also, the in vivo insulin sensitivity was markedly raised by miracle fruit. In conclusion, the results suggest that miracle fruit may be used as an adjuvant for treating diabetic patients with insulin resistance because this fruit has the ability to improve insulin sensitivity.

The effect of echinacea (Echinacea purpurea root) on cytochrome P450 activity in vivo.

BACKGROUND: Echinacea is a widely available over-the-counter herbal remedy. Tinctures of echinacea have been shown to inhibit cytochrome P450 (CYP) in vitro. The effect of echinacea (Echinacea purpurea root) on CYP activity in vivo was assessed by use of the CYP probe drugs caffeine (CYP1A2), tolbutamide (CYP2C9), dextromethorphan (CYP2D6), and midazolam (hepatic and intestinal CYP3A). METHODS: Twelve healthy subjects (6 men) completed this 2-period, open-label, fixed-schedule study. Caffeine, tolbutamide, dextromethorphan, and oral and intravenous midazolam were administered before and after a short course of echinacea (400 mg 4 times a day for 8 days) to determine in vivo CYP activities. RESULTS: Echinacea administration significantly increased the systemic clearance of midazolam by 34%, from 32 +/- 7 L/h to 43 +/- 16 L/h (P =.003; 90% confidence interval [CI], 116%-150%), and significantly reduced the midazolam area under the concentration-time curve by 23%, from 127 +/- 36 microg. h/L to 102 +/- 43 microg. h/L (P =.024; 90% CI, 63%-88%). In contrast, the oral clearance of midazolam was not significantly altered (P =.655; 90% CI, 75%-124%), 137 +/- 19 L/h compared with 146 +/- 71 L/h. The oral availability of midazolam after echinacea dosing was significantly increased (P =.028; 90% CI, 108%-153%), from 0.23 +/- 0.06 to 0.33 +/- 0.13. Hepatic availability (0.72 +/- 0.08 versus 0.61 +/- 0.16; P =.006; 90% CI, 73%-90%) and intestinal availability (0.33 +/- 0.11 versus 0.61 +/- 0.38; P =.015; 90% CI, 125%-203%) were significantly altered in opposite directions. Echinacea dosing significantly reduced the oral clearance of caffeine, from 6.6 +/- 3.8 L/h to 4.9 +/- 2.3 L/h (P =.049; 90% CI, 58%-96%). The oral clearance of tolbutamide was reduced by 11%, from 0.81 +/- 0.18 L/h to 0.72 +/- 0.19 L/h, but this change was not considered to be clinically relevant because the 90% CIs were within the 80% to 125% range. The oral clearance of dextromethorphan in 11 CYP2D6 extensive metabolizers was not affected by echinacea dosing (1289 +/- 414 L/h compared with 1281 +/- 483 L/h; P =.732; 90% CI, 89%-108%). CONCLUSIONS: Echinacea (E purpurea root) reduced the oral clearance of substrates of CYP1A2 but not the oral clearance of substrates of CYP2C9 and CYP2D6. Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites. The type of drug interaction observed between echinacea and other CYP3A substrates will be dependent on the relative extraction of drugs at hepatic and intestinal sites. Caution should be used when echinacea is coadministered with drugs dependent on CYP3A or CYP1A2 for their elimination.

An aqueous extract of the green leafy vegetable Ipomoea aquatica is as effective as the oral hypoglycaemic drug tolbutamide in reducing the blood sugar levels of Wistar rats.

This study was undertaken to compare the oral hypoglycaemic activity of an aqueous extract of the green leafy vegetable Ipomoea aquatica (dose equivalent to 3.3 g starting material /kg body weight) with that of the known oral hypoglycaemic drug tolbutamide (15 mg/kg body weight) in glucose challenged Wistar rats (3 g/kg body weight, administered 30 min after the administration of Ipomoea aquatica or tolbutamide). One and half hours after administration of glucose (equivalent to 2 h after administration of plant extract or tolbutamide), the mean blood glucose level of the Ipomoea aquatica treated group was 47.5% lower than that of the control group treated with distilled water. The tolbutamide treated group showed a mean blood glucose level which was only 33.8% lower than that of the control group. However, statistical analysis indicated that the blood glucose levels of the Ipomoea aquatica treated group were not significantly different from that of the tolbutamide treated group. Our results show that the aqueous extract of Ipomoea aquatica is as effectve as tolbutamide in reducing the blood glucose levels of glucose-challenged Wistar rats.

Effects of sho-saiko-to (xiao chai hu tang), a Chinese traditional medicine, on the gastric function and absorption of tolbutamide in rats.

This study was carried out to investigate the effects of Sho-saiko-to (Xiao Chai Hu Tang), a Chinese traditional medicine, on the gastric function including the gastric emptying rate (GER) and intragastric pH in rats. Additionally, the effects of the GER and intragastric pH on tolbutamide absorption after oral administration were examined. The GER measured at 40 min after dosing was reduced to about 70% by the pretreatment of Sho-saiko-to (500 mg/kg). The plasma tolbutamide concentration in the rats treated with a 250 mg/kg dose of Sho-saiko-to was significantly lower than that in the control group. Plasma tolbutamide concentrations increased along with the GER in the group co-administered Sho-saiko-to, and there were significant correlations between the GERs and plasma levels in both time points at 20 and 40 min after administration. In the study using pylorus-ligated rats, Sho-saiko-to significantly elevated the intragastric pH, but induced no change in the concentrations of tolbutamide dissolved in the gastric content. Additionally, Sho-saiko-to did not change the area under the plasma concentration-time curve (AUC) of tolbutamide up to 60 min after administration into the stomach loop, and gastric absorption has been considered to minimally contribute to whole absorption of tolbutamide in the gastrointestinal tract. These results indicate that Sho-saiko-to has an inhibitory effect on the function of gastric emptying in rats. The reduced gastric emptying could affect gastrointestinal absorption, resulting in the lower plasma concentration of tolbutamide after oral administration. Furthermore, it is suggested that Sho-saiko-to can raise the intragastric pH but affect neither the intragastric dissolution nor the gastric absorption of tolbutamide.

Fatty acids mediate the acute extrahepatic effects of insulin on hepatic glucose production in humans.

We have shown previously in humans that insulin partly suppresses hepatic glucose production (HGP) by an extrahepatic (indirect) mechanism. In the present study, we investigated the role of free fatty acids (FFAs) in mediating the extrahepatic effects of insulin in humans and determined the extent to which insulin can regulate HGP by a non-FFA-mediated effect. Sixteen healthy men received an intravenous tolbutamide infusion for 3 h, and pancreatic insulin secretion was calculated by deconvolution of peripheral C-peptide levels. On a subsequent occasion, equimolar exogenous insulin was infused by peripheral vein. In both studies, glucose was clamped at euglycemia. We have previously validated this method and shown no independent insulin-like activity of tolbutamide. During the clamp, 9 of the 16 subjects received a low dose of heparin and Intralipid to prevent the insulin-induced suppression of FFAs, while 7 subjects received a high dose of heparin and Intralipid to raise FFAs approximately 2.5-fold. In both the high- and low-dose groups, peripheral insulin was higher and calculated portal insulin lower with peripheral versus portal insulin delivery. In the low-dose group, HGP decreased by 68.3 +/- 2.1% with portal insulin delivery and 64.7 +/- 3.7% with peripheral insulin delivery (NS). In the high-dose group, HGP decreased by 58.0 +/- 4.5% with portal insulin and 48.3 +/- 5.0% with peripheral insulin (P < 0.05). Four individuals who participated in the high-dose group underwent an additional peripheral insulin study in which the same dose of exogenous insulin was infused as in the high-dose group but in the absence of heparin and Intralipid. During this latter study, FFA levels declined by approximately 90% during hyperinsulinemia, and HGP was suppressed by 71.8 +/- 5.6%, which was a much greater suppression (P < 0.01) than when FFA levels were raised in these subjects during the equivalent rate insulin infusion. In summary, the previously observed greater suppression of HGP with equimolar peripheral versus portal insulin is eliminated or reversed, depending on plasma FFA levels, if FFAs are prevented from decreasing, suggesting an important role of FFAs in mediating the extrahepatic effects of insulin on HGP. However, the effect of FFA clamping is relatively small with a significant degree of suppression of HGP (by approximately 50%), which remains even when FFAs are elevated above basal levels, suggesting that in the physiological range FFAs only partially influence the suppression of HGP in humans. This suggests that other mechanisms, most likely hepatic, dominate the acute insulin-induced suppression of glucose production.

The effects of gliclazide and other sulfonylureas on low-density lipoprotein oxidation in vitro.

Diabetes is associated with increased oxidant stress. This may contribute to the development of diabetic macrovascular complications through increased oxidation of low-density lipoprotein (LDL), which is thought to be a crucial step in the development of atherosclerosis. The sulfonylurea gliclazide has been shown to have free radical-scavenging activity in vitro, but its effects on LDL oxidation, and these effects of other sulfonylureas, are unknown. To investigate this we studied the effects of in vitro supplementation with gliclazide 1 mumol/L on copper-induced oxidation of LDL isolated from 20 control subjects and 22 type II diabetic patients. The effects of 1 mumol/L vitamin C, a known water-soluble antioxidant, were studied simultaneously. The resistance to oxidation, expressed as the lag time between the addition of copper and commencement of oxidation, was significantly increased by both gliclazide and vitamin C, and the effect was similar for LDL from diabetic and control subjects. The baseline oxidation lag time was 63.4 +/- 2.1 minutes, and increased to 108 +/- 4.4 minutes with gliclazide and 88.7 +/- 5.6 minutes with vitamin C (P = .0001, baseline v either treatment). The increase in lag time with gliclazide of 70% +/- 3% was greater than the 30% +/- 5% increase with vitamin C (P < .0005). In a separate experiment, LDL isolated from eight control and 10 diabetic subjects was supplemented with 1 mumol/L gliclazide, glibenclamide, glipizide, and tolbutamide. For each LDL sample, all drugs were studied simultaneously and the oxidation lag time was compared against that of untreated LDL. Gliclazide increased the lag time from 53.7 +/- 2.4 minutes to 108.4 +/- 4.5 minutes (P = .0001). None of the other sulfonylureas had any effect on lag time. These findings demonstrate that gliclazide is an effective inhibitor of in vitro LDL oxidation, and in this respect, it is more potent on a molar basis than vitamin C. This antioxidant property of gliclazide was not shared by the other sulfonylureas studied.

Effect of D-400, a herbal formulation, on blood sugar of normal and alloxan-induced diabetic rats.

Blood sugar levels of normal rats treated with D-400 showed significant reduction (P < 0.05) as compared to control groups. The fall was seen at one month and remained so uptill 3 months. Hyperglycemic response to adrenaline was significantly lowered (P < 0.05) following D-400 treatment. D-400 potentiated the hypoglycemia following tolbutamide treatment. Blood sugar remained persistently low in tolbutamide plus D-400 treated group after 3 and 4 hours (P < 0.05). In the alloxan-induced diabetic rats, a significant lowering of blood and urinary sugar was noticed on day 20, 30 and 40 following treatment with D-400 (P < 0.05). Liver glycogen depletion was significantly inhibited in the D-400 treated group (P < 0.025). D-400 has significantly potentiated (P < 0.05) the hypoglycemic action of insulin in alloxan-induced diabetic rats.

Beneficial effect of vegetable protein diet supplemented with psyllium plantago in patients with hepatic encephalopathy and diabetes mellitus.

A controlled crossover study was performed in 8 diabetic patients with chronic portal-systemic encephalopathy. After a basal period the patients were treated during periods A and B. During period A, a meat protein diet (0.8 g/kg body wt, approximately 1800 kcal/day) was consumed and neomycin plus laxatives were given. During period B patients received vegetable protein (0.8 g/kg body wt, 1800 kcal/day). This diet was supplemented with psyllium fiber to reach 35 g of fiber per day. Four patients were randomly assigned to receive the treatments in the order A-B and the other 4 patients in the order B-A. At the end of the first experimental period, fasting glucose levels were 204 +/- 86 mg% in the meat protein diet group and 127 +/- 8 mg% in the vegetable protein diet group (p less than 0.014). The patients were receiving 2.5 +/- 0.2 g/day and 2.1 +/- 0.5 g/day of tolbutamide at the end of the meat protein diet and vegetable protein diet, respectively. In all cases, fasting glucose levels decreased at the end of the vegetable diet period regardless of the previous treatment. An improvement of greater than or equal to 25 mg% of fasting glucose levels was observed in 7 of the 8 patients after the vegetable protein diet and in no case after the meat protein diet (p less than 0.0078). The parameters of encephalopathy were comparable at the end of both the meat protein diet and the vegetable protein diet. A significant increase in the number of bowel movements was noticed after the vegetable diet plus fiber (p less than 0.01). We propose the use of vegetable diet plus fiber to facilitate the treatment of patients with both diabetes and hepatic encephalopathy.

Abnormalities in the regulation of growth hormone in chronic renal failure.

Carbohydrate intolerance is a common abnormality in patients with chronic renal failure. In this group of patients we investigated the interrelation among glucose, insulin, and growth hormone and confirmed the presence of carbohydrate intolerance and hyperinsulinemia. In addition we demonstrated alterations in growth hormone regulation, characterized by (1) the lack of suppression of growth hormone by orally induced hyperglycemia and paradoxical increase in serum levels of growth hormone after the administration of intravenous glucose or glucagon; (2) lack of release of growth hormone with induced hypoglycemia and an exaggerated response to levodopa administration. Furthermore, thyrotrophin-releasing hormone stimulated growth hormone release, a phenomenon not observed in the control population. Our studies show an impaired hypothalamic regulation of growth hormones secretion in patients with renal failure undergoing long-term hemodialysis.