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Insulin plays a major role in polycystic ovary syndrome (PCOS). Insulin resistance and resultant hyperinsulinemia stimulate both the ovary and adrenal to produce androgens. Oral antidiabetic agents have been used to alleviate the symptoms and to induce ovulation in women with PCOS. This review focuses on the relation between insulin and PCOS and discusses the use of oral antidiabetic agents.
Theoretical and experimental research data as well as human epidemiological studies on large populations suggest a great difference in influencing cardiovascular processes and alterations among the oral antidiabetic drugs used in the treatment of type II diabetes mellitus. Drugs delaying or inhibiting carbohydrate absorption as well as insulin sensitizers have an unambiguous reducing effect on diabetic cardiovascular complications. Only fluid retention needs precaution during the treatment with thiazolidinedions in patients suffering from heart disease. Among insulin secretizers repaglinid, glibenclamid and glipizide have an ATP-sensitive potassium channel inhibiting effect in the vascular smooth muscle cells, too, reducing hereby vasodilation. Glibenclamide also inhibits ischaemic preconditioning. Therefore, the antidiabetic drug of choice can be decisive in diabetic patients suffering from ischaemic heart diseases or peripheral obliterative disorders. In the case of secondary sulphonylurea resistance and/or severe ischaemic alterations insulin treatment becomes necessary to avoid further cardiovascular complications.
The objective of this work is to investigate the hypoglycemic effect of 12 "antidiabetic" plants used in Mexico. The studies were performed using 27 healthy rabbits with the gastric administration of water, tolbutamide or decoction of the "antidiabetic" plant before the induction of temporary hyperglycemia by subcutaneous injection of 50% dextrose solution (4 ml/kg of weight) at the beginning of the experiment and after 60 min. Blood glucose was determined every 60 min for a period of 5 h. Tolbutamide and eight of the studied plants decreased significantly the hyperglycemia as compared with control test (water) (p < 0.05). The strongest effect was yielded by Guaiacum coulteri, followed by Marrubium vulgare, Crataegus pubescens, Cynodon dactylon, Calea zacatechichi, Buddleia americana, Bauhinia divaricata and Coix lachryma. The decrease of hyperglycemia caused by Physalis phyladelphyca, Pavonia schiedeana and Eucaliptus globulus was not significant (p > 0.05). Urtica dioica increased glycemia slightly.
In the large majority of type 2 diabetics, the initial phase of the disease is characterized by insulin resistance. A primary insulin secretion disorder is seen only in normal-weight patients, and requires a differentiated therapeutic approach. Glinides make possible flexible meal-oriented stimulation of insulin secretion. Insulin resistance can be influenced by insulin sensitizers. In the overweight patient, biguanides (metformin) effectively lower blood sugar, either alone or in combination with other oral antidiabetic agents. Acarbose, and glitazone can delay progression to diabetes. Furthermore, acarbose, biguanides, and in particular glitazone, reduce cardiovascular events. For normal-weight patients, sulfonylureas are considered the first-line drug for monotherapy. Progressive insulin secretion deficiency and usually persistent insulin resistance requires insulin substitution in combination with oral antidiabetic agents or as conventional/intensified insulin therapy.
Antihyperlipidaemic and antioxidant effect of Ocimum sanctum Linn. seed oil (OSSO) was investigated in rabbits. Administration of OSSO (0.8 g/kg body weight/day) for four weeks, in cholesterol (100 mg/kg body weight/day) fed rabbits significantly decreased serum cholesterol, triacylglycerol and LDL-+VLDL-cholesterol as compared to untreated cholesterol fed group. There was significant fall in atherogenic index in OSSO treated group. In addition, treatment with OSSO decreased lipid peroxidation and increased reduced glutathione content in blood. Antidiabetic effect of O. sanctum seed oil was evaluated in alloxan diabetic rabbits. Two weeks treatment of diabetic rabbits with OSSO (0.8 gm/kg/day) showed no significant hypoglycaemic effect. Results of the present study show that OSSO has hypocholesterolaemic and antioxidant effects but it does not have antidiabetic effect.
The author discusses in conjunction with contemporary views on the genesis and development of diabetic neuropathy the view on the neurotoxicity of oral antidiabetics, in particular sulphonyl urea derivatives. He analyzes in more detail different areas of pathogenesis of diabetics neuropathy, the main one being the metabolic and hypoxic one with the common trigger mechanism--hyperglycaemia. Therefore, based on contemporary knowledge, the neurotoxicity of oral antidiabetics can be ruled out.
A group of 15 patients with controlled insulin-independent diabetes (Type 2) were workloaded submaximally by a 15-minute load on a cycle ergometer and 2-3 days later same workload was repeated, but this time 5-patient groups were administered before the workload: 0.1 j.m. of insulin/kg of body mass i.v., 1.0 g tolbutamide sodium i.v. and 150 mg of phenformin orally one hour before the load. The patients who were injected insulin or tolbutamide were also administered glucose solution (intravenously) so as to keep the same level of glycaemia as in the follow-up examination. The time of metabolic observation after workload was 90 min., so the whole examination took 105 minutes. In the first (follow-up) examination, all the probands had in the venous blood an increase in alanine, lactate, pyruvate and the relation lactate: pyruvate (L/P), a decrease in pH, bicarbonates and pO2 (in capillary afterialized blood). The administration of insulin and tolbutamide eliminated or reduced after-effort alaninaemia increase, whereas the administration of phenformin increased the concentration of this amino acid in the blood after effort. Insulin resulted in a greater increase in after-effort lactacidaemia; besides, insulin and tolbutamide increased the relation L/P during and after effort. The influence of antidiabetic drugs on the behaviour of other biochemical parameters after effort was insignificant. The results obtained show that antidiabetic drugs modify the increase in alaninaemia after effort in patients with controlled insulin-independent diabetes (Type 2), the direction of the modification depending on a specific influence of particular drugs on the metabolism of this amino acid. While evaluating the influence of effort on the concentration of alanine in the blood in patients with this type of diabetes one should consider not only the present demand for this gluconeogenes substrate but also a specific influence of the kind of therapy applied at the time.
The experimental findings showed that antidiabetic drugs influence the systems of metabolism of xenobiotics. Insulin, bucarban, glybenclamide, adebit enhance processes of hydroxylation in intact animals. Insulin deficiency in modelled diabetes mellitus produces a weakening of the above processes and administration of the hormone in a therapeutic dose causes normalization of processes of acetylation and hydroxylation. Insulin and glybenclamide enhance processes of acetylation in healthy animals, bucarban and adebit being inductors of microsomal oxidation do not produce such changes. Therefore, in clinical practice one should take into consideration these effects of the antidiabetic drugs in a complex therapy of diabetes mellitus.
In a double-blind cross-over trial on 20 diabetic patients of type IIb we investigated whether a drug interaction between glibenclamide and acemetacin may possibly occur. After hospitalization of all in-patients needing glibenclamide therapy, a one-week period of adaptation to clinical conditions with optimized diet, antidiabetic dosage of the drug and the beginning of a diabetes learning programme followed. Thereafter, in a randomized design, ten out of the 20 patients were treated concomitantly with either 60 mg acemetacin t.i.d. or placebo for 1 week. Furthermore, a cross-over period of one week's duration followed once more. Daily blood glucose profiles (four values) were measured every second day and suggested a continuous improvement of the severe diabetic state previously seen. Blood glucose levels reached an optimal steady-state condition after 1 week of adaptation. Concomitant treatment with acemetacin did not lead to a relevant alteration of the laboratory parameters used in type IIb diabetic patients. This could also be established due to HbA1 values. Contrary to other nonsteroidal anti-inflammatory drugs, interactions between acemetacin and the widely used oral antidiabetic glibenclamide could not be established.
Although biguanides are widely used in the treatment of non-insulin- dependent diabetic patients, the underlying mechanism for their antidiabetic effects is not fully understood. There is circumstantial evidence that their mode of action is multifactorial. It is unknown, however, to what extent the different single effects contribute to the overall antidiabetic effect. Recent studies indicate that metformin treatment improves peripheral insulin action, which might occur both at the receptor level and/or at the postreceptor site. It is now generally accepted that postreceptor defects are of major importance for the insulin resistance of type-II diabetic patients. Findings indicating that metformin might influence postreceptor sites of insulin action seem, therefore, to be more relevant than possible effects on insulin receptor binding.
A review of the complications which are of importance for the use of antidiabetic agents is given. As a consequence of too intensive a hypoglycaemic effect lesions may be provoked by sulfonylureas and insulin. Additionally, under treatment with different insulin preparations allergical side effects are possible. As an essential complication provoked by biguanides a lactic acidosis may be elicited which--though seldom occurring--then in most cases takes a fatal course. Lesions as a consequence of treatment with oral antidiabetic agents to a high degree be avoided by using them in accordance with their indication. In the case insulin the lesions ensuing immunological reactions are only to be avoided or reduced as far as the pharmaceutical industry succeeds in reducing the antigenicity of insulin preparations.
p-[(R)-3-[bis-[(R)-beta-hydroxyphenethyl]amino]butyl]benzamide (Ro 16-8714/000) is one of the most effective compounds, of a new series of calorigenic bis-phenethanolamine derivatives, which combine anti-obesity and antidiabetic qualities. Ro 16-8714 exhibited potent stimulation of oxygen consumption in normal rats and obese mice and rats. Calorigenesis appeared to be directly mediated by beta-adrenoceptors. Ro 16-8714 stimulated brown adipose tissue (BAT) thermogenesis in vitro and increased BAT calorigenic capacity in obese rodents during prolonged treatment. Furthermore, the compound induced fat mobilization and oxidation in normal and obese rats. Subchronic treatment of obese mice revealed potent antidiabetic effects which were mainly due to stimulation of carbohydrate oxidation. Prolonged treatment of obese mice and rats resulted in inhibition of body weight gain and depression of body fat content while body protein was maintained. The compound may, therefore, offer a new approach to the treatment of morbid obesity and maturity-onset diabetes.
The adsorption of the oral antidiabetics metformin hydrochloride, glibenclamide, acetohexamide, tolbutamide, carbutamide, tolazamide and glymidine on various antacids or adsorbents was studied at 37 degrees C. The antacids or adsorbents used were magnesium trisilicate, aluminium hydroxide, calcium carbonate, magnesium oxide, bismuth oxycarbonate, talc, kaolin as well as charcoal. None of the substances tested, with the exception of charcoal, exhibited superior adsorptive properties for all the drugs. Magnesium trisilicate and calcium carbonate were the best adsorbents for metformin hydrochloride. Acetohexamide and glibenclamide were adsorbed to an appreciable extent on most antacids. Tolbutamide showed an adsorption tendency towards talc. Most antacids slightly adsorbed carbutamide, while magnesium trisilicate showed a higher adsorption capacity for tolazamide and glymidine. The dissolution rate of acetohexamide in magnesium oxide suspension (5:400) increased about 40-fold after 10 min, whle in magnesium trisilicate suspension (5:400) it increased about 7-fold. On the other hand, magnesium trisilicate did not influence the dissolution rate of metformin hydrochloride. The probable variation in the bioavailability of orally administered antidiabetics when coadministered with antacids was discussed. However, further in vivo studies are needed before a final assessment for such drug-antacid interaction can be confirmed.
The oral antidiabetic agent 1-(hexahydro-1-H-azepin-1-yl)-3-(p-[2-(5-methyl-isoxazol-3-carboxamido)-ethyl]-phenylsulfonyl)-urea (glisoxepide, BS 4231, Pro-Diaban¿) was studied in a multi-centre open clinical trial comprising 4337 patients and was found to be an effective therapeutic agent for maturity-onset diabetics. About 66% of the patients had been pre-treated with oral antidiabetics. 54.7% of those 3572 patients treated with Pro-Diaban for at least 3 months achieved stabilization, which was classified according to strict criteria as "good", 73.4% achieved at least "satisfactory" stabilization. 12.5% of the cases dropped out after having received at least 12 mg/day because of inadequate efficacy of Pro-Diaban; 51.9% of these patients dropped out in the first 3 months (early failures 6.9% of the total case number). 61.9% received their daily dose in one portion, 29% in two and 10% in three portions. 98% received maximally 16 mg, 70% maximally 8 mg, and 42% 4 mg per day. Hypoglycaemic episodes led in 0.9% to a termination of the trial. In 1.22% of the cases the trial was terminated because of side effects, in 0.18% of cases they consisted of allergic or suspected allergic complaints and in 0.69% they consisted mainly of gastro-intestinal symptoms. Of the side-effects which did not lead to a termination of the trial, dizziness, headache and nausea were the relatively more frequent symptoms. An analysis of the laboratory data under consideration of pathological and normal initial and subsequent values showed that under the influence of Pro-Diaban pathological data reverted to normal more frequently than initially normal values changed to pathological ones. The analysis of laboratory and blood pressure data from 4 subgroups of patients, e.g. patients with diseases of the liver or the kidneys and hyperlipaemic or hypertensive patients, revealed that those data of special interest in each subgroup had mostly improved or remained unchanged under Pro-Diaban.
Thiazolidinedione derivatives are insulin-sensitizing agents with proven antidiabetic activities in vivo. To explore the mechanism of action of this class of compounds, the effects of pioglitazone, CP-86,325, and AD-5075 on elements of the insulin signal transduction pathways were studied in Chinese hamster ovary cells overexpressing human insulin receptor (CHO.T) and L6 myotubes. In CHO.T cells, the binding of insulin to its receptor and the insulin-stimulated tyrosine kinase activity of the receptor were not altered by pioglitazone or CP-86,325. In contrast, treatment of CHO.T cells with the compounds resulted in significant increases in insulin-stimulated phosphatidylinositol (PI) 3-kinase activity. This insulin-enhancing effect was also observed in L6 myotubes treated with CP-86,325. The augmentations in kinase activity observed in CHO.T cells correlated with increases in the amount of PI 3-kinase (p85 subunit) in anti-phosphotyrosine immunoprecipitates of cell lysates. No gross changes in the tyrosine phosphorylation state of the insulin receptor substrate-1 were detected in insulin-stimulated CHO.T cells following treatment with the compounds. Furthermore, the compounds did not enhance insulin stimulation of mitogen-activated protein kinase or DNA synthesis in CHO.T cells. Thus, thiazolidinedione-derived antidiabetic agents may act as insulin sensitizers by augmenting insulin stimulation of PI 3-kinase activity in a rather specific manner.
Oral antidiabetic agents continue to play an important role in the treatment of type 2 diabetes. Of decisive importance is the timing of their use, together with a knowledge of their specific properties. Acarbose, which needs to be initiated at a low, slowly increasing dose, is noted for the fact that it has virtually no systemic side effects. Metformin reduces plasma glucose levels without inducing hyperinsulinemia, and carries virtually no risk of lactic acidosis. Glibenclamide can be used either alone to treat type 2 diabetes or in combination with other oral antidiabetics or insulin. Today, intensified insulin therapy represents the optimal standard of insulin replacement. It permits meal-oriented injection of normal insulin and the use of longer-acting insulin overnight. This form of treatment is now facilitated by the possibilities of plasma glucose selfmonitoring and the use of injection aids (pen). Intensified treatment should be initiated at the time type I diabetes is diagnosed. In the case of a particularly instable metabolic situation or neuropathy, it may become necessary to use insulin pumps.
Effect of the antidiabetic agent pioglitazone on the insulin-mediated activation of protein phosphatase-1 was examined in diabetic hepatocytes. Streptozotocin-induced diabetes in Sprague Dawley rats caused a significant decrease in the activation of glycogen synthase in hepatocytes isolated from these animals. There was an inverse correlation between the in vivo hyperglycemic condition and the in vitro activation of glycogen synthase in liver cells (r = 0.93, p < 0.001). Long term incubation of diabetic hepatocytes with insulin and dexamethasone caused significant (p < 0.001) improvement in the activation of glycogen synthase activation. When incubated along with hormones, pioglitazone enhanced their action (p < 0.05-0.01). Diabetic hepatocytes were also characterized by 50% decrease in the activity of protein phosphatase-1, the enzyme which dephosphorylates and activates glycogen synthase. Pioglitazone potentiated the acute stimulatory effect of insulin on protein phosphatase-1 in normal hepatocytes but not in diabetic hepatocytes. Long term incubation of diabetic hepatocytes with insulin ameliorated the decrease in the protein phosphatase-1 activity in these cells. This stimulatory long-term effect of insulin was significantly (p < 0.05) enhanced by the antidiabetic agent pioglitazone.
In the treatment of type 2 diabetes (NIDDM) we possess three groups of oral hypoglycaemic drugs: sulfonyl urea derivatives, biguanides (metformin) and alpha-glucosidase (acarbose) inhibitors. Oral treatment of diabetes has a favourable impact on the patients metabolic deviations but it involves also certain dangers and pitfalls. The side-effects of oral antidiabetics can be reduced to a minimum by respecting consequentially contraindications of administration of different preparations, knowledge of their mechanism of action and individual selection of a suitable antidiabetic for every patient.