Combined administration of gallic acid and glibenclamide mitigate systemic complication and histological changes in the cornea of diabetic rats induced with streptozotocin

Purpose: To determine the effect of gallic acid or its combination with glibenclamide on some biochemical markers and histology of the cornea of streptozotocin (STZ) induced diabetic rats. Methods: Following induction of diabetes, 24 male albino rats were divided into four groups of six rats each. Groups 1 and 2 (control and diabetic) received rat pellets and distilled water; group 3 (gallic acid) received rat pellets and gallic acid (10 mg/kg, orally) dissolved in the distilled water; and group 4 (gallic acid + glibenclamide) received rat pellets, gallic acid (10 mg/kg, orally), and glibenclamide (5 mg/kg, orally) dissolved in the distilled water. The treatments were administered for three months after which the rats were sacrificed after an overnight fast. Blood and sera were collected for the determination of biochemical parameters, while their eyes were excised for histology. Results: STZ administration to the rats induced insulin resistance, hyperglycemia, microprotenuria, loss of weight, oxidative stress, inflammation, and alteration of their cornea histology, which was abolished following supplementation with gallic acid or its combination with glibenclamide. Conclusions: The study showed the potentials of gallic acid and glibenclamide in mitigating systemic complication and histological changes in the cornea of diabetic rats induced with STZ.

Uso de hipoglicemiantes orales durante la lactancia / Use of oral hypoglycemic agents during breastfeeding

Antecedentes: Los hipoglicemiantes orales son una alternativa emergente en el tratamiento de la diabetes mellitus gestacional (DMG), pero existe poca información acerca de su uso durante la lactancia. Objetivo: Revisar la evidencia respecto a la seguridad del uso de los hipoglicemiantes orales durante la lactancia. Resultados: Encontramos 3 trabajos que evaluaron el paso de metformina a la leche materna: hubo traspaso de metformina a leche materna en todos los casos. La concentración de metformina excretada a la leche fue en promedio 48 por ciento de la concentración plasmática materna. Las dosis calculadas que recibieron los lactantes en promedio fue 0,38 por ciento de la dosis materna, ajustada por peso. La concentración promedio de metformina en los lactantes fue de 0,025 mg/L. No se reportaron efectos adversos en los lactantes, incluso en el seguimiento a 6 meses de vida. Se encontró sólo un trabajo en relación a glibenclamida y lactancia materna, en el que no se detectó excreción del fármaco a la leche materna. Conclusiones: Los hipoglicemiantes orales parecen ser medicamentos seguros durante la lactancia, sin embargo, la evidencia es escasa. Sugerimos el uso de la glibenclamida por sobre metformina, por su nulo paso a la leche materna.

Background: Oral hypoglycemic agents are an emergent therapy for the treatment of gestational diabetes mellitus (GDM), but there is little information about its use during breastfeeding. Objectives: To review the available evidence regarding the use and safety of oral hypoglycemic agents during breastfeeding. Results: We found 3 studies that described the transfer of metformin to breast milk; there was transfer of metformin to breast milk in all cases. The concentration of metformin in breast milk was 48 percent of the maternal plasma concentration. The calculated dose for the infants was 0.38 percent of the maternal weight adjusted dose. The mean concentration of metformin in the infant's plasma was 0.025 mg/L. No adverse effects were reported in the infants, including 6 months of follow-up. Only one study investigated glyburide and breastfeeding, showing no excretion to breast milk. Conclusion: Oral hypoglycemic agents seem to be safe during breastfeeding; however, the available data is scarce. We suggest the use of glyburide over metformin because of its null excretion to breast milk.

The hydrogen sulfide donor, Lawesson's reagent, prevents alendronate-induced gastric damage in rats

Our objective was to investigate the protective effect of Lawesson's reagent, an H2S donor, against alendronate (ALD)-induced gastric damage in rats. Rats were pretreated with saline or Lawesson's reagent (3, 9, or 27 µmol/kg, po) once daily for 4 days. After 30 min, gastric damage was induced by ALD (30 mg/kg) administration by gavage. On the last day of treatment, the animals were killed 4 h after ALD administration. Gastric lesions were measured using a computer planimetry program, and gastric corpus pieces were assayed for malondialdehyde (MDA), glutathione (GSH), proinflammatory cytokines [tumor necrosis factor (TNF)-α and interleukin (IL)-1β], and myeloperoxidase (MPO). Other groups were pretreated with glibenclamide (5 mg/kg, ip) or with glibenclamide (5 mg/kg, ip)+diazoxide (3 mg/kg, ip). After 1 h, 27 µmol/kg Lawesson's reagent was administered. After 30 min, 30 mg/kg ALD was administered. ALD caused gastric damage (63.35±9.8 mm2); increased levels of TNF-α, IL-1β, and MDA (2311±302.3 pg/mL, 901.9±106.2 pg/mL, 121.1±4.3 nmol/g, respectively); increased MPO activity (26.1±3.8 U/mg); and reduced GSH levels (180.3±21.9 µg/g). ALD also increased cystathionine-γ-lyase immunoreactivity in the gastric mucosa. Pretreatment with Lawesson's reagent (27 µmol/kg) attenuated ALD-mediated gastric damage (15.77±5.3 mm2); reduced TNF-α, IL-1β, and MDA formation (1502±150.2 pg/mL, 632.3±43.4 pg/mL, 78.4±7.6 nmol/g, respectively); lowered MPO activity (11.7±2.8 U/mg); and increased the level of GSH in the gastric tissue (397.9±40.2 µg/g). Glibenclamide alone reversed the gastric protective effect of Lawesson's reagent. However, glibenclamide plus diazoxide did not alter the effects of Lawesson's reagent. Our results suggest that Lawesson's reagent plays a protective role against ALD-induced gastric damage through mechanisms that depend at least in part on activation of ATP-sensitive potassium (KATP) channels.

Hipoglicemiantes orales para el tratamiento de la diabetes mellitus gestacional: revisión sistemática de la literatura / Oral hypoglycaemic agents for the treatment of gestational diabetes mellitus: systematic review of the literature

Antecedentes: la diabetes mellitus gestacional (DMG) se asocia a mayor riesgo materno y perinatal. El manejo habitual de ésta patología es la dieta, el ejercicio y la insulina. Los hipoglicemiantes orales (HGO) son una terapia emergente para el tratamiento de la DMG. Objetivos: realizar una revisión sistemática de toda la evidencia tipo I disponible acerca del uso de HGO para tratamiento de DMG y realizar un metaanálisis de los resultados maternos y perinatales significativos. Resultados: diez estudios cumplieron criterios de selección. Tres estudios comparaban metformina vs insulina, cuatro gliburide vs insulina y tres metformina vs gliburide. Los estudios no encontraron diferencias significativas en control glicémico ni en complicaciones perinatales entre metformina vs insulina, gliburide vs insulina y metformina vs gliburide. Nuestro metaanálisis mostró que la glicemia de ayuno es significativamente menor (DM 1,74; IC95 por ciento 0,383,10) y la glicemia postprandial a las 2 horas es significativamente mayor en el grupo insulina vs HGO (DM -2,97; IC95 por ciento -27,24 a -5,36). Nuestro metaanálisis muestra que la incidencia de fetos grandes para edad gestacional fue significativamente menor en el grupo metformina vs gliburide (OR 0,38; IC95 por ciento 0,18-0,78). El fracaso del tratamiento con gliburide fue significativamente menor que con metformina (27,6 por ciento vs 38,5 por ciento, p<0,0001; IC95 por ciento 1,21-1,60). Conclusión: los HGO son un tratamiento seguro y efectivo para DMG. Recomendamos gliburide (glibenclamida) para el tratamiento de las pacientes con DMG que fracasan su control glicémico con dieta y ejercicio, por no cruzar la placenta, tener menor tasa de fallo y ser igualmente efectiva que metformina.

Background: gestational diabetes mellitus (GDM) is associated to a higher maternal and perinatal risk. Usually GDM is controlled with diet, exercise and insulin. Oral hypoglycaemic agents (OHA) are an emergent therapy for the treatment of GDM. Objectives: conduct a systematic review of all class I evidence available regarding the use of OHA for GDM treatment, and perform a metaanalysis of significant maternal and perinatal outcomes. Results: ten studies accomplished inclusion criteria. Three studies compared metformin to insulin, four compared glyburide to insulin and three compared metformin to glyburide. Studies showed no significant differences in glycaemic control or perinatal complications, between metformin and insulin, between glyburide and insulin, or between metformin and glyburide. Our metaanalysis comparing OHA to insulin shows significantly lower fasting blood glucose (MD 1.74; 95 percent IC 0.38-3.10) and larger 2-hr postprandial glucose in the insulin group compared to OHA groups (MD -2.97; 95 percent IC -27.24-5.36). Our metaanalysis comparing shows a significantly lower incidence of large for gestational age in the metformin vs. gliburide group (OR 0.38; 95 percent IC 0.18-0.78). Failure of treatment was significantly lower using gliburide than metformin (27.6 percent vs. 38.5 percent, p<0.0001; 95 percent IC 1.21-1.60). Conclusion: OHA are a safe and effective treatment for GDM. We recommend the use of glyburide (glibenclamide) in GDM patients that fail to obtain glycemic control with diet and exercise, since glyburide does not crosses the placental barrier, has a lower rate of treatment failure and is equally affective as metformin.

Prescription patterns for diabetes mellitus and therapeutic implications: a population-based analysis / Padrões de prescrição e implicações terapêuticas para o diabetes melito: análise de base populacional

OBJECTIVE: To analyze drug prescriptions for insulin and oral antidiabetic drugs in type 1 and type 2 diabetes mellitus patients seen in the Brazilian Public Healthcare System (Unified Health System - SUS) in Ribeirao Preto, SP, Brazil. SUBJECTS AND METHODS: All the patients with diabetes seen in the SUS in the western district of Ribeirao Preto, SP, Brazil between March/2006 and February/2007 were included in the study. RESULTS: A total of 3,982 patients were identified. Mean age of the patients was 60.6 years, and 61.0% were females. Sixty percent of the patients were treated with monotherapy. Doses of oral antidiabetic drugs were lower in monotherapy than in polytherapy. Ten patients received doses of glibenclamide or metformin above the recommended maximum doses, and in elderly patients there was no reduction in drug doses. CONCLUSION: Monotherapy with oral antidiabetic drugs was the predominant procedure, and the doses were not individualized according to age.

OBJETIVO: Analisar as prescrições medicamentosas dos antidiabéticos orais e insulina em pacientes portadores de diabetes melito tipo 1 e tipo 2 atendidos pelo Sistema Único de Saúde (SUS) em Ribeirão Preto, SP, Brasil. SUJEITOS E MÉTODOS: Todos os pacientes com diabetes atendidos no distrito sanitário oeste de Ribeirão Preto, SP, do SUS, entre março/2006 e fevereiro/2007, foram incluídos no estudo. RESULTADOS: Foram identificados 3.982 pacientes com diabetes. Idade média dos pacientes foi de 60,6 anos e 61,0% do gênero feminino. Sessenta por cento foram tratados com monoterapia. A dose dos antidiabéticos foi menor em monoterapia quando comparada à politerapia. Dez pacientes receberam doses de glibenclamida e metformina acima da dose máxima recomendada. Além disso, em pacientes idosos, não houve redução da dose. CONCLUSÃO: A monoterapia com antidiabéticos orais foi prevalente e não houve individualização da dose de acordo com a faixa etária.

Permanent neonatal diabetes due to KCNJ11 gene mutation.

Permanent neonatal diabetes mellitus (PNDM) is characterized by the onset of diabetes within the first six months of life and insulin dependence life long. It has been recently discovered that mutation in KCNJ11 gene encoding Kir6.2, the pore forming subunit of ATP sensitive potassium channel (K ATP) is the most common cause and such patients may respond better to oral sulphonylurea drugs than insulin. Here is a rare case of permanent neonatal diabetes due to R20IC mutation in KCNJ11 gene.

Beneficial effects of triple drug combination of pioglitazone with glibenclamide and metformin in type 2 diabetes mellitus patients on insulin therapy.

BACKGROUND: The thiazolidinediones are a class of antidiabetes medication that enhance the actions of insulin in muscle, liver, and adipose tissue. Data have been lacking on their use in combination with both sulfonylurea and metformin among patients of type 2 diabetes who are on insulin therapy secondary to failure of routine oral hypoglycemic drugs in controlling their diabetes. OBJECTIVE: To determine the effects of pioglitazone in combination with sulphonylurea and metformin on diabetes control in patients being treated with insulin due to secondary failure of oral hypoglycemic agents. PATIENTS: One hundred and twenty-four consecutive type 2 diabetes patients (mean age, 57.13 years) attending four centres in Mumbai, who were being treated with insulin were selected. They were switched on to triple drug combination of glibenclamide 5 mg, metformin 500 mg and pioglitazone 15 mg along with insulin. Study participants were required to have type 2 diabetes mellitus for atleast 5 years. Patients were excluded if they had any of the following: serum creatinine concentration greater than 1.5 mg/dl, alanine aminotransferase (ALT) level more than two times the upper limit of normal, symptomatic angina, cardiac insufficiency or history of myocardial infarction. RESULTS: Pioglitazone 15 mg with glibenclamide 5 mg and metformin 500 mg, significantly decreased hemoglobin HbA1c level from 11.5% to 7.32% (P < 0.001), average fasting blood glucose from 194.8 mg/ dl to 124.06 mg/dl (p < 0.01), average post-prandial blood glucose from 256.24 to 162.32 mg/dl (p < 0.01). At 6 months, 43.35% of patients did not need to be continued on insulin. The total insulin requirement in 124 patients reduced by 71.81%. There were no significant side effects, liver enzymes were within acceptable levels, average weight gain was 2.23 kg, significant hypoglycemia was observed in 28 patients with two requiring hospitalisation, these patients were those who did not stick to follow-up schedules. CONCLUSIONS: With proper patient selection, pioglitazone with glibenclamide and metformin can be safely used in patients receiving insulin with good results.

Response of regimens of insulin therapy in type 2 diabetes mellitus subjects with secondary failure.

OBJECTIVE: To find the response of various regimen of combination therapy (Insulin and Glibenclamide) in type 2 diabetes mellitus subjects who failed to respond to maximum doses of glibenclamide (GBC) plus phenformin. METHODS: A total of 188 subjects with secondary sulfonylurea failure who failed to respond to maximum doses of GBC and phenformin were randomised to receive one of the four regimens. Group A (50 patients) received two doses of insulin; Group B (49 patients) received two doses of insulin and GBC 20 mg/day; Group C (43 patients) received morning dose of insulin with GBC 20 mg/day; and Group D (46 patients) received evening dose of insulin with GBC 20 mg/day. Insulin dose was adjusted to achieve an acceptable blood glucose control. Control of diabetes was revaluated at three months post-treatment period. RESULTS: Age, duration of diabetes, weight, body mass index (BMI) and biochemical parameters were comparable in all four groups at admission. Dose of insulin was 0.83 +/- 0.07, 0.86 +/- 0.06, 0.46 +/- 0.04 and 0.39 +/- 0.03 units/Kg/day in groups A, B, C and D, respectively. Comparing groups A and B, we found that the dose of insulin (IU/kg/day) required to achieve acceptable fasting blood glucose (FBG) did not differ significantly. Similarly, comparison between Groups C and D did not reveal any significant difference in insulin dose. Mean hospital stay required to achieve an acceptable FBG was 8.42 +/- 0.34, 11.95 +/- 1.11, 8.59 +/- 0.61 and 7.10 +/- 0.48 days in groups A, B, C and D, respectively (p = 0.013). On comparing the four treatment regimens, at three months follow-up, there was a significant increase in bodyweight in Group C; also there was an increase in fasting blood glucose in all the groups except in Group D. CONCLUSIONS: Continuation of GBC in type 2 diabetes mellitus subjects who fail to respond to maximum doses of GBC plus phenformin and who need two doses of insulin for control has no added advantage over giving insulin alone. In subjects controlled on a single dose of insulin with glibenclamide it is preferable to give an evening dose rather than a morning dose.

Effect of ATP sensitive potassium channel modifiers on antinociceptive effect of metoclopramide.

Metoclopramide, a prokinetic drug, has been documented to produce antinociceptive response in animal models through opioid pathways. Morphine has been shown to act through ATP sensitive potassium channels (KATP) to produce antinociceptive response. However, such a possibility has not been examined for metoclopramide. The present study investigated this using pharmacological tools. Acetic acid induced abdominal constriction assay procedure was utilized to assess antinociception. The results confirmed that metoclopramide has antinociceptive response. Glibenclamide, a KATP channel blocker, pretreatment antagonized this response. Where as, in minoxidil pretreated animals, metoclopramide elicited an enhanced antinociceptive response. Glibenclamide and minoxidil, which are known KATP channel blocker and opener respectively, interfered with metoclopramide antinociception. These finding are suggestive of a role for KATP channels in metoclopramide antinociception in mice.

Influence of Fluvoxamine Administration on Glibenclamide Pharmacokinetics After Multiple Oral Dosing in Rats

Glibenclamide is extensively metabolized in the liver through oxidative pathways involving the cytochrome P450 system. Fluvoxamine, a potent inhibitor of cytochrome P450 [CYP] isoenzymes may be coadministered with glibenclamide. The aim of this study was to investigate whether or not fluvoxamine influences the pharmacokinetics of glibenclamide after multiple oral doses of both drugs in rats. Eighteen rats were divided into 3 groups for blood sampling. All rats received oral dose of 2.5 mg/kg for 7 days. Blood samples were collected up to 24 h after the initial dose, and on day 7 for glibenclamide. On day 8, a daily oral dose of fluvoxamine [50 mg/kg] was added and the administration of the two drugs were continued for 7 more days. On day 14, blood samples were also collected for the determination of both glibenclamide and fluvoxamine. Results indicated that following the single dose administration, glibenclamide C [max], was 415 +/- 169ng/ml, T[max], was 3.7 +/- 1.4h, t[1/2] was about 12 h and apparent clearance [C1/F] was 629 ml h[-1]kg[-1]. However, multiple dose administration of glibenclamide increased the AUC by 30% compared to the single dose. On the other hand, fluvoxamine coadministration was associated with a 16% increase in ACU. There was no significant change [p>0.05] in either C[max], or T[max]. A twenty% reduction in C1/F of glibenclamide was observed, however the difference was not significant. Therefore, the administration of fluvoxamine did not significantly alter glibenc1amide pharmacokinetic parameters. Further studies in diabetic rats or human should be performed, for a long period of time, to demonstrate if such interaction between fluvoxamine and glibenclamide is of pharmacokinetic and /or pharmacodynamic significance

Eficacia de la combinación glibenclamida-metformina en el descontrol metabólico del paciente diabético no insulinodependiente / Glibenclamide-metformin effiicacy in the treatment of uncontrolled non-insulindependent diabetic patients

Antecedentes: la diabetes mellitus no insulinodependiente (DMNID) es una enfermedad de gran importancia por su incidencia y prevalencia. La DMNID representa casi 90 por ciento del total de pacientes diabéticos del mundo occidental. Su relación con la hiperlipidemia es directa, causa-efecto, y esto incrementa al riesgo de contraer enfermedad coronaría. Su tratamiento incluye: dieta, ejercicio y fármacos. Entre estos últimos se encuentran las biguanidas. Objetivo: evaluar la eficacia de la combinación glibenclamida-metformina en el índice de control metabólico en pacientes diabéticos no insulinodependientes. Material y métodos: estudio clínico abierto, longitudinal y prospectivo. Los criterios de inclusión fueron: a) pacientes de uno y otro sexo b) edad entre 40 y 70 años, c) glucosa sérica y en ayunas = 140 mg/dl pese a tomar dosis máximas de glibenclamida, d) depuración de creatinina en orina de 24 horas = 60 ml/min, e) creatinina sérica < 1.4 mg/dl en hombres y 13 mg/dl en mujeres, f) pruebas de función hepática normales. Se incluyeron, de forma secuencial, a los pacientes que cumplieron los criterios de selección. El esquema de dosis de metformina fue 425 mg en 24 horas, con incremento de la dosis cada dos horas. Se estudiaron durante un período de 16 semanas y se determinó: glucemía en ayuno, porcentaje de HbA1c, colesterol total, HDL, triglicéridos al ingreso y cada dos semanas. Se calculó la frecuencia y medidas de tendencia central, así como la dispersión de todas las variables; y las variables cuantitativas se analizaron mediante la prueba t de Student...

Normoglucemia en diabetes mellitus no dependiente de insulina de reciente diagnóstico. Tratamiento no farmacológico vs. tratamiento farmacológico / Normoglucemia in newly diagnosed no insulin dependent diabetes mellitus. Non pharmacologic therapy vs. pharmacologic therapy

Objetivo: Comparar la efectividad en el control metabólico de las medidas no farmacológicas vs. el tratamiento inicial con drogas (glibenclamida y metformina) en pacientes con DMNDI de reciente diagnóstico. Diseño: Ensayo clínico. Marco de referencia: Hospital de tercer nivel de atención en la ciudad de Monterrey, NL. Pacientes: Noventa pacientes con diabetes mellitus no insulinodependiente de reciente diagnóstico (38 hombres y 52 mujeres, con edad promedio de 38 ñ 7 años), sin embarazo, condiciones que requieran insulina o contraindicaciones al uso de los fármacos. Intervenciones: A todos los enfermos se les exhortó a cambiar su estilo de vida, dándoles a conocer los beneficios de modificar su plan de alimentación y realizar ejercicio en forma regular, posteriormente se dividieron en forma aleatoria en tres gupos: I (n = 32), se les indicó continuar con medidas no farmacológicas, IIA (n = 29) y IIB (n = 29), igual al grupo I, pero además se les agregó glibenclamida (10.20 mg/día) y metformina (850-1,750 mg/día), respectivamante. Mediciones y resultados: Se observa que en el grupo I no hay variación en el control glucémico (248 ñ 38 vs. 219 ñ 30 mg/dl, p = NS), tampoco en el perfil de lípidos, peso o concentraciones de insulina; en el grupo de tratamiento con fármacos, el control glucémico fue igual con glibenclamida y metformina: glucosa de 264 ñ 16 a 149 ñ 30 mg/dl; de 270 ñ 31 a 134 ñ 26 y Hgb A1C de 11.2 ñ 2 a 8 ñ 1.3 por ciento y de 11 ñ 2 a 7.9 ñ 1.2 por ciento (p < 0.001 en ambos grupos); sin embargo, sólo en el gupo con metformina fue evidente una disminución significativa de triglicéridos (p < 0.05) y de insulina (p < 0.05). Conclusiones: El tratamiento farmacológico temprano es más eficaz que el tratamiento "convencional" en el paciente con DMNDI de reciente diagnóstico. El efecto hipoglucemiante entre glibenclamida y metformina es similar

Sensitivity of Leishmania spp. to glibenclamide and 4-Aminopiridine: a tool for the study of drug resistance development

We have demonstrated that Leishmania spp. grown as promastigotes, are sensitive to the K+ channel inhibitors 4-aminopyridine and glibenclamide. Their host cells, the macrophages, are not affected by similar concentrations of the drugs. We have also initiated the molecular characterization of the mechanisms involved in the development of drug resistance to glibenclamide by the parasite. Therefore, we have selected experimentally and begun to characterize the Venezuelan Leishmania (Leishmania) strain, NR resistant to glibenclamide [NR(Gr)]. The analysis of genomic DNA evidenced the existence of a fragment which apparently is amplified in NR(Gr). The fragment recognized by the pgpA probe, related to the Leishmania P-glycoprotein family and which was originally isolated from L. tarentolae, showed a size polymorfism between the sensitive and the resistant strain. These results suggest that the development of resistance to glibenclamide in the strain NR(Gr) might be associated with the amplification of the ItpgpA or related gene(s).

Drug interaction: rifampicin and glibenclamide.

BACKGROUND: Rifampicin is a potent inducer of the hepatic microsomal enzyme system. However, the drug has been shown to cause clinically important interactions with many drugs. This study was designed to test the interaction of rifampicin with the oral hypoglycaemic agent glibenclamide. METHODS: Twenty-nine well-controlled diabetic patients on a combination therapy of diet and glibenclamide, and willing to participate in the trial, received a daily dose of 450 mg (body weight < 50 kg) or 600 mg (body-weight > 50kg) of rifampicin for 10 days. RESULTS: There was a significant (p < 0.001) worsening of fasting and post-prandial blood sugar after administration of rifampicin. Dose modification of glibenclamide was required in 15 of the 17 patients in whom the diabetes became uncontrolled. Blood sugar normalized by day 6 after stopping rifampicin in all patients. CONCLUSION: Rifampicin and glibenclamide interact. Therefore, necessary dose modifications should be made in order to achieve euglycaemia if these two drugs are given together.

Effect of bed time intermediate acting insulin in NIDDM subjects refractory to a combination of sulphonylureas and biguanides.

The effect of a single dose of intermediate acting (Lente) insulin given subcutaneously at 9.00 P.M. in 22 NIDDM subjects refractory to a combination of Sulphonylureas and Biguanides was analysed. Euglycemia was achieved and maintained during the study period of three months with a mean insulin requirement of 14.22 +/- 5.98 units/day. Plasma FFA, Total cholesterol, triglyceride and VLDL-cholesterol also showed significant reduction. The level of FFA modulates hepatic glucose production, which in turn correlates positively with the fasting blood glucose. The therapeutic modality of bed time Lente Insulin based on physiological principles is an effective way of achieving glycemic control in NIDDM subjects who have become non-responsive to oral hypoglycemic agents.

Combination therapy of glibenclamide and insulin in NIDDM patients with secondary failure to oral drugs.

A trial of combination therapy with glibenclamide + insulin was conducted in 26 patients with non insulin dependent diabetes mellitus (NIDDM) who had secondary failure to oral hypoglycaemic agents (OHA). Patients were included in the study if they failed to respond to a dose of 15 mg of glibenclamide under strict dietary regulations. Small doses of insulin were added until satisfactory glucoregulation was achieved. On withdrawal of the OHA, in 20 patients, the post-prandial plasma glucose values (PPBS) increased again by greater than or equal to 25%; they were considered as "responders". Responders were divided into two equal groups of alternate patients; group I was treated with insulin + glibenclamide and group II with insulin + placebo. The patients were then followed up at monthly intervals for 6 months. The dose of insulin required to maintain normal plasma glucose value was significantly lower (P less than 0.05) in group I. Fewer patients in group I needed two injections of insulin per day; however this difference was not statistically significant. Normalisation of serum triglyceride and lowering of HbA1 occurred in both groups. This study shows that addition of glibenclamide to insulin treatment is advantageous in NIDDM patients showing secondary failure to OHA.