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PubMedDate not supplied

[Response of insulin and C-peptide to a mixed meal in non-insulin-dependent diabetics treated with insulin and chlorpropamide].

Glucose control in NIDDM is prone to progressive deterioration due to secondary failure to oral hypoglycemic therapy. Insulin may subsequently be required for optimal control in spite of peripheral hyperinsulinemia. In Mexico, diabetes associated with obesity is common. We therefore designed a prospective study combining insulin and chloropropamide in order to evaluate any improvement in insulin response to a standardized meal load and a consequent amelioration of glucose control. METHODS. Twenty diabetic patients with secondary failure to full doses of hypoglycemic drugs and moderate hyperglycemia were recruited. Therapy was initiated with human insulin 20 IU/day and 500 mg cholopropamide, titrating insulin dosage in order to achieve euglycemia. Before treatment and at the end of the study period, a glucose/insulin/C peptide response curve to a mixed standardized meal was performed. Blood glucose, serum lipids fructosamine and glycosylated hemoglobin levels were also determined. All patients were followed by capillary glucose measurements three times a week and glucose and fructosamine concentrations every two weeks during the study period. RESULTS. All patients required less insulin, and glucose control improved significantly. Glucose, fructosamine and glycosylated hemoglobin levels decreased from 262 mg/dL, 369 mmol/L and 14% to 111 mg/dL, 252 mmol/L, and 8% respectively; all differences were statistically significant. Insulin and C peptide levels increased significantly from 22.2 mU/mL and 1.65 ng/mL to 29.8 mU/mL and 1.97 ng/mL, respectively. When we measured the area under the curve, total values improved from 110 and 7.69 to 127 and 9.37, respectively; this was also statistically significant. Lipids levels decreased significantly, including triglicerides, total and LDL cholesterol whereas HDL cholesterol levels increased. CONCLUSIONS. Glucose control improved in our patient cohort the pancreatic insulin response probably due to a more adequate glycemic microenvironment and a possible enhanced exogenous and endogenous insulin function.

Blood Glucose↗
PubMedDate not supplied

[A comparative evaluation of the hypoglycemic activity of acetyl-alpha-carnitine and chlorpropamide in experimental diabetes].

The comparison of the action shown by acetyl-alpha-carnitine and chloropropamide in rabbits with experimental diabetes has demonstrated that the former has a more pronounced hypoglycemic action. In combined administration, acetyl-alpha-carnitine substantially enhanced the effects of chloropropamide in the animals with experimental diabetes, which should be taken into account by clinicians in its use.

Acetylcarnitine↗
PubMed1981

Water metabolism in diabetes mellitus.

Transcellular shifts of water and changes in the physiology of water excretion are common in diabetes mellitus and its treatment. Recent evidence indicates that hyperglycemia in diabetic patients, but not in normal subjects, is characterized by elevations of circulating levels of arginine vasopressin (AVP; antidiuretic hormone, ADH). The role and importance of these observations remain to be defined since elevations of plasma AVP levels do not decrease water excretion in diabetic patients. Certain oral sulfonylureas, notably chlorpropamide and tolbutamide, are known to decrease renal free water clearance (CH2O), whereas insulin increases CH2O; the insulin and tolbutamide effects may be clinically trivial, whereas that of chlorpropamide is important. The hyponatremic effect of chlorpropamide may be exaggerated in diabetic patients by concomitant diuretic therapy. Euglycemia during chlorpropamide therapy appears to allow full expression of the action of chlorpropamide on CH2O; hyperglycemia with attendant osmotic diuresis protects chlorpropamide-treated patients against hyponatremia. Inhibition of prostaglandin synthesis with nonsteroidal anti-inflammatory agents enhances expression of the ADH effect on the kidney, but it does not appear to potentiate chlorpropamide hyponatremia. Two other oral sulfonylurea agents, tolazamide and glyburide, increase CH2O. Diazoxide is an antihypertensive thiazide which is antidiuretic as well as hyperglycemic. Thus, abnormalities of water metabolism are common in diabetes mellitus. Whether certain of these abnormalities are clinically important depends upon the presence of the osmotic diuresis of hyperglycemia and the pharmacology of diabetic management.

Arginine Vasopressin↗
PubMed1977

Effect of sulfonylureas on triglyceride metabolism in the rat liver: possible role of the lysosomes in hepatic lipolysis.

It has been suggested previously that chlorpropamide and other hypoglycemic sulfonylureas interfere with hepatic triglyceride breakdown. Since ketogenesis from endogenous hepatic lipid stores is a measure of hepatic triglyceride hydrolysis, ketogenesis derived from endogenous lipids as well as ketogenesis derived from exogenously added isotopic oleate was determined in isolated hepatocytes from fasted rats in an attempt to identify the nature of the direct effects of sulfonylureas on hepatic lipid metabolism. Ketogenesis from endogenous lipids was inhibited by 1 mM chlorpropamide, while ketone production from exogenous oleate did not change. The effect of chlorpropamide on hepatic triglyceride metabolism was further studied in the isolated perfused liver of normal rats in the presence of a continuous [3H]oleate infusion and in isolated liver cells incubated in the presence of [3H]oleate. In liver perfusion experiments, 1 mM chlorpropamide enhanced the incorporation of tritium into triglycerides (but not other lipid classes) and increased both liver triglyceride content and triglyceride secretion. Using isolated cells similar effects could be demonstrated at 0.5 mM chlorpropamide. Chlorpropamide, tolbutamide, and carbutamide, all of which inhibited endogenous ketogenesis in isolated liver cells, also inhibited lysosomal triglyceride lipase activity in rat liver homogenates. The drugs were not inhibitory towards alkaline lipase activity. Demethylglycodiazin (2-benzolsulfonamid--5-(beta-hydroxyethoxy)-pyrimidin), which did not inhibit endogenous ketogenesis in isolated liver cells, did not affect lysosomal lipase activity. The lysosomotropic drug chloroquine was markedly antiketogenic when tested in liver cells. The reduction in endogenous ketogenesis, the enhanced accumulation of liver triglycerides, and the stimulation of hepatic triglyceride output by chlorpropamide are ascribed to an interference of the drug with hepatic triglyceride breakdown. The present results also suggest that the lysosomes play a significant role in hepatic lipolysis.

Animals↗
PubMed1980

Carbenoxolone interactions in man--preliminary report.

Carbenoxolone is a potent ulcer-healing drug which is extensively bound to plasma proteins and therefore has the potential for displacement interaction. However, carbenoxolone has been shown to be bound to human serum albumin in vitro at a different class of binding site to many other drugs and does not potentiate the pharmacological activity of warfarin, tolbutamide, chlorpropamide or phenytoin in the rat. In the present study four volunteers each received a single 100 mg dose of Biogastrone and the plasma half-life of carbenoxolone was determined. The procedure was repeated with a concurrent dose of either warfarin 10 mg, tolbutamide 500 mg, chlorpropamide 250 mg or phenytoin 100 mg. Chlorpropamide appeared to delay the absorption of carbenoxolone but no effects were observed with the other drugs. The study with concomitant chlorpropamide treatment was repeated with 6 gastric ulcer patients on an established Biogastrone regimen. In these patients the delayed absorption of carbenoxolone was confirmed although no changes in the glucose-lowering activity of chlorpropamide were evident. Further investigations into this findings are in progress.

Carbenoxolone↗
PubMed1982

Impaired effect of sulfonylurea following increased dosage.

Ten Type 2 diabetics were examined during long-term treatment, at two dosage levels, with chlorpropamide once daily and glipizide t.i.d. Drug concentrations were measured by gas chromatography and high-pressure liquid chromatography, respectively, plasma insulin (IRI) by radio-immunoassay, and blood glucose enzymatically. Both drugs gave continuous sulfonylurea exposure, even at the lower dosage, and the mean plasma concentrations were almost doubled after the increase in dose. Neither the IRI nor the glucose response to meals showed any therapeutic improvement following the increase in chlorpropamide dosage. The lower dosage of glipizide produced better glucose utilization than chlorpropamide. On the other hand, the increased dose of glipizide led to impairment instead of further improvement. As this was associated with enhanced rather than reduced IRI levels, the impairment might have been due to increased peripheral insulin resistance. Thus, glipizide offers a therapeutic advantage over chlorpropamide, but its effectiveness may be restricted not only by limitations set by the disease, but also by counter-regulatory mechanisms that develop during continuous exposure to sulfonylureas at high levels.

Aged↗
PubMed1982

Influence of sulfonylureas on the secretion, disposal and effect of insulin.

The influence of sulfonylurea on the secretion, disposal and effect of insulin was studied in 9 Type 2 diabetics during 3 one-month courses of treatment with a) chlorpropamide (t1/2 greater than 24 h) once daily, b) glipizide (t1/2 = 2-4 h) once daily, and c) glipizide in divided doses. Food intake by each patient was identical during each period. Blood concentrations of immunoreactive insulin (IRI) and C-peptide (radioimmunoassays), and of glucose (enzymatic assay), chlorpropamide (gas chromatography) and glipizide (high-pressure liquid chromatography) were determined before and after breakfast and lunch on the 4th day of each examination period. All comparisons were intraindividual. Despite the lunch-time dose of glipizide given during the divided dose treatment, once-daily administration of this drug led to higher drug concentrations not only after breakfast but also for the first few hours after lunch. Divided dosage, on the other hand, led to higher concentrations later. In contrast to once-daily dosage, continuous exposure to glipizide was found in most patients. Chlorpropamide gave the most continuous sulfonylurea exposure. The blood glucose levels were inversely related to the concurrent sulfonylurea concentrations; glucose levels after breakfast and lunch were lowest during once-daily glipizide, whereas the fasting level was lowest during chlorpropamide treatment. The IRI response to breakfast was 60%-70% higher during once-daily glipizide than during the other two treatments but the C-peptide responses to breakfast were almost identical. Thus, the greater after-breakfast availability of peripheral insulin appeared to be due to an effect of glipizide on the extrapancreatic disposal of the hormone.

Aged↗
PubMedDate not supplied

Effects of prolonged in vitro exposure to sulphonylureas on the function and survival of human islets.

The direct effects of prolonged exposure to sulphonylureas on the function and survival of human islets are unknown. This study assessed the insulin content, glucose-stimulated insulin release, islet cell apoptosis, and mRNA expression of insulin and GLUT-1 in isolated human islets cultured in the presence of therapeutical concentrations of glimepiride (10 microM), glibenclamide (10 microM), or chlorpropamide (600 microM). Islets were prepared by collagenase digestion and density gradient purification from 18 multiorgan donors and were then exposed for 24 h to the different sulphonylureas. Insulin content decreased significantly following culture with any sulphonylurea compound. In response to an acute challenge with 3.3 and 16.7 mM glucose, insulin release from the control islets accounted for 1.9 +/- 0.5% and 4.9 +/- 1.7% of total insulin content (P<.01), respectively. Glucose responsiveness was preserved in islets precultured in the presence of glimepiride, whereas high glucose level did not elicit any significant increase of insulin secretion from islets preincubated with glibenclamide or chlorpropamide. These alterations were reverted by an additional 48-h incubation in drug-free conditions. The amount of apoptotic cells did not differ significantly among the experimental groups. Quantitative RT-PCR studies showed that, compared with the control islets, cells preincubated with glibenclamide or chlorpropamide had an increased expression of insulin mRNA, with no change in the expression of GLUT-1. In conclusion, prolonged exposure of human islets to different sulphonylureas causes different disturbances of islet cell function, with glimepiride showing milder effects, as compared with chlorpropamide and glibenclamide.

Adult↗
PubMed1980

Comparative single-dose kinetics and effects of four sulfonylureas in healthy volunteers.

The single-dose kinetics and effects of tolbutamide (500 mg), chlorpropamide (250 mg), glibenclamide (5 mg) and glipizide (5 mg) were compared in 7 healthy male volunteers by measurements of serum concentrations of the drugs and of plasma insulin and blood glucose. The drugs were administered both on an empty stomach and together with a standardized breakfast. The concentrations of tolbutamide and chlorpropamide were measured by gas chromatography, those of glipizide with high-pressure liquid chromatography, those of glibenclamide and insulin by radioimmunoassay and those of glucose by the hexokinase method. Glipizide and glibenclamide were more potent inducers of insulin release and blood glucose reduction than tolbutamide and chlorpropamide. As the concentrations of the former two drugs were in the range of nmol/l and those of the latter two in the mumol/l range, the findings support the notion that the intrinsic activity of the two second-generation sulfonylureas is at least 1 000 times greater than that of the two first-generation drugs. Glipizide seemed to be a more potent and more rapid insulin releaser than glibenclamide, but this may be secondary to biopharmaceutic differences between the two preparations. The bioavailability of glipizide was apparently greater than that of glibenclamide. Both glibenclamide (t 1/2 = 1.8 h) and glipizide (t 1/2 = 4.3 h) showed much shorter elimination half-lives than tolbutamide (7 h) and chlorpropamide (34 h). It seems probable, however, that these half-lives are not fully informative as to the duration of action of the drugs.

Adult↗