Comparative effects of phenformin,metformin and glibenclamide on metabolic rhythms in maturity-onset diabetics

Summary Twelve hour metabolic rhythms have been performed on six maturity-onset diabetic subjects during successive periods of therapy with phenformin, metformin, and glibenclamide. Moderate control of blood glucose concentration was achieved with phenformin and metformin, the lowest concentrations being found with glibenclamide. Mean blood lactate concentration was grossly elevated during phenformin therapy, moderately elevated with metformin and normal during glibenclamide treatment. Similar patterns were found for the lactate/pyruvate ratio, alanine, glycerol and ketone bodies. Serum triglyceride concentrations were significantly higher during phenformin treatment than with the other two regimes. Serum insulin concentration was higher on glibenclamide than with either biguanide. Most of these effects of the biguanides could be accounted for by an inhibitory effect on hepatic gluconeogenesis. It is concluded that the use of biguanides as hypoglycaemic agents in diabetes is associated with the production of multiple metabolic abnormalities.     

Antihypertensives and their metabolic effects in diabetics

Due to its frequent occurrence in diabetics, hypertension is a serious problem from the aspect of its effect on cardiovascular morbidity and mortality. Evaluation of metabolic and clinical effects of treatment of hypertension in diabetics should precede considerations on the selection of suitable antihypertensive treatment.     

Hormonal and metabolic effects of chlorpropamide,glibenclamide and placebo in a cross-over study in diabetics not controlled by diet alone

Summary Twenty diabetic patients, whose hyperglycaemia had been shown to fail to respond to at least one month's dietary treatment, completed a crossover study in order to: 1) compare the effectiveness of two sulphonylureas, chlorpropamide and glibenclamide, and 2) study the effects of sulphonylureas on insulin secretion and on biochemical indices of glucose intolerance. Fasting blood glucose fell on active treatment from 10.7±0.6 (mean ± SEM) to 6.6±0.7 mmol/l and rose again to 10.6±0.7 after 4 months placebo. A second period of 4 months sulphonylurea therapy resulted in a comparable fall in blood glucose (to 6.9±0.7 mmol/l) and a similar relapse was seen after the second placebo period (to 10.5±0.9 mmol/l). Glucose tolerance and associated insulin secretion improved markedly on active treatment, with ketone bodies, non-esterified fatty acids, and glycerol falling to within the reference range. Sulphonylurea therapy was associated with a small but significant increase in the fasting insulin level. These effects were nearly all reversed 4 months after withdrawal of the sulphonylureas. No marked changes were found in growth hormone, lactate, pyruvate, lactate/pyruvate ratio or fasting cholesterol, triglycerides and lipoproteins. On a weight basis, glibenclamide was 26 times more potent than chlorpropamide and, in the doses used in this study, their biochemical effects were indistinguishable. The effects of these two sulphonylureas seem most likely to be mediated by a direct stimulation of insulin secretion by the B-cell.     

Gastrointestinal and metabolic effects of amylase inhibition in diabetics

A partially purified amylase inhibitor given with a single meal causes maldigestion of carbohydrate, increases delivery of carbohydrate to the ileum, and reduces postprandial plasma glucose. To determine the effect of more prolonged administration of the inhibitor on gastrointestinal function and carbohydrate tolerance, we studied 6 non-insulin-dependent diabetics (3 previously treated with oral agents and 3 treated with diet alone) for 3 wk while they ate a weight-maintenance diet. Patients taking oral agents continued them during the first week. During the second week, 4-6 g of the inhibitor was given with each meal. Capillary blood glucose concentration was measured before each meal and 90 min postprandially. On the last day of each week venous blood samples for glucose, hormones, and lactic acid analysis and a quantitative stool culture were obtained. Total carbohydrate absorption was estimated by comparing postprandial breath hydrogen on study days 7, 14, and 21 with breath hydrogen after ingesting 15 g of lactulose on days 0, 15, and 22. There 24-h stools were collected and weighed at the end of each week and analyzed for carbohydrate, lactic acid, short-chain fatty acids, pH, dry matter, amylase, and fat. The inhibitor significantly (p less than 0.05) reduced postprandial plasma glucose, C-peptide, insulin, and gastric inhibitory polypeptide concentrations, significantly increased (p less than 0.05) breath hydrogen excretion, and caused carbohydrate malabsorption. Diarrhea occurred the first day the inhibitor was ingested, but thereafter cessation of diarrhea was associated with changes in the metabolism of carbohydrate by colonic flora. As the amylase inhibitor improves carbohydrate homeostasis and is not associated with continuing diarrhea, it may be a useful adjuvant in the treatment of patients with non-insulin-dependent diabetes mellitus.     

Lipid abnormalities in untreated maturity-onset diabetics and the effect of treatment

Summary Plasma cholesterol and serum triglyceride levels and frequency of lipoprotein abnormalities were investigated in 126 untreated maturity-onset diabetics and 126 age- and sexmatched control subjects. Serum triglyceride levels were higher (mean: 1.67 mmol/l) and type IV hyperlipoproteinaemia occurred more frequently (16.7%) in the diabetic group as compared with the controls (1.29 mmol/l and 4.8% respectively). These findings were not explained by an excessive frequency of renal disease, hypertension or drug treatment amongst the diabetics. Normal men showed higher serum triglyceride (mean: 1.36mmol/l) and lower plasma cholesterol (mean: 5.6mmol/l) levels than normal women (1.21 mmol/1 and 6.4mmol/l respectively). No sex difference was seen amongst the diabetics. Triglyceride levels fell after one month of dietary treatment but only remained lowered in diabetics who required sulphonylureas for glycaemic control. After treatment for one year the correlation between serum triglycerides and blood glucose rose from r = 0.15 (NS) before treatment to r=0.43 (p<0.001). Similarly the correlation between serum triglycerides and ponderal index rose from r=0.19 (NS) to r=0.28 (p<0.02).     

Contribution to the nutrition-dependent release of insulin in obese maturity-onset diabetics

Summary Female, obese maturity-onset diabetics treated dietetically show a rise of plasma insulin concentration following administration ofbouillon and glucagon, and even after ingestion of proteins. The plasma insulin level changes in this group as well as in tolbutamide treated patients were found to depend on food uptake. The possibility of a disturbance of carbohydrate metabolism independent from the pancreas is discussed as a cause of diabetes in obese persons.Supported by Österreichischer Forschungsrat (Austrian Research Council).     

Metabolic abnormalities during combined sulphonylurea and phenformin therapy in maturity-onset diabetics

Summary Twelve hour metabolic rhythms have been determined in two groups of subjects during combined therapy with a sulphonylurea and phenformin 50 mg twice daily. Subjects with clinical evidence of complications of diabetes showed greater abnormalities in concentrations of blood intermediary metabolites than a group of subjects without complications despite similar mean blood glucose concentrations in the two groups (7.6 mmol/l with complications; 7.3 mmol/l without complications). Mean blood lactate (1.93 mmol/l v 1.39 mmol/l), alanine (0.56 mmol/1 v 0.43 mmol/l), total blood ketone bodies (0.20 mmol/l v 0.14 mmol/l) and several other intermediary metabolites and their ratios were significantly higher in the group with diabetic complications. It is suggested that the differences between the two groups may arise from impaired disposal of phenformin leading to higher blood concentrations in the group with diabetic complications, despite normal liver function tests and plasma creatinine concentration. It is probable that this accumulation of phenformin results in more pronounced effect upon blood glucose and other intermediary metabolites. Thus, the metabolic abnormalities previously reported in patients treated by phenformin alone are also present during combined sulphonylurea and phenformin therapy, and in the presence of diabetic microangiopathy these abnormalities are accentuated.     

Evidence for marked sensitivity to the antilipolytic action of insulin in obese maturity-onset diabetics.

Changes in plasma free fatty acids (FFA) observed during oral glucose tolerance tests in 12 obese maturity-onset diabetic Pima Indians with insulin response to oral glucose averaging only 7 ± 19 μU/ml above fasting were compared to those of 11 obese nondiabetic Pima Indians and 10 obese nondiabetic Caucasions who had mean insulin responses of 252 ± 34 and 73 ± 18 μU/ml, respectively. Fasting free fatty acid levels in the diabetics were higher, but they showed decreases similar to controls (278 ± 55 versus 284 ± 32 for nondiabetic Pima controls and 262 ± 43 μeq/liter below fasting for nondiabetic Caucasions). Plasma glycerol levels showed decreases parallel to those of free fatty acids, indicating that the FFA changes in the diabetics were attributable to inhibition of lipolysis rather than to increased removal. During intravenous glucose tolerance tests (IVGTT) in these diabetics, insulin levels decreased initially and there was no decline in FFA. In a second group of less severe diabetics (N = 6), whose increments in insulin during intravenous glucose tolerance tests averaged 15 ± 4.1 μU/ml above fasting, FFA decreases were again comparable to Pima and Caucasion nondiabetics (214 ± 53, 234 ± 37, and 183 ± 51 μeq/liter below fasting, respectively). These findings demonstrate marked sensitivity to the antilipolytic effects of insulin in individuals considered to be resistant to its glucose-lowering action.     

Comparative effects of amlodipine and nifedipine GITS during treatment and after missing two doses

OBJECTIVE: To compare the antihypertensive efficacy of amlodipine and nifedipine gastrointestinal therapeutic system (GITS) measured by office and ambulatory blood pressure monitoring (ABPM) during treatment and, after patients have missed two doses. METHOD: After a single blind run-in 4-week placebo period, 58 patients were randomly allocated to amlodipine (5mg/daily, n=30) or nifedipine GITS (30mg/daily; n=28) in a double-blind, double dummy fashion. Patients received active medication for 4 weeks. Then, to simulate failure of compliance, patients received two single blinded doses of placebo. Ambulatory blood pressure monitoring was carried out at the end of run-in placebo phase, the first day, the last day of active treatment and up to 72h after the last active dose. RESULTS: Diastolic blood pressure was controlled in 61.9% patients on amlodipine and 52.9% on nifedipine GITS. Reductions in blood pressure were similar in both groups. ABPM showed significant reduction in blood pressure from the first day in the nifedipine GITS group, while amlodipine group had marginal effect. Peak reduction in systolic/diastolic blood pressure was 26/15mmHg at 5-6h after ingestion of amlodipine tablets. The trough reduction was 22/13mmHg; with a trough-to-peak ratio of 84.61% for systolic and 86.67% for diastolic blood pressure. Peak reduction in systolic/diastolic blood pressure with nifedipine GITS was 19/15mmHg and the trough reduction was 21/17mmHg, giving a trough-to-peak ratio of 100% for both systolic and diastolic blood pressure. When patients received placebo after 4 weeks of active treatment, simulating a compliance failure, amlodipine maintained reduction in systolic and diastolic blood pressure for at least up to 72h after the last active dose, maintaining 57.71% of the effect for systolic blood pressure and 60.00% for diastolic blood pressure. In contrast, nifedipine GITS effect was rapidly lost during this study phase, with a reduction in systolic and diastolic blood pressure of only 14-16%, 72h after the last active dose. CONCLUSION: This study showed that amlodipine and nifedipine GITS reduce blood pressure to about the same extent during chronic treatment. In the case of compliance failure, such as missing one or two doses, amlodipine maintained significant and important antihypertensive effect with the trough-to-peak ratio still over 50% 72h after the last active dose. On the other hand, the coverage of nifedipine GITS was limited to about 36h after the last active dose.     

Improved diabetic control in insulin-dependent diabetics treated with insulin and glibenclamide

A randomized double blind trial of insulin and glibenclamide treatment vs insulin and placebo was carried out in 20 insulin-dependent diabetics. Nine patients were C-peptide secretors and all increased their C-peptide output during a 50 g OGTT at the end of the insulin and glibenclamide treatment period by a mean of 47%. At the same time their mean daily blood glucose fell from 8.4 +/- 1.7 to 7.4 +/- 1.5 mmol/l and their HbA1 from 8.1 +/- 0.5 to 7.5 +/- 0.9% (mean +/- SD). There was no change in any of the measurements of diabetic control in C-peptide non-secretors and no evidence for any extra-pancreatic effects of glibenclamide in this group of patients. Combined insulin and glibenclamide treatment may produce a useful improvement of diabetic control in insulin-dependent diabetics who still secrete some endogenous insulin, although further studies are required.     

Labile and stable glycosylated hemoglobin during OGTT in healthy subjects and maturity-onset diabetics

Summary HbA₁ levels were determined by a rapid chromatographic column test in 15 healthy subjects (HS) and in 15 maturity-onset diabetics (MOD), fasting and 2 h after glucose ingestion (100 g for HS, 50 g for MOD). Chromatography was carried out both before and after 6 h of red cell incubation in saline at 37 C. HbA₁ in HS at 0 and 120 min of OGTT was not significantly different, either before (6.24±0.61% and 6.22±0.62%) or after red cell incubation in saline (5.85±0.61% and 5.87±0.55%). Red cell incubation in saline significantly reduced HbA₁ levels both at 0 and 120 min (2p<0.001). HbA₁ in MOD, before red cell incubation in saline, was slightly but significantly higher at 120 min (8.61±1.03%) than at 0 min (8.39±1.01%): 2p<0.001. After incubation in saline, this difference was cancelled (7.86±0.85% at 0 min and 7.97±0.83% at 120 min: n.s.). Post-incubation levels were lower than pre-incubation ones both at 0 and 120 min (2p<0.001). The HbA₁ increment observed in MOD is significantly correlated (p<0.01; r=0.64) to the blood glucose increment observed at the glycemic peak. We conclude that hemoglobin glycosylation may show rapid changes also in MOD, reflecting blood glucose changes, whereas in HS the physiological glycemic excursions are not wide enough to produce rapid HbA₁ changes. Since labile and stable HbA₁ co-elute in the rapid chromatographic methods, red cell incubation in saline for 6 h at 37 C is recommended as a simple procedure which allows the measurement of the stable fraction alone, i.e. the real index of long-term glycemic control, independent of rapid glycemic fluctuations.     

Increased insulin sensitivity and cellular insulin binding in obese diabetics following treatment with glibenclamide.

The aim of the present study was to examine the effect of glibenclamide on the insulin receptors, the insulin sensitivity and the insulin secretion in obese non-ketotic diabetics. Two groups of 9 obese diabetics were studied before and after 10 days' treatment with a 1200 kcal's diet and a 1200 kcal's diet + 10 mg/day of glibenclamide, respectively. In the group treated with diet alone we found no significant alteration of the insulin secretion pattern (P greater than 0.1). However, the insulin sensitivity increased 37% (P less than 0.01). Furthermore, the insulin binding to monocytes increased (P less than 0.01) due to a 36% rise of the binding affinity. In the group treated with glibenclamide and diet the insulin secretory pattern was unchanged, too (p greater than 0.1). The insulin sensitivity, however, increased 83% (P less than 0.01). Moreover, the insulin binding was raised (P less than 0.01) as a result of a 80% rise of the number of insulin receptors. In 4 patients who were treated with diet (1200 kcal/day) plus glibenclamide and in 5 patients who were treated with diet alone (1200 kcal/day) the insulin binding to monocytes was studied during treatment for 1 year. After 1 year we found a significantly (P less than 0.005) higher cellular insulin binding in the glibenclamide treated patients compared to the patients who got diet alone. We conclude that 1) the augmentation of the insulin sensitivity is of great importance for the normalization of the diabetic state in obese, 2) the increase in insulin binding may be of importance for the increase in insulin sensitivity, 3) glibenclamide appears to enhance the insulin sensitivity through an increase in the number of insulin receptors.     

Diets rich in natural fibre improve carbohydrate tolerance in maturity-onset,non-insulin dependent diabetics

Summary The influence of low and high fibre diets upon carbohydrate tolerance was examined in five maturity-onset, non-insulin dependent diabetics. After 14 days on a diet rich in natural fibre (30g/ day), the subjects consumed a high fibre (13 g) test meal. They then ate a low fibre diet (10 g/day) followed by a low fibre (1 g) test meal. Mean basal plasma glucose concentrations were similar after both fibre diets; however, both mean basal plasma. insulin and gastric inhibitory polypeptide (GIP) were significantly lower after the high fibre diet. Affer the high fibre test meal, significantly lower mean plasma glucose, insulin and GIP concentrations were measured. This study is the first study to demonstrate the ability of an institutionally supervised diet of natural foodstuffs rich in fibre to improve carbohydrate tolerance in maturity-onset, non-insulin dependent diabetics. This finding is relevant to the dietary management of diabetics.     

An abnormality of adrenaline,phentolamine stimulated lipolysis in adipose tissue from obese,maturity-onset diabetics

Summary Abnormalities of fat metabolism fromin vitro andin vivo experiments have elsewhere been described in both diabetes and obesity. In these studies adrenaline (100 M) and phentolamine (100 g/ml) stimulated glycerol release has been compared in adipose tissue from groups of non-diabetic, non-obese, diabetic and obese subjects. Adipose tissue from obese diabetics showed a highly significant (p<0.001) diminution in stimulated lipolysis when compared with non-diabetic, non-obese adipose tissue. The conditions of obesity and diabetes are required to be present simultaneously to maintain this difference in lipolysis. Diabetes or obesity per se are responsible for only marginally significant differences in stimulated glycerol release. The possible reasons for this defect in lipolysis in obese elderly diabetics, pertaining to fat cell receptors, the adenyl cyclase system and the hormone sensitive lipase have been discussed.

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Anomalien bei der durch Adrenalin, Phentolamin stimulierten Lipolyse des Fettgewebes von übergewichtigen Patienten mit spätmanifestem Diabetes

Zusammenfassung Beiin vitro- undin vivo-Studien sind anderweitig sowohl für den Diabetes als auch für die Fettsucht Anomalien des Fettmetabolismus beschrieben worden. In dieser Arbeit wurde die durch Adrenalin (100 M@#@) und Phentolamin (100 g/ml) stimulierte Glycerinfreisetzung im Fettgewebe von Patienten ohne Diabetes, von Patienten ohne Übergewichtigkeit und bei Diabetikern mit Übergewicht miteinander verglichen. Das Fettgewebe von übergewichtigen Diabetikern zeigte eine hochsignifikante (p<0,001) Verminderung der stimulierten Lipolyse im Vergleich zum Fettgewebe von Nicht-Diabetikern und Nicht-Übergewichtigen. Übergewichtigkeit und Diabetes müssen gleichzeitig vorhanden sein, um diesen Unterschied in der Lipolyse aufrecht zu erhalten. Diabetes und Übergewicht allein sind nur für gering signifikante Unterschiede bei der stimulierten Glycerinfreisetzung verantwortlich. Die möglichen Ursachen für diesen Mangel in der Lipolyse bei übergewichtigen älteren Diabetikern, die die Fettzellrezeptoren, das Adenyl-Cyclase-System und die hormonempfindliche Lipase betreffen, wurden diskutiert.

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Anomalie de la lipolyse stimulée par l'adrénaline et la phentolamine dans le tissu adipeux provenant de diabétiques âgés et obèses

Résumé Les anomalies du métabolisme de la graisse dans des expériencesin vitro etin vivo ont été décrites ailleurs à la fois pour le diabète et l'obésité. Dans ces études, la libération de glycérol stimulée par l'adrénaline (100 M) et la phentolamine (100 g/ml) a été comparée dans le tissu adipeux provenant de groupes de sujets nondiabétiques, non-obèses, diabétiques et obèses. Le tissu adipeux des diabétiques obèses montrait une diminution très significative (p < 0.001) de la stimulation de la lipolyse par comparaison au tissu adipeux des non-diabétiques et des non-obèses. Les conditions de l'obésité et du diabète doivent être présentes simultanément pour maintenir cette différence dans la lipolyse. Le diabète ou l'obésité en eux-mêmes ne sont responsables que de différences à peine significatives dans la stimulation de la libération de glycérol. Nous avons discuté les raisons pouvant expliquer ce défaut de la lipolyse chez les diabétiques obèses et âgés concernant les récepteurs des cellules adipeuses, le système adényle-cyclase et la lipase dépendante de l'hormone.

     

High doses of L-carnitine in acute myocardial infarction: metabolic and antiarrhythmic effects

Fatty acids accumulate in the muscle cells in some carnitinedeficiency syndromes due to a variety of genetic defects inintermediary metabolism. L-Carnitine administration may relievethis excess by transporting acyl compounds out of the cell asacylcarnitine. Similar fatty acid accumulation occurs duringmyocardial ischae-mia because of the decreased rate of fi-oxidation,and this has been put forward as a cause of ventricular arrhythmias.This study was carried out to investigate whether administrationof high doses of i.v. L-carnitine in patients with acute myocardialinfarction could increase urinary excretion of acylcarnitineand reduce early ventricular arrhythmias. Fifty-six patients suffering from acute myocardial infarction,admitted to the Coronary Unit between 3 and 12 h after the onsetof symptoms, were included in the study. The design of the study was double blind, parallel and placebocontrolled. Allocation of treatment to patients was done randomlyafter stratification (time from onset of pain and site of infarction).The first group (28 patients) received intravenous L-carnitineat a dose of 100 mg kg^–1 b.w. every 12 h for 36 h whilethe second group (28 patients) received placebo intravenously.Immediately before starting treatment two blood samples weretaken (at 5-min intervals) and a further 16 samples were takenat regular intervals over the following 48 h. Patients' urinewas collected over the same period of time. Concentrations offree carnitine, short chain acylcarnitine esters and long chainacylcarnitine esters in serum and urine were measured. On days1 and 2, 24-h ECG monitoring (Holler) was carried out. Analysis of results showed that: (1) in patients receiving placebo,free carnitine serum levels increased significantly during thefirst 48 h after infarction; (2) in the same group of patients,free and total urinary carnitine excretion was significantlyhigher than in normal subjects; (3) administration of high dosesof L-carnitine considerably increased urinary excretion of longand short chain carnitine esters; (4) this metabolic effectmight explain the reduction in premature ventricular beats onthe second day of treatment.     

A comparison of the acute hypotensive effects of two different doses of nifedipine.

To determine whether a dose of 5 mg of nifedipine would be useful in the treatment of hypertensive emergencies, we compared the acute hypotensive effects of two different doses of nifedipine, 5 mg and 10 mg, in patients with severe hypertension. In this prospective, randomized, double-blind study, 30 consecutive black patients with diastolic blood pressure that was equal to or greater than 115 mm Hg received either a 5 mg or 10 mg nifedipine capsule and a placebo capsule, which matched that of the alternative strength. Patients were asked to bite the capsules and swallow the contents. Blood pressure response over 4 hours and adverse effects were monitored. Mean systolic blood pressure was reduced from 191.7 mm Hg (95% confidence interval 170.8 to 212.7 mm Hg) to 157.9 mm Hg (137.0 to 178.9 mm Hg) and 206.1 mm Hg (185.1 to 227.0 mm Hg) to 153.7 mm Hg (132.8 to 174.7 mm Hg) in patients who were given 5 mg and 10 mg doses of nifedipine, respectively. Mean diastolic blood pressure in the group of patients that received 5 mg doses of nifedipine decreased from 128.2 mm Hg (115.6 to 140.7 mm Hg) to 105.2 mm Hg (92.7 to 117.7 mm Hg); the corresponding values in the group that received 10 mg doses of nifedipine were 129.9 mm Hg (117.4 to 142.5 mm Hg) and 97.5 mm Hg (85.0 to 110.1 mm Hg), respectively. The minimum mean systolic blood pressures occurred 20 and 25 minutes after administration of the 5 mg and 10 mg capsules, respectively; the minimum diastolic blood pressures were reached after 20 and 30 minutes, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute effect of glibenclamide upon red cell transglutaminase activity in diabetic patients

The acute effect of glibenclamide, a hypoglycemic sulfonylurea, upon transglutaminase activity was investigated in 6 type II diabetic patients by perfusing 1 mg glibenclamide during 1 h. Blood samples were drawn 0, 10, 20, 30, 60 min during and 30 and 60 min after perfusion to determine insulin, glucose and transglutaminase activity. No significant modifications in plasma insulin, plasma glucose and transglutaminase activity in red cells was induced by glibenclamide perfusion. Nevertheless, glibenclamide induced a significant decrease (p less than 0.005) in transglutaminase activity after 20 min of perfusion (629.83 +/- 53.08 and 521.18 +/- 43.92, mean +/- SE, at 0 and 20 min). No correlation was observed between glucose or insulin plasma levels and transglutaminase activity.