The effect of various hypoglycaemic sulphonylureas on the cardiotoxicity of glycosides and arrhythmogenic activity due to myocardial ischaemia

The effects of different sulphonylureas on the electrical cardiac activity were studied in 145 rabbits and in 103 rats as well as in 278 digitalis-treated, non-smoker non-insulin-dependent diabetics on the same therapy at least during the previous three months. In rabbits and rats glibenclamide (0.0032-100 mumol. kg-1) decreased, while tolbutamide and carbutamide (0.008-1000 mumol. kg-1) increased strophantidin toxicity and myocardial ischaemia induced transitory ventricular fibrillation dose-dependently. The differences between the dose-response curve of glibenclamide and those of tolbutamide or carbutamide were significant. In digitalized non-insulin-dependent diabetics, multifocal ectopic ventricular beats could be observed in none among the 80 glibenclamide-treated diabetics, while in 12 cases of the 71 tolbutamide and in 10 cases of the 61 carbutamide treated diabetics. Two of the 66 non-insulin-dependent diabetics receiving only diet and 7 of the 278 age and sex matched, non-smoker, metabolically healthy patients had multifocal ectopic ventricular beats. No significant difference could be found between the therapeutical groups. It was concluded that instead of tolbutamide, glibenclamide must be preferred in digitalis-treated diabetics, when metabolic control is not satisfactorily achieved by diet and regime alone.     

Comparison of metformin and chlorpropamide in non-obese,maturity-onset diabetics uncontrolled by diet.

The clinical effectiveness of metformin was compared with that of chlorpropamide in closely similar groups of 216 non-obese patients recently diagnosed as cases of maturity-onset diabetes that could not be controlled by diet. The incidences of primary and secondary drug failures in each group and the numbers of patients satisfactorily maintained on each of the hypoglycaemic agents throughout the first year proved remarkably similar. In 61 of the successfully treated patients who were studied by crossover to the other drug and observed for a further year the mean blood glucose concentrations at the end of the year were roughly comparable, but the mean weight response was a small loss of 1.5 +/- 3.8 kg with metformin but a gain of 4.6 +/- 3.9 kg with chlorpropamide. Thus for non-obese, maturity-onset diabetics whose disease cannot be controlled by diet and who require oral treatment sulphonylureas and biguanides are equally effective, the choice depending on whether the patient is underweight and the severity of symptoms.     

A comparison of metformin versus guar in combination with sulphonylureas in the treatment of non insulin dependent diabetes

Twelve non-obese non insulin dependent diabetics whose mean +/- SE fasting blood glucose was 12.9 +/- 0.9 mmol/l despite maximal doses of sulphonylureas, received 8 weeks of guar (5 g tid before meals) and 8 weeks of metformin (0.5 g tid) following a six week washout period, in a cross-over design. Guar significantly lowered fasting cholesterol and triglyceride concentrations but did not alter glucose concentrations. Conversely, metformin significantly reduced fasting and post-prandial glucose concentrations but had no influence on plasma lipids.     

IL-12 serum levels in patients with type 2 diabetes treated with sulphonylureas

Interleukin-12 (IL-12) has been identified as a pro-inflammatory cytokine which is thought to contribute to the development of atherosclerosis. However, to date, the various associations between factors related to the course of type 2 diabetes, like metabolic compensation, beta cell secretory dysfunction, insulin resistance and IL-12 serum levels, remain unclear. Our study involved 41 patients with type 2 diabetes, 19 patients with coronary artery disease (CAD), and 19 healthy controls. We measured serum levels of fasting glucose, HbA₁c, 1,5-anhydro-d-glucitol, and lipids. In addition, serum levels of C-peptide, insulin, proinsulin and IL-12 were assayed. HOMA_IR score was calculated. The serum concentrations of IL-12 were higher in diabetics than in either patients with CAD or healthy controls, and were correlated with BMI, C-peptide, insulin, HOMA_IR, proinsulin and HDL serum levels. Multiple regression analysis revealed that the IL-12 serum level in type 2 diabetics primarily is dependent upon fasting proinsulin concentration. Our results demonstrate that elevated IL-12 serum levels in type 2 diabetics treated with sulphonylureas are induced especially by peripheral insulin resistance and beta cells dysfunction, as expressed by fasting serum proinsulin levels. This finding gives us hope that treatment to decrease peripheral insulin resistance and to avoid excessive proinsulin secretion might be successful in the prevention of IL-12-induced atherosclerosis.     

Decreased response of epinephrine and norepinephrine to insulin-induced hypoglycemia in diabetic autonomic neuropathy

The responses of epinephrine, norepinephrine and other counter-regulatory hormones to insulin-induced hypoglycemia were investigated in 5 diabetics who showed signs of autonomic neuropathy, in 7 age-matched diabetics without autonomic neuropathy and in 7 healthy subjects. The presence of autonomic neuropathy was evaluated by decreased beat-to-beat variation in heat rates during hyperventilation or orthostatic hypotension. Catecholamines were determined by a totally automated plasma catecholamine analyzing system using a two-column system of high performance liquid chromatography. Plasma epinephrine and norepinephrine responses to hypoglycemia in diabetics with autonomic neuropathy were significantly lower than those in diabetics without autonomic neuropathy. Plasma glucagon response in diabetics was apparently attenuated compared to normal controls and there was no significant difference in glucagon response between the two patient groups. Other counter-regulatory hormone responses did not differ among the three groups. The data demonstrate that the responses of plasma epinephrine and norepinephrine to insulin-induced hypoglycemia are impaired in diabetics with autonomic neuropathy.     

Deoxyribonucleic acid polymorphism of the apoprotein AI-CIII-AIV gene cluster and coronary heart disease in non-insulin-dependent diabetes.

The prevalence of an uncommon allelic variant (S2) of the apoprotein AI-CIII-AIV gene cluster was determined in non-insulin-dependent diabetics with or without evidence of coronary heart disease and in controls. Frequencies of the S2 allele were 14% for diabetics with coronary heart disease compared with 2% for non-diabetics with no clinical evidence of occlusive vascular disease. No subject with the S2 allele was detected among a further group of matched diabetics without clinical features of macrovascular disease. The results suggest that a genetic component contributes to the susceptibility to coronary heart disease in non-insulin-dependent diabetics. Whether the observed deoxyribonucleic acid variant is aetiological for atherosclerosis or in linkage disequilibrium with other atherogenic loci on chromosome 11 remains to be clarified.     

Chlorpropamide-alcohol flushing: a dominantly inherited trait associated with diabetes.

A simple test was devised to identify people susceptible to chlorpropamide-alcohol flushing (CPAF). Subjects were given a placebo tablet, followed by sherry 12 and 36 hours later. They then received a chlorpropamide tablet and sherry again after 12 and 36 hours. This single-dose challenge test was given to non-insulin-dependent diabetics, insulin-dependent diabetics, and normal subjects. CPAF was common in the non-insulin-dependent diabetics but rare in the other groups. When the test was used in identical twins and families of affected subjects CPAF appeared to be a dominantly inherited trait. We conclude that facial flushing after alcohol in people taking chlorpropamide is related to non-insulin-dependent diabetes, especially when there is a strong family history of diabetes, but not to insulin-dependent diabetes. It is a dominantly inherited trait.     

Antidiabetic Sulphonylureas Stimulate Acetylcholine Release from Striatal Cholinergic Interneurones Through Inhibition of KATP Channel Activity

Abstract: The sulphonylureas tolbutamide and glibenclamide were shown to stimulate acetylcholine release from rat striatal slices. To determine the mechanism of this effect, whole-cell patch-clamp recordings were made from large neurones within the striatum that displayed morphological, electrophysiological, and pharmacological characteristics typical of cholinergic interneurones. Dialysis of these neurones with a pipette solution containing low concentrations of ATP produced a gradual hyperpolarisation that could be reversed by bath application of the sulphonylureas. In voltage-clamp studies, these compounds were shown to act through the inhibition of a potassium conductance. It is concluded that cholinergic interneurones within the rat striatum express sulphonylurea-sensitive ATP-sensitive potassium channel activity. These channels are probably cytoprotective and may prove to be novel sites of therapeutic modulation.     

ATP-sensitive K+ channels in human isolated pancreatic B-cells

Glucose-stimulated insulin release from rodent pancreatic B-cells is thought to be initiated by the closing of ATP-sensitive K+ channels in the plasma membrane as a consequence of glucose metabolism. We have identified an ATP-sensitive K+ channel in membrane patches excised from human B-cells which is similar to that found in rodent B-cells in conductance, kinetics, ATP sensitivity and its inhibition by sulphonylureas. In man, the ATP-sensitive K+ channel may also have a central role in glucose-stimulated insulin secretion and may be (linked to) the receptor for the hypoglycemic sulphonylureas.     

Diabetic impotence: studies of nocturnal erection during REM sleep.

Nocturnal erections were studied in 30 diabetic patients who complained of impotence and in 11 healthy volunteers. The maximum increase in penile circumference was measured by a penile strain-gauge and recorded on a portable tape-recorder; an external oculogram was recorded simultaneously to identify periods of rapid-eye-movement sleep. The technique gave reproducible results, was acceptable to patients, and was suitable for use in an oridnary hospital ward. Only six diabetics showed a maximum increase in penile circumference of under 15 mm, whereas all but one of the healthy subjects showed maximum increases above this value. Of the six diabetics, five complained of total impotence and had other features of autonomic neuropathy that suggested an organic basis for their impotence. The other patient complained of partial importence, which was probably caused by psychological factors. These findings suggest that the prevalence of organic impotence among diabetics has been overestimated.     

Effect of sera from male type 2 (non-insulin-dependent) diabetics on human aortic smooth muscle cells in culture

The effect of sera from male type 2 (non-insulin dependent) diabetics in variable metabolic control on the proliferation of, and on the synthesis of hyaluronic acid and collagen in human aortic smooth muscle cells (HSMCs) in culture was studied. Pooled sera from diabetics in poor metabolic control either with or without antidiabetic drugs stimulated the proliferation and hyaluronic acid synthesis of the cells more than did pooled serum from healthy controls. On the other hand, pooled serum from diabetics in good metabolic control did not have a higher stimulatory effect on the growth of HSMCs than pooled control serum. Indeed, it increased the synthesis of hyaluronic acid similarly as did the pooled serum from poorly controlled diabetics. The synthesis of collagen was not affected by pooled diabetic sera. When the effects of 14 male diabetic sera were individually measured using the same functions of HSMCs, metabolic control of diabetes did not correlate with various activities of diabetic sera on HSMCs. The results show that sera of type 2 diabetics contain factors affecting the functions of HSMCs. The activity of the factors on cell proliferation is related to some extent to the degree of glycemic control, as shown in experiments with serum pools, but experiments with individual sera show that other serum properties unrelated to the metabolic control of diabetes are also of importance.     

Impaired 6-phosphofructokinase activity in mononuclear leukocytes from patients with type II diabetes mellitus

Seven cytoplasmic enzyme activities were measured in extracts of mononuclear leukocytes (lymphocytes plus monocytes) obtained from 19 type II diabetic humans and 10 healthy control subjects. 6-Phosphofructokinase activity was significantly decreased in cell extracts from diabetics, while other enzyme activities were similar in diabetics and controls. Since the effects of starvation on enzyme activities are sometimes similar to the effects of diabetes, the studies were repeated in 5 control subjects after a 2-day fast. This short period of starvation did not mimic the effect of diabetes on 6-phosphofructokinase activity. The decreased enzyme activity was not correlated with percent specific insulin binding to monocytes in the same cell preparations nor to clinical variables such as obesity or the broad range of fasting plasma glucose values encountered among the diabetics. We conclude that 6-phosphofructokinase activity in mononuclear leukocytes, as in other tissues, may be a marker for a postreceptor lesion associated with the insulin resistance found in type II diabetes mellitus.     

Comparison of insulin receptor binding to monocytes and erythrocytes in newly diagnosed type II diabetes mellitus

Insulin binding to circulating monocytes and erythrocytes was studied in 20 healthy volunteers and in 25 obese hyperinsulinemic newly diagnosed type-II diabetics. In type-II diabetics insulin binding to monocytes as well as to erythrocytes was significantly decreased in comparison with healthy individuals. The lowered insulin binding of the diabetics was mainly caused by a loss of receptor number. Individual analysis of the binding data, however, shows a marked discrepancy between receptor binding to circulating monocytes compared with erythrocytes. Since insulin binding to erythrocytes shows a great variation and seems to be influenced by other factors beside insulin concentrations it is suggested that insulin receptors on monocytes should be preferred for evaluation of peripheral insulin sensitivity.     

Changes in adrenocortical monooxygenase activities in alloxan-diabetic rabbits

Studies were carried out to determine if diabetes mellitus influenced the activities of adrenal steroidogenic enzymes. Adult male rabbits were made diabetic by an i.v. infusion of alloxan (100 mg/kg) and were killed 1 or 2 months later. Mitochondrial cytochrome P-450 concentrations were not affected by diabetes but steroid 11 beta-hydroxylase activity was greater in the diabetics than in controls after both 1 and 2 months. The type I spectral change produced by 11-deoxycorticosterone, the substrate for 11 beta-hydroxylation, was also greater in mitochondria from diabetics. By contrast, mitochondrial cholesterol side-chain cleavage activity was similar in controls and diabetics. Microsomal cytochrome P-450 concentrations were unaffected by diabetes but 21-hydroxylase activity was significantly lower in adrenal microsomes from diabetics than from controls. The results indicate that alloxan-induced diabetes alters adrenocortical steroid metabolism which may contribute to changes in the pattern of steroid secretion noted by other investigators.     

Closed-loop system in evaluation of insulin infusion rates for an open-loop system.

The daily insulin requirements as calculated with a closed-loop system (Biostator), were used for insulin infusion with a portable, miniaturized pump in 6 juvenile-onset, insulin-requiring diabetics. Three diabetics were given insulin in a manner like that of the Biostator, e.g., maximal insulin infusion about 1 hour after start of meals. The MBG was 8.7 +/- 3.9 (SD) mmol/l. Three other diabetics had insulin in a fixed profile with peaks beginning simultaneously with meals. MBG of these patients was 4.4 +/- 1.9 mmol/l. Knowing the daily insulin dosage as calculated from the Biostator, normal blood glucose levels can be achieved with a fixed profile of insulin given by a portable pump.     

Genetic analysis of the BB/W diabetic rat

A large colony of BB/W diabetic rats has been developed as a research model for insulin dependent, type 1 diabetes mellitus. The foundation stock had 8% diabetics which appeared in a sporadic manner. The Worcester (W) colony was inbred by brother X sister matings for 11 generations and the proportion of diabetics increased to over 50%. The age of detection varies from 46 to 250 days. For selection purposes, classification was made at 120 days, which means that 15 to 20% potential diabetics were classified as normal. Evidence from different analyses indicates that the inheritance of diabetes is by a recessive gene or gene cluster with 50% penetrance at 120 days. The selection of breeding stock from diabetic parents raised the proportion of diabetics produced by two normal parents from 12 to 43%. Diallel tests show that diabetic and normal offspring of two diabetic parents have the same diabetic genotype. Outcrosses to other strains of rat indicate that the trait is transferred as a recessive with only 3% diabetics recovered in the F2 where noninbred BB stock was used as the diabetic source, and 36% where partially inbred BB/W was used as the diabetic parent. Since the proportion of diabetics produced by all types of crosses has changed, and may continue to change with changes in the genetic background, we have used the operational term penetrance to describe the frequency of diabetes in individuals homozygous for the diabetes gene cluster. At present the penetrance at 120 days is 59% in the BB/W colony.     

Does adding fibre to a low energy,high carbohydrate,low fat diet confer any benefit to the management of newly diagnosed overweight type II diabetics?

The effect of supplementing a low energy (roughly 5·0 MJ), high carbohydrate (180 g), low fat (roughly 25 g) diet with 10-15 g of either cereal fibre or guar gum was investigated in 24 newly diagnosed overweight non-insulin-dependent (type II) diabetics. The patients were divided into three treatment groups: one received a low fibre control diet throughout the study period of 20 weeks and the other received two supplements of cereal fibre and guar gum in a crossover manner. The nutrient content of the diets was kept constant throughout. Though patients taking the low fibre diet showed a smaller reduction in fasting plasma glucose concentrations over the first eight weeks than patients taking a high fibre diet, this difference was not evident at the end of 20 weeks; reductions in weight and glycated haemoglobin values were similar for each dietary regimen throughout the trial.There was little evidence that supplementing a low energy, high carbohydrate diet with fibre confers any therapeutic benefit to type II diabetics and no evidence that taking fibre as viscous polysaccharides is any more beneficial to overweight diabetics than taking a similar fibre supplement as cereal. On the contrary, guar gum caused more abdominal discomfort and flatulence than the other diets.     

Diabetic dimorphism according to acetylator status.

Two groups of diabetics and 19 normal controls had their rate of acetylation of sulphadimidine measured. Among 47 patients with maturity onset diabetes the 29 fast acetylators were older at diagnosis and, at a given glucose concentration, had a higher pretreatment fasting insulin concentration than slow acetylators. They also had a larger first-phase insulin secretion in response to intravenous glucose both before and after one month''s dietary treatment. The greatest difference between fast and slow acetylators was in the first-phase secretion of insulin after a month''s treatment. The proportion of fast acetylators among the second group of diabetics, who had been admitted to improve their glucose concentrations or for treatment of tissue damage, was similar to that among the normal controls (50% and 47% respectively). The data seem to indicate that diabetics are fast acetylators unexpectedly often, but it is not clear whether the dimorphism according to acetylator status produces a differential risk of neuropathy or of any other type of diabetic tissue damage.     

Serum and urine chromium concentrations in elderly diabetics

The serum and urine chromium concentrations of 57 diabetics and 55 normal fasting subjects were determined by atomic absorption spectrometry (AAS). Our results indicate that the chromium concentration ranges of serum and urine for diabetics are 0.22–0.36 and 4.54–5.90 μg/L, respectively, significantly lower than 0.66–0.84 7.80–9.68 μg/L for the normal (P<0.001), which implies that the elderly diabetics probably lack chromium. Further, it was found that the urine chromium level of the female diabetics was substantially higher than that of the male in the same age group (P<0.01), whereas the serum chromium level was almost the same. However, the urine chromium concentration increases with aging, no matter who the diabetics or the controls are. The serum chromium concentrations of the 24 cases patients with 2-h oral glucose tolerance test (OGTT) were significantly lower than that of those with empty stomach, whereas the urine chromium exhibits a contrary tendency. Our data indicate that the chromium lost and excreted from human body increases with aging and is related to the diabetics. Thus, it is recommended to supplement a certain amount of chromium to the elderly diabetics according to their nutritional level.     

Glycaemic control in diabetic nephropathy.

To investigate the quality of glycaemic control that is achievable in diabetic patients with persistent proteinuria and asymptomatic but declining renal function three matched groups of patients were studied. The first comprised diabetics with proteinuria receiving continuous subcutaneous insulin infusion; the second, diabetics without proteinuria receiving continuous subcutaneous insulin infusion; and the third, diabetics with proteinuria receiving conventional insulin treatment. Glycaemic control in patients receiving continuous subcutaneous insulin infusion was shown to be appreciably worse during the daytime in diabetics with proteinuria than in diabetics without proteinuria, although greatly superior to that in diabetics with proteinuria receiving conventional insulin treatment. The loss of glycaemic control in patients with proteinuria receiving continuous subcutaneous insulin infusion probably occurred as a response to daytime hypoglycaemia and a consequent reduction in the proportion of the total insulin dose given prandially. Difficulty in controlling blood glucose concentrations may be a factor in the failure of intensified insulin regimens to influence the progression of diabetic renal disease.