Management of severely brittle diabetes by continuous subcutaneous and intramuscular insulin infusions: evidence for a defect in subcutaneous insulin absorption.

Severely brittle diabetes is defined as a rare subtype of insulin-dependent diabetes with wide, fast, unpredictable, and inexplicable swings in blood glucose concentration, often culminating in ketoacidosis or hypoglycaemic coma. To assess the role of inappropriate type, amount, or timing of insulin treatment and the route of administration as a cause of severe brittleness six patients with continuous subcutaneous insulin infusion, which provides a high degree of optimisation of dosage with exogenous insulin in stable diabetics. The glycaemic control achieved during continuous subcutaneous insulin infusion was compared with that during continuous intramuscular insulin infusion. Six patients with non-brittle diabetes were also treated by continuous subcutaneous insulin infusion. These patients achieved the expected improvement in glycaemic control (mean +/- SD plasma glucose concentration 5.1 +/- 2.3 mmol/l (92 +/- 41 mg/100 ml)), but not the patients with brittle diabetes remained uncontrolled with continuous subcutaneous infusion (13.6 +/- 5.8 mmol/1 (245 +/- 105 mg/100 ml) compared with 10.3 +/- 4.1 mmol/l (186 +/- 74 mg/100 ml) during treatment with optimised conventional subcutaneous injections). During continuous intramuscular infusion, however, glycaemic control in five of the patients with brittle diabetes was significantly improved (7.7 +/- 2.6 mmol/l (139 +/- 47 mg/100 ml). The remaining patient with brittle diabetes, previously safely controlled only with continuous intravenous insulin, did not respond to continuous intramuscular infusion. It is concluded that in five of the six patients with brittle diabetes studied here impaired or irregular absorption of insulin from the subcutaneous site played a more important part in their hyperlability than inappropriate injection strategies. This absorption defect was presumably bypassed by the intramuscular route.     

Intermediate acting insulin given at bedtime: effect on blood glucose concentrations before and after breakfast.

Six C-peptide deficient diabetics receiving twice daily mixtures of short and intermediate acting insulins were selected for study because of persistently raised blood glucose concentrations before and after breakfast. They were investigated to assess the effect of moving their evening injection of intermediate acting insulin to bedtime. The patients'' usual twice daily insulin treatment was optimised and compared with the bedtime regimen during inpatient metabolic studies and an outpatient crossover study. With the conventional injection regimen blood glucose concentration rose sharply from 0500 to reach a fasting mean value of 10 +/- SE 1 . 6 mmol/l (180 +/- 29 mg/100 ml) and 16 . 8 +/- 2 . 2 mmol/l (303 +/- 40 mg/100 ml) after breakfast. By contrast, when the evening dose of intermediate acting insulin was delayed until bedtime the nocturnal rise in blood glucose concentration started later and was significantly lower both fasting (7 . 5 +/- 1 . 1 mmol/l (135 +/- 20 mg/100 ml); p less than 0 . 02) and after breakfast (13 . 2 +/- 1 . 4 mmol/l(238 +/- 25 mg/100 ml); p less than 0 . 02). Fasting blood concentrations of ketone bodies (3-hydroxybutyrate) were also significantly decreased. Plasma free insulin concentrations showed the predicted changes in five of the six patients. Blood glucose profiles collected over four months during the outpatient study confirmed the beneficial effect of giving intermediate acting insulin at bedtime.     

Salt and the glycaemic response.

The possibility that salt increases plasma glucose and insulin responses to starchy foods was investigated. Six healthy adults took four morning test meals randomly: 50 g carbohydrate as cooked lentils or white bread, with or without 4.25 g of added salt (an amount within the range of salt found in a meal). When salt was added to the lentils the incremental area under the three hour plasma glucose curve was significantly greater than that for lentils alone (43.2 mmol.min/l v 11.1 mmol.min/l (778 mg.min/100 ml v 200 mg.min/100 ml]. When salt was added to bread the peak glucose concentration was significantly higher than that for unsalted bread (6.96 mmol/l v 6.35 mmol/l (125 mg/100 ml v 114 mg/100 ml], and this was followed by relative hypoglycaemia. Plasma insulin concentrations at 45 minutes were higher after a meal of salted lentils and salted bread than after the unsalted foods (p less than 0.05). The high insulin concentration after salted bread was sustained for one hour after the meal, thus the mean area under the three hour curve was 39% greater than that for unsalted bread (p less than 0.05). Salt may increase the postprandial plasma glucose and insulin responses to lentils and bread by accelerating the digestion of starch by stimulating amylase activity or accelerating small intestinal absorption of the liberated glucose, or both. The findings of this preliminary study, if confirmed by others, would support the recommendation that diabetics, as well as the general population, should reduce their intake of salt.     

Nocturnal hypoglycaemia in patients receiving conventional treatment with insulin.

The prevalence of nocturnal biochemical hypoglycaemia--that is, blood glucose concentrations below 3 mmol/l (55 mg/100 ml)--was evaluated in a random sample of 58 insulin dependent diabetics receiving twice daily insulin. Seventeen patients had at least one blood glucose value below 3 mmol/l (55 mg/100 ml) and five a value below 2 mmol/l (36 mg/100 ml) during the night. Both bedtime (2300) and fasting morning (0700) blood glucose concentrations were significantly lower in the group with nocturnal hypoglycaemia compared with the group without (p less than 0.00001). If the bedtime blood glucose concentration was below 6 mmol/l (108 mg/100 ml) the risk of nocturnal hypoglycaemia was 80% (95% confidence limits 51-96%). If the bedtime blood glucose concentration was above 6 mmol/l the likelihood of hypoglycaemia not occurring during the night was 88% (74-96%). The mean glycosylated haemoglobin A1c (HbA1c) concentration in the group with nocturnal biochemical hypoglycaemia (8.2 (range 5.0-12.4)%) was significantly lower than that in the group without (9.4(7.0-14.2)%) (p less than 0.02). The prevalence of nocturnal hypoglycaemia in the patients receiving twice daily insulin (29%) was compared with that in 15 patients receiving thrice daily insulin (47%) and was not found to be significantly different. The likelihood of this risk being greater with thrice daily insulin was, however, 88%. No patient with nocturnal biochemical hypoglycaemia woke up during the night with symptomatic hypoglycaemia. Nocturnal biochemical hypoglycaemia is common during twice daily treatment with insulin, and low values of HbA1c might be associated with a higher risk of such hypoglycaemia. The blood glucose concentration at bedtime is a significant predictor of nocturnal biochemical hypoglycaemia, and HbA1c values might be of help in identifying patients at risk.     

Human ultralente insulin.

The greater solubility of human insulin and its possible faster action have led to doubts about whether a sufficiently long acting formulation could be produced to provide a basal supply for diabetics. In a double blind crossover study in 18 diabetics human ultralente insulin was as effective as beef ultralente insulin in controlling basal plasma glucose concentrations (median 5.7 mmol/l (103 mg/100 ml) with human and 6.3 mmol/l (114 mg/100 ml) with beef ultralente insulin respectively). There was no significant difference between human and bovine insulin in the rise in plasma glucose concentration from 0400 to 0700 after an injection the previous morning and no difference between patients receiving an adequate or insufficient dose of human ultralente insulin. Bovine insulin antibody binding was reduced with human insulin (p less than 0.002), which suggests that human insulin is less antigenic than beef insulin. Once daily human ultralente insulin provides a suitable formulation for the basal insulin requirement of diabetics.     

Role of residual insulin secretion in protecting against ketoacidosis in insulin-dependent diabetes.

The role of preserved beta-cell function in preventing ketoacidosis in type I insulin-dependent diabetes was assessed in eight patients with and seven patients without residual beta-cell function as determined from C-peptide concentrations. After 12 hours of insulin fatty-acid, and glycerol concentrations were all significantly higher in patients without beta-cell function than in those with residual secretion. Mean blood glucose concentrations reached 17.2 +/- SE of mean 1.3 mmol/l (310 +/- 23 mg/100 ml) in the first group compared with 8.8 +/- 1.4 mmol/l (159 +/- 25 mg/100 ml) in the second (P less than 0.01), while 3-hydroxybutyrate concentrations rose to 5.5 +/- mmol/l (57 +/- 5 mg/100 ml) and 1.4 +/- 0.3 mmol/l (15 +/- 3 mg/100 ml) in the two groups respectively (P less than 0.01). Individual mean C-peptide concentrations showed a significant inverse correlation with the final blood glucose values (r = -0.91; P less than 0.02). These findings strongly suggest that even minimal residual insulin secretion is important for metabolic wellbeing in diabetes and may prevent the development of severe ketoacidosis when insulin delivery is inadequate.     

Fasting plasma magnesium concentrations and glucose disposal in diabetes.

Fasting plasma concentrations of magnesium were measured by neutron activation analysis in 30 non-diabetics and 87 diabetics (55 non-insulin-treated, 32 insulin treated). Plasma concentrations of magnesium were lowest in the insulin treated group (mean 0.84 (SEM 0.01) mmol/1; 2.0 (0.02) mg/100 ml), intermediate in the non-diabetics (mean 0.89 (SEM 0.01) mmol/1; 2.2 (0.02) mg/100 ml), and highest in the non-insulin-treated diabetics (mean 0.95 (SEM 0.02) mmol/1; 2.3 (0.05) mg/100 ml). In all diabetics plasma magnesium concentrations were inversely related to plasma glucose values (rs = -0.33; p less than 0.01) and in non-insulin-treated patients to plasma insulin concentrations (rs = -0.28; p less than 0.05), the former confirming previous observations. In 67 of the diabetics the KG constant for disposal rate of glucose during a standard intravenous glucose tolerance test was directly related to fasting plasma magnesium concentrations, and this relation persisted after controlling for age, sex, body mass index, type of treatment, and glucose and insulin values. This direct relation of plasma magnesium concentration with glucose disposal was unexplained by its influence on insulin secretion but was related to insulin sensitivity; hence magnesium may be an important determinant of insulin sensitivity in maturity onset diabetes.     

A portable, pre-programmable insulin infusion system in diabetes mellitus.

A miniaturized portable pump has been developed in order to study the effects of pre-programmed insulin infusion patterns on the blood glucose levels in juvenile-onset, insulin-requiring diabetics. Six diabetics undergoing 7 insulin infusion periods of up to 4 days were studied. The mean blood glucose was 7.0 +/- 2.3 (SD) mmol/l and the mean amplitude of glycemic excursions was 5.0 +/- 1.4 mmol/l. Success in achieving normoglycemia will depend on choosing the correct dose of insulin for infusion.     

A glucose-controlled insulin infusion system for diabetic women during labour.

A glucose-controlled insulin infusion system was used to control blood glucose concentration during labour or caesarean section in six insulin-dependent diabetics. The mean blood glucose concentration during the four hours of labour immediately before delivery was 4.6-5.2 mmol/1 (82.9-93.7 mg/100 ml). Feedback control of insulin delivery by blood glucose concentration should decrease the risk of postpartum hypoglycaemia in the infant and allow normal obstetric management for the insulin-dependent diabetic in labour.     

Brittle diabetes: long-term control with a portable,continuous, intravenous insulin infusion system.

A young woman had severe brittle diabetes mellitus that was critically unmanageable with all conventional insulin treatment. Continuous subcutaneous and intramuscular infusions of insulin also failed to control her metabolic instability. Use of a continuous intravenous infusion, however, whereby a portable, variable-rate, battery-operated syringe pump delivered insulin through a subcutaneously tunnelled central venous catheter, resulted in good control. When she was receiving hourly intramuscular insulin injections (a mean of 778 IU daily) mean blood glucose concentrations had been 22.1 +/- 1.4 mmol/l (398 +/- 25 mg/100 microliters). After she had received the intravenous infusion for one month as an outpatient mean blood glucose concentration was 8.2 +/- 0.46 mmol/l (148 +/- 8 mg/100 microliters) and only 80 IU insulin daily was required. Follow-up after over five months of use showed that few complications had occurred. The system is simple to use and safe, and the diabetes had been stabilised such that she could enjoy a near-normal life style.     

Insulin resistance in offspring of hypertensive parents.

OBJECTIVE--To determine if insulin resistance is present in normotensive adults at increased risk of developing hypertension. DESIGN--Normotensive subjects with at least one hypertensive parent were paired with offspring of normotensive parents (controls), being matched for age, sex, social class, and physical activity. SETTING--Outpatient clinic. SUBJECTS--30 paired subjects (16 men and 14 women) with and without a family history of hypertension, aged 18-32, with a body mass index < 25 kg/m2, with blood pressure < 130/85 mm Hg, and not taking drugs. INTERVENTIONS--Euglycaemic glucose clamp (two hour infusion of insulin 1 mU/kg/min) and intravenous glucose tolerance test (injection of 100 ml 20% glucose). MAIN OUTCOME MEASURES--Insulin mediated glucose disposal and insulin secretion. RESULTS--The offspring of hypertensive parents had slightly higher blood pressure than did the controls (mean 117 (SD 6) v 108 (5) mm Hg systolic, p = 0.013; 76 (7) v 67 (6) mm Hg diastolic, p = 0.017). Their insulin mediated glucose disposal was lower than that of controls (29.5 (6.5) v 40.1 (8.6) mumol/kg/min, p = 0.002), but, after adjustment for blood pressure, the difference was not significant (difference 6.9 (95% confidence interval -1.5 to 15.3), p = 0.10). Insulin secretion in the first hour after injection of glucose was slightly but not significantly higher in the offspring of hypertensive patients (9320 (5484) v 6723 (3751) pmol.min/l). The two groups had similar concentrations of plasma glucose (5.2 (0.3) v 5.1 (0.4) mmol/l), serum cholesterol (4.4 (0.8) v 4.6 (0.8) mmol/l), serum triglyceride (0.89 (0.52) v 0.68 (0.27) mmol/l), and serum low density lipoprotein cholesterol (2.81 (0.65) v 2.79 (0.61) mmol/l). The offspring of hypertensive parents, however, had lower serum concentrations of high density lipoprotein cholesterol (1.24 (0.31) v 1.56 (0.35) mmol/l, p = 0.002) and higher serum concentrations of non-esterified fatty acids (0.7 (0.4) v 0.4 (0.4) mmol/l, p = 0.039). CONCLUSIONS--Young normotensive subjects who are at increased risk of developing hypertension are insulin resistant.     

Effect of intravenous infusion of insulin in diabetics with acute myocardial infarction.

Diabetes mellitus is associated with a high mortality after myocardial infarction. To see whether this may be decreased by improved diabetic control the effect of an insulin infusion regimen was studied in patients with acute myocardial infarction. From April 1982 to April 1983, 33 diabetics were admitted with acute myocardial infarction. Those being treated with diet alone or oral hypoglycaemic drugs continued with this unless control was poor, when they were changed to a "sliding scale" regimen of subcutaneous insulin injections thrice daily. Those already receiving insulin were maintained on thrice daily subcutaneous injections. From April 1983 to April 1984, 29 diabetics had acute myocardial infarction. Those receiving treatment with oral hypoglycaemic drugs or insulin were changed to continuous intravenous infusion of insulin, the aim being to maintain the blood glucose concentration at 4-7 mmol/I (72-126 mg/100 ml). Those being treated with diet alone continued with this if blood glucose concentrations were acceptable. Total mortality fell from 42% in the first year to 17% in the second (p less than 0.05). Over the same period mortality among non-diabetic patients with myocardial infarction did not change significantly. There was a significant fall in cardiac arrhythmias (expressed as the percentage of patients in whom arrhythmias were recorded) from 42% to 17% (p less than 0.05). The most significant fall in the incidence of complications occurred in those who had been receiving oral hypoglycaemic drugs on entry to the study (87% to 50%, p less than 0.05).     

Effect of near normoglycaemia for two years on progression of early diabetic retinopathy,nephropathy, and neuropathy: the Oslo study.

Forty five insulin dependent diabetics were randomised to treatment with continuous subcutaneous insulin infusion (CSII), multiple insulin injections (five or six daily), or conventional twice daily insulin injections. Near normoglycaemia was obtained with CSII and multiple injections but not with conventional treatment (p less than 0.01). Hypoglycaemic coma was observed less frequently with CSII than with multiple injections and conventional treatment (p less than 0.001), but blood glucose concentrations below 2.5 mmol/l (45 mg/100 ml) were more common. After two years fewer retinal microaneurysms and haemorrhages had developed in the patients given CSII and multiple injections compared with those given conventional treatment, in whom the number had increased significantly (p less than 0.01). Motor nerve conduction velocity deteriorated in the patients given conventional treatment; in those given CSII it was unchanged during the first year but had improved after two years (p less than 0.01). Glomerular hyperfiltration was reduced with CSII, but no change occurred in urine albumin excretion rates. Long term near normoglycaemia may prevent the progression of early stages of late diabetic complications.     

The effect of exogenous growth hormone on insulin requirements during closed loop insulin delivery in insulin-dependent diabetes mellitus

The amount of insulin required to maintain similar blood glucose concentrations during an eight hour infusion of either saline or growth hormone (2 micrograms/kg/hr) was determined in five fed, insulin-dependent diabetic subjects during closed-loop insulin delivery. Elevations of serum growth hormone concentrations to levels previously observed in poorly controlled diabetic subjects were not accompanied by differences in the amount of insulin required to maintain blood glucose concentrations at levels comparable to those observed during the saline infusion. Specifically, no early insulin-like nor late anti-insulin effects of physiologic increases in serum growth hormone concentrations (10.27 +/- 0.23 mg/ml vs 5.69 +/- 1.5 mg/ml, P less than 0.05) on mean hourly blood glucose levels or mean hourly insulin requirements were observed. These studies suggest that serum growth hormone concentrations similar to those observed in poorly controlled diabetics do not affect the insulin requirements of well-insulinized diabetic subjects.     

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.     

Self-monitoring of blood glucose in diabetic pregnancy.

Admission to hospital is usually recommended to achieve the best possible diabetic control during pregnancy. We have used blood glucose monitoring at home to find out if patients can achieve equally good control outside hospital. Twenty-five consecutive diabetic patients were studied, of whom 20 had taken insulin before pregnancy. Six of their 14 previous pregnancies had ended in perinatal death. The 25 women performed 4247 blood glucose measurements during their pregnancies. Overall the mean blood glucose concentration was 7.1 mmol/l (128 mg/100 ml); before meals the mean was 6.5 mmol/l (117 mg/100 ml). Mean concentrations were lower in the third trimester, but at no stage was control in hospital significantly better than at home. The mean hospital stay before delivery was 22 days, and all patients had live babies. Monitoring blood glucose concentrations at home produces greater understanding and motivation among patients, improves control early in pregnancy, and shortens time spent in hospital.     

Plasma lipid and coagulation factor concentrations in insulin dependent diabetics with microalbuminuria.

OBJECTIVE--To determine whether insulin dependent diabetics with microalbuminuria have significant abnormalities in concentrations of lipoproteins, apolipoproteins AI and B, fibrinogen, and clotting factor VII which could result in increased cardiovascular risk. DESIGN--Case-control study. SETTING--Outpatient department of a metabolic ward. PATIENTS--Group of 20 insulin dependent diabetics with urinary albumin excretion rates greater than 30 micrograms/min (microalbuminuria) and 20 individually matched insulin dependent diabetics with normal urinary albumin excretion rates (below 30 micrograms/min) matched for age, sex, and duration of diabetes. INTERVENTIONS--Fasting venous blood samples were taken for determination of concentrations of glucose, glycated haemoglobin, lipoproteins, apolipoproteins AI and B, fibrinogen, and factor VII. Height, weight, arterial pressure, and usual insulin dose were recorded, and each patient was given a dietary questionnaire to be completed at home. END POINT--Comparison of blood pressure and concentrations of lipoproteins, apolipoproteins AI and B, and fibrinogen in the diabetics with microalbuminuria and the controls. MEASUREMENTS AND MAIN RESULTS--Patients with microalbuminuria had significantly higher concentrations of low density lipoprotein cholesterol (mean 3.33 (SE 0.20) v 2.84 (0.12) mmol/l) and very low density lipoprotein cholesterol (0.30 (0.05) v 0.17 (0.03) mmol/l) than controls but significantly lower concentrations of high density lipoprotein 2 subfraction cholesterol (0.32 (0.04) v 0.54 (0.04) mmol/l). Concentrations of total triglyceride (1.11 (0.14) v 0.68 (0.08) mmol/l), very low density lipoprotein triglyceride (0.56 (0.10) v 0.30 (0.05) mmol/l), apolipoprotein B (0.88 (0.06) v 0.67 (0.03) g/l) and fibrinogen (2.2 (0.1) v 1.9 (0.1) g/l), and diastolic arterial pressure (80 (2) v 74 (2) mm Hg), were also higher in patients with microalbuminuria. CONCLUSIONS--Cardiovascular risk factors--namely, disturbances in lipoprotein and apolipoprotein concentrations, increased fibrinogen concentration, and increased arterial pressure--are already present in insulin dependent diabetics with microalbuminuria. The increased risk of coronary heart disease in patients with clinical proteinuria may result from prolonged exposure to these risk factors, which are present before any impairment of renal function.     

Does random blood glucose sampling outdate testing for glycosuria in the detection of diabetes during pregnancy?

A random blood glucose concentration was determined in 2403 pregnant women attending an antenatal clinic at between 28 and 32 weeks'' gestation. The calculated 99% cut off values were 6.1 mmol/l (110 mg/100 ml) within two hours after a meal and 5.6 mmol/l (101 mg/100 ml) more than two hours after a meal. Patients with a blood glucose concentration in excess of these values were referred for a 75 g oral glucose tolerance test. Of 59 referred, four were found to have previously unsuspected but unequivocal diabetes mellitus and another four to have impaired glucose tolerance on the basis of the World Health Organisation''s criteria. Screening all antenatal patients by randomly measuring blood glucose concentrations is not only cheap and efficient but also does not interfere with the routine of busy antenatal clinics.     

Home blood glucose concentrations in maturity-onset diabetes.

Blood glucose concentrations during normal daily activities were measured in 106 patients with maturity-onset diabetes from capillary blood samples collected on to filter paper. Samples were taken before and two hours after main meals, before going to bed, and, in 51 cases, during the night. Fasting and mid-morning values were closely correlated with the mean values over 24 hours irrespective of the type of anti-diabetic treatment being given. Postprandial blood glucose concentrations remained below 11.5 mmol/l (207 mg/100 ml) when the fasting blood glucose value was 7.0 mmol/l (126 mg/100 ml) or less, and repeated fasting blood glucose values exceeding 7.0 mmol/l were associated with raised blood glycosylated haemoglobin concentrations. Diabetic control in maturity-onset diabetes may be satisfactorily monitored by regular measurement of fasting or mid-morning blood glucose values.     

Mortality from coronary heart disease and stroke in relation to degree of glycaemia: the Whitehall study.

In the Whitehall study of 18 403 male civil servants aged 40-64 years the 10 year mortality rates from coronary heart disease and stroke showed a non-linear relation to two hour blood glucose values, with a significantly increased risk for glucose intolerant subjects with concentrations above the 95th centile point (5.4-11.0 mmol/l; 96-199 mg/100 ml) and for diabetics (blood glucose greater than or equal to 11.1 mmol/l; greater than or equal to 200 mg/100 ml). Multiple logistic analysis showed that between one half and three quarters of the relative risks for deaths from coronary heart disease and stroke were "unexplained" by between group differences in risk factors such as age, blood pressure, obesity, smoking, cholesterol concentration, and electrocardiographic abnormalities. Within the glucose intolerant and diabetic groups the risk factors most strongly related to subsequent death from coronary heart disease were age and blood pressure, with less consistent relations for smoking, cholesterol concentration, and obesity. This study confirms the importance of hypertension as a cardiovascular risk factor in groups with glucose intolerance and diabetes, and this may have important preventive implications.