A multiple injection regimen using an insulin injection pen and pre-filled cartridged soluble human insulin in adolescents with diabetes

A multiple insulin injection regimen using a self-contained injection device Novopen (Novo Industries, Bagsvaerd, Copenhagen, Denmark) was assessed in 11 adolescents (age range 12.1-16.9 years) with diabetes. Ten patients completed the 3-month study period and eight expressed a wish to continue with the regimen, finding that the advantages it offered out-weighed the inconvenience of multiple injections. Mean glycosylated haemoglobin fell over the 3 months of the study period from 13.7 +/- 2.7% to 11.7 +/- 3.4% (NS) and there was a trend towards lower mean blood values which reached significance at the pre-lunch measurement (p less than 0.02).     

Impact of injection sites for soluble insulin on glycaemic control in Type 1 (insulin-dependent) diabetic patients treated with a multiple insulin injection regimen

Summary The absorption rate of rapid acting (soluble) insulin is slow from the subcutaneous tissue of the thigh compared to intramuscular injection into the thigh and s.c. injection into the abdominal wall. The aim of the study was to evaluate the impact of soluble insulin injected either intramuscularly into the thigh (IMT), s.c. into the abdominal wall (SCA) or s.c. into the thigh (SCT) on glycaemic control in Type 1 (insulin-dependent) diabetic outpatients treated with the basal bolus insulin delivery regimen. Fifty-five, C-peptide negative Type 1 diabetic outpatients were included in a randomised 3-month intervention study. The insulin doses were adjusted frequently by blinded observers based on the patients' self-monitored blood glucose values and reported hypoglycaemic episodes. The serum fructosamine value was within normal limits in three patients in the IMT group, in six patients in the SCA group and in none of the patients in the SCT group following the intervention period (p<0.01). However, the difference in mean serum fructosamine values did not reach statistical significance (IMT: 1.24 mmol/l (95 % confidence interval; 1.17 to 1.31), SCA: 1.25 mmol/l (1.18 to 1.32), SCT: 1.34 mmol/l (1.26 to 1.41), (p=0.09)). Blood glucose excursions were larger in the SCT group than in the SCA and IMT group from post-lunch to pre-dinner measurements and from pre- to post-dinner measurements. A higher number of measured low nocturnal blood glucose values (less than 4 mmol/l) was observed in the SCT group (34 of 85) than in the IMT (14 of 64) and SCA (21 of 81) group (p<0.05). Three patients in the IMT group, two in the SCA group, and seven in the SCT group experienced severe hypoglycaemic episodes (p=0.14). In conclusion s.c. injection of soluble insulin into the abdominal wall is preferable compared to s.c. injection into the thigh in the basal bolus insulin delivery regimen. Furthermore, soluble insulin injection s.c. into the thigh during daytime has important clinical implications for the development of nocturnal hypoglycaemia independently of the NPH insulin injection at bedtime.     

Comparison of continuous subcutaneous insulin infusion with multiple insulin injections using the NovoPen

Twenty-one patients with insulin-dependent diabetes mellitus (IDDM) participated in a 20-week randomized cross-over comparison of continuous subcutaneous insulin infusion (CSII) with intensified conventional treatment (ICT) using the NovoPen. The Medix or the Auto-Syringe pumps were used for CSII and, during ICT with NovoPen, conventional plastic syringes were used for injections of intermediate-acting insulin at bedtime. At entry HbA1c, was 8.7 +/- 0.4% (mean +/- SE) in CSII patients and 8.8 +/- 0.5% in the ICF group. HbA1c declined significantly in both groups (ICT 7.6 +/- 0.2%; CSII 7.6 +/- 0.2%) though there was no significant difference between the responses. Overall mean blood glucose was slightly but significantly lower during CSII than during ICT (CSII: 7.6 +/- 0.2 mmol/l; ICT: 8.7 +/- 0.4 mmol/l, p less than 0.05). The number of hypoglycaemic episodes did not differ significantly between patients treated with NovoPen and CSII. At the end of the study, a questionnaire revealed that all but one patient preferred ICT with NovoPen to conventional therapy. Given the choice for future treatment, 6 patients chose CSII, 12 patients preferred ICT with NovoPen and 1 was unsure.     

Miscibility of semisynthetic human ultralente insulin with short-acting insulin in insulin-dependent diabetic patients

Summary In 15 insulin dependent diabetics (IDDM), treated with human monocomponent insulin, the absorption of Actrapid HM mixed with Ultratard HM was evaluated. Thirty U of Ultratard HM and 10 U of Actrapid HM were injected separately or together immediately after mixing. Free insulin and plasma glucose (PG) were measured four hours after the administration. Free insulin levels were significantly higher after 15 (2p<0.01), 60 (2p<0.05) and 90 min (2p<0.005) when the two insulins were injected separately. PG values were significantly lower (2p<0.05) (7.63±4.06 mmol/1) at 120 min when the two insulins were injected separately compared to the mixture (9.45±4.22 mmol/l). In conclusion, mixing Ultratard HM and Actrapid HM 3:1, we observed a decrease of early Actrapid absorption and a slower lowering of PG values.     

Prostaglandin E1 accelerates subcutaneous insulin absorption in insulin-dependent diabetic patients

The powerful vasodilator, prostaglandin E1 (PGE1), was added to Actrapid insulin to try to accelerate the early phase of subcutaneous insulin absorption through increasing injection site blood flow. Actrapid insulin alone (6U) and insulin containing PGE1 (7.5 X 10(-6) M) were injected on different days into 13 fasting insulin-dependent diabetics. With the insulin/PGE1 mixture, increases in both free and total plasma insulin concentrations were greater at all times up to 120 minutes after injection than with insulin alone, with significant differences in the first 40 minutes. With insulin/PGE1 the area under the total plasma insulin curve increased significantly more rapidly between 80 and 120 minutes. Plasma glucose concentrations fell consistently more rapidly with insulin/PGE1 than with insulin alone although the differences were small (mean fall +/- S.E.M. at 120 minutes: 4.9 +/- 0.5 mmol/l vs 4.0 +/- 0.6; p = 0.02). Addition of local hyperaemic agents to short-acting insulin preparations could be therapeutically useful in hastening insulin entry to the circulation at mealtimes.     

Dermatoglyphics in insulin-dependent diabetic patients with limited joint mobility

Hand and palm dermatoglyphics were studied in 158 insulin-dependent diabetic children and adolescents [85 with limited joint mobility (LJM) and 73 without]. The findings in this group were compared with those in 400 control subjects, with a similar racial distribution. The main dermatoglyphics alterations found in diabetic patients with LJM, as compared with non-LJM diabetic patients and controls, may be summarized as follows: (a) decrease in digital total ridges count (TRC); (b) higher frequency in the number of arches; (c) decrease in the sum of a line and cubital loops, particularly in the women; (d) increase in the number of t-axial triradii. These alterations suggest a genetic aetiology of this complication. Further studies are recommended in order to provide more insight into the origin of this disorder.     

Prevalence of diabetes among children of insulin-dependent diabetic mothers

Summary Eight diabetics were found among 464 children, mean age 11.2 years, of 311 unselected insulin-treated mothers. By a method of age correction the total diabetes prevalence among the children at the age of 25 years was calculated as 3.4%. Three children were non-insulin dependent and these patients and their mothers may belong to the autosomal dominant type of diabetes, so-called MODY. In two of the other five families the fathers also had insulin-dependent diabetes; in two more cases first or second degree paternal relatives were insulin-dependent diabetics. Thus the prevalence of insulin-dependent diabetes among the children of insulin dependent mothers married to non-diabetics is calculated as 1.5% at the age of 25 years.     

Hormone-fuel metabolism during exercise of insulin-dependent diabetic patients treated with an artificial B-cell unit

Summary The effects of restoration of glucose homeostasis on hormone-fuel metabolism of diabetic individuals during exercise (40% maximal O₂ consumption) were determined by monitoring fuel oxidation rates and levels of substrates and hormones in nine normal subjects and five insulin-dependent diabetic patients while on conventional insulin therapy and after 3 days on artificial B-cell directed glucose regulation. The non-protein respiratory quotient (npRQ) and carbohydrate oxidation rate of the conventionally-treated diabetic subjects (0.908±0.002 and 538±5 mg/m²·min) were lower and the lipid oxidation rate (101±2 mg/m²·min) was significantly higher than those of the normal group during the bicycle exercise (0.937±0.004, 582±8, and 70±4 mg/m²·min, respectively). After 3 days of artificial B-cell insulin therapy, the npRQ and carbohydrate oxidation rate of the exercising diabetics significantly increased to 0.965±0.004 and 693±13 mg/m²·min, while the lipid oxidation rate declined to 39±4 mg/m²·min (p<0.001). We conclude that artificial B-cell directed insulin therapy increases carbohydrate oxidation and decreases lipid oxidation in exercising insulin-dependent diabetic subjects. However, if restoration of metabolic response identical to that of exercising normals is desired, the excess in carbohydrate oxidation coincident with elevated blood lactate and pyruvate levels suggest that the artificial B-cell therapy may not have been completely optimal, probably due to the hyperinsulinization of the diabetic patients. Research supported by NIH grants AM 15191 and AM 20530, Howard Hughes Medical Institute (U.S.A.), and FAPESP (Brazil) (n ^o 78/1131)     

Persistent insulin secretion,assessed by plasma C-peptide estimation in long-term juvenile diabetics with a low insulin requirement

Summary In order to investigate whether patients with long-standing juvenile diabetes mellitus (onset of diabetes before the age of 30) and a low daily insulin requirement (< 0.50 units/kg body weight) still have functioning B-cells, plasma C-peptide was determined after stimulation (OGTT and glucagon/ tolbutamide) in 64 patients with diabetes of more than 18 years' duration (mean 31 years). Measurable endogenous insulin production was found in 24% of the patients. The prevalence of severe retinopathy was lower in the secretors than in the non-secretor group. There was no difference in insulin antibody concentration between the two groups. Furthermore, the insulin requirement in the secretor group was relatively constant during the course of diabetes. Metabolic control was similar in both groups. It is concluded that a persisting but low activity of endogenous insulin production can be found in many long-term juvenile diabetics with a low insulin requirement, while others without any residual betacell function develop a low insulin requirement for unknown reasons.     

Effect of nicotinamide treatment on the residual insulin secretion in Type 1 (insulin-dependent) diabetic patients

Summary In vivo and in vitro experiments have shown that nicotinamide enhances the regeneration of rat B cells. Nicotinamide has been administered to human subjects at a dose of 3 g/day for more than one year without any serious side effects. A trial was conducted to study if nicotinamide could protect B cells in Type I (insulin-dependent) diabetic patients with established diabetes, but still with residual insulin secretion, the latter being evaluated throughout the study period. A randomized double-blind study was carried out on 26 Type I diabetic patients aged 15 to 40 years who had been treated with insulin for 1 to 5 years but who had a residual insulin secretion characterized by a glucagon stimulated C-peptide level higher than 0.1 nmol/l. They were given either 3 g/day of nicotinamide or a placebo for nine months. At baseline the treated and control groups did not differ according to age, diabetes duration, insulin dose, HbA_1c or C-peptide levels. Three patients dropped out of the study. At 9 months there were no significant changes in the insulin doses required. However, HbA_1c rose in the control group (8.1±0.4 vs 9.8±0.5%, p<0.05) but not in the nicotinamide treated group (7.5±0.5 vs 6.9±0.4%). Insulin secretion deteriorated in the control patients (fasting C-peptide: 0.28±0.05 vs 0.12±0.03 nmol/l, p<0.05; post glucagon C-peptide: 0.34±0.07vs 0.14±0.02, p<0.05) but not in the treated patients (fasting C-peptide: 0.22±0.04 vs 0.24±0.05 nmol/l; post glucagon C-peptide: 0.30±0.04 vs 0.33±0.07). At six and nine months, fasting and stimulated C-peptide were higher in the treated than in the non-treated group. The C-peptide response to a meal test gradually declined in the placebo group, whereas it was stable in the nicotinamide treated group. No serious side effects were noted; in particular, hepatic function and plasma lipid content remained unchanged. These results suggest that nicotinamide treatment may protect residual B-cell function in Type 1 diabetes; but further studies are needed to assess the clinical implications of such treatment.     

Glycosylated haemoglobin in children with insulin-dependent diabetes mellitus

Summary Glycosylated haemoglobin (HbA₁) was measured serially by microcolumn chromatography in 38 children with newly diagnosed insulin-dependent diabetes. Initial HbA₁ levels of 13.6±0.5% fell significantly from day 0 (prior to therapy) both to day 1 (1.6±0.2% decrease) and to day 3–5 (2.6±0.4% decrease) (p < 0.001). This drop correlated closely with changes in blood glucose (p < 0.001), less closely and inversely with plasma bicarbonate levels (p < 0.01), but not with prior duration of symptoms or changes in serum cholesterol and triglyceride concentrations. HbA₁ levels reached a nadir of 8.2±0.3% 3 weeks to 6 months after diagnosis, and correlated with decreasing insulin dosage (p < 0.001). HbA₁ levels rose again to 11.4±0.5% in 21 patients followed for more than 3–6 months. Our results indicate that (1) HbA₁ levels change rapidly during initial stabilization of insulin-dependent diabetes suggesting that glycosylation may not be entirely irreversible, and (2) HbA₁ levels are consistent with clinical assessment of control during remission and postremission phases.     

Blood levels of alloxan in children with insulin-dependent diabetes mellitus

Alloxan is a well-known and universally used agent for evoking experimental diabetes through its toxic effect on the B cells of the Langerhans islets. In our study, blood levels of alloxan in children with insulin-dependent diabetes mellitus were investigated. The observations were made in 68 children aged 6–15 years and in a control group of 44 healthy children in the same age range. Alloxan levels were estimated spectrophotometrically. The mean level of alloxan in blood from children with insulin-dependent diabetes mellitus was 8.76±9.64 g/ml and in blood from healthy children was 1.53±1.10 g/ml. The difference was statistically significant (P<0.05). The metabolism of alloxan leads to the production of free superoxide radicals which, as is well known, injure cells and cause conditions conducive to the occurrence of diseases from autoimmunity. The results obtained suggest therefore that higher levels of alloxan in diabetic children are of significance in the onset of insulin-dependent diabetes mellitus.     

Long-term effects of eating sucrose on metabolic control of type 1 (insulin-dependent) diabetic outpatients

Summary The aim of the study was to investigate the effects of regularly eating a moderate amount of sucrose (30 g/day) in 12 type 1 (insulin-dependent, IDDM) diabetic outpatients in fair blood glucose and lipid control. Two diets, each lasting two month, were compared in a randomized cross-over study. The former was a high-carbohydrate high-fiber diet for diabetic patients with Italian alimentary habits, the latter had the same composition except that 30 g of sucrose replaced 30 g of complex carbohydrates with high glycemic index (bread). The two diets contained equal amounts of carbohydrates, proteins and lipids; the only difference being the contribution of oligosaccharides to total carbodhydrates (22%vs 34%) and cholesterol amount. During the control diet, glycosylated hemoglobin was substantially unchanged in both control and sucrose diet periods (control diet: 6.91±0.29 (SE)vs 6.80±0.25%; sucrose diet: 6.75±0.31vs 6.91±0.36%). This was true also for fructosamine (control diet: 3.92±0.21vs 3.76±0.18%; sucrose diet: 3.50±0.14vs 3.64±0.20 mmol/l). Circulating blood lipid levels, body weight and daily insulin dose did not show any significant variations during the study. Moderate amounts of sucrose may be allowed to IDDM patients with Italian alimentary habits without worsening diabetic control.     

Analysis of direct cost of standard compared with intensive insulin treatment of insulin-dependent diabetes mellitus and cost of complications

Insulin-dependent diabetes mellitus (type 1) is accompanied by long-term complications: retinopathy, nephropathy, neuropathy, as well as macrovascular complications. We compared the direct cost of standard insulin treatment in type 1 patients with that of intensified treatment as well as the direct cost of their complications during the two treatment modes for 35 years' duration of disease. According to our model calculations, the direct cost of basic intensified insulin treatment is $3300 per year, about three times more than that of the standard insulin treatment. However, for the period of 35 years, the cost of complications associated with intensified insulin treatment is lower, while the total cost of intensified treatment, over 35 years, is higher than that of the standard treatment. Thus, looking from the health provider point of view and relating only to economic analysis, intensified insulin treatment encompassing all type 1 patients is not cost-beneficial. Therefore, the decision to adopt this type of therapy should be based on the combination of medical, ethical, political, and economical principles, and applied to selected, well motivated, and prepared patient groups, in whom compliance to intensified treatment would be expected to prevent or delay the onset of complications. According to cost analysis, nephropathy is the most common and severest complication, and intensive treatment promises to be most effective in this group of patients.     

Ophthalmological follow-up of Type 1 (insulin-dependent) diabetic patients after kidney and pancreas transplantation

We studied the effect of successful kidney and pancreas transplantation on visual function and diabetic retinopathy in 18 patients with long-term Type 1 (insulin-dependent) diabetes mellitus (17 to 38 years) and with advanced proliferative retinopathy. The average age of the patients was 42 years. Prior to transplantation, 5 eyes were in end-stage ophthalmic complication due to neovascular glaucoma. An ophthalmological follow-up was performed between 1–6 years post-surgery. Analysis of the results showed that the diabetic retinopathy had stabilized after transplantation in 12 cases (66 %) with a supplementary photocoagulation in the majority of cases. The proliferation continued in 4 patients (22 %) leading to blindness in 2 patients and recurrence of vitreous haemorrhages despite the photocoagulation in the other 2 cases. An improvement was observed on fluorescein angiography in a patient with pre-papillar glial proliferation without photocoagulation. Ten patients were reported to have a cataract and were operated on in two cases before transplantation; in one patient, the cataract increased following transplantation. In conclusion, the kidney and pancreas transplantation was not effective in our patients in reversing the clinical and angiographic signs of diabetic retinopathy. Moreover, a worsening of the lesions was observed in some cases; this was probably due to the irreversible microangiopathic lesions due to advanced evolution of diabetes.     

Prevalence of insulin-dependent diabetes mellitus in Asian children

A survey was conducted in 1984-85, within Leicester City boundaries, which contains 64,535 children below the age of 15 years (20,267 Asian and 44,268 White Caucasian) to ascertain the prevalence of insulin-dependent diabetes mellitus (IDDM) using a central register maintained for the changeover to U-100 insulin, diabetic health visitor index cards, hospital admissions of diabetic children, and individual registers maintained by us. Overall prevalence per thousand for children aged 0-15 years was 0.54 for Asian and 0.99 for White Caucasians; for ages 10-15 years they were 0.97 and 1.87, and for ages 0-9 years, 0.31 and 0.38, respectively. This was not statistically different at the 5% level. Ours is the first population based study of its kind in Asian children, and challenges the view that there is a large difference in the prevalence of IDDM between Asians and White Caucasians. A wider analysis of this observation incorporating a large population base is suggested.     

Frequency of insulin-dependent diabetes mellitus in Turkish adult-onset diabetic population

The frequency of insulin-dependent diabetes mellitus in the Turkish adult-onset diabetic population has not been assessed previously. In the present study, we retrospectively evaluated the medical records of 801 Turkish patients with adult-onset (30 years) diabetes to determine the frequency of cases diagnosed as insulin-dependent diabetes. Fifty-two (6.5%) patients met our criteria of adultonset insulin-dependent diabetes mellitus. At disease onset, 20 patients presented with ketoacidosis (38.5%), while 32 patients (61.5%) were non-ketotic. In the insulin-dependent diabetic group, islet cell antibodies were positive in 10 out of 16 (62.5%) patients studied. In contrast, none of the 16 patients had positive reactions with respect to insulin autoantibodies. Twelve out of 20 patients (60%) had glucagon-stimulated C-peptide levels above 0.6 nmol/l, suggesting a sufficient insulin secretory reserve. In view of these observations, we conclude that insulin-dependent diabetes mellitus is not rare among patients with adult-onset diabetes in the Turkish population. In a majority of cases, the disease onset is non-ketotic. Beta-cell function is relatively preserved, and insulin autoantibodies do not develop at diagnosis. In contrast, islet cell antibodies are frequently present at the onset of clinical insulin-dependent diabetes, possibly indicating continuing beta-cell destruction.     

Urinary insulin excretion rate: an index of free insulinaemia in insulin-dependent diabetics

In 25 insulin-dependent diabetics, 14 managed by conventional insulin injection treatment (CIT) and 11 treated by continuous subcutaneous insulin infusion (CSII), there was a highly significant correlation between urinary insulin excretion rate (IER) per 1.73 m2 and mean serum free insulin concentration (r = 0.73, p less than 0.001), measured over a 24 h period. Urinary IER and mean daily serum free insulin levels were significantly higher in diabetics than in non-diabetics. CSII-treated patients had significantly lower mean 24 h plasma glucose levels than CIT-treated patients despite similar values of urinary IER and mean daily serum free insulin in the two groups. Urinary IER may be a useful indicator of average insulinaemia in large scale studies, avoiding the problems of multiple blood sampling and immunoassay in the presence of anti-insulin antibodies.     

Severe diabetic ketoacidosis: the need for large doses of insulin.

A 21-year-old female with Type 1 diabetes mellitus (DM) presented in ketoacidosis. She received intravenous normal saline and insulin at 6 U/h and 1.26% sodium bicarbonate solution. After the blood glucose had fallen to 9.5 mmol/l, the saline infusion was changed to 5% glucose solution and the insulin infusion rate to 2 to 3 U/h. The next day the patient became more drowsy (Glasgow coma scale 13/15, later falling to 4/15). Computed tomography (CT) scan suggested cerebral oedema and the patient was treated with dexamethasone and mannitol. She remained critically ill for 48 h, eventually making a full recovery. Insulin was given at rates of 8 to 14 U/h, with 10% or 20% glucose infusion to maintain the blood glucose above 5 mmol/l; despite this it was not until the fifth day that her serum bicarbonate became normal. Textbooks usually advise starting insulin at 6 U/h and reducing the infusion rate to 1-4 U/h when the blood glucose falls below a certain level. In this case, even with high rates of insulin infusion, it took 5 days before the patient's serum bicarbonate returned to normal. Thus, in severe diabetic ketoacidosis (DKA), protocols should advise that the insulin infusion be continued at high dose (4 to 6 U/h or more), with appropriate glucose infusion to prevent hypoglycaemia, until the serum bicarbonate is normal or nearly so.     

The variability of overnight urinary albumin excretion in insulin-dependent diabetic and normal subjects

The variability of overnight urinary albumin excretion rate (AER) and albumin to creatinine ratio was assessed in eight normal subjects and two groups of insulin-dependent diabetic patients divided on the basis of an initial overnight urinary albumin excretion rate below (n = 15) or above (n = 12) 30 micrograms/min. The latter group is known to be at risk of developing clinical diabetic nephropathy. An albumin to creatinine ratio of 2.6 and above identified all patients with an initial albumin excretion rate greater than 30 micrograms/min. The mean of the coefficients of variation, calculated from five successive overnight urine collections, for all subjects was 38% for albumin excretion rate and 37% for albumin to creatinine ratio. There was no significant difference in the variation of albumin excretion rate and albumin to creatinine ratio within or between the groups. Subsequent AERs from diabetics with an initial rate greater than 30 micrograms/min changed category more often (chi 2 = 11.9, p less than 0.001) than those from diabetics with lower initial rates and normal subjects. This was due to four subjects with initial values close to the cut-off level, whose subsequent values varied around it. Albumin excretion rates in normal subjects never exceeded 11 micrograms/min. Whether a patient's risk status is influenced by the degree of variation of albumin excretion rate around a risk level, or whether the classification of risk is improved by multiple collections, awaits testing in prospective subjects.