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Diabetes education or self-management programmes are complex interventions. Their evaluation is difficult because of problems in identifying and separately assessing the effect of the various components of the intervention. A phased approach defining sequential stages of a continuum of increasing evidence has been proposed as a framework for the design and evaluation of such complex interventions. As an example we present the available evidence for diabetes treatment and teaching programmes implemented in Germany. Evidence is compiled for structured group treatment and teaching programmes for Type I diabetes, non-insulin dependent Type II diabetes, and hypertension according to the following sequential stages of increasing evidence: (i) preclinical or theoretical phase; (ii) modelling the components of the intervention; (iii) exploratory trials; (iv) randomized controlled trials; (v) phase of implementation including replication and transfer to different settings. Evidence for most of these phases has been generated for the three programmes, although individual studies do not fulfill all important quality criteria by today's standards. The time span for gathering the evidence from the theoretical phase to surveillance after implementation was about 20 years. It can only be speculated which parts of the programmes are the most active ones. The presentation of a continuum of increasing evidence for diabetes education or self-management programmes could provide useful information for the appraisal of such complex interventions. Since this evidence cannot be readily extracted from databases we suggest that other research groups present their data in a similar way.

Aims/hypothesis: To compare causes of death assessed by a clinical review committee, the information given on death certificates, and ICD-codes provided by the State Documentation Office in deceased persons with Type 1 (insulin-dependent) diabetes mellitus., Methods: A cohort of 3674 patients were monitored for 10+/-3 (mean +/- SD) years. Vital status and end-stage diabetic complications were documented for 97%; 251 patients had died. Causes of death were assessed by a clinical review committee and compared to the information provided by death certificates and ICD-9 codes., Results: The review committee defined a leading cause of death in 94% of cases, whereas death certificates were available for 73% and ICD-codes for 79% of patients; 10% of death certificates could not be evaluated due to insufficient information. Diabetes was mentioned on 71% of death certificates, and renal disease in 75% of cases with renal replacement therapy. There was acceptable agreement between the committee, death certificates and ICD-codes only for deaths due to neoplasma, and between the committee and death certificates for deaths due to acute myocardial infarction, cerebrovascular events and accidents. In only one out of four deaths due to hypoglycaemia and in four of seven deaths due to ketoacidosis was this diagnosis mentioned on the death certificate. No death due to hypoglycaemia or ketoacidosis and 41% due to suicide were identifiable by ICD-codes., Conclusion/interpretation: Reliance on death certificates or ICD-codes as the only sources of information on the cause of specific mortality does not provide data of sufficient reliability for evaluation of clinical outcome in Type I diabetes.

Aims/hypothesis: A reduction of diabetes-related blindness by at least one third was declared a primary objective for Europe in 1989 (St. Vincent Declaration). To ascertain a potential change of incidence rates, we collected data on blindness in a German district (population: about 5 million) over 9 years., Methods: We obtained complete lists of newly registered blindness-allowance recipients between 1990 and 1998 and population data on Württemberg-Hohenzollern, Germany. We estimated incidence rates of blindness in the general population and the diabetic population. To ascertain any time trend, we applied Poisson regression models., Results: There were 6371 newly registered blindness allowance recipients (1990-1998). Of these 67% were women and 27 % had diabetes. Mean age was 71.7 years. Standardised results in the diabetic population (incidence rates per 100,000 person-years; standard: diabetic population; 95 % CI): 1990: 72 (61;82); 1991: 88 (76;100); 1992: 77 (67;88); 1993: 82 (71;93); 1994: 62 (53;72); 1995: 82 (71;93); 1996: 70 (60;80); 1997: 69 (59;79); 1998: 59 (49;68). The Poisson model estimated a 3 % decrease of incident blindness in the diabetic population for each year (Relative risk per year 0.97; CI: 0.95; 0.99). No significant change could be observed in the non-diabetic population (Relative risk: 0.99; CI: 0.98; 1.00). Relative risks for each year varied between sub-groups according to sex, diabetic status and cause of blindness between 0.94 and 1.01., Conclusion/interpretation: A slight reduction of incident blindness could be shown but a reduction by one third has not been reached. Several possible sources of bias in the data have to be considered.

The objective of this study was to identify possible risk factors of severe hypoglycaemia (SH) in a prospective population based study of adult Type I (insulin-dependent) diabetic patients. A representative sample of 684 patients (41% women, mean +/- SD age 36 +/- 11, diabetes duration 18 +/- 11 years), living in the district of Northrhine (9.5 million inhabitants), Germany, were examined in their homes using a mobile ambulance. A comprehensive baseline assessment of possible predictors of SH included sociodemographic and disease related variables, hypoglycaemia awareness, diabetes management, and attitudes and behavioural aspects as expressed by the patients. After a mean of 19 +/- 6 months 669 (98%) patients were interviewed about events of SH since the baseline examination. Using the multiple Cox proportional hazards model, five risk factors of SH were identified: SH during the preceding year [hazard ratio (HR) 2.7, 95% confidence intervals (CI) 1.8-4.2], any history of SH (HR 1.9, CI 1.1-3.4), C-peptide negativity (HR 4.0, CI 1.2-12.7), social status (HR 0.8 for a difference of 5 units for a value range of 0-24, CI 0.6-0.9), and patients' determination to reach normoglycaemia (HR 0.7 for a difference of 1 unit for a value range of 1-6, CI 0.5-0.9), indicating that the lower the social status and the higher the patients' determination to reach normoglycaemia, the higher the risk of SH. After eliminating the history of hypoglycaemia from the model, impaired hypoglycaemia awareness and patients' inappropriate denial of SH as their particular problem became additional significant risk factors of SH. In conclusion, in this population based study of adult Type I diabetic patients, C-peptide negativity, a previous event of SH, patients' determination to reach normoglycaemia and social class were risk factors of SH.

Unlabelled: The objective of this study was to assess the degree of diabetes care and education achieved for Type I (insulin-dependent) diabetes mellitus at the community level in relation to social status and to elucidate potential pathways that mediate any social class gradient. A population-based sample of 684 adults with Type I diabetes (41% women, mean +/- SD age 36 +/- 11, diabetes duration 18 +/- 11 years) in the district of North-Rhine (9.5 million inhabitants), Germany, were examined in their homes using a mobile ambulance., Results: HbA1c (normal 4.3-6.1%) 8.0 +/- 1.5%, incidence of severe hypoglycaemia (injection of glucose or glucagon) 0.21 cases per patient-year; 62% of patients had participated in a structured group treatment and teaching programme for intensification of insulin therapy; 70% used 3 or more insulin injections per day, 9% were on continuous subcutaneous insulin infusion; 91% reported to have had measurements of HbA1c during the preceding year, and 80% to have had an examination of the retina by an ophthalmologist. Care was insufficient with respect to the quality of blood pressure control (70% of patients on antihypertensive drugs had blood pressure values > or = 160/95 mmHg), patient awareness of proteinuria/albuminuria (27% of patients had not heard about it) and prevention of foot complications (only 42% with a diabetes duration over 10 years had remembered to have a foot examination during the preceding 12 months). There was a pronounced social gradient with respect to micro- and macrovascular complications (prevalence of overt nephropathy 7 vs 20% for highest vs lowest quintiles of social class [OR 3.5, 95% CI 1.6-7.5, p = 0.002]) and diabetes-specific quality of life. HbA1c, blood pressure and smoking accounted for part of the association between social class and microvascular complications. The social class gradient was not due to inequality to access to health services, but to lower acceptance among low social class patients of preventive and health maintaining behaviour. In conclusion, achieved standards of care are high with respect to the implementation of intensified treatment regimens, the level of patient education achieved, treatment control and eye care, whereas areas for improvement are blood pressure control and preventive measures for foot care. A substantial social gradient in diabetes care persists despite equal access of patients to health services.

The objectives of the present analyses were to assess the association between HbA1c levels and severe hypoglycaemia (SH, treatment with glucose i.v. or glucagon injection) and to identify predictors of SH in a prospective multicentre trial. The study population consisted of 636 insulin-dependent diabetic patients who had participated in a structured 5-day in-patient group treatment and teaching programme for intensification of insulin therapy (ITTP) in one of 10 hospitals and who were re-examined after 1, 2, 3, and 6 years including assessment of demographic, disease and treatment related parameters, diabetes-related knowledge, behaviour, and emotional coping. At baseline, age (mean +/- SD) was 27 +/- 7 years, diabetes duration 9 +/- 7 years and HbA1c 8.3 +/- 1.9 %. During the 6-year follow-up, the mean HbA1c value improved to 7.6%, and in patients with a diabetes duration of more than 1 year at entry into the study (n = 538) the incidence of SH decreased from 0.28 cases/patient/year during the year preceding the ITTP to 0.17 cases/patient/year. The patient group was divided into decile groups according to mean follow-up HbA1c values. In each group more than 230 patient years could be analysed. Groups with mean HbA1c values of 5.7, 7.0, 7.4, 7.7 and 8.9% had comparable risks of SH (0.15-0.19 cases/patient/year). In a logistic regression analysis, mean HbA1c during follow-up, a history of SH during the year preceding the ITTP, C-peptide level, emotional coping, carrying emergency carbohydrates (as assessed at the 1-year follow-up), and age at onset of diabetes were significant independent predictors of SH. The incidence of SH between centres varied between 0.05 and 0.27 cases/patient/year. In conclusion, in the present analyses no linear or exponential relationship between HbA1c and severe hypoglycaemia could be identified by using simple group comparisons. Applying complex regression analyses, various patient-related predictors of severe hypoglycaemia were identified.

A number of insulin analogues have been developed by genetic engineering in order to improve the possibilities of substituting prandial and basal insulin requirements in diabetic patients by subcutaneous injection. For some short acting insulin analogues, in particular for [Lys(B28),Pro(B29)]-human insulin, preclinical and clinical trials have been performed. Despite the favourable pharmacokinetic and pharmacodynamic characteristics of these shortacting insulin analogues resulting in an attenuation of prandial hyperglycaemia following subcutaneous injection in diabetic patents, up to now, actual clinical benefits have not become apparent when they were used in clinical trials.

The objectives of the study were to assess the effects of moderate sodium restriction on blood pressure in insulin-dependent diabetic (IDDM) patients with nephropathy and high normal or mildly hypertensive blood pressure (primary objective), and to document possible associated changes of exchangeable body sodium, body volumes, components of the renin-angiotensin-aldosterone system, atrial natriuretic peptide, and catecholamines (secondary objective). Sixteen patients with untreated systolic blood pressure > or = 140 < 160 mmHg and/or diastolic blood pressure > or = 85 < 100 mmHg were included in a double-blind, randomized, placebo-controlled trial. After a 4-week run-in period on their usual diet and a 2-week dietary training period to reduce sodium intake to about 90 mmol/day, eight patients received 100 mmol/day sodium supplement (group 2) and eight patients a matching placebo (group 1) for 4 weeks while continuing on the reduced-sodium diet. Patients were examined at weekly intervals. Main response variables were mean values of supine and sitting systolic and diastolic blood pressure as measured in the clinic and by the patients at home. The differences in blood pressure between the beginning and the end of the blinded 4-week study period were calculated and the differences in changes between the two patient groups were regarded as the main outcome parameters. During the blinded 4-week study period, average urinary sodium excretion was 92 +/- 33 (mean +/- SD) mmol/day in group 1 and 199 +/- 52 mmol/day in group 2 (p = 0.0002). The differences in blood pressure changes between the two patient groups were 3.9(-1.2 to 9) mmHg [mean (95% confidence intervals)] for systolic home blood pressure, 0.9(-3.7 to 5.5) mmHg for diastolic home blood pressure, 4.9(-3.3 to 13.1) mmHg for clinic systolic blood pressure and 5.3(1 to 9.7 mmHg, p = 0.02) for clinic diastolic blood pressure. Combining all patients, there were relevant associations between changes of urinary sodium excretion and blood volume (Spearman correlation coefficient r = 0.57), blood pressure and angiotensin II (diastolic: r = -0.7; systolic: r = -0.48), and exchangeable body sodium and renin activity (r = -0.5). In conclusion, in this study of IDDM patients with nephropathy and high normal or mildly hypertensive blood pressure, a difference in sodium intake of about 100 mmol/day for a period of 4 weeks led to a slight reduction of clinic diastolic blood pressure. Studies including larger numbers of patients with various stages of nephropathy and hypertension are needed to definitely clarify the effects of sodium restriction in IDDM.

Patients with diabetic nephropathy face an increased risk of dying due to cardiac causes. The aim of this follow-up trial was to describe the association between the length of the QT interval, as a marker of myocardial electrical stability, and the risk of death in insulin-dependent (IDDM) diabetic patients with overt diabetic nephropathy. A consecutive sample of 85 IDDM patients with overt diabetic nephropathy (i.e. persistent proteinuria > or = 500 mg/24 h) were followed-up until death or for a period of 5-13 years. QT intervals were measured once at baseline in a 12-lead ECG and corrected for heart rate (QTc). During the follow-up period 33 patients (39%) died. In the Cox proportional hazards model independent predictors of death were age (p = 0.0007), the length of the maximum QTc period (p = 0.0049), presence of autonomic neuropathy (p = 0.0068), diabetes duration (p = 0.0163) and RR variation (p = 0.0395). In conclusion, in nephropathic IDDM patients QT prolongation is associated with an increased mortality risk which is independent of the presence of autonomic neuropathy. Further studies are needed to determine whether this risk might be reduced by therapeutic interventions.

In order to improve the basis upon which to advise women with diabetic nephropathy about pregnancy, we studied the effect of diabetic nephropathy on the course of pregnancy, perinatal outcome, infant development and long-term outcome of the mothers. All pregnancies of women with diabetic nephropathy (defined as proteinuria > 400 mg/day (n = 26), creatinine clearance < 80 ml/min and hypertension in the first trimester (n = 10)) followed at our centre from 1982 to 1992 were identified (34 White class F and 2 White class T) and the women and their children re-examined in the spring 1993. From the first to the third trimester the percentage of women with proteinuria over 3 g/day increased from 14 to 53% and those treated with antihypertensive medication from 53 to 97%. There were no intrauterine or perinatal deaths, but one child died suddenly 4 weeks postpartum. Of 36 newborns (gestational week at birth 36(3), birth weight 2384(834) g)), 11 were born before week 34 and 8 had respiratory distress syndrome. Renal function in the first trimester, diastolic blood pressure in the third trimester and an HbA1c above normal were predictive of gestational age at delivery and low birth weight (stepwise regression analysis). At follow up of the children (n = 35, age 4.5 (0.4-10) years) the majority (n = 27) were normally developed but seven had psychomotor retardation (four of them major). One child had a severe motor retardation due to a congenital anomaly. At follow up, 21 of the 29 mothers had preserved renal function (creatinine 1.3 (0.8-4.3) mg/dl and 8 had developed end stage renal disease and required dialysis (2 of whom were White class T) within 3 (1-9) years postpartum.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin and glucose responses to glibenclamide were studied in comparison to a novel non-sulphonylurea drug (AG) by means of the euglycaemic clamp technique. Nine fasting male subjects were connected to a Biostator and 1.75, 3.5 or 7.0 mg glibenclamide or 1.0, 2.0 or 4.0 mg AG were given and blood glucose concentrations were clamped at 10% below basal values. Glucose infusion rates were registered over 10 h after administration of the tablet. Maximal glucose infusion rates after glibenclamide were 40% higher compared to AG (1.75 vs 1.0 mg, 3.5 vs 2.0 mg, 7.0 vs 4.0 mg, respectively) and were reached after 3-3.5 h for all doses. After glibenclamide, area under the glucose infusion curves and maximal incremental serum insulin responses were higher by 25-40% and by 30% compared to AG when low, medium and high doses of each drug were tested. However, a linear dose relationship was obtained for both drugs when the glucose infusion rate was plotted against the area under the insulin curve. In fact, both drugs were equipotent on a molecular weight basis. The hypoglycaemic index of both drugs (integrated glucose infusion rate divided by integrated insulin release) expressed per mumol of drug revealed a dose-dependent and parallel inverse curvilinear relation to increasing doses. This methodological approach allowed us to quantify and compare the metabolic effects of oral hypoglycaemic agents under standardised experimental conditions.

Subcutaneous insulin absorption kinetics were assessed in 50 healthy study subjects (21 female, 29 male; age 26 +/- 3 years, BMI 22.5 +/- 1.8 kg/m2; mean +/- SD) during 45 min after periumbilical injection of soluble human U40- or U100-insulin (0.15 IU/kg). Subcutaneous fat thickness was measured by ultrasound, and skin temperature at the injection site was registered. Serum insulin concentrations increased within 30 min from basal values of 37 +/- 15 to 140 +/- 46 pmol/l after U40-insulin and from 36 +/- 10 to 116 +/- 37 pmol/l after U100-insulin (p < 0.001). After 45 min serum insulin concentrations were 164 +/- 43 pmol/l with U40-insulin and 128 +/- 35 pmol/l with U100-insulin (p < 0.001). Decline in blood glucose levels and suppression of C-peptide were comparable. The serum insulin levels reached 30 and 45 min after U40- and U100-insulin injection were positively correlated with skin temperature (p < 0.0008), and negatively correlated with subcutaneous fat thickness (p < 0.009). In conclusion, the lower insulin concentration of U40-insulin, higher skin temperature, and a thinner subcutaneous fat tissue at the injection site are associated with accelerated and enhanced subcutaneous insulin absorption.

In a prospective controlled trial the effects of a 5-day in-patient treatment and teaching programme for Type 1 (insulin-dependent) diabetes mellitus on metabolic control and health care costs were studied in Moscow. Two different intervention programmes were compared, one based upon urine glucose self-monitoring (UGSM, n = 61) and one using blood glucose self-monitoring (BGSM, n = 60). Follow-up was 2 years. A control group (n = 60) continued the standard treatment of the Moscow diabetes centre and was followed-up for 1 year. Costs and benefits with respect to hospitalizations and lost productivity (according to average wage) were measured in November 1992 rubles (Rb.), with respect to imported drugs and test strips in 1992 German marks (DM). In the intervention groups there were significant decreases of HbA1 values [UGSM: 12.5% before, 9.4% after 1 year, 9.2% after 2 years (p < 0.0001); BGSM: 12.6% before, 9.3% after 1 year, 9.2% after 2 years (p < 0.0001) compared to no change in the control group (12.2% before, 12.3% after 1 year)], and of the frequency of ketoacidosis. The frequency of severe hypoglycaemia was comparable between the UGSM (10 cases during 2 years), BGSM (10 cases during 2 years), and the control group (8 cases during 1 year).(ABSTRACT TRUNCATED AT 250 WORDS)

Up to now all published experience with intensified insulin therapy has originated from specialized diabetes centres. However, even in diabetes centres and under research conditions intensification of insulin therapy may substantially increase the risk of severe hypoglycaemia. The aim of the present study was to demonstrate the feasibility of effectively and safely transferring intensified insulin therapy based upon a 5-day in-patient treatment and teaching programme from a University diabetes centre to non-specialized general hospitals. A total of nine general hospitals were recruited; the University diabetes centre served as a reference centre. From each general hospital a nurse and a dietitian were trained as diabetes educators, and a diabetes unit with about 10 beds was organized within each department of internal medicine. A total of 697 consecutively admitted Type 1 (insulin-dependent) diabetic patients (age 26 +/- 7 years, duration of diabetes 8 +/- 7 years) who participated in the programme either in one of the general hospitals (n = 579) or in the reference centre (n = 118) were re-examined after 1, 2 and 3 years. Insulin therapy was intensified to a similar extent in the reference centre and the general hospitals; at the 3-year follow-up about 80% of the patients injected insulin at least three times daily or used continuous subcutaneous insulin infusion (10%), and about 70% reported measuring blood glucose levels more than twice per day. HbA1 levels were lowered (p < 0.0001) to comparable levels, i.e. from 10.6% (reference centre) and 9.9% (general hospital), respectively, at baseline to 9.4% and 9.3%, respectively, at the 3-year follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)

We have investigated the hypothesis that insulin is a causal and independent risk factor for blood pressure elevation in humans by comparing pre- and post-operative blood pressure values of 34 consecutive patients with histologically-confirmed diagnosis of insulinoma and 34 age- and sex-matched control patients. In patients with insulinoma hypoglycaemic symptoms were present for 18 (9-36) months. (Values are given as median and 95% confidence interval or mean and SD). After removal of insulinoma fasting plasma insulin levels decreased from 22 (16-28) mU/l to 11 (6-20) mU/l (p less than 0.003) and minimal fasting plasma glucose concentrations increased from 2.5 (2.0-3.0) to 4.4 (4.2-5.7) mmol/l (p less than 0.002) while blood pressure values remained unchanged. Body mass index before operation was comparable between the groups: 25.5 (5.4) kg/m2 in insulinoma patients and 24.8 (4.7) kg/m2 in control subjects. Pre-operative and post-operative blood pressure values did not differ between the groups, being (systolic/diastolic) 133 (18)/82 (9) mm Hg in insulinoma patients and 128 (15)/78 (10) mm Hg in control subjects before and 129 (19)/80 (10) mm Hg and 125 (11)/76 (7) after surgery. Chronic hyperinsulinaemia in patients with insulinoma is not associated with a detectable elevation of blood pressure values. Correction of hyperinsulinaemia after surgery for insulinoma does not result in blood pressure changes. These results argue against the hypothesis that insulin is an independent causal factor in the development of essential hypertension in humans.

Using a mobile ambulance the quality of diabetes care was evaluated, according to the recommendations of the St. Vincent Declaration, in 95% of all known diabetic patients (n = 395) in a geographically defined rural area of Austria with 7871 inhabitants. Fourteen of the 395 patients had Type 1 (insulin-dependent) diabetes with age at onset of diabetes below 30 years. Of the 375 patients examined (women 61%, age 66 +/- 13 years, median diabetes duration 6 years) 16% were treated with insulin and 47% with oral agents; HbA1c levels were 7.3 +/- 1.7%. Prevalence of known hypertension was 54%; 68% of these patients had their blood pressure uncontrolled (systolic greater than or equal to 160 and/or diastolic greater than or equal to 95 mmHg); a further 15% of patients with previously unknown hypertension had blood pressure values of greater than or equal to 160 and/or greater than or equal to 95 mmHg. Urinary albumin concentrations of greater than 200 mg/l were found in 15% of patients, 2% had a serum creatinine level of greater than 177 mumol/l, no patient had renal replacement therapy. Six patients (1.5%) were blind. Screening for retinopathy identified six patients (out of 317 in whom the retina could be evaluated) for whom consultation with an ophthalmologist as soon as possible was recommended. Of the total patient group (n = 395) 20 patients (5%) had foot complications (amputations and/or ulcers): 14 patients had a total of 21 lower limb amputations (eight above knee, six below knee, seven below ankle); eight of these 14 patients lived in a nursing home; 11 patients had a total of 13 foot ulcers.(ABSTRACT TRUNCATED AT 250 WORDS)

The study was performed to investigate the effects of mild to moderate exercise on blood glucose levels, metabolite concentrations and responses of counterregulatory hormones in tightly controlled Type 1 (insulin-dependent) diabetic patients treated by continuous subcutaneous insulin infusion, and to quantify the measures necessary to prevent acute and late exercise-induced hypoglycaemia. Seven male patients started a 60 min exercise period 90 min after an insulin bolus and a standard breakfast; they were monitored during a post-exercise resting period of 5 h 30 min. Different basal and premeal insulin infusion rates were applied. (Near)normoglycaemia prevailed throughout the study during the control protocol when the subjects did not exercise and received their usual insulin dose. When they exercised without changing the insulin dose, four patients were forced to stop due to hypoglycaemia. This effect of exercise could be attenuated but not completely avoided if the basal infusion rate of insulin was discontinued during the exercise period. The pronounced increase in catecholamine and growth hormone concentrations during exercise were not sufficient to prevent hypoglycaemic reactions. Hypoglycaemia during exercise could only be prevented when the premeal insulin bolus was reduced by 50% in addition to the discontinuation of the basal insulin infusion during exercise. In order to reduce late hypoglycaemic reactions after exercise the best measure proved to be a reduction of the basal insulin infusion rate by 25% during post-exercise hours. Administration of only 50% of the basal insulin infusion rate during this time was associated with blood glucose levels being raised up to 8 mmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Recombinant DNA technology allows the production of insulin analogues with faster absorption rates from subcutaneous tissue as compared to conventional human regular insulin. We report the time-action profiles of 12 U subcutaneously injected insulin analogues (B9Asp + B27Glu or B10Asp) as evaluated against human regular insulin by means of the euglycaemic clamp technique (blood glucose 5.0 mmol/l) in healthy men. After injection of 12 U of either insulin preparation identical values were found for maximal insulin action (maximal glucose infusion rate, time to peak action), total amount of glucose infused as well as area under the curve of glucose infusion rate. Half-maximal glucose infusion rate was reached significantly earlier after injection of modified insulins (mean +/- SD 38 +/- 7 and 43 +/- 5 min) as compared to regular insulin (56 +/- 14 min, p less than 0.01). Forty-five min after injection of both insulin analogues glucose infusion rate had increased by 7.4 +/- 1.8 or 6.1 +/- 1.8 mg.kg-1.min-1, reflecting 83 +/- 27 or 67 +/- 15% of maximal regular insulin action. In conclusion, the two tested insulin analogues showed similar action profiles, but a significantly faster onset of action as compared to regular insulin.

The effect of physical training on glucose tolerance in vivo and skeletal muscle glucose metabolism in vitro was investigated in normal rats. Treadmill running for 10 days up to 240 min/day led to a decrease of basal and glucose-stimulated plasma insulin levels without major alterations of the IV glucose tolerance (1 g/kg body weight). Swim training of two weeks' duration, i.e. exercise up to 2 X 75 min/day, which did not induce significant changes in body composition, skeletal muscle glycogen levels or citrate synthase activity, resulted in a significant improvement of IV glucose tolerance and substantial reductions of basal and glucose-stimulated plasma insulin levels. Associated with this apparent improvement of insulin sensitivity in vivo, significant increases of the insulin-stimulated glucose uptake (+ 55%) and lactate oxidation + 78%) in vitro were found on perfusion of the isolated hindquarter of swim-trained animals. It is suggested that mild physical training can improve glucose tolerance and insulin sensitivity in normal rats, at least in part, due to an increase of insulin sensitivity of skeletal muscle glucose metabolism.

A follow-up study of 116 Type 1 (insulin-dependent) diabetic patients on long-term continuous subcutaneous insulin infusion was conducted after 4.5 +/- 0.2 years. The average HbA1c-value of these patients decreased by 1% to 6.7 +/- 0.1% during this observation period. Typical side effects of continuous subcutaneous insulin infusion such as skin inflammation at the catheter insertion site occurred with similar frequency as has been reported previously by other authors. Diabetic ketoacidosis (0.14 per patient year) and disabling hypoglycaemia (0.1 per patient year, including 0.05 hypoglycaemic coma per patient-year) occurred at substantially lower rates than in other comparable studies with Type 1 diabetic patients at a similar degree of metabolic control. Subgroup evaluation suggested that a normal (less than 5.6%) HbA1c-value at follow-up was associated with increased incidence of disabling hypoglycaemia, whereas poor metabolic control (HbA1c greater than 7.5%) was associated with increased rates of skin complications and hospital treatment for ketoacidosis. Thus, under the policies of this diabetes centre, continuous subcutaneous insulin infusion has proved to be beneficial to a large proportion of experienced adult Type 1 diabetic patients, who voluntarily had opted for, and continued with, this particular mode of insulin treatment.

The role of variations in plasma insulin concentrations as a factor possibly involved in abnormalities of haemostatic functions, and (or) the development of arterial disease, has been the subject of controversy. This study examines the "in vivo" effect of hyperinsulinaemia on haemostatic parameters in seven healthy men. Two studies were carried out in random order: (a) Hyperinsulinaemia study. Human insulin was infused by a calibrated infusion pump (0.7 mU kg-1 min-1, for 8 h) during a euglycaemic glucose clamp, and (b) Control study 0.15 mmol/l NaCl solution was infused over 8 h. Plasma epinephrine and norepinephrine concentrations remained constant throughout the studies. Mean insulin levels during the hyperinsulinaemia study were 46.2 +/- 1.6 microU/ml, i.e. approximately eightfold higher than those at baseline, whereas plasma glucose levels remained constant at 4.9 +/- 0.1 mmol/l. During the control study, mean insulinaemia was 5.0 +/- 0.9 microU/ml, and plasma glucose 5.2 +/- 0.1 mmol/l. No statistically significant changes were observed during, or after insulin or 0.15 mmol/l NaCl infusions with regard to platelet parameters, blood coagulation, and coagulation inhibitors. These data suggest that abnormalities of the haemostatic function described during insulin-induced hypoglycaemia or in hyperinsulinaemic patients are not due to a direct action of insulin.

The effects of Ca2+ and calcitonin infusions on circulating glucagon, glucose, C-peptide, Ca2+, and calcitonin were investigated in hyper-glucagonaemic insulin-dependent diabetics. In 14 insulin-deprived diabetics and 12 healthy volunteers 2h infusions of saline (0.154 mol/1), Ca2+ (0.375 mmol/kg body weight), and calcitonin (4.5 IU/kg body weight) were performed. There were no significant changes during saline infusion. In the diabetics, Ca2+ infusions induced a rise of plasma Ca2+ up to 3.2 +/- 0.1 mmol/1 and a fall of circulating glucagon (-26.4 +/- 5.7%; p less than 0.001) and glucose (-23.3 +/- 3.6%; p less than 0.05). Plasma calcitonin rose to twice basal values (p less than 0.025). During calcitonin infusions plasma Ca2+ decreased slightly to 2.1 +/- 0.2 mmol/1; a fall was found in both glucose (-24.4 +/- 4.0%; p less than 0.05) and circulating glucagon (-22.5 +/- 4.3%; p less than 0.001). Two groups of 6 healthy volunteers were subjected to saline and Ca2+, or to Ca2+ and calcitonin infusions. Both Ca2+ and calcitonin infusions induced a fall of serum insulin (-30.1 +/- 6.6%; p less than 0.05). Calcitonin depressed circulating glucagon by -18.6 +/- 4.4% (p less than 0.025), whereas during Ca2+ infusions glucagon decreased only by -6.5 +/- 1.9% (p greater than 0.1). We conclude from our results that an increase of circulating calcitonin induced by Ca2+ infusions or by exogenous calcitonin administration appears to depress elevated circulating glucagon and glucose in insulin-dependent diabetics.

The absorption of subcutaneously injected insulin was examined by injecting semisynthetic [3H] insulin in anaesthetized pigs and subsequently analysing the tissue excised from the injection site. Contrary to previously accepted views, a significant proportion of insulin was degraded at the injection site. The disappearance of intact [3H] insulin from the injection site followed a monoexponential function with a half-time of 59 min.

It has been questioned whether aiming at near-normoglycaemia by intensified insulin treatment regimens is feasible and safe for the majority of patients with insulin-dependent diabetes. In this study, intensified insulin injection therapy (including blood glucose self-monitoring and multiple insulin injections) based upon a 5-day inpatient group teaching programme was evaluated in Type 1 (insulin-dependent) diabetes mellitus in the centralised health care system of Bucharest. One hundred patients (group A, initial HbA1 12.5%) were followed for 1 year on their standard therapy (individual teaching, no metabolic self-monitoring), and thereafter for 1 year on intensified therapy. Another 100 patients (group B, HbA1 12.3%) were followed for 2 years on intensified therapy. A third 100 patients (group C, HbA1 11.7%) were assigned to a basic 4-day inpatient group teaching programme with conventional insulin therapy (including self-monitoring of glucosuria and acetonuria) and followed for 1 year. Mean HbA1 remained unchanged after standard treatment (group A: 12.8% at 12 months), but decreased during intensified therapy (group A: 10.1% at 24 months; group B: 9.3% at 12 months, 9.5% at 24 months; p less than 0.0001). In group C, no change was found compared to standard treatment (i.e. group A at 12 months). Incidence rates of ketoacidosis were 0.16 episodes per patient per year during standard treatment, 0.01 during intensified treatment (p less than 0.01) and 0.04 in group C (p less than 0.025). Hospitalisation rates were reduced by 60% during intensified therapy and by 40% in group C. Frequency of severe hypoglycaemia was not significantly different between the three treatment regimens. Thus, under the condition that insulin treatment is based upon a structured and comprehensive training of the patient, intensified insulin injection therapy performed as routine treatment of Type 1 diabetes significantly lowers HbA1 levels without increasing the risk of severe hypoglycaemia.