Insulin, insulin antibody and glucose in plasma of newborn infants of diabetic women.
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Biomedical subjects
Publications and source records attributed to T Deckert.
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Which comes first when developing clinical diabetic nephropathy, the blood pressure rise or the increasing urinary albumin excretion? This issue is discussed based on recent literature of studies in humans with Type 1 (insulin-dependent) diabetes mellitus. We conclude that hypertension has a central role in the progression of diabetic nephropathy and has deleterious effects on the life expectancy of patients who already have signs of diabetic renal disease in terms of elevated urinary albumin excretion. However, blood pressure is preceded by small increments of urinary albumin excretion rates, an indicator of universally increased vascular leakiness, and thus does not seem to be the cause of diabetic nephropathy.
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All IDDM patients without late complications have blood pressures similar to the nondiabetic background population, and those who develop clinical nephropathy in Denmark have no familial predisposition to hypertension. Blood pressure remains normal until after development of microalbuminuria, indicating no primary role for hypertension in the pathogenesis of nephropathy. When microalbuminuria is present it does, however, play a crucial role in the progression of nephropathy. Sodium retention, possibly induced by hyperinsulinemia, and perhaps glucose-coupled sodium reabsorption in insulin treated patients, seem to play a central role in elevating the blood pressure, but this needs further clarification.
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Angiotensin-converting enzyme (ACE) inhibitors are known to reduce urinary albumin excretion (UAE) in diabetic patients. Animal studies have shown that, besides diminishing the glomerular capillary pressure, ACE inhibitors might reduce albuminuria by influencing glomerular charge selectivity through glomerular preservation of heparan sulphate proteoglycan. In humans, an indirect measurement of glomerular charge selectivity can be obtained by calculating the glomerular charge selectivity index (SI), a clearance ratio of IgG/IgG4, two identically sized but differently charged molecules. The aim of the present study was to evaluate the effect of ACE inhibition on charge selectivity by comparing SI in type I (insulin-dependent) diabetic patients with microalbuminuria after 6 years of treatment either with or without captopril. Thirty-five of 45 patients participating in a prospective randomized study evaluating the effect of captopril in preventing the development of diabetic nephropathy were included in the present study, 17 being treated with captopril, 18 left as untreated controls. The selectivity index was calculated after measuring s-IgG, u-IgG, s-IgG4, and u-IgG4. The results demonstrated a higher selectivity index in the captopril-treated group [1.21 (0.51-1.94) median (range)] compared to the control group [0.94 (0.31-1.87)], however, the difference was not statistically significant (p = 0.16). A negative correlation between the selectivity index and UAE was demonstrated in the captopril-treated group (r = -0.77; p = 0.0004), whereas the correlation in the control group did not reach statistical significance (r = -0.3; p = 0.2).(ABSTRACT TRUNCATED AT 250 WORDS)
The concept of microalbuminuria is reviewed. Measuring the urinary albumin excretion rate and testing for microalbuminuria is well established in the control and treatment of patients with insulin-dependent diabetes mellitus. Microalbuminuria predicts nephropathy and early cardiovascular death. In the presence of microalbuminuria frequent examinations are warranted for early detection of retinopathy, blood-pressure rise, and for optimizing the glycemic control. In patients with non-insulin-dependent diabetes, the independent value of microalbuminuria as a cardiovascular risk factor is not yet clarified. The urinary albumin excretion rate should be measured at diagnosis, because the indications are that presence of microalbuminuria reinforces the urge to intervene against other well-documented cardiovascular risk factors (hypertension, dyslipidemia, tobacco, and obesity). In the nondiabetic population, there is accumulating evidence that an elevated urinary albumin excretion rate is associated with early cardiovascular morbidity and mortality. Large scale cross-sectional and prospective studies are needed in order to clarify further the role of microalbuminuria as an independent risk factor in the background population.
Sixty-six patients with insulin-dependent diabetes mellitus (IDDM) initiated insulin pump treatment under routine conditions. Four patients (6%) discontinued treatment. One patient died. 61 patients were followed for a total period of 130 patient years. A sustained decrease in HbA1c was obtained during insulin pump treatment. The frequency of the following acute side effects was: ketoacidosis 0.06 episodes per patient per year, severe hypoglycaemia 0.09 episodes per patient per year and infection at the injection site 0.06 episodes per patient per year. Insulin pump treatment was well accepted by the patients; all but one wanted to continue insulin pump treatment. The major advantages were greater quality of life, greater flexibility as to meal times and better blood glucose regulation. The major disadvantages were technical problems: blockage of the infusion system, greater treatment expenses and the large pump size. We conclude that insulin pump treatment is well accepted as long-term treatment in selected IDDM patients. The improvement in metabolic control can be sustained through several years, and the frequency of severe hypoglycaemia during pump treatment is comparable to that of conventional insulin treatment. The risk of ketoacidosis requires more attention from the physician.
Urinary albumin excretion in a representative sample of 679 patients with Type I (insulin-dependent) diabetes, 18 to 50 years of age, was investigated. Patients on antihypertensive therapy were excluded. Urinary albumin excretion was examined in one 24 hour urine sample using an ELISA technique. Twenty-three per cent of the patients had microalbuminuria, i.e., 30-300 mg albumin/24 h. The prevalence of microalbuminuria was independent of sex, age, insulin dose and diabetes duration. In the majority of those cases in which microalbuminuria was found during the first 10 years of diabetes, the concentrations were in the lower range, i.e., 30-50 mg/24 h. The prevalence of incipient nephropathy (urinary albumin excretion in a single urine sample of 51-300 mg/24 h) increased with diabetes duration. In patients with incipient nephropathy hemoglobin A1c tended to be, and blood pressure was, elevated compared with age, sex, and duration matched patients with normal urinary albumin excretion rates (p = 0.08 and p less than 0.001, respectively). Urinary albumin excretion and blood pressure were significantly correlated in the total group (n = 401, r = 0.2, p less than 0.001). On the basis of these findings practical guidelines for the handling of patients with microalbuminuria are proposed.
The association between the incidence of diabetic retinopathy and the development of diabetic nephropathy was studied in 110 Type I (insulin-dependent) diabetic patients during a period from 10 years before to 5 years after the onset of persistent proteinuria. This group of patients was compared with 110 diabetic patients, who were matched according to sex, age, and diabetes duration, but who were without proteinuria during the observation period. The cumulative incidence of proliferative retinopathy was 74% in patients with clinical nephropathy and 14% in patients free of proteinuria. The incidence of background retinopathy was 93% and 37%, respectively, and the incidence of retinopathy increased dramatically 5 years before the onset of proteinuria. Neither gender, age at onset of diabetes, nor blood pressure seemed to have much influence on the incidence of severe retinopathy. It is concluded that development of clinical diabetic nephropathy implies an extremely high risk of developing severe retinopathy. A common pathogenetic link may be suspected.
In patients with insulin-dependent diabetes mellitus (IDDM), albuminuria reflects widespread vascular dysfunction. Albuminuria has been associated to defects of heparan sulfate proteoglycan (HSPG) within the extracellular matrix. Our hypothesis is that loss of HSPG in vascular walls reduces the HSPG-bound lipoprotein-lipase activity (LPLA), thereby causing elevated levels of plasma triglyceride (TG) seen in IDDM patients with albuminuria. The aim of the present study was to evaluate whether LPLA in muscle capillaries could be related to TG in IDDM patients with and without albuminuria. This is a cross-sectional study including ten healthy control subjects (group C), nine patients with IDDM and urinary albumin excretion rate (AER) of 30 mg/24 h or less (group D0) and 20 patients with IDDM and AER greater than 30 mg/24 h (group DA). Muscle LPLA, plasma TG, total cholesterol, high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and very-low-density lipoprotein cholesterol (VLDL) were measured. Between groups no difference in total cholesterol, TG, VLDL, and LDL was found. In patients with albuminuria, LPLA was reduced compared to controls, however, the difference between the groups was not statistically significant [median (range)] 35.9 mU/g (20.4-103) versus 44.6 mU/g (28.2-57.2) and 40.9 mU/g (21.7-53.5) in group DA, C, and D0, respectively, p = 0.76. AER was not correlated to LPLA. An overall negative correlation between TG and LPLA was found; r = -0.33, p = 0.04, supported by an overall significant positive correlation between LPLA and HDL; r = 0.32, p = 0.045. We conclude that, in insulin-dependent diabetes mellitus, skeletal muscle lipoprotein-lipase activity is associated with plasma triglyceride, while an association between lipoprotein-lipase activity and urinary albumin excretion is questionable.
All 906 patients with insulin-dependent diabetes mellitus (IDDM) diagnosed before the age of 31 years, prior to 1943, and admitted to the Steno Memorial Hospital were followed until death or until 1 January 1984. In an attempt to identify factors of prognostic importance, we compared patients dying within 35 years of the onset of diabetes with patients surviving for 40 years or more. Three hundred and seventy-seven patients survived for 40 years or more; of these 224 were still alive and invited to a re-examination, in which 184 participated. After 40 years of diabetes, the most frequent complications were impaired vision (due to diabetic retinopathy) and persistent proteinuria. However, 53% had no major complications despite 40 years with IDDM. The 184 re-examined patients (median age 60 years, median diabetes duration 47 years) were all genuine IDDM patients, as defined by stimulated C-peptide levels. Proliferative retinopathy or visual impairment was found in 56% of the 184 patients, abnormal ECG or amputations in 26%, and elevated urinary albumin excretion rate (AER) greater than or equal to 30 mg/24 h) in 45%. Twenty-five per cent had none of these complications. Proliferative retinopathy was associated with elevated AER and raised systolic blood pressure, macroangiopathy with the use of antihypertensive drugs, and proteinuria with low age at diagnosis, large increase in systolic blood pressure, smoking, and insulin-binding antibodies. Sex, age and diabetes duration were not associated with any of these three late diabetic complications.
Forty per cent of all Danish insulin-dependent diabetic (IDDM) patients survive for at least 40 years after diagnosis. In an attempt to identify factors influencing the probability of surviving for 40 years or more, we followed all IDDM patients diagnosed before 1943 and admitted to the Steno Memorial Hospital. Patients surviving greater than or equal to 40 years were compared with patients dying within 35 years of diabetes diagnosis. Patients dying within 35 years were characterized by male preponderance (p less than 0.01), poor metabolic control (p less than 0.05), and by less frequent attendance at a specialized care unit (p less than 0.0001). Death due to uraemia/diabetic nephropathy was also characterized by male preponderance, poor metabolic control, and few contacts with a specialized care unit but in patients dying from cardiovascular disease (CVD), no effect of sex was found, indicating that the protection from CVD found in the female non-diabetic population is absent in IDDM patients. We conclude that long-term survival with IDDM may be determined by factors susceptible to intervention such as metabolic regulation and patient attitude to their disease.
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Physicochemically, NPH and lente insulins differ in size of crystals, content of protamine and zinc, and often in species composition, since lente always contains beef insulin. The duration of the hypoglycemic effect of lente insulin seems to be longer than 24 h, whereas that of NPH insulin does not exceed 24 h when given in amounts of 0.2-0.3 U/kg body wt. Moreover, NPH and lente insulins differ in their ability to form stable mixtures with neutral insulin solutions, since only NPH insulin can be mixed with regular insulin without changing the specific course of effect of regular insulin. Highly purified porcine NPH and the lente-like porcine insulin preparation. Monotard, do not seem to differ regarding side effects (lipoatrophy, immunogenicity). However, highly purified lente insulin (containing beef insulin) seems to be more immunogenic than highly purified porcine NPH insulin.
The absorption and miscibility of subcutaneously injected 125I-regular porcine insulin was examined in 20 insulin-treated diabetic patients. The disappearance half-life (t1/2) was 2.1 +/- 0.8 h (SD) after injection of regular insulin (40 U/ml) and 2.3 +/- 0.7 h when mixed with porcine NPH insulin (NS). A significant inverse relation was demonstrated between insulin concentration and absorption, as t1/2 was 1.8 +/- 0.7 h (P less than 0.05) when using 20 U/ml. The interindividual coefficients of variation for absorption of regular insulin were 30.9-41.6% and independent of the presence of NPH insulin. The intrapatient variability, however, was much smaller, 14.5-23.6%.