Alpha-glucosidase inhibitors in diabetes. Introduction.
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Biomedical subjects
Publications and source records attributed to A C Kruseman.
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We have evaluated the effects of repaglinide, a new non-sulphonylurea oral hypoglycaemic agent that has a stimulatory effect on insulin secretion. Forty-four patients with NIDDM, already treated with a sulphonylurea, took part in an open, randomised, group comparison study of 12 weeks duration, during which they received either repaglinide or glibenclamide twice daily. While glibenclamide had a greater effect on fasting blood glucose (10.4 to 8.6 mmol.l-1), repaglinide significantly lowered postprandial blood glucose (13.8 to 12.2 mmol.l-1). Glycosylated haemoglobin remained unchanged in both groups, and serum fructosamine showed a tendency to fall. With both treatments total cholesterol was significantly decreased after 12 weeks, while HDL-cholesterol and triglycerides did not change. Fasting plasma insulin in the repaglinide group decreased from 80 (median value) to 67 pmol.l-1; it did not change in the glibenclamide group. Two patients in the repaglinide group did not complete the study, one for personal reasons, and one because of a rise in blood glucose. No abnormal findings attributable to repaglinide were observed in clinical and laboratory examinations, and no hypoglycaemic symptoms caused by it were observed.
The accumulation of advanced glycosylation end-products (AGEs) on collagen and the subsequent stiffening of this matrix protein in diabetes has been described many years ago. Structural modification of collagen in the arterial wall might have important effects on arterial elasticity. Aminoguanidine is known to decrease the formation of AGEs. In this study we evaluated the effects of aminoguanidine treatment on different parameters reflecting arterial wall elasticity in diabetic rats. We demonstrated that treatment of diabetic rats with aminoguanidine resulted in a significant increase in carotid static compliance (+39%, P < 0.01 under control conditions, and +27%, P < 0.01 after abolition of vascular tone by KCN), and a decrease in characteristic aortic input impedance (-40%, P < 0.01). The arterial pulse pressure in aminoguanidine-treated rats was decreased (-15%, P < 0.05) and the pulsatile component of left ventricular power output was relatively diminished (-35%, P < 0.05). In addition, we observed a lower fluid filtration across the carotid wall. These results indicate an increased vascular elasticity, an improved left ventricular-arterial coupling, and a decreased vascular permeability in diabetic rats after aminoguanidine treatment, suggesting that AGE-accumulation on collagen negatively affects arterial wall properties in experimental diabetes.
OBJECTIVES: We wished to determine whether women with multinodular goitre and spontaneous subclinical hyperthyroidism have decreased bone density. DESIGN AND SUBJECTS: Bone density was measured at the distal and proximal forearm. Data were expressed as Z-scores relative to the mean values out of 125 control subjects matched for age and menopause. The Z-scores of 23 women with subclinical hyperthyroid goitre (TSH < 0.1 mU/l and normal values for FT4 and total T3) and of 54 women with euthyroid goitre were compared. MEASUREMENTS: Bone density was measured by single photon absorptiometry. TSH was measured by IRMA, FT4 by RIA. RESULTS: Relative to the euthyroid goitre subjects the mean +/- SEM Z-scores of both the distal and proximal forearm density were lower (-0.69 +/- 0.17 vs -0.1 +/- 0.18, P < 0.05 and -0.5 +/- 0.18 vs 0.07 +/- 0.18, P < 0.05, respectively). Median (range) FT4 in the subclinical hyperthyroid goitre subjects was significantly higher than euthyroid goitre subjects (15.6 (11-23.2) pmol/l vs 11.9 (8.3-18.3) pmol/l, P < 0.001) although still within the normal range. FT4 correlated inversely with Z-scores of both distal and proximal forearm bone density in the subjects with subclinical hyperthyroidism (r = -0.42, P < 0.05 and r = -0.43, P < 0.05, respectively), but not in the euthyroid goitre subjects. CONCLUSION: These findings indicate that women with untreated multinodular goitre and subclinical hyperthyroidism have reduced bone density in the forearm.
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The effects of guar incorporated into a complex spaghetti meal on the glycaemic response in 11 healthy and 6 non-insulin dependent diabetic (NIDDM) subjects was studied. To this end, subjects consumed spaghetti made of either Triticum aestivum or Triticum durum wheat with or without 20 g% guar, as part of a complex meal containing 27% fat, 19% protein and 51% carbohydrate. In both the healthy as well as the NIDDM subjects the incremental integrated postprandial glucose and C-peptide responses after ingestion of a guar spaghetti meal were not different from the values found after a spaghetti meal without guar. In NIDDM subjects the incremental glucose and C-peptide levels were lower at 60 and 90 min and 90 and 150 min respectively after ingestion of guar aestivum spaghetti. Our negative results of effects of guar on postprandial glucose values may be explained by the presence of normal quantities of fat and protein in the meal and imply that addition of dietary fibre to a complex meal is not useful in the dietary management of NIDDM.
The predictive values of fasting blood glucose and serum fructosamine for monitoring longterm diabetic control were investigated in 98 non-insulin dependent diabetic patients. The HbA1c percentage was taken as standard in this study. Despite a significant correlation, the predictive values of the parameters studied for an acceptable HbA1c-value appeared to be low (37% and 44% respectively), possibly due to differences in periods of time in which these parameters can change during variable metabolic control. In addition, the serum fructosamine value may vary due to variations in serum albumin and lipid content. It is concluded that the fasting blood glucose and serum fructosamine values cannot replace HbA1c measurement for monitoring diabetic control, but are additional for assessment of this control over short-and longterm periods of time.
The value of Micro-Bumintest tablets and the albumin/creatinine ratio in first morning (FM) urine samples to screen for micro-albuminuria in diabetic patients was evaluated. The A/C ratio in FM urine was highly correlated with the urinary albumin excretion (UAE) rate in micrograms/min in timed overnight (0) urine (R = 0.95, p < 0.001). The sensitivity, specificity and positive and negative predictive values of an A/C ratio > 3.0 to predict micro-albuminuria defined as an UAE > 20 micrograms/min were 94, 92, 92 and 94% respectively. The day-to-day fluctuation of albumin excretion varied between 10 and 105%. The sensitivity, specificity and positive and negative predictive values of micro-bumintest tablet reactions on FM urine samples to predict an A/C ratio > 3.0 were 93, 59, 63 and 91% respectively. It is concluded that for screening of micro-albuminuria the A/C ratio in FM urine is as precise as timed 0 urine collection, but with more comfort for the patient. Micro-Bumintest tablets are useful as an initial screening test and will decrease the number of quantitative albumin measurements in the screening programme by about 30% if only urine samples with positive tablet test are selected for a further investigation. Because of considerable day-to-day fluctuation of urinary albumin excretion several urine samples should be investigated before presence of incipient diabetic nephropathy is assumed.
Periodic fever syndromes usually do not show a clear fixed periodicity, and hence cannot be described by the mean and the standard deviation of the interval length. In those cases statistical tools must be used. Fever interval data can be described as a random point process; the renewal density function and its Fourier transform can be used to uncover hidden periodicities. In this report the estimation and evaluation of the renewal density function are described. The data of three patients with periodic fever were investigated. In one of these patients, suffering from periodic fever originating at the level of the hypothalamus, a 30-day periodicity was observed. In a female patient with hyperimmunoglobulinaemia D and periodic fever, menstruation often coincided with or was preceded by a fever episode. In the third patient with a Familial Hibernian Fever-like syndrome, an irregular fever pattern and no periodicity were found. The computerized analysis of the fever intervals may be useful in assessing various periodic fever syndromes.
A patient with the combination of pheochromocytoma and renal cell carcinoma is reported, matching a forme fruste of von Hippel-Lindau disease. A review of the literature on this combination is given and a possible relation between the overlap syndrome, von Hippel-Lindau disease and the combination pheochromocytoma-renal cell carcinoma, is discussed.
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CRF-41 and vasopressin are the major part of the hypothalamic complex responsible for the release of ACTH. The potentiated response of the corticotroph to mixtures of the peptides and their co-localization in the same neurosecretory vesicles would indicate their obligatory co-secretion in many stress situations. The occurrence of CRF at peripheral sites especially in the placenta and in the plasma of women in their third trimester of pregnancy is suggestive of further roles for this peptide although care should be exercised in interpreting simple immunohistochemical staining in certain tissues. When ACTH is released from the pituitary several other peptides which form part of its precursor are co-released. The effect of these peptides on the adrenal gland and the way their activity is expressed has led to a post-secretional proteolytic control mechanism being proposed.
Bombesin-like immunoreactivity (BLI) in 20 human endocrine tumors was studied using an antiserum directed toward the C-terminal region of bombesin. Additionally, plasma BLI was assayed in normal subjects and patients with known BLI-containing tumors. In 7 tumors (medullary carcinoma of the thyroid, n = 2; carcinoid of the lung, n = 3; hepatic carcinoid, n = 1; pheochromocytoma, n = 1), the BLI content ranged from 6-2000 pg/mg wet wt of tissue. Sephadex G-50 gel chromatography of tumor extracts under acid-dissociating conditions revealed 2 peaks of BLI: 1 coeluting with porcine gastrin-releasing peptide (GRP) and 1 with bombesin. Reverse phase ODS silica HPLC analysis of the G-50 peaks using a methanol-trifluoroacetic acid gradient showed that human tumor BLI more closely resembled porcine GRP and its C-terminal fragment GRP-(14-27) than bombesin itself. Partial tryptic digestion of the tumor GRP-like peptide generated a product which, on HPLC, was similar to GRP-(14-27). Elevated plasma BLI was detected in the peripheral circulation of three subjects and in the vessels draining the tumor metastases of one of these patients. BLI was undetectable in normal subjects. These results indicate 1) that BLI is present in and may be secreted by various human endocrine tumors, and 2) that human tumor BLI closely resembles porcine GRP and its C-terminal fragment GRP-(14-27).
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Thirty pancreatic islet cell tumours were histologically classified and analysed for their possible peptide hormone content using the immunohistoperoxidase method. Seven tumours contained insulin, six tumours contained gastrin and eight tumours contained glucagon. One tumour contained all three hormones. In the insulin and gastrin-containing tumours, the cells were usually arranged in solid nests of cells, with tubular and acinar formations in about half the cases. In the glucagon-containing tumours the cells were mainly arranged in anastomosing ribbons consisting of one of two layers of small cells. Most of the hormone-containing tumours were argyrophilic using Grimelius' silver reaction. All but one of the glucagon-containing tumours were incidental findings at autopsy. About half of the other tumours had metastasized. It is concluded that a relation exists between the histological pattern of growth and immunohistochemically defined endocrine function of pancreatic islet cell tumours.
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A case of metastic choriocarcinoma after term pregnancy, with tumor localization in the kidney of a hydropic stillborn infant, is presented. The primary tumor was found in a scraping four weeks after delivery. The identity and nature of the malignant growth in mother and child were substantiated by identical immunohistochemical patterns for gonadotropin activity. Because of a positive Kleihauer test it was assumed that massive feto-maternal transfusion had caused the hydrops and intrauterine death. Now, four and a half months after starting methotrexate therapy, the mother seems to be free of tumor. Plasma human chorionic gonadotropin titers have decreased to normal.