Insulin: understanding its action in health and disease.
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Biomedical subjects
Publications and source records attributed to P Sonksen.
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To determine the effect of insulin on regional cerebral blood flow (rCBF) and glucose metabolism (CMRglu), we performed quantitative dynamic PET scanning of labeled water (H215O) and deoxyglucose (18FDG) using two protocols in 10 diabetic men. In protocol A, to test reproducibility of the technique, insulin was infused at 1.5 mU.kg-1.min-1 twice (n = 5). In protocol B, low (0.3 mU.kg-1.min-1) and high (3 mU.kg-1.min-1) dose insulin was given on separate occasions (n = 5). Euglycemia (5 mmol/L) was maintained by glucose infusion. In protocol A, CMRglu was 6% higher during the first infusion, and catecholamines were also increased, indicating stress. Blood flow was not different. Changing free insulin levels from 20.5 +/- 4.8 to 191 +/- 44.5 mU/L (P < 0.001, low versus high dose, protocol B) did not alter total or regional CMRglu (whole brain 36.6 +/- 4.0 versus 32.8 +/- 6.2 mumol.100 g-1.min-1, P = 0.32) or CBF (41.7 +/- 5.1 and 45.6 +/- 9.7 mL.100 g-1.min-1, P = 0.4) or rCBF. In cerebellum, CMRglu was lower than in cortex and the ratio between rate constants for glucose uptake and phosphorylation (K1 and k3) was reversed. There are regional differences in cerebral metabolic capacity that may explain why cerebral cortex is more sensitive to hypoglycemia than cerebellum. Brain glucose metabolism is not sensitive to insulin concentration within the physiologic range. This suggests that intracerebral insulin receptors have a different role from those in the periphery.
The study investigates the neurological substrate in children with congenital disorders of the peripheral visual system (CDPVS), i.e. disorders of the anterior visual pathways and the globe. The design is retrospective; brain MRI and/or CT scans were traced and reviewed for 79 of 254 children with CDPVS on our database. The neuroradiological findings were considered in the context of degree of visual impairment (profound [PVI] and severe [SVI]), developmental outcome (setback and non-setback), and mode of imaging (MRI and CT). Scans were abnormal in 40 of 79 (51%) children; 23 of 40 (58%) had more than one lesion; and in some children lesions not previously reported were found. The number of abnormalities per child was significantly higher in the PVI than the SVI group (P<0.05); the level of significance varied according to the method of scanning (MRI, P<0.001; CT, ns). Seven children were known to have had developmental setback; significantly more brain abnormalities per child were found in the group with setbacks than in the group without (P<0.001). Eighty-six percent (24 of 28) of MRI compared with 38% (22 of 58) of CT scans were abnormal. MRI detected more lesions per child than CT (P< 0.001). Thus, a significant amount of brain pathology occurs in children with CDPVS. The number of lesions varies directly with degree of visual impairment and both correlate with developmental outcome. As brain pathology will be only one of many factors influencing developmental progress in visually impaired children, prospective multifactorial studies of the CDPVS population, which include MRI studies of the neurological substrate, will be required to clarify the latter.
The relationship between visual and perceptual-motor abilities at 6 years of age was investigated in a cohort of 141 prematurely born children without cerebral palsy. Visual acuity was assessed using the Sonksen-Silver Acuity System and stereopsis with the Titmus stereo test. Perceptual motor abilities were evaluated using the Movement Assessment Battery for Children and the Developmental Test of Visual-Motor Integration. The results showed a higher incidence of abnormalities both of linear acuity and stereopsis in the study group when compared to a group of reference children. Whereas abnormalities of linear acuity were not associated with perceptual-motor difficulties, abnormal stereopsis was significantly associated with poor performance on both perceptual-motor tests. Our results suggest that infants born preterm, even in the absence of other major neurological signs, are at risk for abnormal visual function and perceptual-motor difficulties. As these could interfere with everyday life and school performance, a longitudinal assessment of both areas of competencies is recommended so that diagnosis and possible intervention can take place as early as possible.
Diabetes mellitus is a common condition which has several serious complications associated with it. In this paper a mixture model, based on one previously used to predict the onset of AIDS, is used to predict the onset of one of these complications, diabetic retinopathy, the major cause of adult blindness in the U.K. This model differs from the previous AIDS model by introducing covariates into the model and using a wider choice of mixture distributions. The fit and distributional assumptions of the model are then discussed for this example. The model is fitted to the data by maximum likelihood. It is important that the training set contains balanced numbers of individuals with and without retinopathy.
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The standardization of methodology and the provision of age-related reference values have been addressed for the design of and interpretation of data from a multicentre neuropathy trial. Age-related reference values were generated from 120 healthy volunteers. Vibration perception thresholds (VPT) deteriorated significantly with age (p less than 0.001). Patients were selected on the basis of age-related abnormal VPT and peroneal motor nerve conduction velocity. They were assessed at the beginning and end of a placebo run-in period (baseline data). The coefficients of variation (CV%) for VPT at the medial malleolus (16.81 per cent, n = 316) and great toe (19.23 per cent, n = 313) were lower compared to results in healthy volunteers (29.7 per cent and 20.8 per cent, respectively, n = 49). The CV% for expiratory:inspiratory (E:I) ratio (4.82 per cent, n = 215), Valsalva manoeuvre (10.84 per cent, n = 249) and 30:15 ratio (7.73 per cent, n = 292) from patients corresponded to those recorded in volunteers (7.6 per cent, n = 45 11.0 per cent, n = 49 9.5 per cent, n = 48, respectively). Most patient values for VPT at the great toe fell beyond the 95 centile line for volunteers. E:I ratio for volunteers showed a more variable relationship with age, although patient values appeared to be located below the 5 centile line for volunteer data.
The effects of chronic subcutaneous infusion of luteinising hormone-releasing hormone (LHRH) have been studied in a group of 17 male patients with hypogonadotrophic hypogonadism (HH). Ten of the patients had primary and seven secondary failure of gonadotrophin release, and all but four had previously been treated with gonadotrophin injections. Treatment was continued for between one and 18 months and was well tolerated by all except one patient who became allergic to LHRH. An increase in the basal gonadotrophin concentrations occurred in all except four patients within one week of the initiation of therapy, and this was associated with a rise in the serum testosterone level in eight patients. Increased spermatogenesis was demonstrated in seven cases and three pregnancies have resulted thus far. Pituitary desensitisation to the effects of LHRH was found in five subjects with primary HH who failed to produce any increase in testosterone secretion despite an initial stimulation of gonadotrophin release. We conclude that chronic pulsatile infusion of LHRH is an effective technique for the treatment of some cases of hypogonadotrophic hypogonadism.