Diabetologia

Wong, H.; Elts, S.; Phillips, J.; Williams, K.

doi: 10.1007/BF00399927pmid: 1397776

125 35 35 9 9 H. C. Wong S. M. Elts J. W. Phillips K. A. Williams Department of Ophthalmology Flinders Medical Centre Bedford Park South Australia Australia Department of Biochemistry and Chemical Pathology Flinders Medical Centre Bedford Park South Australia Australia Summary Within the central nervous system, pericyte degeneration in diabetes mellitus occurs only in the retinal microcirculation and is not seen in the brain. This study sought to elucidate differences between bovine retinal and brain pericytes. When pairs of retinal and brain pericytes from individual calves were cultured in vitro, the morphological organisation of early post-confluent retinal pericyte cultures was consistently different from that of brain pericyte cultures. When retinal and brain pericyte cultures were grown to second passage in high or normal glucose medium supplemented with fetal calf serum, brain pericyte cultures grew significantly faster than retinal pericytes in either medium (p<0.0001). Brain pericytes thus appeared to grow intrinsically faster than retinal pericytes and this effect was largely independent of glucose concentration. Brain pericytes also grew faster than retinal pericytes in high glucose medium containing human diabetic or control serum ( p <0.002). The proliferative effect of serum from diabetic patients with non-proliferative diabetic retinopathy on pericytes grown in high glucose medium was not significantly different from that of control serum. Both brain and retinal pericytes showed variation in their ability to replicate in high concentrations of glucose. The selectivity of pericyte degeneration to the retinal circulation does not appear to be due to changes in the mitogenic activity of diabetic serum for retinal pericytes, but may relate to the intrinsic relative inability of the retinal pericyte to reproliferate in response to the metabolic injury of diabetes mellitus.

Bendtson, I.; Gade, J.; Theilgaard, A.; Binder, C.

doi: 10.1007/BF00399939pmid: 1397787

125 35 35 9 9 I. Bendtson J. Gade A. Theilgaard C. Binder Steno Diabetes Center Gentofte Department of Medical Informatics and Image Analysis Aalborg University Aalborg Department of Clinical Psychology, Rigshospitalet State University Hospital Copenhagen Denmark Summary Eight Type 1 (insulin-dependent) diabetic patients with no diabetic complications were studied on two consecutive and one subsequent overnight occasions. The aim was to evaluate the influence of nocturnal hypoglycaemia on neuropsychological and reaction time tests the following morning. Hypoglycaemia was induced by i. v. insulin infusion, blood glucose nadir was 1.5±0.3 mmol/l. Duration of hypoglycaemia (blood glucose < 3 mmol/l) was 101±38 min. Whole night sleep statistics for all patients showed no statistical differences between the normoglycaemic and hypoglycaemic nights, however, there was a tendency of prolongation of the second sleep cycle in the nights with hypoglycaemia. Each patient was used as his own control and periods with blood glucose concentration less than 3 mmol/l were compared to exactly the same periods in nights with blood glucose level over 5 mmol/l. During hypoglycaemia the amount of deep sleep was reduced and replaced by superficial sleep and arousals of short duration. Further, the reduction in deep sleep was replaced later at night. Neuropsychological test scores and reaction time measurements in the morning showed no differences between the normoglycaemic and hypoglycaemic nights. In conclusion: despite sleep disturbances, nocturnal hypoglycaemia did not impair cognitive function the following morning in Type 1 (insulin-dependent) diabetic patients.

Jenner, M.; Bradish, G.; Stiller, C.; Atkison, P.

doi: 10.1007/BF00399937pmid: 1397785

125 35 35 9 9 M. Jenner G. Bradish C. Stiller P. Atkison The London Diabetes Study Group Department of Paediatrics, Children's Hospital of Western Ontario University of Western Ontario Canada Multi-Organ Transplant Service University Hospital London Ontario Canada Summary Several studies have demonstrated the efficacy of cyclosporin A in modifying the initial course of Type 1 (insulin-dependent) diabetes mellitus in older children and adults but none have reported the effects in very young children. We treated 14 newly-diagnosed Type 1 diabetic patients aged 22 months to 95 months with cyclosporin A. Mean insulin dose at entry was 0.7±0.07 IU · kg −1 · day −1 . Initial cyclosporin A dose was 10 mg · kg −1 · day −1 . Insulin dose reached a nadir of 0.13 IU · kg −1 · day −1 by 180 days. Mean glucagon-stimulated connecting peptide levels were maximal at 6 months (0.75 nmol/l) and were maintained while on cyclosporin A. Insulin was discontinued in four patients for 4,12,15 and 30 months respectively. In five other patients the insulin dose was less than 0.15 IU · kg −1 · day −1 for at least 3 months. Glycated haemoglobin levels for all patients were within the normal range. Side effects included anorexia, stomach pains, poor weight gain, hypertrichosis, gum hyperplasia, mild anaemia and elevated creatinine. All patients have now discontinued cyclosporin A and all but one have been followed for 5 years after discontinuation. Reasons for discontinuing cyclosporin A included exposure to chicken pox (varicella), non-resolving otitis media, incomplete or no response and relapse. All side effects have resolved since the treatment was discontinued. Following discontinuation of cyclosporin A insulin requirements and glycated hemoglobin levels increased while glucagon-stimulated connecting peptide levels declined dramatically. In summary, a small number of very young patients treated with cyclosporin A achieved non-insulin requiring remissions while partial remissions occurred in several other patients and endogenous insulin production was maintained. Side effects to the drug occurred although there have been no long-term consequences.

Ibbotson, S.; Walmsley, D.; Davies, J.; Grant, P.

doi: 10.1007/BF00399933pmid: 1397782

125 35 35 9 9 S. H. Ibbotson D. Walmsley J. A. Davies P. J. Grant Academic Unit of Medicine The General Infirmary Leeds UK Summary A possible association between plasma coagulant activity and the presence of vascular complications in patients with diabetes mellitus was studied by measuring the generation of thrombin in plasma of 20 control subjects and 50 diabetic patients classified according to the presence or absence of microvascular complications. Thrombin production was determined in defibrinated plasma using a semiautomated technique with measurement of thrombin activity using chromogenic peptide S2238. Values determined were the lag time to appearance of thrombin activity and time taken to generate 50% maximal thrombin activity. Thrombin activity was related to concentrations of coagulant factor VIII activity and fibrinopeptide A and these were correlated with HbA 1C levels. The median time to generate 50% maximal thrombin activity was not significantly reduced in diabetic patients compared with control subjects (53 vs 54 s, p =0.076) and there were no significant differences between patients with and without microvascular complications. There were no differences in median fibrinopeptide A concentrations between the diabetic and control subjects (1.5 vs 2.2 nmol/l, p =0.169).Time to 50% maximal thrombin activity correlated inversely with factor VIII: C concentrations in diabetic patients ( r =−0.344, p =0.015, n =50) and both this and lag time correlated with factor VIII: C in diabetic patients and control subjects combined ( r =-0.395, p <0.01; r = −0.327, p =0.006, n =70). Factor VIII: C concentrations increased with age of the subject and with HbA 1C concentrations. The results failed to show enhancement of coagulation in contact-activated diabetic plasma compared with control plasma and suggest that a relationship between high levels of factor VIII:C in diabetes and the development of microvascular complications is unlikely to be mediated through procoagulant activity in plasma.

Ziegler, D.; Hübinger, A.; Mühlen, H.; Gries, F.

doi: 10.1007/BF00399928pmid: 1397777

125 35 35 9 9 D. Ziegler A. Hübinger H. Mühlen F. A. Gries Diabetes Research Institute Heinrich-Heine-University Düsseldorf FRG Summary To determine whether the degree of previous glycaemic control may modify cognitive responses to hypoglycaemia, the glycaemic thresholds for, and magnitude of cognitive dysfunction as assessed by P300 event-related potentials as well as subjective and hormonal responses during hypoglycaemia were evaluated. Hypoglycaemia was induced by intravenous insulin infusion in 18 Type 1 (insulin-dependent) diabetic patients, 7 of whom were strictly controlled (HbA 1c : 6.3±0.3%; mean±SEM; Group 1) and 11 of whom were poorly controlled (HbA 1c : 9.1±0.4%; Group 2). Within 60 min, mean blood glucose declined from 5.6 and 5.7 mmol/l (baseline) to a nadir of 1.6 and 1.8 mmol/l followed by an increase to 5.6 and 4.3 mmol/l after 120 min in Group 1 and 2, respectively. There was no significant difference between the groups in regard to P300 latency at baseline, but between 50 and 70 min a significant prolongation of this component was noted in Group 2 as compared with Group 1 at blood glucose levels between 1.6 and 2.3 mmol/l ( p <0.05). The glycaemic thresholds at which a significant increase of P300 latency over baseline was first noted were 1.6±0.2 mmol/l in Group 1 and 3.5±0.2 mmol/l in Group 2 ( p <0.05). The glucose thresholds at which this prolongation was no longer demonstrable were 1.9±0.1 mmol/l in Group 1 and 3.8±1.4 mmol/l in Group 2, respectively ( p <0.05). The glycaemic threshold at which the P300 amplitude was first significantly reduced was 2.2 mmol/l in Group 2, whereas no such reduction was observed in Group 1. The glycaemic thresholds for the perception of subjective symptoms were 1.7±0.2 mmol/l in Group 1 and 2.5±0.2 mmol/l in Group 2 ( p <0.05), and those for the first significant rise of the counter-regulatory hormones were 2.3±0.1 and 1.6±0.2 mmol/l in Group 1 as well as 2.8±0.1 mmol/l in Group 2 ( p <0.05). Thus, the glycaemic threshold for and magnitude of, cognitive dysfunction during hypoglycaemia are reduced in strictly-controlled as compared with poorly-controlled Type 1 diabetic patients. In the latter group, cognitive impairment may precede the onset of counter-regulatory hormone responses and symptom awareness. These findings support the concept of cerebral adaptation to previous low blood glucose levels.

Bruce, D.; Chisholm, D.; Storlien, L.; Kraegen, E.; Smythe, G.

doi: 10.1007/BF00399929pmid: 1397778

125 35 35 9 9 D. G. Bruce D. J. Chisholm L. H. Storlien E. W. Kraegen G. A. Smythe Garvan Institute of Medical Research St. Vincent's Hospital Sydney Australia Summary The sympathetic nervous system may contribute to excessive hepatic glucose output in Type 2 (non-insulin dependent) diabetes mellitus and could be implicated in the interrelated problem of hypertension. The aim of these studies was to determine whether subjects with Type 2 diabetes had normal sensitivity (compared with age- and weight-matched non-diabetic subjects) to noradrenaline infusion (60 ng · kg −1 · min −1 for 60 min) and to compare the responses with oral tyramine administration (800 mg), and psychological stress (using competitive computer games). Noradrenaline infusion caused significantly greater plasma glucose (mean increment 2.1±0.4 vs 0.6±0.1 mmol/l, p <0.005) and pressor responses (mean systolic increment 21±3 vs 11±1mm Hg, p <0.02) in the diabetic subjects. The excessive glycaemia was due to increased hepatic glucose output rather than reduced glucose disposal. Tyramine administration caused significantly increased hepatic glucose output and plasma glucose levels, but with similar responses in the diabetic and non-diabetic subjects; the pulse and pressor responses were also similar between the groups. The psychological stressor induced significant increases in pulse, blood pressure and non-esterified fatty acid levels in the combined group of subjects ( p <0.01) but did not influence plasma glucose levels in either diabetic or non-diabetic subjects. We conclude that pharmacologically-induced sympathetic nervous stimulation can induce hyperglycaemia. Subjects with uncomplicated Type 2 diabetes have increased sensitivity to exogenous noradrenaline but may not hyperrespond to endogenous sympathetic activation.

Bendtsen, T.; Nyengaard, J.

doi: 10.1007/BF00399930pmid: 1397779

125 35 35 9 9 T. F. Bendtsen J. R. Nyengaard Stereological Research Laboratory, University Institute of Pathology and Second University Clinic of Internal Medicine, Institute of Experimental Clinical Research Aarhus University Aarhus Denmark Summary The number of glomeruli per kidney in Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetic patients was estimated by an unbiased stereological method: the fractionator. No significant differences were observed between Type 1 and Type 2 diabetic patients without severe diabetic glomerulopathy and non-diabetic patients. Diabetic patients with proteinuria who were in the early stages of diabetic nephropathy also had a normal number of glomeruli. On the other hand, a subgroup classified as Type 1 diabetic patients with severe diabetic glomerulopathy had significantly less glomeruli compared with Type 1 diabetic patients with mild or no glomerulopathy. A probable explanation is that Type 1 diabetic patients lose glomeruli in relation to the progression of diabetic glomerulopathy. A more theoretical alternative is, however, that development of diabetic glomerulopathy is facilitated by a low number of glomeruli.

Helgason, T.; Danielsen, R.; Thorsson, A.

doi: 10.1007/BF00399936pmid: 1397784

125 35 35 9 9 T. Helgason R. Danielsen A. V. Thorsson Diabetic Clinic and Department of Medicine, Landspítalinn University Hospital Iceland Department of Paediatrics St. Joseph's Hospital Reykjavík Iceland Summary Through use of primary and secondary data sources for registration and validation, the incidence and prevalence of Type 1 (insulin-dependent) diabetes mellitus in children aged 0–14 years in Iceland has been completely ascertained for the years 1970–1989. The age-adjusted mean annual incidence per 100,000 for the 20-year period was 9.4 (95% confidence interval 7.8–11.3); similar for boys (9.9; 7.7–12.7) and girls (8.8; 6.7–11.5). Between 1970–1979 the incidence was 8.0 (6.0–10.6) and between 1980–1989 it was comparable at 10.8 (8.4–13.8) ( p >0.10). By Poisson regression analysis the variation in incidence was related to age at diagnosis ( p <0.001), while a linear trend for calendar year at diagnosis did not reach statistical significance ( p =0.07). A quadratic curve, however, better described the temporal variation in incidence ( p <0.05). The total prevalence per 1,000 by the end of 1979 and 1989 was similar, 0.45 (0.30–0.65) and 0.57 (0.40–0.79), respectively. In conclusion, this study confirms that both the incidence and prevalence of childhood Type 1 diabetes in Iceland are low compared to the other Nordic countries. The findings may suggest a causative role for environmental factors that are not related to latitude or ambient temperature.

Østerby, R.

doi: 10.1007/BF00399925pmid: 1397774

125 35 35 9 9 Dr. R. Østerby Institute of Experimental Clinical Research, Second University Clinic of Internal Medicine and Institute of Pathology University of Aarhus Arhus Denmark Electron Microscopy Laboratory Institute of Pathology Kommunehospitalet DK-8000 Århus C Denmark Summary Diabetic nephropathy is caused primarily by advanced glomerulopathy, the renal expression of diabetic microangiopathy. With stereological methods a quantitative description of the structural changes is achieved. The glomerulopathy is characterized by an increase in basement membrane material: thickening of the capillary wall and an increase in mesangial volume relative to glomerular volume, comprising increase in matrix. Among groups of patients conformity between renal function stage and structure exists. The parameters measuring glomerulopathy are normal at the onset of diabetes; patients with normoalbuminuria may show slight basement membrane thickening, or normal parameters; the microalbuminuric group shows a measurable, but moderate glomerulopathy; patients with overt nephropathy have advanced lesions; at this stage heterogeneity among glomeruli makes the estimates weaker. Recent data indicate that the changes in peripheral basement membrane and in mesangial matrix develop in concert and both contribute to the early stage of glomerulopathy in patients with microalbuminuria. As to the consequences of the structural changes the mechanism of albuminuria is not clear. It is suggested that the early glomerulopathy entails other structural modifications, including formation of new vessels which may be the site of leakage. The marked deviations in glomerular filtration rate correspond well with estimates of filtration surface area: in the early hyperfunction state it is increased; in advanced nephropathy it is decreased, due to advanced glomerulopathy in conjunction with glomerular occlusion. The diabetic state is the necessary condition for the glomerulopathy. In relating structural changes to presumed contributing causes no supporting evidence of a relationship with glomerular hyperfunction or hypertrophy was observed. The structural parameters may be useful tools in clinical trials aiming at arresting the development of glomerulopathy, and thereby providing a prevention of diabetic nephropathy.

doi: 10.1007/BF00399942pmid: N/A