Diabetologia

Lam, K.; Cheng, I.; Janus, E.; Pang, R.

doi: 10.1007/BF00400731pmid: 7489845

125 38 38 5 5 Dr. K. S. L. Lam I. K. P. Cheng E. D. Janus R. W. C. Pang Department of Medicine University of Hong Kong, Queen Mary Hospital Pokfulam Road Hong Kong Clinical Biochemistry Unit University of Hong Kong, Queen Mary Hospital Hong Kong Summary There is experimental evidence to suggest that hypercholesterolaemia may play a pathogenetic role in progressive glomerular injury. We investigated the effect of cholesterol-lowering therapy on the progression of diabetic nephropathy in 34 patients with non-insulin-dependent diabetes mellitus. Patients were randomly assigned in a single-blind fashion to treatment with either lovastatin, an HMG CoA reductase inhibitor ( n =16; mean dose 30.0±12.6 mg/day) or placebo ( n =18) for 2 years. Renal function was assessed by serially measuring the serum creatinine, glomerular filtration rate (using Cr 51 -EDTA), and 24-h urinary protein excretion. Lovastatin treatment was associated with significant reductions in total cholesterol ( p <0.001), LDL-cholesterol ( p <0.001) and apo B ( p <0.01), the reductions at 24 months being 26, 30 and 18%, respectively. Beneficial effects on serum triglyceride, HDL-cholesterol and apo A1 levels were also observed. Lp(a) showed no significant change in both groups. Glomerular filtration rate deteriorated significantly in the placebo group after 24 months ( p <0.025) but showed no significant change in the lovastatin-treated patients. The increase in serum creatinine was statistically significant ( p <0.02) in placebo-treated patients at 12 and 24 months, and in the lovastatin group after 24 months. Twenty-four hour urinary protein excretion increased in both groups ( p <0.05). Lovastatin treatment was not associated with significant elevations in liver or muscle enzymes. We conclude that effective normalisation of hypercholesterolaemia may retard the progression of diabetic nephropathy.

Ueda, H.; Ikegami, H.; Yamato, E.; Fu, J.; Fukuda, M.; Shen, G.; Kawaguchi, Y.; Takekawa, K.; Fujioka, Y.; Fujisawa, T.; Nakagawa, Y.; Hamada, Y.; Shibata, M.; Ogihara, T.

Moreo, G.; Mariani, E.; Pizzamiglio, G.; Colucci, G.

doi: 10.1007/BF00400726pmid: 7489840

125 38 38 5 5 Dr. G. Moreo E. Mariani G. Pizzamiglio G. B. Colucci Divisione di Medicina Generale Istituti Clinici di Perfezionamento Via S. Barnaba, 8 I-20122 Milan Italy Servizio di Neurofisiologia Istituti Clinici di Perfezionamento Milan Italy Summary In order to assess the possible progression of neurological abnormalities over time and the value of visual evoked potential alterations in predicting stability and severity of diabetes-related optic pathway disease, a longitudinal study in non-insulin-dependent diabetic patients was performed. Neurological examination, visual evoked potentials with pattern reversal, motor and sensory nerve conduction velocities and metabolic control were studied in 18 non-insulin-dependent diabetic patients and in 35 normal control subjects at baseline and again after 4.6±0.8 years (range 4–6). At the first recording the peak P100 wave latencies were significantly delayed in the diabetic patients compared with the control subjects; signs of peripheral neuropathy were detected in five patients, clinical in three and in two there was only neurophysiological alteration without clinical signs. The second recording revealed no significant alterations of P100 latencies in patients compared with baseline, but the number with clinical signs and/or neurophysiological alterations with no clinical signs of peripheral neurological disease was increased to seven. In conclusion, we observed that visual evoked potential alterations were stable over time whereas peripheral neurological disease progressed and correlated positively with metabolic control.

Nielsen, F.; JØrgensen, L.; Ipsen, M.; Voldsgaard, A.; Parving, H.

doi: 10.1007/BF00400729pmid: 7489843

125 38 38 5 5 Dr. F. S. Nielsen L. N. JØrgensen M. Ipsen A. I. Voldsgaard H. -H. Parving Steno Diabetes Center Niels Steensens Vej 2 DK-2820 Gentofte Denmark Novo Nordisk A. S. BagsvÆrd Denmark Summary Recombinant DNA technology allows the production of insulin analogues with faster absorption rates from subcutaneous tissue as compared to soluble human insulin. The human insulin analogue B10Asp (mono/dimeric) is absorbed twice as fast as soluble human insulin (hexameric). A double blind, randomised crossover study with a 1-month run-in period and two 2-month treatment periods was performed in 21 male insulin-dependent diabetic (IDDM) patients aged 18–40 years in order to compare the metabolic control obtained with equimolar doses of the analogue B10Asp vs soluble human insulin (Actrapid) given as mealtime insulin and intermediate acting isophane insulin (Protaphane) at bedtime. At the end of each 2-month study period, the patients were admitted to the metabolic ward. We found significantly higher plasma insulin/analogue levels after breakfast, lunch and dinner with B10Asp as compared to Actrapid ( p <0.05). The plasma insulin/analogue levels were significantly lower before lunch and dinner with B10Asp as compared to Actrapid ( p <0.05). Also, the plasma insulin/analogue level tended to be lower at bedtime when comparing B10Asp to Actrapid. The 24-h blood glucose profiles showed identical fasting blood glucose, significantly lower blood glucose after breakfast with the analogue ( p <0.05), no differences in blood glucose after lunch and dinner but a significantly higher blood glucose at midnight using the analogue ( p <0.05). The overall 24-h mean blood glucose concentrations, the daily insulin dose, HbA 1c , diet, home blood glucose monitoring and frequency of hypoglycaemia were almost identical in the two treatment periods. In conclusion, the overall glycaemic control remained unchanged and quite good when Actrapid was exchanged dose for dose with the insulin analogue B10Asp in IDDM patients treated with a basal bolus regime.

Roglić, G.; Pavlić-Renar, I.; šestan-Crnek, S.; Prašek, M.; Kadrnka-Lovrenčić, M.; Radica, A.; Metelko, Ž.

doi: 10.1007/BF00400723pmid: 7489837

125 38 38 5 5 G. Roglić I. Pavlić-Renar S. šestan-Crnek M. Prašek M. Kadrnka-Lovrenčić A. Radica Ž. Metelko The Vuk Vrhovac Institute for Diabetes, Endocrinology and Metabolic Diseases Zagreb Croatia Department of Pediatrics Clinical Hospital “Sestre Milosrdnice” Zagreb Croatia Department of Pediatrics Clinical Hospital “Rebro” Zagreb Croatia Summary The objective of this study was to determine the incidence of insulin-dependent diabetes mellitus (IDDM) in the population of Zagreb, Croatia, during 1988–1992. A centralized diabetes registry was the primary source of data, while secondary sources were used to assess ascertainment. A total of 282 new cases of IDDM were diagnosed in the study period, the primary and secondary sources identifying annually 93–100% of the cases. The annual incidence rate ranged from 5.6 per 100,000 to 6.6 per 100,000. Early fatality in persons older than 50 years was the major cause of underascertainment. The incidence peaked in the 10–14 years age group (12.4 per 100,000), and remained stable after age 24 years. Males had a significantly higher incidence in the 5–9 and 24–44 years age groups. In the 45–54 years age group, females had a significantly higher incidence. No seasonality was observed. Despite the war conditions in Croatia, the low overall IDDM incidence rates did not change significantly during the study period.

Sakamoto, K.; Kikkawa, R.; Haneda, M.; Shigeta, Y.

doi: 10.1007/BF00400721pmid: 7489835

125 38 38 5 5 K. Sakamoto Dr. R. Kikkawa M. Haneda Y. Shigeta The Third Department of Medicine Shiga University of Medical Science Otsu 520-21 Shiga Japan Summary The contribution of atrial natriuretic peptide (ANP) to the development of glomerular hyperfiltration in diabetes was investigated by examining the effects of HS-142-1, a non-peptide antagonist of biological receptors for ANP, on glomerular filtration rate (GFR) and renal plasma flow (RPF) in rats with streptozotocin-induced diabetes. Three to four weeks after streptozotocin injection, the plasma concentration of ANP, urinary cyclic GMP excretion rate, GFR, and RPF were significantly higher in diabetic rats than in control rats. The increase in GFR and RPF in diabetic rats was significantly reduced, in a dose-dependent manner, by a single intravenous injection of HS-142-1; the maximal effect was apparent at a dose of 10 mg per kg of body weight. Continuous subcutaneous administration of HS-142-1 with an osmotic minipump for 3 to 4 weeks, beginning 2 days after streptozotocin injection, prevented the increases in urinary cyclic GMP excretion rate, GFR, and RPF observed in untreated diabetic rats. These results highlight the importance of ANP in the development of diabetic glomerular hyperfiltration and indicate that this condition can be prevented by continuous inhibition of the action of ANP.

Jeandidier, N.; Boivin, S.; Sapin, R.; Rosart-Ortega, F.; Uring-Lambert, B.; Réville, Ph.; Pinget, M.

doi: 10.1007/BF00400727pmid: 7489841

125 38 38 5 5 Dr. N. Jeandidier S. Boivin R. Sapin F. Rosart-Ortega B. Uring-Lambert Ph. Réville M. Pinget Service d'Endocrinologie et des Maladies de la Nutrition HÔpitaux Universitaires, HÔpital Civil Strasbourg France Institut de Physique Biologique HÔpitaux Universitaires, HÔpital Civil Strasbourg France Institut d'Immunologie HÔpitaux Universitaires, HÔpital Civil Strasbourg France Service d'Endocrinologie et Maladies Metaboliques HU Strasbourg I Place de l'hÔpital F-67091 Strasbourg France Summary Intraperitoneal insulin infusion using implantable devices in insulin-dependent diabetic (IDDM) patients is promising since it improves diabetic control and decreases frequency of hypoglycaemia. However, preliminary data show a striking increase in plasma levels of anti-insulin antibodies with this therapy. In order to more precisely evaluate the immunogenicity and its consequences, anti-insulin antibody levels in 62 IDDM patients were assessed every 3 months during a 2-year period following pump implantation. At the same time, diabetes control was evaluated with HbA 1c , mean blood glucose levels, standard deviation of the daily blood glucose levels and the frequency of low blood glucose (<3.58 mmol/l). Factors involved in antibody formation such as age, gender, HLA typing, and complement C4 alleles were also studied. After implantation, anti-insulin antibody levels increased significantly from 3.14% (range 0–26%) to 8.34% (0–49%) after 1 year and remained elevated. Patients were divided into two groups: responders able to show at least one antiinsulin antibody titre higher than 15% and non-responders whose titres were always lower than 6%. None of the factors studied was shown to statistically influence the anti-insulin antibody titres. Non-responders had significantly better metabolic results than the responders. Severe hypoglycaemic episodes decreased dramatically in both groups. Insulin requirements were comparable at time 0 and decreased initially in both groups. They remained low for the non-responders but returned to pre-implantation values for responders. Intraperitoneal insulin infusion led to a high immunogenetic response towards insulin in about half of the patients, leading to only moderately deleterious effects on metabolic control. Further studies are necessary to document other consequences (such as the role of circulating immune complexes).

Stephenson, J.; Fuller, J.; Viberti, G.; Sjolie, A.; Navalesi, R.

doi: 10.1007/BF00400730pmid: 7489844

125 38 38 5 5 Dr. J. M. Stephenson J. H. Fuller G. -C. Viberti A. -K. Sjolie R. Navalesi The EURODIAB IDDM Complications Study Group Department of Epidemiology and Public Health University College London 1-19 Torrington Place WC1E 6BT London UK Metabolic Unit Guy's Hospital London UK Eye Department Aarhus University Hospital Aarhus Denmark Unità Operativa di Malattie del Ricambio Istituto di Clinica Medica II Pisa Italy Summary Several studies have shown an association between blood pressure and nephropathy, but few have been large enough to examine whether, or how, this relation is influenced by retinopathy. We have therefore examined the independent relations of blood pressure to urinary albumin excretion and retinopathy in a cross-sectional observational study of over 3000 insulin-dependent diabetic patients (the EURODIAB IDDM Complications Study). The relation of blood pressure to urinary albumin excretion differed strikingly between patients with (46%) and without (54%) retinopathy. In those with retinopathy, mean urinary albumin excretion rate was normal (<20 Μg/min) below median diastolic pressure (75 mm Hg) and increased steeply ( p <0.001) with blood pressure above this level. However, in patients without retinopathy, mean albumin excretion rate was normal across the range of diastolic pressure. This finding could not be explained by differences in glycaemic control or duration of diabetes between patients with and without retinopathy. These data identify a subgroup of patients whose high risk of nephropathy may reflect abnormal renal vulnerability to mildly raised blood pressure. Retinopathy is a close correlate of this vulnerability. Detection of even mild retinopathy, together with raised blood pressure, may be important in assessing nephropathy risk.

Arslanoğlu, İ.

doi: 10.1007/BF00400735pmid: 7489849

Utriainen, T.; Malmström, R.; MÄkimattila, S.; Yki-JÄrvinen, H.

doi: 10.1007/BF00400724pmid: 7489838

125 38 38 5 5 T. Utriainen R. Malmström S. MÄkimattila Dr. H. Yki-JÄrvinen Second Department of Medicine Helsinki University Central Hospital Helsinki Finland Third Department of Medicine Helsinki University Central Hospital Haartmaninkatu 4 FIN-00290 Helsinki Finland Summary To resolve some of the controversy regarding insulin regulation of blood flow, we performed in 20 normal subjects a) a reproducibility study of plethysmographic, Doppler ultrasound and laser Doppler blood flow measurements ( n =7), b) a sequential insulin dose-response study with measurement of forearm (plethysmography), leg (Doppler ultrasound) and skin (laser Doppler) blood flow ( n =12), and c) a sequential insulin dose-response study with comparison of forearm (plethysmography) and calf (plethysmography) blood flow ( n =8). We also searched for factors which might explain the interindividual variation in the blood flow response to insulin. During sequential insulin infusions (2 h each, 61±2, 139±6, 462±15 mU/l), forearm blood flow increased by 17±6, 50±14 and 113±17% ( p <0.05 or less between steps), respectively. The increase at the 61±2 mU/l insulin concentration barely exceeded methodological variation (13±2%). In contrast to the continuous increase in blood flow, the glucose arterio venous difference reached its maximum (1.7±0.2 mmol/l) at the lowest 61±2 mU/l insulin concentration and remained constant thereafter. Forearm and calf blood flow responses to insulin were virtually identical when determined with plethysmography. In contrast, only a 27% increase was detected in femoral flow index as determined by Doppler ultrasound. Forearm blood flow (per forearm volume) was highly correlated with the relative forearm muscle content (mean 59±5%, range 24–81%) both basally ( r =0.86, p <0.001, n =12) and at all insulin concentrations ( r =0.85–0.92, p <0.001) indicating that the percent of forearm that is muscle explains 70–85% of interindividual variation in blood flow. In conclusion 1) physiological insulin concentrations stimulate glucose uptake mainly by increasing glucose extraction while supraphysiological insulin concentrations increase forearm glucose uptake predominantly via increases in blood flow. 2) The dose-response characteristics of insulin stimulation of forearm and calf blood flow are similar when determined with strain-gauge plethysmography. 3) Relative forearm muscle content is a key factor in determining both basal forearm blood flow and the interindividual variation in its response to insulin in normal subjects.