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doi: 10.1046/j.1464-5491.1999.00209.xpmid: 10656225
Summary It is often said that the introduction of insulin into clinical medicine made a ‘dramatic’ difference to the mortality resulting from diabetic coma. This is true in the sense that before 1922 it was almost uniformly fatal, but until the 1950s the mortality in many large hospitals was as high as 30–50%. Often autopsy did not establish a cause of death. Many may have been a result of hypokalaemia, a complication which was not recognized until 1946; in that year in the Journal of the American Medical Association, Jacob Holler described a patient who developed respiratory paralysis 12 h into treatment that, after several hours in an iron lung, was cured by potassium infusion. In the 5 years after Holler’s paper there were many reports of deaths resulting from hypokalaemia, as well as several ‘near misses’, but clinicians were extremely cautious about early replacement probably, as an editorialist in The Lancet suggested, because ‘the frightening effects of intravenous injections of potassium made clinicians reluctant to believe in a lack of potassium as a cause of trouble, except in very rare conditions such as familial periodic paralysis’. It had been known since 1923 that insulin lowered serum potassium, but this was not of great interest because the symptoms of hypokalaemia were not known. Also, potassium was not an electrolyte with which clinicians were familiar. Until the introduction of flame photometry in 1950, it was only measured in research studies as chemical methods took several hours to complete.
Nejentsev, S.; Sjöroos, M.; Soukka, T.; Knip, M.; Simell, O.; Lövgren, T.; Ilonen, J.
doi: 10.1046/j.1464-5491.1999.00186.xpmid: 10656226
Summary Aims To improve sensitivity and specificity of the diabetes risk assessment of the population‐based genetic screening used in the Finnish Diabetes Prediction and Prevention (DIPP) trial. Methods One thousand consecutive newborns enrolled in the DIPP were compared with 316 samples from children with Type 1 diabetes mellitus. A modification of the previously described technique based on hybridization of relevant PCR products with five lanthanide‐labelled probes detected by time‐resolved fluorometry (TRF) was used. A new probe was designed and allowed discrimination between DQB1*0602 and *0603 alleles, in addition to DQB1*02, *0301 or *0302, each of which required specific probes. A new, added screening strategy was developed for individuals carrying low‐risk genotypes through specific typing of DQA1*05 and *0201 alleles in DQB1*02 positive, and DRB1 typing for DR4 subtypes in DQB1*0302 positive subjects, with a new specifically designed high‐resolution TRF‐based DR4 subtyping technique. Results This two‐step screening approach enhanced the sensitivity of the detection of genetic risk for Type 1 diabetes mellitus in this cohort up to 85.4%. In the general population cohort, 24.4% were identified for prospective follow‐up, 2.6% of these are expected to develop Type 1 diabetes mellitus before the age of 15 years. Exclusive typing for HLA‐DQB1 locus as an alternative screening strategy had sensitivities of 26.3–77.2% with general population cohorts of 2.3–23.1% identified for follow‐up. Conclusions The described strategy for genetic prediction of Type 1 diabetes mellitus relies on the convenient genotyping procedure and could be applied in large scale screening projects such as DIPP.
Pinkney, J. H.; Downs, L.; Hopton, M.; Mackness, M. I.; Bolton, C. H.
doi: 10.1046/j.1464-5491.1999.00191.xpmid: 10656227
Summary Aims To examine the hypothesis that increased susceptibility of low density lipoproteins (LDL) to oxidation predisposes to endothelial dysfunction in patients with Type 1 diabetes mellitus. Methods A cross‐sectional study of 46 non‐nephropathic diabetic and 39 control subjects and in the diabetic patients, a 3‐month duration, randomized, placebo‐controlled double‐blind trial of vitamin E 500 U/day. Flow‐mediated vasodilatation (FMD) was measured in the forearm by high resolution ultrasound. LDL oxidation by Cu2 + was measured in vitro. Results Diabetic patients had greater basal and reactive forearm blood flow (geometric mean ( sd%) flow (ml/min) 110.15 (19.19%) vs. 74.99 (23.17%); P= 0.045, and 344.35 (20.84%) vs. 205.17 (21.48%); P= 0.007), compared with controls, but there was no difference in FMD (median (interquartile range) 0.00 ( − 0.01–0.02) vs. 0.02 ( − 0.01–0.02) cm2; P= 0.78). Diabetic LDL oxidation lag time correlated with postdilatation brachial artery area (r= 0.32; P= 0.05) but not with FMD. Lag‐times and total LDL oxidation by Cu2 + , lipoprotein and vitamin E concentrations were similar in diabetic and control groups. Antibody titres to oxidized LDL (oxLDL) were higher in non‐diabetic than diabetic subjects, and were unrelated to FMD. In diabetic patients, vitamin E increased mean ( sd) plasma vitamin E levels (24.0 (6.5) to 47.5 (7.5) μmol/l; P= 0.0006) and resulted in increased FMD (Δ 0.00 ( − 0.02–0.01) vs. 0.01 (0.01–0.02)) cm2; P= 0.0036), but no changes in LDL Cu2 + oxidation profiles were observed. Conclusions FMD is no different in Type 1 diabetic and non‐diabetic subjects and nor are indices of lipid peroxidation and in vitro LDL oxidation although levels of antibody to oxLDL are lower in diabetes. Vitamin E supplementation increases plasma vitamin E levels and may enhance FMD in diabetes but, in the absence of changes in LDL oxidation, this may not be mediated by reduced oxidation of LDL.
Flechtner‐Mors, M.; Ditschuneit, H. H.; Jenkinson, C. P.; Alt, A.; Adler, G.
doi: 10.1046/j.1464-5491.1999.00189.xpmid: 10656228
Summary Aims Metformin has been reported to decrease the plasma concentrations of non‐esterified fatty acids in Type 2 diabetic subjects. This study investigated the effects of metformin on basal and catecholamine‐stimulated lipolysis in abdominal subcutaneous adipose tissue of obese, hyperinsulinaemic, hypertensive subjects. Methods Fourteen subjects with severe obesity (12 female, two male, age 35.4 ± 4 years, body mass index 48.2 ± 2 kg/m2, body fat mass 63.3 ± 5 kg) were recruited. Glycerol and lactate concentrations were determined in the presence of metformin and after administration of catecholamines using microdialysis. Simultaneously, blood flow was assessed with the ethanol escape method. Results Glycerol release was lowered by metformin during the 3‐h experiment (P < 0.01). The lipolytic activity of catecholamines was suppressed when adipose tissue was pre‐treated with metformin (P < 0.001). Lactate concentration increased after application of metformin (P < 0.01) and catecholamines (P < 0.001). Blood flow was decreased in the presence of adrenaline (P < 0.01), but this effect was abolished by metformin. Conclusions The present data demonstrate the effects of metformin on lipolysis in subcutaneous adipose tissue in vivo. In the large body fat mass of obese subjects, a reduction of lipolysis in adipose tissue may contribute to a decrease of VLDL synthesis in the liver resulting in a lowered plasma triglyceride concentration.
Byrne, C. D.; Maison, P.; Halsall, D.; Martensz, N.; Hales, C. N.; Wareham, N. J.
doi: 10.1046/j.1464-5491.1999.00184.xpmid: 10656229
Summary Aims Cross‐sectional studies have demonstrated an association between high non‐esterified fatty acid (NEFA) concentrations and glucose intolerance. However, the direction of causality in these studies is uncertain. The aim of this study was to examine whether NEFA levels predicted the development of glucose intolerance in a prospective population‐based cohort study. Methods Four hundred and eighty‐one women and 345 men participated in a prospective cohort study in which NEFA concentrations and glucose tolerance were measured at baseline and then repeated at follow‐up 4.5 years later. Results The data do not show longitudinal relationships between baseline NEFA levels and either glucose intolerance or other features of the metabolic syndrome at follow‐up. In contrast, strong cross‐sectional associations were observed between NEFA measures and glucose intolerance (and other features of the metabolic syndrome) in both baseline and follow‐up studies. At follow‐up, fasting NEFA levels and two measures of NEFA suppression were markedly different in subjects with features of the metabolic syndrome, compared to subjects with normal glucose tolerance (NGT) (NGT vs. metabolic syndrome for each NEFA value, P < 0.001). Conclusions These results support the hypothesis that plasma NEFA levels change as a consequence of the metabolic syndrome and do not support the notion that increased NEFA levels cause either the metabolic syndrome or diabetes.
Gregorio, F.; Ambrosi, F.; Manfrini, S.; Velussi, M.; Carle, F.; Testa, R.; Merante, D.; Filipponi, P.
doi: 10.1046/j.1464-5491.1999.00201.xpmid: 10656230
Summary Aims To assess the effects and safety of increasing sulphonylurea dosages or adding metformin in poorly controlled elderly Type 2 diabetic patients. Methods A 18‐month multicentre clinical study was performed on sulphonylurea‐treated diabetic patients over 70 years of age with well‐preserved renal function, steady fasting blood glucose ≥ 200 mg/dl and HbA1c≥ 9%. Patients were randomly assigned to sulphonylurea increased up to its maximum dosage (1st group) or to addition of metformin (2nd group). Glycaemic control, lipid pattern, haemostatic status and safety were monitored during run‐in, at baseline and at scheduled intervals for 18 months. Results(85 patients in the 1st group and 89 patients in the 2nd with complete data. Results Similar improvements in glycaemic levels were observed with both treatments within the first month and a similar decrease in HbA1c within the third month. No further changes occurred in glycaemic control. In the 1st group, fasting glucose (mmol/l, mean ± se) decreased from 14.21 ± 0.49 to 9.88 ± 0.21, average day‐long glucose from 14.87 ± 0.27 to 10.69 ± 0.19 and HbA1c (%) from 10.32 ± 0.13 to 8.66 ± 0.13. In the 2nd treatment group fasting glucose decreased from 14.59 ± 0.61 to 9.05 ± 37.28, average day‐long glucose from 15.09 ± 0.29 to 10.32 ± 0.21 and HbA1c from 10.33 ± 0.13 to 8.77 ± 0.12 (for all P < 0.0005). In this 2nd group, a decrease in LDL‐cholesterol (P < 0.05) and an increase in HDL‐cholesterol levels (P < 0.02) were also observed. In the 1st group, anthrombin III activity increased significantly (P < 0.01). In the 2nd group, significant reductions in markers of platelet function (FP4 and βTG, P < 0.01), thrombin generation (FPA, F1 + 2 and D‐D, P < 0.01), and fibrinolysis inhibition (PAI‐1 activity, PAI‐1 antigen, P < 0.001) were observed. Increases in some fibrinolytic activation markers (t‐PA activity, and AT‐III activity, P < 0.01) occurred. Fasting lactate concentrations were unchanged in the metformin‐treated group. No serious adverse effects were observed in either group. Conclusions These results suggest that either high sulphonylurea dosages or a therapy combining lower sulphonylurea dosages with metformin are effective and safe in an aged but healthy population. Metformin provides additional benefits counteracting several cardiovascular risk factors but must be administered with caution, bearing in mind the general contra‐indications for the drug but not age alone.
Fear, N. T.; McKinney, P. A.; Patterson, C. C.; Parslow, R. C.; Bodansky, H. J.
doi: 10.1046/j.1464-5491.1999.00204.xpmid: 10656231
Summary Aims To test the hypothesis that increased exposure to infections, through parental jobs involving high levels of social mixing, reduces the risk of childhood Type 1 diabetes mellitus. Methods Two population‐based case–control studies of children diagnosed with Type 1 diabetes mellitus from Yorkshire (0–15 years) and Northern Ireland (0–14 years) included 220 and 189 cases and 433 and 465 controls, respectively. Parental occupations were coded using a standard occupational classification. Each job was allocated to high, medium or low levels of social mixing according to a predefined categorization. Odds ratios (OR) for the risk of childhood Type 1 diabetes were estimated for parental social mixing by age at diagnosis. Results Childhood Type 1 diabetes mellitus was not associated with high levels of parental occupational social mixing (Yorkshire – mothers: OR 1.07, 95% confidence interval (CI) 0.76–1.50; fathers: 1.15, 0.75–1.76; Northern Ireland – heads of household, usually the father: 0.78, 0.49–1.25). A larger proportion of mothers (39%) compared to fathers (18% Yorkshire, 17% Northern Ireland) had jobs involving high levels of social mixing. Mothers with high social mixing jobs conferred a nonsignificant reduced risk of Type 1 diabetes among children diagnosed under 5 years of age (0.58, 0.24–1.38) compared to those diagnosed at age 5 years and above (1.14, 0.77–1.69). Conclusions No association between parental occupational social mixing and the risk of childhood Type 1 diabetes mellitus was detected for all ages combined. Mothers were more likely to have jobs involving high levels of social mixing than fathers. The possible protective effect of maternal high occupational social mixing on children diagnosed below 5 years of age merits further investigation.
Zhao, H. X.; Stenhouse, E.; Soper, C.; Hughes, P.; Sanderson, E.; Baumer, J. H.; Demaine, A. G.; Millward, B. A.
doi: 10.1046/j.1464-5491.1999.00175.xpmid: 10656232
Summary Aims To determine the incidence of Type 1 diabetes mellitus (DM) in children aged 0–15 years in the far south‐west of England between 1975 and 1996. Methods Patient information was collected to set up the Cornwall and Plymouth Children’s Diabetes Register (CPCDR) through two main data sources; hospitals and the general practitioners in all surgeries in the study region. All children under 16 years living within Cornwall and the Isles of Scilly, and the former Plymouth Health Authorities and diagnosed as having Type 1 DM during the study period were included. The case ascertainment was estimated by a capture–recapture method. Trends and differences in incidence of sex, age, time period and district of diagnosis were analysed by Poisson regression analysis. Roger’s method was used to estimate the seasonal variations. Results A total of 522 subjects aged between 0 and 15 years were identified from 01/01/1975 to 31/12/1996, giving an overall crude incidence of 14.9/100 000 population/year. The case ascertainment was 94.4% (95% confidence interval (CI) 91.4– 97.6%) for the whole register. Poisson regression analysis showed that a significant increase of incidence (2.49% per year) was observed throughout the 22‐year study period, which was mainly a result of the significant increase in the 0–4 year age‐group (6.29% per year). The incidence significantly differed among the 22‐years (P= 0.007), the three age groups (0–4, 5–9 and 10–14 years, P < 0.001) and different sexes (P= 0.049). The significant seasonal variations were detected with peak incidence appearing in autumn and winter. Conclusions The first validated childhood‐onset diabetes register has been set up in the far south‐west of England. The incidence of childhood Type 1 DM in this region has increased significantly over the past two decades, especially in children under 5 years.
Song, K. ‐H.; Ahn, Y. ‐B.; Yoon, K. ‐H.; Cha, B. ‐Y.; Lee, K. ‐W.; Son, H. ‐Y.; Kang, S. ‐K.
doi: 10.1046/j.1464-5491.1999.00183.xpmid: 10656233
Summary Aims To examine whether long‐term glycaemic control affects lipoprotein(a) (Lp(a)) levels in patients with Type 2 diabetes mellitus. Methods Eighty‐nine Type 2 diabetic patients (38 men, 51 women) were recruited from the diabetes clinic. Based on HbA1c concentrations at baseline, patients were divided into two groups: those with HbA1c < 8.0% (n= 45) and those with HbA1c≥ 8.0% (n= 44). Comparisons of Lp(a) levels were made between both groups. The effect of long‐term glycaemic control on Lp(a) levels was investigated in a subgroup of 20 patients, selected from those with baseline HbA1c≥ 8%. All these patients were treated with a goal of HbA1c < 7%. Results Lp(a) levels were not significantly different between those with HbA1c < 8.0% and those with HbA1c≥ 8.0%. No correlation between Lp(a) and HbA1c or fasting blood glucose levels was noted in diabetic patients as a whole. After 2 years of intensive glycaemic control, all patients exhibited remarkable improvement of therapy: their average HbA1c levels were 6.5 ± 0.7%, being < 7% in 70% of patients. However, no change in Lp(a) levels were observed after 2 years (19.5 ± 14.8–21.4 ± 13.4 mg/dl, P= 0.390). Conclusion These results indicate that improvement of glycaemic control does not affect serum Lp(a) levels in patients with Type 2 diabetes mellitus.
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