Diabetologia

Paolisso, G.; Tagliamonte, M. R.; Rizzo, M. R.; Gualdiero, P.; Saccomanno, F.; Gambardella, A.; Giugliano, D.; D'Onofrio, F.; Howard, B. V.

doi: 10.1007/s001250051041pmid: 9794097

Studies have shown that a high plasma non-esterified fatty acid concentration may inhibit glucose induced insulin secretion in vitro and in vivo. The effect of lowering the fatty acid concentration on the acute insulin response was investigated in first degree relatives of people with Type II diabetes in a double-blind, randomised, placebo-controlled trial. Fifty first degree relatives of people with Type II diabetes volunteered for the study. Twenty five were given acipimox (250 mg/day, four times daily) and 25 placebo. The group treated with acipimox had a lower 2-h plasma glucose concentration (6.1 ± 0.2 vs 7.7 ± 0.3 vs mmol/l, p < 0.01); better insulin-mediated glucose uptake (35.4 ± 0.5 vs 28.3 ± 0.4 μmol/kg fat free mass per min, p < 0.01), acute insulin response (68 ± 4.4 vs 46 ± 7.3 mU/l, p < 0.01) and respiratory quotient (0.81 ± 0.02 vs 0.77 ± 0.03, p < 0.05); and a rise in the plasma glucagon (164 ± 63 vs 134 ± 72 ng/l, p < 0.05), growth hormone (1.31 ± 0.13 vs 0.97 ± 0.21 μg/l, p < 0.03) and cortisol (325 ± 41 vs 284 ± 139 nmol/l, p < 0.05) concentrations. The difference in the acute insulin response persisted, even after adjustment for the 2-h plasma glucose concentration, insulin-mediated glucose uptake, the fasting plasma glucagon concentration and the growth hormone concentration ( p < 0.05). In a subgroup of eight patients acipimox was compared with acipimox plus intralipid. The acute insulin response (44 ± 5.1 vs 71 ± 5.3 mU/l, p < 0.01) and the insulin-mediated glucose uptake (27.4 ± 0.4 vs 36.7 ± 0.5 μmol/kg fat free mass per min, p < 0.003) were lower with acipimox plus intralipid treatment than with acipimox alone. It is concluded that long term acipimox treatment lowers the plasma fasting free fatty acid concentration and improves the acute insulin response and the insulin mediated glucose uptake. (Diabetologia (1998) 41: 1127–1132)

McKeigue, P. M.; Lithell, H. O.; Leon, D. A.

doi: 10.1007/s001250051042pmid: 9794098

Although several studies have shown that reduced size at birth predicts glucose intolerance and insulin resistance in adult life, the relation has been inconsistent and usually stronger for ponderal index than for birthweight. We examined glucose tolerance and insulin sensitivity (by the euglycaemic clamp method) in relation to size at birth in 709 men aged 69–73 years in Uppsala, Sweden. After adjusting for adult body mass index, prevalence of glucose intolerance (defined as diabetes or impaired glucose tolerance) was inversely related to birthweight. In men born at term, there was a positive monotonic relation of insulin sensitivity with birthweight, strongest in those who were overweight at age 70. This relation was reversed in men born before term ( p = 0.005 for interaction between pre-term birth and birthweight effect). Glucose intolerance and insulin resistance showed inverted U-shaped relations with ponderal index, in contrast with the monotonic inverse relation seen in this cohort at earlier ages. This change in form of the relations was partly accounted for by selective loss to follow-up between ages 60 and 70 years. These results confirm that the association between reduced fetal growth and glucose intolerance is mediated through insulin resistance and depends upon an interaction with obesity in adult life. This relation is obscured when pre-term births are included. Failure to stratify by gestational age in previous studies could account for inconsistencies in the relations of insulin resistance and glucose intolerance to size at birth and for the detection of stronger associations with ponderal index than with birthweight. (Diabetologia (1998) 41: 1133–1138)

Mühlhauser, I.; Overmann, H.; Bender, R.; Bott, U.; Jörgens, V.; Trautner, C.; Siegrist, J.; Berger, M.

doi: 10.1007/s001250051043pmid: 9794099

The objective of this study was to assess the degree of diabetes care and education achieved for Type I (insulin-dependent) diabetes mellitus at the community level in relation to social status and to elucidate potential pathways that mediate any social class gradient. A population-based sample of 684 adults with Type I diabetes (41 % women, mean ± SD age 36 ± 11, diabetes duration 18 ± 11 years) in the district of North-Rhine (9.5 million inhabitants), Germany, were examined in their homes using a mobile ambulance. Results: HbA 1c (normal 4.3–6.1 %) 8.0 ± 1.5 %, incidence of severe hypoglycaemia (injection of glucose or glucagon) 0.21 cases per patient-year; 62 % of patients had participated in a structured group treatment and teaching programme for intensification of insulin therapy; 70 % used 3 or more insulin injections per day, 9 % were on continuous subcutaneous insulin infusion; 91 % reported to have had measurements of HbA 1c during the preceding year, and 80 % to have had an examination of the retina by an ophthalmologist. Care was insufficient with respect to the quality of blood pressure control (70 % of patients on antihypertensive drugs had blood pressure values ≥ 160/95 mmHg), patient awareness of proteinuria/albuminuria (27 % of patients had not heard about it) and prevention of foot complications (only 42 % with a diabetes duration over 10 years had remembered to have a foot examination during the preceding 12 months). There was a pronounced social gradient with respect to micro- and macrovascular complications (prevalence of overt nephropathy 7 vs 20 % for highest vs lowest quintiles of social class (OR 3.5, 95 % CI 1.6–7.5, p = 0.002)) and diabetes-specific quality of life. HbA 1c , blood pressure and smoking accounted for part of the association between social class and microvascular complications. The social class gradient was not due to inequality to access to health services, but to lower acceptance among low social class patients of preventive and health maintaining behaviour. In conclusion, achieved standards of care are high with respect to the implementation of intensified treatment regimens, the level of patient education achieved, treatment control and eye care, whereas areas for improvement are blood pressure control and preventive measures for foot care. A substantial social gradient in diabetes care persists despite equal access of patients to health services. (Diabetologia (1998) 41: 1139–1150)

doi: 10.1007/s001250051044pmid: 9794100

The characteristics of familial Type I (insulin-dependent) diabetes mellitus – that is Type I diabetes in a first degree relative were investigated for children diagnosed before the age of 15 years using data from an international network of population-based registries (the E urodiab A ce network) and from a case-control study (E urodiab A ce Substudy 2) conducted by eight of the network's centres. Ecological analysis across the 18 centres showed a positive association between the population incidence rate of Type I diabetes and the prevalence of Type I diabetes in fathers of affected children (Spearman's rank correlation coefficient r s = 0.70, p < 0.001). A similar association was observed with the prevalence in sibling ( r s = 0.71, p < 0.001), but the association with prevalence in mothers was weaker and not significant. Pooling results from all centres showed that a greater proportion of fathers (3.4 %) of affected children had Type I diabetes than mothers (1.8 %) giving a risk ratio of 1.8 (95 % CI 1.4 to 2.5). Affected girls were more likely to have a father with Type I diabetes than affected boys (odds ratio 1.56, 95 % CI 1.07 to 2.27), but there was no evidence of a similar finding for mothers or siblings. Children with disease onset in the 0–4 year age-range were more likely to have an affected father than were children who were older at onset, and similar although weaker associations were seen in mothers and siblings. This suggests that familial Type I diabetes patients have a younger age at onset than non-familial patients. In conclusion, a positive association between the prevalence of familial Type I diabetes and the population Type I diabetes incidence rate was shown and the characteristics of familial Type I diabetes (younger age at onset and preferential transmission of disease from tather to child and particularly from father to daughter) were described. (Diabetologia (1998) 41: 1151–1156)

Salbe, A. D.; Fontvieille, A. M.; Pettitt, D. J.; Ravussin, E.

doi: 10.1007/s001250051045pmid: 9794101

Children of women who have diabetes during pregnancy are more likely to become obese by early adulthood than those of women with normal glucose tolerance during pregnancy. Obesity can result from either excess food intake, low levels of energy expenditure or both. In our study, we tested whether maternal diabetes status influences total energy expenditure (TEE by doubly labelled water), resting metabolic rate (RMR by ventilated hood) and physical activity level (PAL = TEE/RMR and assessed by activity questionnaire). Measurements were taken in 88 5-year-old Pima Indian children, 24 children of women with diabetes (2-h plasma glucose ≥ 11.1 mmol/l) diagnosed before or during pregnancy and 64 children of women with normal glucose tolerance (2-h plasma glucose < 7.8 mmol/l during pregnancy and no prior history of abnormal glucose tolerance). Although birth weight was higher in children of diabetic than of nondiabetic women (mean ± SD; 3.8 ± 0.6 vs 3.5 ± 0.4 kg, p < 0.03), there were no differences in weight (26.4 ± 6.9 vs 24.2 ± 5.6 kg) or per cent body fat ( 18 O dilution; 33 ± 8 vs 31 ± 8 %) between the groups at 5 years of age. There was no difference in TEE (6508 ± 1109 vs 6175 ± 942 kJ/d) or in RMR (4674 ± 786 vs 4483 ± 603 kJ/d) expressed as absolute values or after adjustment for weight and sex (TEE) or fat-free mass, fat mass, and sex (RMR). Physical activity level was also similar between the groups (1.40 ± 0.12 vs 1.38 ± 0.12). These results suggest that maternal diabetes status does not influence energy expenditure in the children by 5 years of age. Thus the greater obesity seen at older ages in the children of women with diabetes could be due to excess energy intake. Alternatively, if energy expenditure does have a role in the aetiology of obesity in these children, perhaps it does so only in older children. (Diabetologia (1998) 41: 1157–1162)

Crowther, N. J.; Cameron, N.; Trusler, J.; Gray, I. P.

doi: 10.1007/s001250051046pmid: 9794102

A number of studies have shown that glucose tolerance falls with decreasing birth weight and that people with low birth weight and high body mass index (BMI) as adults are those at greatest risk of developing Type II (non-insulin-dependent) diabetes mellitus. No such studies have been carried out in African populations. Therefore we investigated the relation between glucose tolerance and birth weight in a group of 7-year-old black South Africans for whom longitudinal anthropometric data were available. Oral glucose tolerance tests (OGTTs) were carried out on 152 subjects and inverse correlations were found between birth weight and the total amount of insulin secreted during the first 30 min ( r = –0.19, p = 0.04) and last 90 min ( r = –0.19, p = 0.04) of the oral glucose tolerance test and also between birth weight and the 30 min glucose concentrations ( r = –0.20, p = 0.02). Children born with low birth weights but who had high weights at 7 years had higher insulin concentrations and indices of obesity compared with those with low birth weights and low weights at 7 years. There were also positive correlations between weight velocity and BMI ( r = 0.24, p = 0.02) and weight velocity and insulin resistance ( r = 0.18, p = 0.04) as measured using homeostasis model assessment (HOMA). Thus, low birth weight in conjunction with rapid childhood gains in weight especially as subcutaneous fat, produces poor glucose tolerance in 7-year-old children and can make them susceptible to the development of Type II diabetes later in life. (Diabetologia (1998) 41: 1163–1167)

Bakker, S. J. L.; Hoogeveen, E. K.; Nijpels, G.; Kostense, P. J.; Dekker, J. M.; Gans, R. O. B.; Heine, R. J.

doi: 10.1007/s001250051047pmid: 9794103

Epidemiologic studies have shown an association between the intake of dietary fibres and 2-h glucose values. Food rich in dietary fibres is often also rich in thiamine. Animal studies have shown that thiamine deficiency can induce glucose intolerance. Our aim was to investigate the association between fibre consumption and thiamine intake on the one hand and glucose tolerance on the other hand. We used data from the Hoorn Study, a study of glucose tolerance among 1008 men and 1188 women, aged 50–75 years, without diabetes. In linear regression analyses, fibre intake was inversely associated with fasting glucose. There was also an inverse association between fibre intake and 2-h glucose but it disappeared for the greater part after adjustment for fasting glucose. Fibre intake appeared to be strongly correlated with thiamine intake, and this correlation explained the remaining part of the association between fibre intake and 2-h glucose. Thiamine intake appeared to have a strong and relevant association with 2-h glucose, which was independent of fibre intake and fasting glucose. This association was borderline after adjustment for potential confounders. In women, but not in men, the effect of thiamine intake on 2-h glucose seemed to be modified by fibre intake, independent of potential confounders. In conclusion, part of the association between fibre intake and glucose tolerance is possibly attributable to concomitant thiamine intake. (Diabetologia (1998) 41: 1168–1175)

Bernardi, M.; La Rocca, E.; Castoldi, R.; Di Carlo, V.; Caldara, R.; Furiani, S.; Giudici, D.; Pozza, G.; Secchi, A.

doi: 10.1007/s001250051048pmid: 9794104

Monoclonal components (MC) are detected in as high as 30 % of renal transplant recipients. Our aim was to evaluate the incidence, relevance and consequence of monoclonal components in patients with Type I (insulin-dependent) diabetes who received kidney ( n = 22), kidney and whole pancreas ( n = 41), kidney and segmental pancreas ( n = 24) and kidney and islets ( n = 12) transplants. Immunosuppression was based on prophylactic anti-lymphocyte globulins, corticosteroids, azathioprine and cyclosporin in all patients; acute rejection was treated with steroids or anti-lymphocyte monoclonal immunoglobulin therapy (OKT3) or both. Serum immunofixation was carried out in all patients before transplantation and then after at 6 months and then yearly. Monoclonal components were detected in 81 of 99 patients (82 %); 52 patients (52 %) developed them within 6 months of transplantation, 15 (15 %) between 6 and 12 months, with a peak prevalence at 1 year post-transplant (58 %) and a decrease thereafter (10 % at 9 years). Kidney recipients showed a lower incidence of monoclonal components when compared with those who received kidneys and segmental pancreases and those who received kidneys and whole pancreases. Monoclonal components were more often detected in patients who had previously experienced an acute renal rejection. Cytomegalovirus infection and acute rejection occurring in the same patient further increased the risk of developing monoclonal components, the development of which did not correlate with OKT3 treatment. A Post-transplant lymphoproliferative disorder was developed by two patients (2 %), one with 5 and the other with 6 monoclonal components. In conclusion, diabetic patients receiving kidney and/or Pancreas transplantation, experiencing both cytomegalovirus infection and acute rejection, are at greatest risk of developing monoclonal components but they appear to be benign and transient; multiple band detection is a marker for the subsequent development of post-transplant lymphoprolifertive disorder. (Diabetologia (1998) 41: 1176–1179)

Toft-Nielsen, M.; Madsbad, S.; Holst, J. J.

doi: 10.1007/s001250051049pmid: 9794105

The plasma concentrations of the insulinotropic incretin hormone, glucagon-like peptide-1 (GLP-1) are abnormally high after oral glucose in partially gastrectomised subjects with reactive hypoglycaemia, suggesting a causal relationship. Because of the glucose-dependency of its effects, it is impossible to induce hypoglycaemia in normal subjects in the basal state by exogenous GLP-1, regardless of dose. To further assess the role of the incretin hormones in reactive hypoglycaemia, we reproduced the glucose and hormone profiles of the patients with reactive hypoglycaemia in 8 healthy volunteers in 4 separate protocols: 1) i. v. infusion of glucose (25 g) alone, 2) glucose together with i. v. GLP-1 infusion, and 3) and 4) glucose together with i. v. infusion of the other incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), at two different infusion rates. The plasma glucose, GLP-1 and GIP concentrations (low dose) obtained were comparable with those of the patients. With GLP-1, infusion of a total of 33.4 ± 1.3 g glucose was required to obtain plasma glucose concentrations similar to those obtained by glucose infusion alone; with low GIP, 28.0 ± 1.2 g and with high GIP 38.4 ± 3.5 g. Insulin concentrations increased 10-fold with GLP-1 compared with i. v. glucose alone, but less with high and low GIP. In contrast, C-peptide concentrations were similar after GLP-1 and high GIP. After termination of i. v. glucose the lowest glucose concentrations were 4.5 (3.7–4.9) (median, range) for glucose alone; 2.4 (1.9–2.8) mmol/l with GLP-1; 3.7 (2.6–4.0) with low GIP and 3.3 (2.1–4.2 ) with high GIP. Thus, the exaggerated GLP-1 response to nutrients in patients with accelerated gastric emptying could be responsible for their high incidence of postprandial reactive hypoglycaemia. (Diabetologia (1998) 41: 1180–1186)

O'Harte, F. P. M.; Abdel-Wahab, Y. H. A.; Conlon, J. M.; Flatt, P. R.

doi: 10.1007/s001250051050pmid: 9794106

Glucagon-like peptide-1(7–36)amide (truncated GLP-1, tGLP-1) is a potent insulin releasing hormone of the enteroinsular axis. This study has examined glycation of tGLP-1 and effects of such structural modification on insulin secretion. Monoglycated tGLP-1 (M r 3463.8, determined by plasma desorption mass spectrometry) was prepared by incubation with glucose under reducing conditions and purified by reversed-phase high performance liquid chromatography. Automated Edman degradation indicated that tGLP-1 was specifically glycated at the amino terminal His 7 site. In extracts from mouse small intestine, glycated tGLP-1 represented approximately 14 % of the total tGLP-1 content. Effects of glycated and non-glycated tGLP-1 on insulin secretion were examined using glucose-responsive clonal BRIN-BD11 cells. In acute (20 min) incubations, 10 –9 mol/l tGLP-1 enhanced insulin release by 2.2-fold and 1.5-fold at 5.6 and 11.1 mmol/l glucose, respectively. In contrast, 10 –9 mol/l glycated tGLP-1 failed to stimulate secretion and insulin output was decreased by 34–73 % following glycation. At 5.6 mmol/l glucose, non-glycated tGLP-1 (3 × 10 –10 mol/l–10 –8 mol/l) exerted a 2.3-fold to 3.2-fold increase in insulin secretion compared with controls. The effect of glycated tGLP-1 at 10 –9 mol/l and 3 × 10 –9 mol/l was reduced by 51–55 % compared with non-glycated peptide, and its insulinotropic action was effectively abolished. These data indicate that when tGLP-1 is glycated at the amino terminal His 7 , this modification substantially reduces the glucose-dependent insulinotropic action of the peptide. (Diabetologia (1998) 41: 1187–1193)