Diabetologia

Gay, L. J.; Schneiter, Ph; Schutz, Y.; Di Vetta, V.; Jequier, E.; Tappy, L.

doi: 10.1007/s001250050141pmid: 8056191

SummaryA novel approach to the study of hepatic glycogen kinetics and fractional gluconeogenesis in vivo is described. Ten healthy female subjects were fed an iso-caloric diet containing 55 % carbohydrate energy with a 13C abundance of 1.083 atom percent for a 3-day baseline period; then, a diet of similar composition, but providing carbohydrate with a 13C abundance of 1.093 atom percent was started and continued for 5 days. Resting respiratory gas exchanges, urinary nitrogen excretion, breath 13CO2 and plasma 13C glucose were measured every morning in the fasting state. The enrichment in 13C of hepatic glycogen was calculated from these measured data. 13C glycogen enrichment increased after switching to a 13C enriched carbohydrate diet, and was identical to the 13C enrichment of dietary carbohydrates after 3 days. The time required to renew 50 % of hepatic glycogen, as determined from the kinetics of 13C glycogen enrichment, was 18.9 ± 3.6 h. Fractional gluconeogenesis, as determined from the difference between the enrichments of glucose oxidized originating from hepatic glycogen and plasma glucose 13C was 50.8 ± 5.3%. This non-invasive method will allow the study of hepatic glycogen metabolism in insulin-resistant patients.

Chaillous, L.; Elmansour, A.; Charbonnel, B.; Saí, P.; Delamaire, M.; Maugendre, D.; Allannic, H.; Rohmer, V.; Joseph, M. G.; Limal, J. M.; Lecomte, P.

doi: 10.1007/s001250050137pmid:

Reach, G.; Poitout, V.

doi: 10.1007/BF03035165pmid: N/A

Bangstad, H. -J.; Dahl-Jørgensen, K.; Hanssen, K. F.; østerby, R.; Berg, K. J.; Hartmann, A.

doi: 10.1007/s001250050136pmid: 8056186

SummaryWe investigated in a randomized, prospective study the influence of improved blood glucose control during 2-3 years in young insulin-dependent diabetic (IDDM) patients with microalbuminuria, which is indicative of early nephropathy. Patients were randomized either to intensive treatment by continuous subcutaneous insulin infusion (CSII) (n = 9) or CT (n = 9). Kidney biopsies were taken at baseline and after 26-34 months. End points were structural changes in the glomeruli. Sensitive, quantitative, mor-phometric methods were used. The blood glucose control improved significantly (p = 0.01) during the study in the CSII-group as glycated haemoglobin (HbAlc) fell from 10.1 % ([95 % CI] 8.9-11.3) to 8.6 % (7.9-9.2), but not in the CT-group, 10.1% (8.3-11.9) vs 9.7% (8.7-10.8). Mean HbAlc during the study period was significantly lower in the CSII-group than in the CT-group, 8.7% (8.1-9.3) vs 9.9% (8.5-11.3), p = 0.04. Basement membrane thickness (BMT) increased in both groups, most (CT vs CSII, p = 0.03) in the CT-group: 140 nm (50-230) vs CSII: 56 nm (27-86). In the CT-group only an increase was seen in matrix/mesan-gial volume fraction (p = 0.006) and matrix star volume (p = 0.04). Furthermore, a positive correlation between mean HbAlc during the study and change from baseline in BMT (r = 0.70, p = 0.001) and ma-trix/glomerular volume fraction (r = 0.33, p = 0.09, NS) was demonstrated. Albumin excretion rate correlated significantly to BMT and most of the matrix parameters. The present study shows that during a period of only 2.5 years, a close relationship between the level of mean blood glucose and progression of glomerular morphological changes in early diabetic nephropathy can be demonstrated. [Diabetologia (1994) 37: 483-490]

Tomoda, T.; Kurashige, T.; Taniguchi, T.

doi: 10.1007/s001250050135pmid: 8056185

SummaryThe IL-2 system which involves IL-2 production, IL-2 receptor expression, and response to IL-2, is associated with autoimmune phenomena. Immunologi-cal abnormalities including autoimmune phenomena are believed to contribute to the pathogenesis of IDDM. In this study, the production of IL-2, the responses to IL-2 and IL-2 receptor expression by peripheral blood T lymphocytes were compared in IDDM and normal non-diabetic children. The percentage of IL-2 receptor-positive circulating T cells was significantly increased in diabetic children, although IL-2 receptor expression induced by con A stimulation did not differ in the diabetic and control children. IL-2 production was significantly decreased in diabetic children compared with the control children. The response of stimulated T cells to IL-2 did not differ in IDDM and control children. In IDDM, IL-2 production by CD4-positive T lymphocytes within the IL-2 system is thought to be selectively defective. On the other hand, IL-4, which is also produced by CD4-positive T lymphocytes, was increased. Since IL-4 did not suppress IL-2 production, it would seem that the IL-2 producing subset in CD4+HLA-DR+ T cells is decreased in IDDM. These results suggest that in recent onset IDDM, IL-2 receptor-positive circulating T cells require an IL-2 supply.[Diabetologia (1994) 37: 476-482]

Lampeter, E. F.; Kolb, H.; Seifert, I.; Lohmann, D.; Heise, J. W.; Bertrams, J.; Christie, M. R.; Kolb-Bachofen, V.

doi: 10.1007/s001250050134pmid: 8056184

SummaryThe hypothesis was tested that islet autoimmunity is induced by ongoing islet cell destruction in subjects with susceptibility genes HLA-DR 3 and/or DR 4. Sixty-one patients with confirmed chronic pancreatitis were analysed, 30 of whom expressed HLA-DR 3 and/or DR 4. Electron microscopy studies in 10 patients showed that the inflammatory process also affected islets, as recognisable from islet cell lysis, intrainsular fibrosis and immune cell infiltrates. None of the sera tested contained any of three markers of islet autoimmunity, ICA, IAA or GAD antibodies. A correlation was seen between the loss of exocrine function, as determined by the ALTAB-test, and of beta-cell function, as determined by the C-peptide response to i.v. glucagon. However, there was no preferential loss of beta-cell function in patients with HLA-DR 3 and/or DR 4. We conclude that islet cell destruction occurs during chronic pancreatitis, but does not trigger islet autoimmunity, even in the presence of HLA-DR 3 and/or DR 4.

Couper, J. J.; Ferrante, A.; Littleford, K. D.; Couper, R. T. L.; Nakamura, T.

doi: 10.1007/s001250050143pmid: 8056193

SummaryHepatocyte growth factor is a recently cloned potent mitogen to hepatocytes, but its extrahe-patic roles are not completely defined. It causes proliferation of endothelial and epithelial cells implicating potential action in the glomerulus. We aimed to determine whether cultured human mesangial cells secrete hepatocyte growth factor and the effect of high glucose conditions. Mesangial cells were isolated from the normal cortex of a child’s kidney. After differential glome-rular sieving and trypsin digestion of glomeruli, mesangial cells were cultured in 20 % fetal calf serum/RPMI. Glucose concentration in the medium was adjusted to 5 mmol/1,11 mmol/1, 25 mmol/1 or 5 mmol/1/20 mmol/1 mannitol to correct for osmolality. After 0, 24, 48, 72 h incubation, hepatocyte growth factor was measured in the supernatant by enzyme immuno assay using recom-binant hepatocyte growth factor and monoclonal antibodies to human hepatocyte growth factor. Hepatocyte growth factor was secreted by cultured mesangial cells. High glucose and hyperosmolar conditions caused a 100-200 % increase in hepatocyte growth factor secretion at 48-72 h (p = 0.001). Hepatocyte growth factor secretion at 48 h in 5 mmol/1 glucose was 16.46 ± 1.09 ng/ml (mean ± SEM), 11 mmol/1 glucose: 32.98 ± 4.54, 25 mmol/1 glucose: 33.32 ±7.89, 5 mmol/1 glucose/20 mmol/1 mannitol: 34.05 ±3.64; at 72 h in 5 mmol/1 glucose: 23.92 ± 2.85 ng/ml, 11 mmol/1 glucose: 28.26 ±2.03, 25 mmo/l glucose: 62.04 ±12.2, 5 mmol/1 glucose/20 mmol/1 mannitol: 45.76 ± 6.25. Trypan blue exclusion demonstrated membrane integrity. These findings demonstrate for the first time that cultured human mesangial cells secrete hepatocyte growth factor and there is stimulation by high glucose and hyperosmolar conditions. Hepatocyte growth factor may have a renotropic role in the pathogenesis of diabetic nephropathy.

Fujimoto, W. Y.; Bergstrom, R. W.; Leonetti, D. L.; Newell-Morris, L. L.; Shuman, W. P.; Wahl, P. W.

doi: 10.1007/s001250050142pmid: 8056192

SummarySince second-generation (Nisei) Japanese Americans are prone to develop the insulin resistance syndrome, younger third-generation (Sansei) Japanese Americans from a cross-sectional 10% volunteer sample of Sansei men (n = 115) and women (n = 115) 34 years or older in King County, Washington with normal glucose tolerance or IGT were examined for metabolic and adipose risk factors associated with this syndrome. After an overnight 10-h fast, blood samples were taken for measurement of glucose, insulin, C-pep-tide, lipids, and lipoproteins, followed by a 3-h 75-g oral glucose tolerance test with blood samples taken for glucose, insulin, and C-peptide measurement. BMI (kg/m2), skinfolds, and body fat areas (by computed tomography) were measured. IGT was diagnosed in 19 % of the men and 31 % of the women. Men with IGT had more adiposity, both overall and in thoracic and visceral sites, had higher fasting plasma insulin and C-peptide, and tended to have higher fasting triglyceride and lower HDL cholesterol than men with normal glucose tolerance. Women with IGT had more thoracic subcutaneous fat and intra-abdominal fat and lower fasting HDL cholesterol than women with normal glucose tolerance, and tended to have higher fasting triglyceride and LDL cholesterol. Women with IGT also had higher fasting plasma insulin than women with normal glucose tolerance but tended to be less hyperinsuli-naemic than men. Differences in fasting insulin, C-peptide, and lipids were best predicted by intra-abdominal fat. Thus metabolic (higher fasting insulin and a tendency to higher triglyceride and lower HDL cholesterol) and adipose (visceral adiposity) risk factors associated with the insulin resistance syndrome are identifiable among Sansei men and women with IGT, who may therefore be at increased risk of future development of NIDDM and CHD.

Davies, A. J.; Bone, A. J.; Wilkin, T. J.; Cole, D. R.; Rokos, H.

doi: 10.1007/s001250050133pmid: 8056183

SummaryTetrahydrobiopterin (BH4) is a pteridine product which is released by rodent macrophages on ac-tivation by cytokines. We have used serial pancreatic biopsy, and measurement of serum biopterin at 30,60,90 and 120 days in the BB/S rat to relate histological change to macrophage activation during the course of pre-diabetes. Using immunohistochemistry, and an arbi-trary scoring system read blind and standardised against day 30, we found that pancreatic MHC class I, MHC class II and infiltrating macrophage staining were up-regulated in the BB/S diabetes-prone rats (n = 17) at day 60, markedly so at day 90, and less so at day 120. Staining for resident pancreatic macrophages remained unchanged throughout in diabetes prone, diabetes resis-tant and Wistar (n = 28) control animals. Serum biop-terin fell progressively and identically with age in BB diabetes resistant rats (n = 11) and Wistar controls. No change in weight gain or biopterin levels was observed in the biopsied animals. Mean serum biopterin levels in diabetes prone rats (of which 13 of 17 became diabetic at median 85 days) were the same as in diabetes resistant and Wistar rats at days 30,60 and 120, but showed a strik-ing and highly significant elevation (p > 0.001) atday 90. Although macrophages infiltrate the islet early in pre-diabetes, the timing of their activation is unknown. The rise in biopterin we observed is a potentially important immunological event which occurred late in the pro-gression of pre-diabetes. This acute terminal event has not been reported previously, and may modify current concepts concerning the tempo of cell destruction during pre-diabetes.

Reach, G.; Poitout, V.

doi: 10.1007/bf03035165pmid: N/A