Diabetologia

Tchobroutsky, Georges

doi: 10.1007/BF00500374pmid: 2065850

Kuttler, B.; Dunger, A.; Volk, H.; Diamantstein, T.; Hahn, H.

doi: 10.1007/BF00500375pmid: 2065851

125 34 34 2 2 B. Kuttler A. Dunger H. D. Volk T. Diamantstein H. J. Hahn Institute of Diabetes “G. Katsch” Karlsburg Institute of Medical Immunology, Charite Humboldt-University Germany Institute of Immunology, Klinikum Steglitz Free University Berlin Germany Summary To prove whether a cell-mediated mechanism is responsible for maintaining long-term normoglycaemia in BB/OK rats with a proved immune attack (insulitis, reduced Beta-cell volume), we transferred lymphocytes obtained from those rats into normoglycaemic diabetes-prone BB/OK rats or into diabetic BB/OK rats receiving a simultaneous syngeneic islet graft. Our results show the presence of a lymphocyte population in the long-term normoglycaemic BB/OK rats, which is able to arrest pancreatic Beta-cell destruction in diabetes-prone BB/OK rats detected by a decreased diabetes incidence following single lymphocyte transfusion. Syngeneic islets were destroyed by recurrence of the autoimmune process when transplanted into diabetic BB/OK rats. Lymphocytes obtained from long-term normoglycaemic BB/OK rats were able to protect the syngeneic BB/OK islet graft from autoimmune destruction in diabetic BB/OK rats, whereas allogeneic islet destruction was not prevented. The phenotype of the effective lymphocyte population is not yet clear, but it is negative for RT6. We conclude that the mechanism responsible for maintaining normoglycaemia in long-term normoglycaemic BB/OK rats is cell mediated, because this property can be transferred to prevent autoimmune destruction of pancreatic Beta cells.

Patel, N.; Misra, V.; Dandona, P.; Thomas, P.

doi: 10.1007/BF00500376pmid: 2065852

125 34 34 2 2 N. J. Patel V. P. Misra P. Dandona P. K. Thomas Department of Neurological Science Royal Free Hospital School of Medicine London UK Department of Chemical Pathology and Metabolic Medicine Royal Free Hospital School of Medicine London UK Summary The permeation of native and non-enzymatically glycated albumin and immunoglobulin G into the endoneurium of the sciatic nerve of rats was examined in acute experiments. Low amounts of native albumin entered both in control and streptozotocin-diabetic animals with no significant difference between them. The entry of glycated albumin was significantly greater both in control and diabetic rats, especially in the former. Permeation of native and glycated immunoglobulin G was not detectable over the time course of the experiment. It is concluded that glycation of albumin enhances its permeation into the nerve. This may be relevant to the increased amounts of endoneurial albumin that are detectable in human diabetic neuropathy.

Holemans, K.; Aerts, L.; Assche, F.

doi: 10.1007/BF00500377pmid: 2065853

125 34 34 2 2 K. Holemans L. Aerts F. A. Van Assche Department of Obstetrics and Gynaecology Katholieke Universiteit Leuven Leuven Belgium Summary Our previous work has suggested the presence of an insulin resistance in the adult offspring of streptozotocindiabetic pregnant rats. In this study we used the euglycaemic hyperinsulinaemic clamp technique with an isotope-dilution method to define and quantify this postulated insulin resistance in adult offspring of streptozotocin-diabetic rats. Under basal conditions, these rats had a lower body weight than control rats, but their glucose and insulin concentrations were normal. During the hyperinsulinaemic clamp, the steady-state glucose infusion rate was significantly lower in the offspring of streptozotocin-diabetic rats than in both ageand weight-matched controls, indicating insulin resistance. Basal peripheral tissue glucose utilization was normal in the offspring of streptozotocin-diabetic rats, but the dose-response curve was shifted to the right: insulin concentrations causing half-maximal stimulation of glucose utilization were increased by about 60% in the offspring of diabetic rats; the maximal stimulation of glucose utilization, however, was unaltered. Basal hepatic glucose production was normal, but again, half-maximal suppression of glucose production occurred at insulin concentrations 50% higher than in control rats; in addition, the maximal suppression of glucose production was significantly decreased, even at insulin concentrations of 5700 μU/ml. These data are evidence for an insulin resistance in the adult offspring of streptozotocin-diabetic rats, characterized by: (1) a decreased insulin sensitivity by peripheral glucose-utilizing tissues, and, (2) a decreased sensitivity and responsiveness of the liver.

Suzuki, Y.; Hashimoto, N.; Shimada, F.; Taira, M.; Mimura, M.; Nozaki, O.; Tawata, M.; Onaya, T.; Makino, H.; Yoshida, S.

doi: 10.1007/BF00500378pmid: 1648521

125 34 34 2 2 Y. Suzuki N. Hashimoto F. Shimada M. Taira M. Mimura O. Nozaki M. Tawata T. Onaya H. Makino S. Yoshida Second Department of Internal Medicine Chiba University School of Medicine Chiba Third Department of Internal Medicine University of Yamanashi Medical School Yamanashi Japan Summary Defects in insulin receptor function lead to impairment of the insulin response. We treated a patient with the typical phenotype of type A syndrome of insulin resistance whose insulin receptor seemed to lack the transmembrane region and cytoplasmic domain. Hyperinsulinaemia and resistance to exogenous insulin were evident, and insulin binding to cells and uptake of 2-deoxyglucose into fibroblasts were greatly decreased. Molecular weight of the α-subunit of the insulin receptor was normal, but autophosphorylation and kinase activity were impaired. In the pedigree analysis, defects in insulin binding were also observed in the mother, maternal grandfather and two maternal aunts, corresponding with the abnormality of the insulin receptor gene and mild insulin resistance. In the mother, much the same kinase defects as were seen in the patient became evident. However, no relatives had clinical symptoms similar to those seen in the patient. In the father there was a mild insulin resistance in the glucose clamp study and a borderline impaired glucose tolerance. Although insulin binding to cells was normal in the father, both autophosphorylation and kinase activity were reduced. Our findings suggest that insulin resistance in the patient may be caused by the defects in insulin receptor kinase activity as well as by a reduction in insulin binding activity.

Vardi, P.; Crisa, L.; Jackson, R.; Dumont Herskowitz, R.; Wolfsdorf, J.; Einhorn, D.; Linarelli, L.; Dolinar, R.; Wentworth, S.; Brink, S.; Starkman, H.; Soeldner, J.; Eisenbarth, G.

Cook, J.; Patel, P.; Clark, A.; Höppener, J.; Lips, C.; Mosselman, S.; O'Rahilly, S.; Page, R.; Wainscoat, J.; Turner, R.

doi: 10.1007/BF00500380pmid: 1676684

125 34 34 2 2 J. T. E. Cook P. P. Patel A. Clark J. W. M. Höppener C. J. M. Lips S. Mosselman S. O'Rahilly R. C. Page J. S. Wainscoat R. C. Turner Diabetes Research Laboratories Radcliffe Infirmary UK Department of Heamatology John Radcliffe Hospital Oxford UK Institute of Molecular Biology The Netherlands Department of Internal Medicine, University Hospital University of Utrecht The Netherlands Summary Type 2 (non-insulin-dependent) diabetes is associated with the deposition of islet amyloid. The major formative peptide, islet amyloid polypeptide, has recently been characterised and an abnormality of the structure or expression of this gene is a possible candidate for the inherited component of Type 2 diabetes. A restriction fragment length polymorphism of the gene has been identified with Pvu II. To study the relationship between the islet amyloid polypeptide gene and Type 2 diabetes, two distinct genetic approaches have been undertaken. Firstly, non-linkage has been demonstrated in four pedigrees, with four normoglycaemic first degree relatives having an allele associated with diabetes in other family members, and one affected relative not having the putatively associated allele. The LOD score taking age-related penetrance into account was −1.68, making linkage unlikely ( p =0.02). Secondly, in a population-based restriction fragment length polymorphism survey, no linkage disequilibrium of the alleles was found between a population of unrelated Caucasian subjects with Type 2 diabetes and a normal population. A mutation in or near the islet amyloid polypeptide gene is thus unlikely to be a common cause of Type 2 diabetes.

Jenkins, D.; Mijovic, C.; Jacobs, K.; Penny, M.; Fletcher, J.; Barnett, A.

doi: 10.1007/BF00500381pmid: 2065845

125 34 34 2 2 Dr. D. Jenkins C. Mijovic K. H. Jacobs M. A. Penny J. Fletcher A. H. Barnett Department of Medicine University of Birmingham and East Birmingham Hospital Birmingham UK Department of Medicine Queen Elizabeth Hospital B15 2TH Edgbaston Birmingham UK Summary Trans-racial analysis of disease associations has improved mapping of MHC-linked susceptibility to Type 1 (insulin-dependent) diabetes mellitus. In this study the contributions of the MHC class II DQA1 and DQB1 genes were investigated. Sequence-specific oligonucleotide gene probing in Type 1 diabetic and control subjects of North Indian origin supported the DQw1.18 allele of the DQB1 gene as a determinant of inherited protection against Type 1 diabetes (RR=0.12, p c <0.05). The A3 allele of the DQA1 gene was positively associated with the disease, (RR=3.6, p c <0.05), as was the DQw2 allele of the DQB1 gene (RR=4.6, p c <0.01). Trans-racial comparison of these disease associations indicates that DQ alleles may directly determine an element of inherited susceptibility to Type 1 diabetes.

Stenvinkel, P.; Saggar-Malik, A.; Wahrenberg, H.; Diczfalusy, U.; Bolinder, J.; Alvestrand, A.

doi: 10.1007/BF00500382pmid: 1829692

125 34 34 2 2 P. Stenvinkel A. K. Saggar-Malik H. Wahrenberg U. Diczfalusy J. Bolinder A. Alvestrand Department of Renal Medicine, Karolinska Institute Huddinge University Hospital Stockholm Sweden Department of Medicine, Karolinska Institute Huddinge University Hospital Stockholm Sweden Department of Clinical Chemistry, Karolinska Institute Huddinge University Hospital Stockholm Sweden Summary Type 1 (insulin-dependent) diabetes mellitus is characterized by impaired sodium excretion following NaCl infusion. To investigate the possible role of dopamine in the impaired natriuresis in diabetes, intrarenal sodium handling, sodium excretion and urinary dopamine output, reflecting intrarenal dopamine formation, were studied following a 2 h 0.9% NaCl infusion (25 ml/kg) in eight diabetic patients and nine control subjects. The increase in sodium excretion in response to NaCl infusion was significantly ( p <0.01) reduced in diabetic patients (19±7%) as compared with control subjects (46±8%). Fractional proximal tubular sodium reabsorption (determined by lithium clearance) decreased in the control group ( p <0.001) following NaCl infusion but not in the diabetic group. Fractional distal tubular reabsorption decreased similarly in both groups. In response to NaCl urinary dopamine excretion increased by approximately 15% ( p <0.01) in the control group but did not change in the diabetic group. The mean urinary dopamine excretion above basal was significantly greater in the control group (8.4±2.1 nmol/h) than in the diabetic group (−2.2±2.1 nmol/h; p <0.01). The urinary sodium/dopamine excretion ratio did not differ significantly between the two groups in the basal state or following NaCl. Baseline plasma levels of atrial natriuretic peptide did not differ between control and diabetic patients. In the control group atrial natriuretic peptide levels increased significantly ( p <0.01) in response to NaCl whereas atrial natriuretic peptide levels did not change in the diabetic group. The results of this study show that patients with Type 1 diabetes have a blunted natriuresis in response to isotonic NaCl. This abnormality seems mainly to be due to impaired inhibition of proximal tubular sodium reabsorption, which may be the result of defective intrarenal dopamine mobilisation.

Torlone, E.; Rambotti, A.; Perriello, G.; Botta, G.; Santeusanio, F.; Brunetti, P.; Bolli, G.

doi: 10.1007/BF00500383pmid: 2065846

125 34 34 2 2 E. Torlone A. M. Rambotti G. Perriello G. Botta F. Santeusanio P. Brunetti G. B. Bolli Istituto di Patologia Speciale Medica e Metodologia Clinica Università di Perugia Perugia Italy Summary To assess the effects of ACE-inhibition on insulin action in Type 2 (non-insulin-dependent) diabetes mellitus associated with essential hypertension, 12 patients with Type 2 diabetes (on diet and oral hypoglycaemic agents) and arterial hypertension were examined on two occasions, in a single blind, cross-over study, after two days of treatment with either captopril or a placebo. The study consisted of a euglycaemic-hyperinsulinaemic clamp (two sequential steps of insulin infusion at the rates of 0.25 mU·kg −1 ·min −1 and 1 mU·kg −1 ·min −1 , 2 h each step), combined with an infusion of 3- 3 H-glucose to measure the rate of hepatic glucose production and that of peripheral glucose utilization. The results show that blood pressure was lower after captopril (sitting, systolic 148±5 mmHg, diastolic 89±2 mm Hg) compared to placebo (155±6 and 94±2 mm Hg) ( p <0.05). Captopril treatment resulted in a more suppressed hepatic glucose production (2.7±0.4 vs 4.94±0.55 μmol·kg −1 ·min −1 ), and a lower plasma non-esterified fatty acid concentration (0.143±0.05 vs 0.200±0.05 mmol/l) (captopril vs placebo, p <0.05) at the end of the first step of insulin infusion (estimated portal plasma insulin concentration 305±28 pmol/l); and in a greater glucose utilization (36.5±5.1 vs 28±3.6μmol·kg −1 ·min −1 , p <0.001) at the end of the second step of insulin infusion (arterial plasma insulin concentration of 604±33 pmol/l). We conclude that captopril improved insulin sensitivity in Type 2 diabetes associated with hypertension at the level of the liver and extrahepatic tissues, primarily muscle and adipose tissue. Thus, in contrast to other antihypertensive drugs such as diuretics and beta-blockers which may have a detrimental effect on insulin action, ACE-inhibitors appear to improve insulin action in Type 2 diabetes and essential hypertension, at least on a short-term basis.