Diabetologia

Tuomilehto, J.; Podar, T.; Tuomilehto-Wolf, E.; Virtala, E.

doi: 10.1007/BF00400588pmid: 7589885

125 38 38 8 8 Dr. J. Tuomilehto T. Podar E. Tuomilehto-Wolf E. Virtala Department of Epidemiology and Health Promotion National Public Health Institute Mannerheimintie 166 FIN-00300 Helsinki Finland Republic Endocrinology Center Tartu University Tartu Estonia Summary The risk of developing diabetes is higher in offspring of fathers than of mothers with insulin-dependent diabetes mellitus (IDDM). The reasons for this sex differential are unclear, as early studies were often selected and relatively small. We conducted a prospective study on the risk of IDDM in a cohort of 9,453 offspring from 5,255 Finnish parents with diabetes diagnosed before age 30 years. Age of first admission to the hospital was considered to be the age of diagnosis of IDDM in the offspring; IDDM occurred in 248 offspring. The risk of IDDM tended to be lower in the offspring of the same gender as the diabetic parent (adjusted risk ratio (RR) 0.78; p =0.50). When offspring were of same gender as the diabetic parent, male offspring had a higher risk of IDDM than female offspring (RR 2.28; 95% confidence interval 1.53–3.38), whereas if the gender of the diabetic parent and the offspring were different, the risk in male offspring was lower (RR 0.43; 95% confidence interval 0.31–0.62). For the offspring of diabetic fathers, the cumulative risk by the age of 20 was higher (7.6%) than for those with diabetic mothers (3.5%) ( p <0.0001). In a multivariate analysis statistically significant predictors of IDDM in the offspring were the sex of the parent, the year of birth and the birth order of the offspring. The risk of IDDM in the offspring increased by 9% per year of birth cohort. By age 20, the cumulative risk of developing IDDM in the offspring of diabetic parents was 5.3%, 10 times higher than in the background population. It is likely that genetic factors seem to have played a major role in the continuous increase of IDDM incidence in Finnish children.

Fujisawa, T.; Ikegami, H.; Yamato, E.; Takekawa, K.; Nakagawa, Y.; Hamada, Y.; Ueda, H.; Fukuda, M.; Ogihara, T.

doi: 10.1007/BF00400589pmid: 7589886

125 38 38 8 8 T. Fujisawa Dr. H. Ikegami E. Yamato K. Takekawa Y. Nakagawa Y. Hamada H. Ueda M. Fukuda T. Ogihara Department of Geriatric Medicine Osaka University Medical School 2-2 Yamadaoka, Suita 565 Osaka Japan Department of Ophthalmology Osaka Teishin Hospital Osaka Japan Summary A possible pathogenic mutation in the glucagon receptor gene causing a Gly to Ser change at codon 40 (Gly40Ser) was reported to be associated and linked with non-insulin-dependent diabetes mellitus (NIDDM), in France and Sardinia, Since the frequency of the mutation (Gly40Ser), about 5% in the French population of familial NIDDM and 8% in randomly chosen diabetic patients in Sardinia, was much higher than that of any of the previously reported mutations in candidate genes, it is important to clarify whether the contribution of this mutation to NIDDM is universal. In this study, we investigated the association of this mutation with diabetes mellitus in a large number of Japanese diabetic patients (383 NIDDM and 53 insulin-dependent diabetic patients) by polymerase chain reaction-restriction fragment length polymorphism analysis. None of the Japanese diabetic patients showed Gly40Ser mutation and the association of this mutation with NIDDM was significantly different ( p <4·10 −5 vs French, p <3·10 −6 vs Sardinian by Fisher's exact test). The results not only indicate that the mutation plays little, if any, role in susceptibility to diabetes in Japan, but also indicate the genetic heterogeneity in NIDDM and further emphasize the importance of studies on genetic susceptibility to NIDDM and other complex traits in different ethnic groups.

Beech, J.; Williams, S.; Iles, R.; Cohen, R.; Nolan, K.; Evans, S.; Going, T.

doi: 10.1007/BF00400576pmid: 7589873

125 38 38 8 8 J. S. Beech S. C. R. Williams R. A. Iles Professor R. D. Cohen K. M. Nolan S. J. W. Evans T. C. D. Going Cellular Mechanisms Research Group The London Hospital Medical College London UK Magnetic Resonance Spectroscopy Unit, Queen Mary and Westfield College University of London London UK Department of Epidemiology and Medical Statistics The London Hospital Medical College London UK Medical Unit The Royal London Hospital Whitechapel Road E1 1BB London UK Summary To examine factors determining the haemodynamic and metabolic responses to treatment of diabetic ketoacidosis with alkali, groups of anaesthetised and ventilated rats with either diabetic ketoacidosis (mean arterial pH 6.86–6.96, mean arterial blood pressure 63–67 mm Hg) or hypovolaemic shock due to blood withdrawal (mean pH a 7.25–7.27, mean arterial blood pressure 36–41 mmHg) were treated with sodium chloride (‘saline’), sodium bicarbonate or ‘Carbicarb’ (equimolar bicarbonate plus carbonate). In the diabetic ketoacidosis series, treatment with either alkali resulted in deterioration of mean arterial blood pressure and substantial elevation of blood lactate, despite a significant rise in myocardial intracellular pH determined by 31 P-magnetic resonance spectroscopy. These effects were accompanied by falling trends in the ratios of myocardial phosphocreatine and ATP to inorganic phosphate. Erythrocyte 2,3-bisphosphoglycerate was virtually absent in animals with diabetic ketoacidosis of this severity and duration. In contrast, in shock due to blood withdrawal, infusion of saline or either alkali was accompanied by a transient elevation of mean arterial blood pressure and no significant change in the already elevated blood lactate; erythrocyte 2,3-bisphosphoglycerate was normal in these animals. The effect of alkalinization in rats with severe diabetic ketoacidosis was consistent with myocardial hypoxia, due to the combination of very low initial erythrocyte 2,3-bisphosphoglycerate, alkali-exacerbated left shift of the haemoglobin-oxygen dissociation curve and artificial ventilation. No evidence was found for any beneficial effect of ‘Carbicarb’ in either series of animals; ‘Carbicarb’ and sodium bicarbonate could be deleterious in metabolic acidosis of more than short duration.

Sundkvist, G.; Bottini, P.

doi: 10.1007/BF00400593pmid: 7589870

Rafaeloff, R.; Barlow, S.; Rosenberg, L.; Vinik, A.

doi: 10.1007/BF00400578pmid: 7589875

125 38 38 8 8 Dr. R. Rafaeloff S. W. Barlow L. Rosenberg A. I. Vinik The Diabetes Institutes, Department of Internal Medicine Eastern Virginia Medical School Norfolk Virginia USA Department of Surgery McGill University Montreal Quebec Canada The Diabetes Institute, Molecular Biology Laboratory Eastern Virginia Medical School 855 West Brambleton Avenue 23510 Norfolk VA USA Summary We have reported previously that cellophane wrapping of the hamster pancreas is a stimulus that leads to the induction of duct epithelial cell proliferation, followed by endocrine cell differentiation and new islet formation. Reg is a candidate gene that has been reported to be expressed in regenerating pancreatic islets, suggesting a role in islet growth. We examined Reg gene expression in the cellophane-wrap model by isolating total RNA from hamster pancreata at various times after wrapping. Northern blot analysis using a rat cDNA Reg probe showed no expression of Reg in control non-wrapped hamster pancreas, whereas a strong signal was detected in control wrapped rat pancreas. Using reverse transcription of RNA followed by polymerase chain reaction (PCR) we amplified, isolated and sequenced a 194 base pair product which showed homology to rat Reg in both control and wrapped hamster pancreas. When the PCR product was used as a probe for Northern blot analysis, no signal was detected in control non-wrapped pancreata. In contrast, a strong signal was detected 1 and 2 days after wrapping, which then returned to basal between 4 and 6 days after wrapping. A similar temporal pattern was observed using in situ hybridization to localize the Reg gene. One- and 2-day wrapped but not control pancreas expressed Reg in acinar cells, but not in islets. In conclusion, (a) Reg expression is low in the control hamster pancreas; (b) in the cellophane-wrap model of islet neogenesis, increased Reg mRNA is found within acinar tissue; (c) Reg gene may thus be involved as an acinar paracrine effector of duct cell proliferation in the initial step of islet neogenesis, but may also participate in the inflammatory response to traumatic stimuli.

Odawara, M.

doi: 10.1007/BF00400594pmid: 7589871

Zawalich, W.; Kelley, G.

doi: 10.1007/BF00400590pmid: 7589887

Kihara, M.; Schmelzer, J.; Low, P.

doi: 10.1007/BF00400579pmid: 7589876

125 38 38 8 8 M. Kihara J. D. Schmelzer Dr. P. A. Low Neurophysiology Laboratory, Department of Neurology Mayo Foundation Rochester Minnesota USA Mayo Clinic 200 First Street Southwest 55905 Rochester MN USA Summary Two proposed mechanisms of diabetic neuropathy are microvascular ischaemia and a reduction in Na,K-ATPase activity. We evaluated the effect of cilostazol, a drug that is both a potent phosphodiesterase inhibitor that normalizes nerve Na,K-AT-Pase and a vasodilator, on nerve blood flow (NBF) to determine whether it would improve experimental diabetic neuropathy. We examined whether epineurally applied cilostazol acted as a vasodilator on the peripheral nerve of normal and diabetic rats, and whether feeding the rats a cilostazol-supplemented diet could improve diabetic neuropathy. Cilostazol increased nerve blood flow (NBF) in a dose-dependent fashion with an EC 50 of 10 −5.74 mol/l. Cilostazol also normalized NBF in experimental diabetic neuropathy with a 10 −4 mol/l local application on the sciatic nerve. In diabetic neuropathy, a cilostazol-supplemented diet improved both NBF and nerve conduction in a dose- and time-dependent fashion. Potential mechanisms of action of cilostazol on the nerve include its effect on NBF, Na, K-ATPase, and restoration of the thromboxane:prostacyclin ratio. Cilostazol may have potential in the treatment of diabetic neuropathy.

Cummings, M.; Watts, G.; Umpleby, A.; Hennessy, T.; Naoumova, R.; Slavin, B.; Thompson, G.; Sönksen, P.

doi: 10.1007/BF00400586pmid: 7589883

125 38 38 8 8 M. H. Cummings G. F. Watts A. M. Umpleby T. R. Hennessy R. Naoumova B. M. Slavin G. R. Thompson P. H. Sönksen Department of Medicine St. Thomas' Hospital, United Medical and Dental School of Guys and St. Thomas' London UK University Department of Medicine University of Western Australia Perth Australia Lipoprotein Team MRC Clinical Sciences Centre, Hammersmith Hospital London UK Department of Chemical Pathology St. Thomas' Hospital, United Medical and Dental School of Guys and St. Thomas' London UK Summary We measured the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 (VLDL apoB) using a stable isotope gas-chromatography mass-spectrometry method in six patients with non-insulin-dependent diabetes mellitus (NIDDM) (four males, two females, age 57.5±2.2 years (mean±SEM), weight 88.2±5.5 kg, glycated haemoglobin (HbA 1 ) 8.5±0.5%, plasma total cholesterol concentration 5.7±0.5 mmol/l, triglyceride 3.8±0.9 mmol/l, high-density lipoprotein (HDL) cholesterol 1.0±0.1 mmol/l) and six non-diabetic subjects matched for age, sex and weight (four males, two females, age 55.7±2.8 years, weight 85.8±5.6 kg, HbA 1 6.5±0.1%, plasma total cholesterol concentration 5.7±0.5 mmol/l, triglyceride 1.2±0.1 mmol/l, HDL cholesterol 1.4±0.1 mmol/l). HbA 1 , plasma triglyceride and mevalpnic acid (an index of cholesterol synthesis in vivo) concentrations were significantly higher in the diabetic patients than in the non-diabetic subjects ( p =0.006, p =0.02 and p =0.004, respectively). VLDL apoB absolute secretion rate was significantly higher in the diabetic patients compared with the non-diabetic subjects (2297±491 vs 921±115 mg/day, p <0.05), but there was no significant difference in the fractional catabolic rate of VLDL apoB. There was a positive correlation between VLDL apoB secretion rate and (i) fasting C-peptide ( r =0.84, p =0.04) and (ii) mevalonic acid concentration ( r =0.83, p <0.05) in the diabetic patients but not in the non-diabetic subjects. There was also a significant positive association between plasma mevalonic acid and plasma C-peptide ( r =0.82, p <0.05) concentrations in the diabetic patients. We conclude that in NIDDM, there is increased hepatic secretion of VLDL apoB which may partly explain the dyslipoproteinaemia seen in this condition. We suggest that increased secretion of this apolipoprotein may be a consequence of resistance to the inhibitory effect of insulin on VLDL apoB secretion. Insulin resistance may also be the mechanism by which cholesterol synthesis, a regulator of apoB secretion, is increased in NIDDM.

Trovati, M.; Massucco, P.; Mattiello, L.; Cavalot, F.; Mularoni, E.; Hahn, A.; Anfossi, G.

doi: 10.1007/BF00400582pmid: 7589879

125 38 38 8 8 Prof. M. Trovati P. Massucco L. Mattiello F. Cavalot E. Mularoni A. Hahn G. Anfossi Diabetes Unit Department of Clinical and Biological Sciences of the University of Turin, San Luigi Gonzaga Hospital I-10043 Orbassano Torino Italy Research Department Basel University Basel Switzerland Summary It has been suggested that insulin exerts a vasodilating effect, but the mechanisms involved are not completely understood. Since cyclic nucleotides mediate the vasodilation induced by endogenous substances, such as prostacyclin and nitric oxide, we aimed to investigate the influence of insulin (concentration range 240–960 pmol/l) on both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) content in human vascular smooth muscle cells. Insulin dose-dependently increased both nucleotides (cAMP: from 0.7±0.1 to 2.6±0.4 pmol/10 6 cells, p =0.0001; cGMP: from 1.3±0.2 to 3.4±0.7 pmol/10 6 cells, p =0.033). This increase is receptor-mediated, since it was blunted when cells were preincubated with the tyrosine kinase inhibitor genistein. The effect of insulin remained significant ( p =0.0001) when preincubation with the phosphodiesterase inhibitor theophylline prevented cyclic nucleotide catabolism. The increase of cGMP was blunted when the cells were preincubated with the guanylate cyclase inhibitor methylene blue, and with the nitric oxide-synthase inhibitor N G -monomethyl- l -arginine. At all the concentrations tested, insulin potentiated the increase of cAMP induced by the stable prostacyclin analogue Iloprost ( p =0.0001), whereas only at 1920 pmol/l did it potentiate the cGMP increase induced by glyceryltrinitrate ( p =0.05). This study demonstrates that the vasodilating effects exerted by insulin may at least in part be attributable to an increase of both cGMP and cAMP via a receptor-mediated activation of adenylate and guanylate cyclases in human vascular smooth muscle cells and that the insulin effect on cGMP is mediated by nitric oxide.