The pancreas in idiopathic Addison''s disease—a search for a prediabetic pancreas

Autopsy pancreases were studied from 14 patients who had idiopathic Addison's disease. One patient had been diabetic for 12 years and three patients were found to be diabetic during their terminal admission. While there was no evidence of diabetes or destruction of insulin-secreting beta cells in the remaining 10 patients, islets in one pancreas exhibited many of the histological and immunohistochemical features seen in the patients with recent onset diabetes. These included the presence of alpha-interferon in endocrine cells, hyper-expression of class I major histocompatibility complex molecules by endocrine cells in islets where alpha-interferon was also present, aberrant expression of class II major histocompatibility complex molecules by endocrine cells and the presence of insulitis. Since the combination of these changes has only been described in type 1 diabetes it is thought that the appearances seen in this pancreas were those of prediabetes.     

The occurrence of low insulin response to glucose infusion in children

Summary Insulin response to glucose infusion was studied in 42 children with a normal intravenous glucose tolerance, 7–16 years of age. The majority of these children had at least one first degree relative with diabetes mellitus. Low and delayed insulin response similar to the one found in 15–20% of healthy adult subjects also occurred in 15–20 per cent of the children in this material. These findings support our previous suggestion that the low and delayed insulin response to glucose is probably genetically determined.

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Das Vorkommen von verringerter Insulinausschüttung nach Glukoseinfusion bei Kindern

Zusammenfassung Die Insulinausschüttung nach Glucoseinfusion wurde bei 42 Kindern, 7–16 Jahre alt, mit normaler intravenösen Glucosetoleranz untersucht. Die Mehrzahl dieser Kinder hatte einen diabeteskranken Eltern-oder Geschwisterteil. Eine verzögerte und verringerte Insulinfreisetzung, ähnlich denen, die bei 15–20% von gesunden Erwachsenen gefunden worden waren, war bei 7 von 42 Kindern zu sehen. Dieser Befund stützt unsere frühere Ansicht, daß die verzögerte und verringerte Insulinausschüttung bei Hyperglykämie wahrscheinlich genetisch bedingt ist.

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L'existence de réponse insulinique réduite à la perfusion de glucose chez l'enfant

Résumé La réponse insulinique à la perfusion de glucose a été étudiée chez 42 enfants âgés de 7 à 16 ans et ayant un test de tolérance au glucose normal. Chez la plupart des enfants au moins un des parents ou frères et surs avait le diabète. Une réponse insulinique réduite et retardée, similaire à celle observée chez 15 à 20% des adultes en bonne santé, a été démontrée chez 7 enfants sur les 42. Ces résultats confirment notre suggestion que ce type de réponse insulinique réduite et retardée est probablement déterminée par des facteurs héréditaires.

     

Diabetes,prediabetes and uricaemia

Summary Three diabetes surveys carried out at two yearly intervals on 10000 men aged 40 years and over have enabled us to compare four groups of subjects with regard to their serum uric acid level in relation to carbohydrate metabolism. Prediabetics, that is, persons who screened negative at previous surveys and subsequently developed diabetes, had a higher mean uric acid level than normals (p < 0.001). Their uric acid level was considerably higher than in diabetics, who had a mean value lower than normals (up top < 0.001). Men, without diabetes, but having an abnormal GTT were found to have a mean value higher than the normals at each survey.     

Dynamics of Insulin Release from the Foetal and Neonatal Rat Pancreas

Abstract. The dynamics of glucose-stimulated insulin release from pieces of foetal and neonatal rat pancreas were studied in an in vitro perifusion system. During an initial 60-min. equilibration period, the tissue was perifused with a phosphate-buffered medium containing 0.4 mg/ml glucose. This was followed by a 40-min. stimulation period, in which the medium glucose concentration was 3.0 mg/ml. Tissue obtained from foetuses of 21.5 days' gestation displayed only a small initial peak of insulin release when exposed to a high glucose concentration. At one day post partum, a low initial response to glucose was followed by a small but significant secondary rise in insulin secretion. At six days of age, a pronounced immediate response and a subsequent constant high level of insulin output were recorded during the stimulation period. At one day of age, the addition of 5 mM arginine to the perifusion medium during the stimulation period caused a marked increase of insulin output during both the early and the late phase, compared with glucose alone. – The present data indicate that the mechanism responsible for the initial phase of glucose-stimulated insulin release is already present in the rat during late foetal life, although it is probably not completely mature. The development of the second phase of the secretory response seems to be an essentially postnatal event. The dynamics of insulin release in the immature rat appear to be similar to those reported in prediabetic and some diabetic individuals. The intriguing possibility that the predisposition to diabetes may be associated with a lack of normal development of the insulin secreting mechanism seems to deserve further consideration.     

Serum transforming growth factor ��1 during diabetes development in non-obese diabetic mice and humans

Recent data show that regulatory cells with transforming growth factor (TGF)‐β1‐dependent activity are able to restore self‐tolerance in overtly diabetic non‐obese diabetic (NOD) mice. Thus, TGF‐β1 seems to have a relevant role in protection from autoimmune diabetes. Our aim was to investigate the possible significance of serum TGF‐β1 measurement in the natural history of diabetes in NOD mice, as well as in children positive for at least one islet‐related antibody. Serum TGF‐β1 (both total and active) was measured by enzyme‐linked immunosorbent assay at monthly intervals in 26 NOD mice during the spontaneous development of diabetes and, on a yearly basis, in nine siblings of patients with type 1 diabetes (T1D) with a follow‐up of 4 years. Diabetes appeared between the 12th week of age and the end of the study period (36 weeks) in 17 mice. TGF‐β1 serum level variations occurred in the prediabetic period in both NOD mice and humans and diabetes diagnosis followed a continuing reduction of active TGF‐β1 (aTGF‐β1) serum levels. In mice, aTGF‐β1 serum levels measured at 4 weeks of age correlated positively with severity of insulitis, and negatively with percentage of insulin‐positive cells. Our findings suggest that in NOD mice serum TGF‐β1 levels during the natural history of the diabetes reflect the course of islet inflammation. The measurement of aTGF‐β1 in islet‐related antibody‐positive subjects may provide insights into the natural history of prediabetic phase of T1D.     

Monocyte-suppressing effect of high-dose metformin in fenofibrate-treated patients with impaired glucose tolerance

BackgroundFibrates were found to reduce cytokine release and low-grade inflammation in patients with impaired glucose tolerance. The aim of this study was to investigate whether these effects of fibrates may be potentiated by metformin treatment.MethodsThe study included 43 patients with isolated impaired glucose tolerance and normal plasma lipids who had been treated for at least 6 months with micronized fenofibrate (200 mg daily). These subjects were randomly assigned to 12 weeks’treatment with either high dose metformin (3 g daily in three divided doses) or placebo. Plasma lipids, glucose homeostasis markers, monocyte cytokine release and plasma C-reactive protein levels were determined before randomization and at the end of the treatment.ResultsMetformin treatment reduced plasma C-reactive protein levels and monocyte release of tumor necrosis factor-α and interleukin-6, as well as tended to reduce monocyte release of interleukin-1β and monocyte chemoattractant protein-1, which was accompanied by an improvement in insulin sensitivity.ConclusionsOur results show that high-dose metformin produces monocyte-suppressing and systemic anti-inflammatory effects in fibrate-treated patients with isolated impaired glucose tolerance. This suggests that fibrate-metformin combination therapy may bring clinical benefits to impaired glucose tolerance patients at high cardiovascular risk.