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Free access

Christoph D Dieterle, Helmut Arbogast, Wolf-Dieter Illner, Susanne Schmauss and Rüdiger Landgraf

Design: Successful pancreas transplantation results in insulin independence and normoglycemia. This prospective study was performed to investigate long-term metabolic changes after pancreas transplantation.

Methods: Thirty-eight type 1 diabetic patients after simultaneous pancreas/kidney transplantation (SPK) with a pancreas graft survivalfor at least10years were studied in a prospective manner. HbA1c and glucose levels before and during an oral glucose tolerance test (OGTT) were analyzed from 3 months to 10 years after SPK. In addition, insulin secretion and glucagon response were measured.

Results: Fasting glucose increased slightly and continuously from 3 months to 10 years (from 78 ± 3 to 91 ± 2 mg/dl). Even HbA1c levels showed a mild but significant increase from 3 months to 10 years after SPK. Glucose tolerance deteriorated markedly 10 years after SPK. Insulin secretion during OGTT remained stable for 10 years. Parameters of insulin resistance and sensitivity did not change significantly but glucagon secretion increased significantly during the course after SPK. Late after SPK, glucagon levels were higher in patients with an impaired or diabetic glucose tolerance.

Conclusions: Pancreas transplantation is able to restore endogenous insulin secretion for 10 years or more. Especially, late after SPK, a deterioration of glycemic control was detected, even if glucose values were within the normal range. During prospective long-term follow-up, an increase of glucagon secretion but no decrease of insulin secretion was detected.

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Claus Kühl and Peter J. Hornnes

Abstract. Glucose tolerance deteriorates in normal human pregnancy but 99% of all pregnant women retain normal glucose tolerance whereas the remaining 1% develop abnormal glucose tolerance and are designated gestational diabetics. The possibility that glucose tolerance deteriorates in pregnancy because of diabetes-like changes in the secretory function of the endocrine pancreas has been investigated in gestational diabetics and healthy controls. Even though the insulin responses to oral glucose and mixed meals are equally large in gestational diabetics and normal pregnant women, the insulin responses of the gestational diabetics differ in two pertinent ways from those of the normals. First, a delayed insulin response is frequently seen, and second, the insulin response per unit of glycaemic stimulus (the 'insulinogenic index') is normally significantly lower than that of the normal pregnant women. Diabetes-like changes in the secretion of glucagon are not seen in neither group. Insulin degradation is unaffected by pregnancy and the proinsulin share of the total plasma insulin immunoreactivity does not increase in pregnancy. It is therefore likely that the main reason for the diabetogenicity of pregnancy is insulin resistance. Most pregnant women are able to increase their insulin secretion and thus overcome the resistance. Some pregnant women do, however, seem to have a more limited insulin secretory capacity which eventually may lead to the development of gestational diabetes.

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Ove Berglund, Barbara J. Frankel and Bo Hellman


Genetically diabetic mice (C57BL/KsJ-db/db) were used as a model to study the development of defects of insulin secretion in relation to common metabolic indicators (body weight, serum glucose and insulin, and islet insulin contant). Consistent with the idea of a protective effect of oestrogen on the pancreatic β-cell, the female diabetic mice survived longer than the males. In males, while serum insulin decreased in the later stages of the disease, serum glucose increased progressively with age. Perfusion of the diabetic pancreases revealed a rise and subsequent fall with age of the basal insulin released at 3 mm glucose. Despite previous reports of β-cell hyperplasia, progressive impairment of the insulin response to 20 mm glucose, or to 20 mm glucose and 1 mm 3-isobutyl-1-methylxanthine, was seen with increasing age in experiments with perfused pancreas or microdissected islets. Islet content of insulin also decreased progressively with age in the diabetic animals.

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Yoshimasa Tasaka, Koji Marumo, Yukiko Inoue and Yukimasa Hirata

Abstract. The content of insulin and C-peptide-like immunoreactivity (CPR) were determined in the tail of pancreas from 35 autopsied diabetic and 21 non-diabetic subjects. In the 28 diabetics who had been followed for more than 6 months, the relation between the amount of insulin or CPR in the pancreas and the stability of fasting serum glucose during diabetic life before death was analyzed together with the relation between the serum CPR response to the breakfast tolerance test before death and insulin content at autopsy. As an index of the instability of the blood sugar level, the standard deviation of the mean of 15 successive determinations of fasting serum glucose was used. Both insulin and CPR content in the pancreas were significantly decreased in diabetics as compared with non-diabetics. sd of the mean fasting serum glucose and insulin or CPR content in the tail of pancreas showed a significant inverse correlation on a logarithmic scale (P < 0.01, r = −0.704 and P < 0.01, γ = −0.757, respectively). Serum CPR value during the breakfast tolerance test correlated significantly with the insulin content in the pancreas of diabetic subjects. These findings suggest that one of the causes of the instability of fasting serum glucose levels is the devastation of pancreatic β-cells and that the pancreatic insulin content is logarithmically and inversely related to fluctuations in fasting serum glucose.

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E. Gerhards and M. Rühl


The insulin secretion pattern of the isolated perfused pancreas of the non-diabetic Chinese hamster after stimulation with glucose and tolbutamide is described. Stimulation with 100–800 mg glucose/100 ml leads to an increasing acute insulin secretion. The initial insulin peak reaches its maximum 2–3 min after the beginning of the stimulation with glucose. The amount of insulin initially secreted from the pancreas of fasted hamsters is larger than that of fed animals. The initial insulin peak is followed by a second short-term insulin release. The maximum of the second peak occurs approximately 10–15 min after the initial stimulation with glucose. With 100 mg glucose/100 ml the insulin secretion proceeds in a practically linear manner for a period of 140 min. With 200 and 400 mg glucose/100 ml the insulin secretion remains linear for approximately 80 min. With 200 mg glucose/100 ml about 10 000 μU insulin are secreted within 120 min, with 400 mg glucose/100 ml approximately 20 000 μU are secreted in the same period of time.

The insulin secretion is described following repeated short-term stimulation with 200 mg glucose/100 ml and increasing glucose concentrations up to 500 mg/100 ml for 5 min each. In perfusion studies with 400 mg glucose/100 ml and 8 mg puromycin/100 ml the amount of insulin secreted in 150 min is reduced by about 50%. The insulin secretion stimulated by 100 mg glucose/100 ml was greatly increased by 10 mg tolbutamide/100 ml. The insulin secretion pattern at a glucose concentration of 50 mg/100 ml is shown following repeated stimulation with 10 mg tolbutamide/100 ml alternating with tolbutamide-free resting phases of 10 min. The mechanism of insulin secretion following stimulation with glucose and β-cytotrophic antidiabetics is discussed. The isolated perfused pancreas of the Chinese hamster is suitable for the study of the dynamics of insulin secretion.

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Annika M Svensson, Samy M Abdel-Halim, Suad Efendic, Leif Jansson and Claes-Göran Östenson

Svensson AM, Abdel-Halim SM, Efendic S, Jansson L, Östenson C-G. Pancreatic and islet blood flow in F1 -hybrids of the non-insulin-dependent diabetic GK-Wistar rat. Eur J Endocrinol 1994:130:612–16. ISSN 0804–4643

Previous studies have indicated that various conditions under which an increased functional load is posed on the pancreatic islets, e.g. partial pancreatectomy and continuous glucose infusions, may influence the microcirculation of the pancreas. To investigate further the effects of elevated functional demand on the islets, the blood perfusion of the whole pancreas and the pancreatic islets was measured with a microsphere technique in an animal model presenting impaired glucose tolerance and mild hyperglycemia, namely F 1-hybrids of the spontaneously non-insulin-dependent diabetic GK-Wistar rat. Normal Wistar rats served as controls. All hybrids had a pathological intraperitoneal glucose tolerance test 1 week before the blood flow measurements, which were performed in 10–12-week-old rats. Both the whole pancreatic and the islet blood flows were increased in the hybrids compared to controls. The fractional islet blood flow, i.e. the fraction of whole pancreatic blood flow diverted through the islets, also was increased in the hybrid rats (12.6 ±0.6% vs 9.8 ±0.5% in controls, p <0.01). A bilateral abdominal vagotomy performed 30 min before the blood flow measurement markedly decreased the blood flow values of the islets and the whole pancreas in both groups of rats. After vagotomy, the islet blood flow in the hybrid rats was similar to that of the vagotomized control animals (8.2 ± 0.8 and 7.5 ± 1.4%, respectively). It is concluded that the increased pancreatic and islet blood perfusion observed in F 1-hybrids of the GK-Wistar rat depends on a mechanism mediated by the vagus nerve.

Annika M Svensson, Department of Medical Cell Biology, Biomedical Centre, PO Box 571, S-75123 Uppsala, Sweden

Free access

T Jevdjovic, C Maake, E Eppler, E Zoidis, M Reinecke and J Zapf

BACKGROUND: In GH-deficient humans, GH and IGF-I treatment cause opposite effects on serum insulin concentrations and insulin sensitivity. This finding contrasts with the somatomedin hypothesis that IGF-I mediates GH action, as postulated for skeletal growth, and raises the question whether GH-induced IGF-I acts on the endocrine pancreas in the same way as administered IGF-I. OBJECTIVE: To compare the effects of the two hormones on the endocrine pancreas of hypophysectomized rats. METHODS: Animals were infused for 2 days, via miniosmotic pumps, with IGF-I (300 microg/day), GH (200 mU/day) or vehicle. We measured (i) glucose, IGF-I, insulin, C-peptide and glucagon in serum and (ii) IGF-I, insulin and glucagon mRNAs and peptides in the pancreas by radioimmunoassay, immunohistochemistry and northern analysis. RESULTS: Both GH and IGF-I treatment increased serum and pancreatic IGF-I but, unlike GH, IGF-I treatment strongly reduced serum insulin and C-peptide (and, to a lesser extent, serum glucagon). Nevertheless, the animals did not become hyperglycaemic. GH, but not IGF-I, increased pancreatic insulin and glucagon content, as also indicated by immunohistochemistry, and increased IGF-I mRNA. Neither GH nor IGF-I caused significant changes in insulin and glucagon mRNA. CONCLUSIONS: The decrease in serum insulin and C-peptide by IGF-I treatment without significant changes in insulin gene expression and pancreatic insulin content suggests inhibition of insulin secretion. Within this setting, the absence of hyperglycaemia points to enhanced insulin sensitivity, although an insulin-like action of infused IGF-I may have partially compensated for the decreased insulin concentrations. GH-induced circulating or pancreatic IGF-I, or both, does not mimic the pancreatic effects of infused IGF-I in the absence of GH, suggesting that GH may counteract the action of GH-induced IGF-I on the endocrine pancreas.

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Suzan Lenz, Claus Kühl, Palle Wang, Lars Mølsted-Pedersen, Hans Orskov and Ole K. Faber


The metabolic effects of a one hour intravenous infusion of the β-2-receptor stimulating drug ritodrine were studied in seven normal pregnant women, three White class A pregnant diabetics and eight White class B-D pregnant diabetics.

During ritodrine infusion all subjects in the three groups exhibited increases in plasma glucose (1.0, 1.6 and 2.1 mmol/l respectively), free fatty acids (360, 850 and 1150 μmol/l), lactate (0.43, 0.80 and 0.86 mmol/l) and β-hydroxybutyrate and decreases in standard bicarbonate. The rise in plasma glucose, free fatty acids and lactate was more pronounced in insulin treated diabetic. The rises in β-hydroxybutyrate and decreases in standard bicarbonate were of the same magnitude in all three groups. Plasma potassium fell in all subjects, whereas no detectable changes in plasma sodium were observed.

The endocrine pancreatic function was assessed by measuring plasma insulin (White class A and normals), C-peptide (White class B-D) and glucagon (all subjects). Plasma insulin increased in normals (22 μIU/ml) and White class A diabetics (33 μIU/ml), whereas plasma C-peptide of the insulin treated patients (White class B-D) were below measurable concentrations. Plasma glucagon and cortisol concentrations were not influenced by ritodrine.

The results suggest that the diabetogenic changes induced by ritodrine are augmented with the severity of diabetes but not ascribable to a diabetes-like change in the function of the endocrine pancreas.

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P. P. G. Gerber, E. R. Trimble, L. Herberg and A. E. Renold

Abstract. The effect of previous exposure to glucose on subsequent glucose-stimulated insulin and somatostatin secretion has been investigated using the isolated perfused rat pancreas. As expected, when the pancreases of non-diabetic rats were exposed to 16.7 mM glucose on two occasions, 20 min apart, insulin secretion during the second period of exposure to high glucose was greater than that during the first period. By contrast, there was no potentiation of somatostatin secretion during the second glucose stimulation with respect to that of the first. Indeed, when the basal glucose concentration was low (1.4 or 2.8 mm) somatostatin secretion during the second glucose stimulation was lower than that during the first.

Since exogenous insulin is known to inhibit glucoseinduced somatostatin secretion, it seemed possible that lack of visible potentiation of glucose-induced somatostatin secretion by glucose could have been due to partial D cell inhibition by simultaneously augmented insulin secretion during the second glucose stimulation. In an attempt to exclude such an interaction between B and D cells, somatostatin secretion was also studied in the pancreases of spontaneously diabetic, Wistar (BB) rats (these animals are insulin deficient and are maintained by daily injections of insulin). However, even though insulin secretion was not detectable from these pancreases, glucose potentiation of glucose-induced somatostatin secretion did not occur.

Although the pancreatic B and D cells are known to respond in a similar manner to many secretagogues the present results show that glucose potentiation of glucosestimulated somatostatin secretion is not found under circumstances where potentiation of insulin secretion does occur. In addition, the absence of potentiated somatostatin secretion could not be attributed to partial inhibition of the D cell by insulin.

Free access

M Barbera, V Fierabracci, M Novelli, M Bombara, P Masiello, E Bergamini and V De Tata

OBJECTIVE: To explore the adaptive response of the endocrine pancreas in vivo and in vitro and the possible beneficial effect of the insulino-mimetic agent vanadyl sulfate (VOSO(4)), using glucocorticoid treatment to increase insulin resistance, in aging rats. DESIGN AND METHODS: Dexamethasone (Dex) (0.13 mg/kg b.w.) was administered daily for 13 days to 3- and 18-month old Sprague-Dawley rats and oral VOSO(4) was given from the 5th day. Plasma glucose, insulin and free fatty acids (FFA) concentrations were measured during these treatments and the insulin secretory response of the isolated perfused pancreas was assessed at the end of the experiment. RESULTS AND CONCLUSIONS: In both young and aging rats, particularly in the latter, hyperinsulinemia and increased in vitro insulin responsiveness to glucose were observed in response to Dex treatment, concomitant with an increase in plasma FFA concentrations. Thus, in glucocorticoid-treated animals, the beta-cell adaptive response occurred in both age groups and could possibly be mediated by increased circulating FFA; however, it was insufficient to prevent hyperglycemia in 60% of aging animals. Oral VOSO(4) administration failed to correct Dex-induced alterations in glucose and lipid metabolism, although it influenced in vitro beta-cell responsiveness to stimuli in aging rats.