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Patricia Lemieux, S John Weisnagel, Annabelle Z Caron, Anne-Sophie Julien, Anne-Sophie Morisset, Anne-Marie Carreau, Jonathan Poirier, André Tchernof, Julie Robitaille, Jean Bergeron, André Marette, Marie-Claude Vohl and Claudia Gagnon

Objective

To determine whether vitamin D3 supplementation improves insulin sensitivity, using the hyperinsulinemic-euglycemic clamp.

Design

This single-centre, double-blind, placebo-controlled trial randomised 96 participants at high risk of diabetes or with newly diagnosed type 2 diabetes to vitamin D3 5000 IU daily or placebo for 6 months.

Methods

We assessed at baseline and 6 months: (1) primary aim: peripheral insulin sensitivity (M-value using a 2-h hyperinsulinemic-euglycemic clamp); (2) secondary aims: other insulin sensitivity (HOMA2%S, Matsuda) and insulin secretion (insulinogenic index, C-peptide area under the curve, HOMA2-B) indices using a 2-h oral glucose tolerance test (OGTT); β-cell function (disposition index: M-value × insulinogenic index); fasting and 2-h glucose post OGTT; HbA1c; anthropometry.

Results

Baseline characteristics were similar between groups (% or mean ± s.d.): women 38.5%; age 58.7 ± 9.4 years; BMI 32.2 ± 4.1 kg/m2; prediabetes 35.8%; diabetes 20.0%; 25-hydroxyvitamin D (25(OH)D) 51.1 ± 14.2 nmol/L. At 6 months, mean 25(OH)D reached 127.6 ± 26.3 nmol/L and 51.8 ± 16.5 nmol/L in the treatment and placebo groups, respectively (P < 0.001). A beneficial effect of vitamin D3 compared with placebo was observed on M-value (mean change (95% CI): 0.92 (0.24–1.59) vs −0.03 (−0.73 to 0.67); P = 0.009) and disposition index (mean change (95% CI): 267.0 (−343.4 to 877.4) vs −55.5 (−696.3 to 585.3); P = 0.039) after 6 months. No effect was seen on other outcomes.

Conclusions

In individuals at high risk of diabetes or with newly diagnosed type 2 diabetes, vitamin D supplementation for 6 months significantly increased peripheral insulin sensitivity and β-cell function, suggesting that it may slow metabolic deterioration in this population.

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E. Gerhards and M. Rühl

ABSTRACT

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.

Free access

Thomas G K Breuer, Laura Borker, Daniel R Quast, Andrea Tannapfel, Wolfgang E Schmidt, Waldemar Uhl and Juris J Meier

Introduction

Gastrin has been shown to promote beta-cell proliferation in rodents, but its effects in adult humans are largely unclear. Proton pump inhibitors (PPIs) lead to endogenous hypergastrinaemia, and improved glucose control during PPI therapy has been reported in patients with diabetes. Therefore, we addressed whether PPI treatment is associated with improved glucose homoeostasis, islet cell hyperplasia or increased new beta-cell formation in humans.

Patients and methods

Pancreatic tissue specimens from 60 patients with and 33 patients without previous PPI therapy were examined. The group was subdivided into patients without diabetes (n = 27), pre-diabetic patients (n = 31) and patients with diabetes (n = 35).

Results

Fasting glucose and HbA1c levels were not different between patients with and without PPI therapy (P = 0.34 and P = 0.30 respectively). Beta-cell area was higher in patients without diabetes than in patients with pre-diabetes or diabetes (1.33 ± 0.12%, 1.05 ± 0.09% and 0.66 ± 0.07% respectively; P < 0.0001). There was no difference in beta-cell area between patients with and without PPI treatment (1.05 ± 0.08% vs 0.87 ± 0.08%, respectively; P = 0.16). Beta-cell replication was rare and not different between patients with and without PPI therapy (P = 0.20). PPI treatment was not associated with increased duct-cell replication (P = 0.18), insulin expression in ducts (P = 0.28) or beta-cell size (P = 0.63).

Conclusions

These results suggest that in adult humans, chronic PPI treatment does not enhance beta-cell mass or beta-cell function to a relevant extent.

Free access

I Rietveld, A Hofman, H A P Pols, C M van Duijn, S W J Lamberts and J A M J L Janssen

Objective: Microalbuminuria (MA) is related to cardiovascular disease both in diabetic patients and non-diabetic subjects.

Design: We investigated whether a polymorphism near the promoter region of the IGF-I gene was related to the development of MA.

Methods: For this study, 1069 participants of the Rotterdam study were selected (440 participants with an abnormal glucose tolerance (AGT), 220 participants with type 2 diabetes and 254 subjects with pre-diabetes, and 595 subjects with a normal glucose tolerance (NGT).

Results: 787 subjects were carriers of the wild type IGF-I genotype (73.6%) and 282 subjects were variant carriers (26.4%) of this IGF-I gene polymorphism. Compared to subjects with NGT the risk for microalbuminuria was higher (Odds Ratio (OR): 3.1 (95% CI: 1.2–7.7); P = 0.02) in variant carriers with AGT than in carriers of the wild type of this IGF-I gene polymorphism (OR: 2.2 (95% CI: 1.2–4.0); P = 0.009). Compared with wild type carriers with AGT, the relative risk for MA was unadjusted and non-significantly increased in variant carriers with AGT (1.6; 95% CI: 0.8–2.9). However, after adjustment for possible confounding factors (age, gender, mean blood pressure, fasting insulin, fasting glucose and smoking) this risk became significant (OR: RR 2.1; 95% CI:1.1–4.4; P = 0.04).

Conclusions: In subjects with AGT, a higher risk for MA was observed in variant carriers than in carriers of the wild type genotype of this IGF-I gene polymorphism. Since MA is primarily associated with cardiovascular disease in subjects with AGT, our study suggests that variant carriers have a higher risk for cardiovascular disease than carriers of the wild type when they develop an AGT.

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

ABSTRACT

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.

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Seiki Ito, Satoko Isemura, Eiichi Saitoh, Kazuo Sanada, Toshimitsu Suzuki and Akira Shibata

Abstract. An immunohistochemical study using antisera against proline rich salivary peptide P-C and insulin, glucagon, somatostatin and pancreatic polypeptide antisera was carried out on the foetal pancreas at different stages and on the newborn infant's, infant's, child's and adult pancreas to examine the time at which salivary peptide P-C like immunoreactivity appeared in the human pancreas. Salivary peptide P-C like immunoreactive cells first appeared as a few scattered cells in the foetal pancreas after 16 weeks of gestation and gradually increased in numbers during gestation. The cells corresponded only to insulin immunoreactive cells in the foetal, newborn infant's, infant's, child's and adult pancreas. Only some of the insulin immunoreactive cells in the foetal pancreas contained salivary peptide P-C like immunoreactivity while the majority of those in the infant's pancreas and all those in the child's and adult pancreas did so. The findings, together with the fact that the full sequence of salivary peptide P-C is identical to the COOH-terminal 44 amino acid residues of Salivary Protein C, led to the possibility that peptide P-C like immunoreactivity in the human pancreatic B-cells was not a moiety of the precursor of insulin and pro-insulin, but a moiety of Salivary Protein C. It has been suggested that, in saliva, Salivary Protein C aids in maintenance of the calcium concentration. Based on the hypothesis that peptide P-C like immunoreactivity in the human pancreatic B-cells may play some role in insulin release through the maintenance of the calcium concentration, the present finding seems to explain the fact that the mechanism for insulin release in the foetal pancreas is immature in spite of sufficient biosynthesis of insulin.