Abstract. To investigate effects by i-glutamine on pancreatic A-cell secretion and intermediary metabolism, isolated pancreatic islets from normal and streptozotocin treated guinea pigs (A-cell rich islets) were incubated in the presence of glucose (5.5 mm) ± l-glutamine (10 mm). Glutamine significantly enhanced glucagon release from 297 ± 54 to 528 ± 53 pg/μg DNA/h in normal islets and from 553 ±31 to 806 ± 50 pg/μg DNA/h in A-cell rich islets. All results were expressed on the basis of islet DNA concentration, being 66 ± 4 ng DNA per normal islet and 32 ± 2 ng DNA per A-cell rich islet. Simultaneously, glutamine suppressed glucose oxidation to 64 per cent in normal islets and to 47 per cent of basal oxidation in A-cell rich islets. Islet content of ATP was also reduced by glutamine to about 60 per cent in A-cell rich islets, but not significantly changed in normal islets. Glutamine oxidation, at 5.5 mm-glucose, was considerably higher in A-cell rich islets (911 ±65 pmol/μg DNA/h) than in normal islets (313 ± 52 pmol/μg DNA/h). Addition of porcine insulin (25 mU/ml) counteracted these effects by glutamine, i.e. suppressed glucagon release but increased glucose oxidation and ATP content of the A-cell rich islets. The present findings demonstrate that glutamine stimulates glucagon release and is readily metabolized by the A-cells, Furthermore, the regulation of glucagon secretion by glutamine appears to be reciprocally related to factors affecting glucose metabolism and ATP-levels in the A-cell.
Claes-Göran Östenson and Carin Grebing
Katarina Drakenberg, Claes-Göran Östenson and Vicki Sara
A variant of IGF-I with a truncated aminoterminal region has been isolated and shown to display increased biological activity in vitro, but weak affinity of binding to the IGF binding proteins compared with intact IGF-I. In the present study, the circulating molecular forms and biological activity of intact and truncated IGF-I were compared after in vivo administration. Adult and 10-day-old rats were given 125I-truncated or 125I-intact IGF-I iv. In both adult and 10-day-old rats 125I-truncated IGF-I showed weaker affinity of binding to the IGF binding proteins and greater degradation than 125I-intact IGF-I. Serum half-life was 2 h for 125I-truncated IGF-I and 3 h for 125I-intact IGF-I in adult rats. The half-life in 10-day-old rats was 20.5 min for 125I-truncated IGF-I and 27 min for 125I-intact IGF-I. The uptake of 125I-truncated IGF-I into the kidney, liver and brain of 10-day-old rats was significantly higher than for 125I-intact IGF-I 15 min after iv administration. The insulin-like effects of the IGF-I peptides were examined in vitro and in vivo. Truncated IGF-I stimulated [3-3H]glucose incorporation into free fatty acids in adipocytes in vitro to a greater extent than did intact IGF-I. In vivo administration of both intact and truncated IGF-I to adult rats significantly decreased serum glucose levels and significantly increased the incorporation of [U-14C]glucose into glycogen. Thus, the present results demonstrated that truncated IGF-I displays reduced binding to the IGF binding proteins in vivo compared with intact IGF-I.
Ewa-Carin Långberg, Harvest F Gu, Sofia Nordman, Suad Efendic and Claes-Göran Östenson
Objective: Previously, it has been demonstrated that receptor protein tyrosine phosphatase σ (RPTPσ) is involved in glucose homeostasis and insulin signaling in several animal models. The aim of this study was to evaluate whether polymorphisms in this gene influence the development of type 2 diabetes (T2D) in humans.
Design: We investigated how genetic variations in the RPTPσ gene influence susceptibility to impaired glucose tolerance (IGT) and T2D, in Swedish men and women.
Methods: Genotyping of single nucleotide polymorphisms (SNPs) was performed by dynamic allele-specific hybridization in a total of 1057 Swedish Caucasians including 497 subjects with normal glucose tolerance (NGT), 262 subjects with IGT, and 298 patients with T2D.
Results: SNPs rs1143699, rs4807015, and rs1978237 were found to be associated with T2D. SNP rs1143699 was associated with male T2D patients when compared with NGT controls (odds ratio; OR = 1.57; P = 0.029). SNP rs4807015 showed association with T2D patients when compared with NGT controls (OR = 1.32; P = 0.025). Finally, SNP rs1978237 was associated with T2D patients when compared with NGT controls (OR = 1.59; P = 0.002). Logistic regression analysis demonstrated that for SNP rs1143699 in men, C/C homozygosity conveys an increased risk of T2D (OR = 2.19; P = 0.035), while SNP rs4807015 was associated with an increased risk of T2D in both men and women (OR = 1.74; P = 0.029). SNP rs1978237 also demonstrated a risk of T2D in men and women (OR = 1.59; P = 0.026).
Conclusions: This study provides evidence for association of SNPs in the RPTPσ gene with T2D in Swedish Caucasians. SNPs rs1143699, rs4807015, and rs1978237 confer an increased risk of developing T2D.
Claes-Göran Östenson, Bo Ahrén, Sven Karlsson, Jens Knudsen and Suad Efendic
Östenson C-G, Ahrén B, Karlsson S, Knudsen J, Efendic S. Inhibition by rat diazepam-binding inhibitor/ acyl-CoA-binding protein of glucose-induced insulin secretion in the rat. Eur J Endocrinol 1994;131:201–4. ISSN 0804–4643
Diazepam-binding inhibitor (DBI) has been localized immunohistochemically in many organs. In porcine and rat pancreas, DBI is present in non-B-cells of the pancreatic islets. Porcine peptide also has been shown to suppress insulin secretion from rat pancreas in vitro. Recently, acyl-CoA-binding protein (ACBP) was isolated from rat liver and shown to be identical structurally to DBI isolated from rat brain. Using this rat DBI/ACBP, we have studied its effects on glucose-stimulated insulin secretion in the rat, both in vivo and in isolated pancreatic islets. Infusion iv of rDBI/ACBP (25 pmol/min) during glucose stimulation induced a moderate and transient reduction of plasma insulin levels. Moreover, rDBI/ACBP suppressed insulin release from batch-incubated isolated islets, stimulated by 16.7 mmol/l glucose, by 24% at 10 nmol/l (p < 0.05) and by 40% at 100 nmol/l (p < 0.01). The peptide (100 nmol/l) also inhibited the insulin response to glucose (16.7 mmol/l) from perifused rat islets by 31% (p < 0.05), mainly by affecting the acute-phase response. Finally, incubation of isolated islets in the presence of rDBI/ACBP antiserum (diluted 1:100 and 1:300) augmented the insulin response to 16.7 mmol/l glucose (p < 0.05 or even less). We conclude that rDBI/ACBP, administered iv or added to the incubation media, suppresses insulin secretion in the rat but that the effect is moderate despite the high concentration used. It is therefore unlikely that the peptide modulates islet hormone release, acting as a classical hormone via the circulation. However, the occurrence of DBI/ACBP in the islets and the enhancing effect by the rDBI/ACBP antibodies on glucose-stimulated insulin release suggest that the peptide is a local modulator of insulin secretion.
C-G Östenson, Department of Endocrinology, Karolinska Hospital, S-171 76 Stockholm, Sweden
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
Moira S Lewitt, Agneta Hilding, Kerstin Brismar, Suad Efendic, Claes-Göran Östenson and Kerstin Hall
Low levels of IGF-binding protein 1 (IGFBP1) are associated with metabolic syndrome and predict diabetes development in men. The aim of this study was to determine the levels of IGFBP1 in women who later develop diabetes, in relation to abdominal obesity, and to compare these levels with those of men.
IGFBP1 levels were determined at baseline and after 8 years in a case–control, prospective study of Swedish women aged 35–56 years. Individuals with normal oral glucose tolerance test (OGTT) who developed abnormal glucose regulation (n=240) were pair matched to controls for age and family history of diabetes and also compared to men of the same age (n=355).
Low fasting IGFBP1 and increased waist measurement predicted development of diabetes in women (n=60; odds ratio (OR) 70, 95% confidence interval (CI) 8–661, lowest tertile and OR 27, 95% CI 5–141, highest tertile). In women developing diabetes, baseline IGFBP1 levels were lower than expected for fasting insulin values, were associated with impaired suppression after OGTT and increased during 8 years despite an increase in fasting insulin. All individuals in the highest tertile for waist and with ≤40% suppression of IGFBP1 developed diabetes within 8 years. Circulating IGFBP1 concentrations were higher in women compared to men. Women and men who developed diabetes had a similar degree of abdominal obesity, corrected for height.
We conclude that low IGFBP1 and elevated waist measurement predict diabetes development and that IGFBP1 production is suppressed by a novel factor(s) in women developing diabetes. Increasing levels of IGFBP1 during the emergence of diabetes in men and women suggest the emergence of hepatic insulin resistance.