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C G Ostenson

Publications and source records attributed to C G Ostenson.

At least 37 records · Page 2Linked to original sources
PubMed2000

Regulation of in vitro maturation of stimulus-secretion coupling in fetal rat islet beta-cells.

We have studied the maturation of a glucose-responsive insulin release from fetal rat islets, and specifically investigated the impact of nutrients, alpha-adrenoceptors, imidazoline receptors, and cyclic adenosine monophosphate (cAMP). Islets were isolated from 21 -d-old fetal rats and maintained for 7 d in tissue culture at 3.3 or 11.1 mM glucose and various supplements. Culture in the presence of the nonglucidic nutrient alpha-ketoisocaproic acid (KIC), markedly enhanced both basal and stimulated insulin release from islets cultured at either low or high glucose. Additionally, KIC significantly elevated the insulin content of islets maintained in low glucose, whereas it slightly lowered it in islets cultured at high glucose. Culture with phentolamine, an antagonist of alpha-adrenergic and imidazoline receptors, markedly amplified both basal and glucose-stimulated insulin secretion when added with islets cultured in either low or high glucose. By contrast, the pure alpha2-adrenoceptor antagonist benextramine had no such effects. Addition to culture media of a membrane-permeant agonist (Sp-cAMP[S]) or antagonist (Rp-cAMP[S]) of cAMP-dependent protein kinases types I and II failed to influence basal or glucose-responsive insulin secretory rates at either glucose concentration during culture as well as islet insulin content. In conclusion, islet beta-cell differentiation and functional maturation of the stimulus-secretion coupling can be accelerated in vitro in fetal rat pancreatic tissue by nutrient stimulation, and by interference with imidazoline receptors, whereas cAMP seems virtually ineffective in this respect. These effectors may be of regulatory significance in the in vivo development of glucose-sensitive beta-cells.

Adrenergic alpha-Antagonists↗
PubMed1999

Effects of vasopressin-mastoparan chimeric peptides on insulin release and G-protein activity.

Two chimeric peptides, consisting of the linear vasopressin receptor V1 antagonist PhAc-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr, in the N-terminus and mastoparan in the C-terminus connected directly (M375) or via 6-aminohexanoic acid (M391), have been synthesised. At 10 microM concentration, these novel peptides increased insulin secretion from isolated rat pancreatic islet cells 18-26-fold at 3.3 mM glucose and 3.5-5-fold at 16.7 mM glucose. PTX pretreatment of the islets decreased the peptide-induced insulin release. M375 and M391 bind to V1a vasopressin receptors with affinities lower than the unmodified vasopressin antagonist, but with K(D) values of 3.76 nM and 9.02 nM, respectively, both chimeras are high affinity ligands. The GTPase activity and GTPgammaS binding in the presence of these peptides has been characterised in Rin m5F cells. Comparison of the influence of the peptides M375 and M391 on GTPase activity in native and pertussis toxin-treated cells suggests a selective activation of G alpha(i)/G alpha(o) subunits, combined with a suppression of other GTPases, primarily G alpha(s). However, the GTPgammaS binding data show that the peptides retain some of the activating property even in PTX-treated cell membranes. In conclusion, the conjugation of mastoparan with the V1a receptor antagonists produce peptides with properties different from the parent peptides that could be used to elucidate the role of different G proteins in insulin release.

Animals↗
PubMed1999

Different modes of action of the imidazoline compound RX871024 in pancreatic beta-cells. Blocking of K+ channels, mobilization of Ca2+ from endoplasmic reticulum, and interaction with exocytotic machinery.

The imidazoline compound RX871024 glucose-dependently potentiates the release of insulin in pancreatic islets and beta-cell lines. This activity of the compound is not related to its action by stimulating alpha 2-adrenoceptors and I1- and I2-imidazoline receptors. There are at least three modes of action of RX871024 in beta-cells: (1) RX871024 blocks the ATP-dependent, Ca(2+)-activated, and delayed rectifier K+ channel activity; (2) RX871024 causes mobilization of Ca2+ from thapsigargin-sensitive intracellular stores, the effect probably controlled by cytochrome P450; and (3) the stimulatory activity of RX871024 on insulin release involves interaction of the compound with the exocytotic machinery, unrelated to the changes in membrane potential and cytoplasmic-free Ca2+ concentration, whereas protein phosphorylation plays an important role in this process. The maximal insulinotropic effect of RX871024 is much higher than that of the sulfonylurea glibenclamide. RX871024 stimulates insulin release and normalizes blood glucose levels in rats in vivo without affecting blood pressure and heart rate.

Animals↗
PubMed1999

[Gastrointestinal peptides among new therapeutic agents used in type 2 diabetes].

The pharmacological arsenal available today for the treatment of type II diabetes is often insufficient to allow optimal control of the disease. Each agent corrects only one or a few of the multiple defects that characterise type II diabetes. Currently, new drugs are under development that target several of the clinical abnormalities. These agents include the gastrointestinal peptides, glucagon-like polypeptide-1 (GLP-1) and amylin, and their analogues. New rapid- and long-acting insulin analogues will also constitute interesting treatment alternatives.

Diabetes Mellitus, Type 2↗
PubMed1999

Dysfunction of the islet lysosomal system conveys impairment of glucose-induced insulin release in the diabetic GK rat.

Accumulated evidence links an important signal involved in glucose-stimulated insulin release to the activation of the islet lysosomal glycogenolytic enzyme acid glucan-1,4-alpha-glucosidase. We have analyzed the function of the lysosomal system/lysosomal enzyme activities in pancreatic islets of young (6-8 weeks), spontaneously diabetic, GK (Goto-Kakizaki) rats and Wistar control rats in relation to glucose-induced insulin release. The insulin secretory response to glucose was markedly impaired in the GK rat, but was restored by the adenylate cyclase activator forskolin. Islet activities of classical lysosomal enzymes, e.g.. acid phosphatase, N-acetyl-beta-D-glucosaminidase, beta-glucuronidase, and cathepsin D, were reduced by 20-35% in the GK rat compared with those in Wistar controls. In contrast, the activities of the lysosomal alpha-glucosidehydrolases, i.e.. acid glucan-1,4-alpha-glucosidase and acid alpha-glucosidase, were increased by 40-50%. Neutral alpha-glucosidase (endoplasmic reticulum) was unaffected. Comparative analysis of liver tissue showed that lysosomal enzyme activities were of the same magnitude in GK and Wistar rats. Notably, in Wistar rats, the activities of acid glucan-1,4-alpha-glucosidase and acid alpha-glucosidase were approximately 15-fold higher in islets than in liver. Other lysosomal enzymes did not display such a difference. Normalization of glycemia in GK rats by phlorizin administered for 9 days did not influence either the lysosomal alpha-glucosidehydrolase activities or other lysosomal enzyme activities in GK islets. Finally, the pseudotetrasaccharide acarbose, which accumulates in the lysosomal system, inhibited acid glucan-1,4-alpha-glucosidase activity in parallel with its inhibitory action on glucose-induced insulin release in intact Wistar islets, whereas no effect was recorded for either parameter in intact GK islets. In contrast, acarbose inhibited the enzyme activity equally in islet homogenates from both GK and Wistar rats, showing that the catalytic activity of the enzyme itself in disrupted cells was unaffected. We propose that dysfunction of the islet lysosomal/vacuolar system is an important defect impairing the transduction mechanisms for glucose-induced insulin release in the GK rat.

Acarbose↗
PubMed1999

Deficiency of phosphofructo-1-kinase/muscle subtype in humans is associated with impairment of insulin secretory oscillations.

In healthy humans, insulin is secreted in an oscillatory manner. While the underlying mechanisms generating these oscillations are not fully established, increasing evidence suggests a central role for phosphofructo-1-kinase/muscle subtype (PFK1-M), which also serves as the predominantly active PFK1 subtype in the pancreatic beta-cell. The fact that normal oscillatory secretion is impaired in subjects with impaired glucose tolerance and healthy relatives of patients with type 2 diabetes suggests that this defect may be involved in the secretory dysfunction. To evaluate a possible link between inherited PFK1-M deficiency in humans (Tarui's disease or glycogenosis type VII) and altered insulin oscillations, in vivo studies were performed. We determined basal insulin oscillations during 2 h of frequent plasma sampling in two related teen-aged individuals with homozygous and heterozygous PFK1-M deficiency compared with nondeficient, unrelated control subjects. As predicted by the underlying hypothesis, normal oscillations in insulin secretion were completely abolished in the individual with homozygous deficiency of PFK1-M and significantly impaired in the heterozygous individual, as shown by spectral density and autocorrelation analyses. Thus, deficiency of PFK1-M subtype in humans appears to be associated with an impaired oscillatory insulin secretion pattern and may contribute to the commonly observed secretion defects occurring in type 2 diabetes.

Adult↗
PubMed1999

Low birth weight, family history of diabetes, and glucose intolerance in Swedish middle-aged men.

OBJECTIVE: To investigate the association between low birth weight and glucose intolerance in relation to family history of diabetes. RESEARCH DESIGN AND METHODS: We conducted a population-based cross-sectional study of 2,237 men born in 1938-1957 in four municipalities in the outskirts of Stockholm, 50% of whom had a family history of diabetes (at least one first-degree or two second-degree relatives with diabetes). Oral glucose tolerance testing detected 35 cases of type 2 diabetes, 102 cases of impaired glucose tolerance, and 57 cases of impaired fasting glucose. RESULTS: In subjects without a family history of diabetes, low (< or = 3,000 g) birth weight was associated with an odds ratio of 2.3 (95% confidence intervals = 0.4-14.4) for diabetes, 1.8 (0.7-4.3) for impaired glucose tolerance, and 3.3 (1.0-10.4) for impaired fasting glucose. In subjects with a family history of diabetes, the corresponding figures were approximately similar, except for diabetes, for which the odds ratio was 5.4 (2.0-14.9). For men with low birth weight in combination with a family history of diabetes, the odds ratio was 10.9 (2.9-41.2) for diabetes, 2.4 (1.1-5.6) for impaired glucose tolerance, and 5.9 (2.1-16.3) for impaired fasting glucose. CONCLUSIONS: This study indicated that low birth weight is associated with type 2 diabetes, impaired glucose tolerance, and impaired fasting glucose in men. This finding was most pronounced in subjects with diabetes in the family, but it was also indicated in those without a family history of diabetes. Men with the combination of low birth weight and family history of diabetes seem to be at particularly high risk of developing type 2 diabetes.

Adult↗
PubMed1998

An endogenous peptide isolated from the gut, NK-lysin, stimulates insulin secretion without changes in cytosolic free Ca2+ concentration.

We have recently isolated and cloned a novel endogenous peptide from pig intestine, NK-lysin (NKL). In the present study we show that NKL (1-100 nM) potently and reversibly stimulates insulin secretion in rat pancreatic islets and in the beta-cell line HIT T15. This effect of NKL was not accompanied by changes in cytoplasmic free calcium concentration. The stimulatory activity of NKL on insulin release was also observed in permeabilized islets under Ca2+-clamped conditions. Preincubation of HIT T15 cells with NKL for 1 h or 24 h did not influence cell viability. Possible mechanisms of insulinotropic activity of NKL are discussed.

Animals↗
PubMed1998

Weight history, glucose intolerance, and insulin levels in middle-aged Swedish men.

The association between weight history and glucose intolerance was examined in a cross-sectional study consisting of 3,128 Swedish men aged 35-56 years, 52 percent of whom had a family background of diabetes mellitus. Oral glucose tolerance testing detected 55 cases of type 2 (non-insulin-dependent) diabetes and 172 cases of impaired glucose tolerance. Among men with no family history of diabetes, the estimated odds ratios for impaired glucose tolerance associated with short (<5 years) and long (> or =10 years) durations of obesity (body mass index (weight (kg)/height2 (m2) > or =25.0) were 1.3 (95% confidence interval (CI) 0.2-7.7) and 11.8 (95% CI 3.3-41.9), respectively. Among men with a family history of diabetes, the odds ratios were 2.0 (95% CI 0.8-4.7) and 4.0 (95% CI 1.8-9.1), respectively. Corresponding estimates of the odds of type 2 diabetes, adjusted for family history of diabetes, were 1.9 (95% CI 0.5-7.1) and 7.3 (95% CI 2.2-23.7), respectively. The odds of high (> or =30.0 mU/liter) fasting insulin levels in subjects with impaired glucose tolerance were 6.9 (95% CI 0.6-74.2) and 21.0 (95% CI 2.1-206.4) for short and long durations of obesity, respectively. Corresponding estimated odds of low 2-hour insulin response (< or =71.9 mU/liter) were 0.7 (95% CI 0.2-2.9) and 3.3 (95% CI 1.2-8.9). Homeostasis model assessment of insulin resistance yielded an odds ratio of 6.7 (95% CI 0.6-73.4) for a short duration of obesity and 20.0 (95% CI 2.0-200.6) for a long duration. Examination of beta-cell function with homeostasis model assessment resulted in odds ratios of 0.2 (95% CI 0.0-1.6) and 2.0 (95% CI 0.7-5.4) for short and long durations of obesity, respectively. These data indicate that obesity decreases glucose tolerance by way of progressively increased insulin resistance and, in the case of prolonged duration, by decreased insulin secretion as well.

Body Mass Index↗
PubMed1998

Increased glucocorticoid sensitivity in islet beta-cells: effects on glucose 6-phosphatase, glucose cycling and insulin release.

Glucose-6-phosphatase (G6Pase) activity and the rate of glucose cycling are increased in islets from animal models of Type II (non-insulin-dependent) diabetes mellitus. Glucocorticoid treatment further stimulates these processes and inhibits glucose-induced insulin release. To determine whether these effects result from a direct action of glucocorticoids on the beta-cells, we used isolated islets. The islets were from transgenic mice overexpressing the glucocorticoid receptor in their beta-cells to increase the cells' sensitivity to glucocorticoid. Islets from transgenic and non-transgenic control mice utilized and oxidized the same amount of glucose. In contrast, islet G6Pase activity was 70 % higher, glucose cycling was increased threefold and insulin release was 30 % lower in islets from transgenic mice. Hepatic G6Pase activity was the same in transgenic and control mice. Dexamethasone administration increased G6Pase activity and glucose cycling and decreased insulin release in both transgenic and control mouse islets. We conclude that glucocorticoids stimulate islet G6Pase activity and glucose cycling by acting directly on the beta-cell. That activity may be linked to the inhibition of insulin release.

Animals↗
PubMed1998

Preserved initiatory and potentiatory effect of alpha-ketoisocaproate on insulin release in islets of glucose intolerant rats.

Insulin responses to glucose and non-glucose secretagogues were studied in short-term cultured pancreatic islets and perfused pancreata of the glucose intolerant F1 hybrid rats of spontaneously diabetic Goto-Kakizaki and control Wistar rats. After culture at 5.5 mmol/l glucose, hybrid islet responses to 11.1, 16.7 and 27.0 mmol/l glucose were between 60 and 40% of control islet responses. A combination of 1 mmol/l isobutylmethylxanthine and 16.7 mmol/l glucose induced a pronounced insulin release, which was of similar magnitude in hybrid and control rat islets. This response was not further augmented by addition of glibenclamide and arginine. The slope of potentiation of arginine (10 mmol/l)-stimulated insulin secretion by glucose (5.5-16.7 mmol/l) was greatly impaired in hybrid islets. In contrast to glucose, alpha-ketoisocaproate (KIC), which is metabolized in Krebs cycle, dose-dependently stimulated insulin secretion to similar levels in hybrid and control islets, cultured at 5.5 mmol/l glucose. Also in hybrid islets depolarized by potassium chloride (30 mmol/l) and with adenosine triphosphate-sensitive K+-channels kept open by diazoxide, insulin responses to glucose were greatly impaired but intact to KIC. Furthermore, KIC potentiated normally the insulin response to arginine in hybrid islets. In the isolated perfused pancreas, KIC induced similar insulin responses in hybrid rats and control rats. The potentiating effect by 5.5 mmol/l glucose on the KIC-stimulated insulin responses was, however, greatly reduced in isolated islets and absent in the perfused pancreata of hybrid rats. Taken together, these findings suggest an intact capacity for insulin release, although the initiating and potentiating effect by glucose on insulin release are defective in the Goto-Kakizaki-hybrid rats. An abnormal beta-cell glucose metabolism proximal to the Krebs cycle is likely to account for the impairment of insulin release.

1-Methyl-3-isobutylxanthine↗
PubMed1998

The glutathione levels are reduced in Goto-Kakizaki rat retina, but are not influenced by aminoguanidine treatment.

PURPOSE: To examine the levels of the free radical protecting enzyme glutathione and the endothelial/pericyte ratio in retinal capillaries in the Goto-Kakizaki (GK) Wistar rat, with and without aminoguanidine treatment. METHODS: Eight-month-old GK rats, with non-obese, spontaneous non-insulin-dependent diabetes mellitus (NIDDM), were examined after a six month period of aminoguanidine treatment. Glutathione levels were measured with high performance liquid chromatography and the endothelial/pericyte ratio was calculated in trypsin digested vessel preparations. RESULTS: The levels of glutathione in GK rat retina were significantly lower compared to controls (p = 0.0108). There was no difference in the endothelial/pericyte ratio compared to matched control rats (1.8 +/- 0.2 vs. 1.8 +/- 0.1, respectively). Aminoguanidine treatment did not influence either the degree of hyperglycemia, the levels of glutathione or the endothelial/pericyte ratio in GK or control rat retina. CONCLUSIONS: The results indicate that impaired glucose metabolism may influence one of the defense mechanisms for oxidative stress, but also suggest that decreased glutathione levels occur prior to morphological signs of pericyte loss and/or endothelial cell proliferation in this animal model of hereditary NIDDM.

Animals↗
PubMed1998

Signaling and sites of interaction for RX-871024 and sulfonylurea in the stimulation of insulin release.

The objective of this study was to compare effects of RX-871024, a compound with imidazoline structure, and the sulfonylurea glibenclamide, representatives of two groups of ATP-dependent potassium channel (KATP) blockers, on insulin secretion and cytoplasmic free calcium concentration ([Ca2+]i). Furthermore, we studied the interaction of the compounds on these two parameters. The experiments were performed in the perfused rat pancreas, isolated rat pancreatic islets, and dispersed beta-cells. At maximal effective concentrations of the compounds, RX-871024 had a more pronounced insulinotropic effect than glibenclamide, but the increase in [Ca2+]i was similar. Glibenclamide enhanced the insulinotropic effect of suboptimal concentrations of RX-871024 at 3.3 and 16.7 mM glucose. Notably, glibenclamide and RX-871024 also stimulated insulin secretion under Ca(2+)-clamped conditions, i.e., during plasma membrane depolarization with KCl and glucose or in permeabilized islets. The magnitudes of insulin stimulation under the latter types of conditions were similar for both compounds. It is concluded that RX-871024 and the sulfonylurea glibenclamide promote insulin secretion by two mechanisms, namely closure of KATP channels and a direct stimulation of exocytosis. At a similar increase in [Ca2+]i, the maximal stimulatory effect of RX-871024 on insulin secretion was stronger than that of glibenclamide, implying that RX-871024 also affects insulin secretion by a signal transduction pathway that is not activated by glibenclamide.

Animals↗
PubMed1998

Food frequency questionnaire versus 7-day weighed dietary record information on dietary fibre and fat intake in middle-aged Swedish men.

To study the magnitude of agreement between a short self-administered food frequency questionnaire and a 7-day weighed dietary record regarding the consumption of fibre and fat, we collected information from 92 randomly selected middle-aged Swedish men. The participants first recorded all foods and drinks consumed over seven consecutive days by means of a digital scale. One month after the 7-day weighed record had been completed, a self-administered food frequency questionnaire on habitual consumption of foods containing fibre or fat during the preceding month was sent to the subjects. The 20 largest contributors of fibre and fat in the diet accounted for 71% and 52% of the total intake, respectively, based on the 7-day weighed record. The estimated mean consumption of fibre was 19.0 grams per day based on the 7-day weighed record and 18.3 grams per day based on the food frequency questionnaire. Corresponding estimated mean consumption of fat was 88.6 grams per day versus 46.9 grams per day. Men with high physical activity and low BMI, respectively, had higher intake of fibre and fat. These differences were seen for both dietary measurement methods but were more marked using the 7-day weighed record. The agreement between methods for each individual was also assessed. Based on five categories of fibre consumption, 61% of the respondents in the highest quintile according to the 7-day weighed record were classified in one of the two highest quintiles according to the food frequency questionnaire. The corresponding figure for fat intake was 56%. We conclude that the short self-administered food frequency questionnaire used in the present study can assess the absolute intake of fibre, but not of fat, with good precision. Also, the ranking of individuals in broad categories of consumption of fibre and fat was not largely misclassified based on this short questionnaire.

Adult↗
PubMed1998

Glucose metabolism in Goto-Kakizaki rat islets.

Islets from Goto-Kakizaki (GK) rats from our colony, despite marked impairment of glucose-induced insulin release, used glucose and produced CO2 at a rate 3 times that of islets from control Wistar rats. Almost all glucose used was accounted for in CO2 and lactate production. The percentages of glucose carbon used collected in CO2 and lactate were similar for control and GK islets. GK islets also oxidized 40% more acetate and leucine to CO2 than did control islets. The fraction of carbon leaving the Krebs cycle relative to CO2 production was the same in GK and control islets. The capacities of mitochondria from GK islets to generate ATP from glutamate and malate were similar and that to generate ATP from succinate and rotenone was somewhat less from GK islets. The reason for the enhanced utilization of substrates by islets of the GK rat is not apparent. In conclusion, there is no decrease in islet glucose utilization, glucose oxidation, Krebs cycle function, or the electron transport system evident from these measurements to explain the impaired insulin release in islets from GK rats.

Acetates↗
PubMed1997

Identification, isolation, and characterization of daintain (allograft inflammatory factor 1), a macrophage polypeptide with effects on insulin secretion and abundantly present in the pancreas of prediabetic BB rats.

A bioactive macrophage factor, the polypeptide daintain/allograft inflammatory factor 1 (AIF1), has been isolated from porcine intestine. It was discovered when searching for intestinal peptides with effects on insulin release, and its purification was monitored by the influence of the peptide fractions on pancreatic glucose-induced insulin secretion. Daintain/AIF1 is a 146-aa residue polypeptide with a mass of 16,603 Da and an acetylated N terminus. An internal 44-residue segment with the sequence pattern -KR-KK-GKR- has a motif typical of peptide hormone precursors, i.e., dibasic sites for potential activation cleavages and at the sequentially last such site, the structure GKR. The latter is a signal for C-terminal amide formation in the processing of peptide hormones. Daintain/AIF1 is immunohistochemically localized to microglial cells in the central nervous system and to dendritic cells and macrophages in several organs. A particularly dense accumulation of daintain/AIF1-immunoreactive macrophages was observed in the insulitis affecting the pancreatic islets of prediabetic BB rats. When injected intravenously in mice, daintain/AIF1 at 75 pmol/kg inhibited glucose (1 g/kg)-stimulated insulin secretion, with a concomitant impairment of the glucose elimination, whereas at higher doses (7.5 and 75 nmol/kg), daintain/AIF1 potentiated glucose-stimulated insulin secretion and enhanced the glucose elimination. Its dual influence on insulin secretion in vivo at different peptide concentrations, and the abundance of macrophages expressing daintain/AIF1 in the pancreatic islets of prediabetic rats, suggest that daintain/AIF1 may have a role in connection with the pathogenesis of insulin-dependent diabetes mellitus.

Amino Acid Sequence↗
PubMed1997

Characterization of dopuin, a polypeptide with special residue distributions.

A 62-residue polypeptide, dopuin, has been isolated from pig small intestine. It is distinguished by an N-terminal part with a high content of proline (7 in a 26-residue segment), a C-terminal part with a high proportion of histidine (3 in a 9-residue segment), and six half-cystine residues in three intrachain disulphide bridges (connecting positions 22-25, 23-54 and 35-44). The Cys and Pro distributions suggest a tight and special conformation. In contrast to PEC-60 and somatostatin, it has no established inhibitory effect on insulin secretion. At 10 nM concentration, a weak inhibitory tendency is less than half of that of the other two peptides. Like gastrointestinal trefoil peptides, dopuin has three disulphide bridges, Ala-Pro segments, and many charged residues, but they are differently distributed and dopuin belongs to a separate, apparently novel family. However, dopuin is similar to a peptide corresponding to an expressed-sequence-tag cDNA of human fetal liver and spleen, establishing the nature of the mature form of the product of this cDNA, and showing a general tissue, age, and species distribution of this peptide. A truncated form of vimentin, composed of its C-terminal 37 residues, vimentin-C37, was also purified and structurally characterized. These two peptides increase the complexity of known intestinal polypeptides and at least dopuin has properties compatible with specific biofunctions.

Amino Acid Sequence↗