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Biomedical subjects

C G Ostenson

Publications and source records attributed to C G Ostenson.

At least 19 recordsLinked to original sources
PubMed2001

Different domains in the third intracellular loop of the GLP-1 receptor are responsible for Galpha(s) and Galpha(i)/Galpha(o) activation.

It has previously been shown that the GLP-1 receptor is primarily coupled to the adenylate cyclase pathway via activation of Galpha(s) proteins. Recent studies have shown that the third intracellular loop of the receptor is important in the stimulation of cAMP production. We have studied the effect of three synthetic peptide sequences derived from the third intracellular loop of the GLP-1 receptor on signal transduction in Rin m5F cell membranes. The whole third intracellular loop strongly stimulates both pertussis toxin and cholera toxin-sensitive G proteins, while the N-terminal half exclusively stimulates cholera toxin-sensitive G proteins and the C-terminal half only stimulates pertussis toxin-sensitive G-proteins as demonstrated by measurements of GTPase activity. These data confirm that the principal stimulatory G-protein interaction site resides in the third intracellular loop, but also suggest that the GLP-1 receptor is not only coupled to the Galpha(s) but also to the Galpha(i)/Galpha(o) type of G proteins and that distinct domains within the third intracellular loop are responsible for the activation of the different G-protein subfamilies.

Adenylate Cyclase Toxin↗
PubMed2001

Walking campaign: a model for developing participation in physical activity? Experiences from three campaign periods of the Stockholm Diabetes Prevention Program (SDPP).

The Stockholm Diabetes Prevention Program (SDPP) is implementing a model for community-based intervention of type 2 diabetes in three municipalities, of which one has focused on increasing physical activity among the inhabitants. The purpose was to emphasize the integration of walking into daily routines. The campaign was promoted throughout residential areas, organizations and local media. Leaders for organized walking were recruited as volunteers by advertising in local media. After a short education in leadership, practice, and first aid, the 27 volunteers ran organized walking groups in several residential areas. During three of seven walking campaigns the participants were followed and evaluated. The study showed that those individuals who participated one to three times a week were predominantly married women with a good health and regular physical activity. Nevertheless, more important was that one third of the participants had never been exercising regularly before. Most remarkable was to find the voluntary leaders so easily recruited and their great interest to remain as leaders for walking tours.

Adult↗
PubMed2001

The pathophysiology of type 2 diabetes mellitus: an overview.

Type 2 diabetes mellitus is a heterogeneous disorder characterized by chronic hyperglycaemia. The aetiological heterogeneity is suggested by genetic inheritance and its interplay with environmental factors. Impaired insulin secretion and decreased insulin sensitivity are the main pathophysiological features, responsible for development of hyperglycaemia in type 2 diabetes. However, the genetic basis of these defects has been demonstrated only in small subgroups of patients. Whether impaired secretion or action of insulin is the primary defect in the majority of patients is not known, although it is generally agreed that defective insulin release is a requirement for the disease to develop.

Diabetes Mellitus, Type 2↗
PubMed2001

Acute hyperglycemia increases soluble P-selectin in male patients with mild diabetes mellitus.

The aim of this study was to examine if acute hyperglycemia (an oral glucose tolerance test) activates platelet function, endothelial cells or thrombin generation in diabetic patients and healthy controls. Eleven males with mild type II diabetes mellitus and 11 healthy male volunteers, matched for age and body mass index, were investigated before and after the glucose load. Soluble P-selectin, von Willebrand factor antigen and markers of thrombin generation in plasma were determined by immunoassays, and platelet P-selectin expression (unstimulated and agonist-stimulated) by flow cytometry in whole blood. Acute hyperglycemia elevated plasma soluble P-selectin from 32.5 to 50.9 ng/ml in the diabetic group (P = 0.05) but not in the controls (from 27.3 to 28.8 ng/ml; P = 0.6). Also, soluble P-selectin levels were higher in patients with diabetes than in healthy controls during hyperglycemia, but not in the fasting state. Adenosine diphosphate- and thrombin-induced platelet P-selectin expression was slightly, but significantly, decreased by the glucose load, whereas platelet P-selectin expression in unstimulated samples was not affected. Plasma levels of von Willebrand factor and thrombin generation were similar in patients and controls, and were not altered by hyperglycemia. In conclusion, we found that acute hyperglycemia elevates soluble P-selectin in plasma in males with mild type II diabetes mellitus. Our observation of unaltered plasma levels of the endothelial marker von Willebrand factor is in agreement with platelets being the main source of P-selectin released into plasma following hyperglycemia. Thus, platelets in individuals with type II diabetes may be more susceptible to hyperglycemia than platelets in non-diabetic individuals.

Adenosine Diphosphate↗
PubMed2001

Hyperglycemia contributes to impaired insulin response in GK rat islets.

Insulin secretion and glucose metabolism were compared in pancreatic islets from type 2 diabetic GK rats treated with phlorizin or vehicle. Treatment of control and GK rats with phlorizin for 30 days did not affect body weight, islet glucose utilization, or islet glucose oxidation. In phlorizin-treated GK rats, glucose-induced insulin release was about twofold higher at 11.0 and 16.7 mmol/l glucose compared with vehicle, treated GK rats, whereas phlorizin had no effect on control Wistar rats. However, also in phlorizin-treated GK rats, the amount of insulin released by the islets was significantly less than that from control rats (5.29+/-0.33 vs. 7.50+/-1.31 pmol x min(-1) islet(-1) at 16.7 mmol/l glucose; P<0.001). Islet glucose-6-phosphatase activity was significantly higher in GK rats than in control rats; phlorizin treatment significantly decreased this activity. These findings demonstrate that hyperglycemia per se constitutes an important factor for impaired insulin release in GK rats. Correction of hyperglycemia normalizes islet glucose-6-phosphatase activity, which may be an underlying factor for the partial improvement of glucose-induced insulin release.

Animals↗
PubMed2001

Insulin sensitivity of suppression of endogenous glucose production is the single most important determinant of glucose tolerance.

Hyperglycemia results from an imbalance between endocrine pancreatic function and hepatic and extrahepatic insulin sensitivity. We studied 57 well-matched Swedish men with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or mild diabetes. Oral glucose tolerance and insulin release were assessed during an oral glucose tolerance test (OGTT). Insulin sensitivity and glucose turnover were determined during a two-step euglycemic insulin clamp (infusion 0.25 and 1.0 mU. kg(-1). min(-1)). High-performance liquid chromatography-purified [6-(3)H]glucose was used as a tracer. During low-insulin infusion, the rate of endogenous glucose production (EGP) decreased more in subjects with NGT than in subjects with IGT or diabetes (delta rate of appearance [R(a)] 1.25 +/- 0.10 vs. 0.75 +/- 0.14 vs. 0.58 +/- 0.09 mg. kg(-1). min(-1), P < 0.001). The corresponding rates of glucose infusion during the high-dose insulin infusion (M values) were 8.3 +/- 0.6 vs. 5.4 +/- 0.9 vs. 4.7 +/- 0.4 mg. kg(-1). min(-1) (P < 0.001). A total of 56% of the variation in glucose area under the curve (AUC) during OGTT (glucose AUC) was mainly explained by delta R(a) (increase in multiple R(2) 0.42) but also by delta R(d) (rate of disappearance) (increase in multiple R(2) 0.05), and the early insulin response during OGTT contributed significantly (increase in multiple R(2) 0.07). When M value was included in the model, reflecting extrahepatic insulin sensitivity, it contributed to 20% of the variation in glucose AUC, and together with the incremental insulin response (increase in multiple R(2) 0.21), it explained 45% of the variation. In conclusion, insulin sensitivity of suppression of EGP plays the most important role in the determination of blood glucose response during OGTT.

Diabetes Mellitus↗
PubMed2000

Preoperative feeding does not reverse postoperative insulin resistance in skeletal muscle in the rat.

Metabolic studies on injured and postoperative patients have shown impaired glucose disposal in peripheral tissues after trauma. Using small-bowel resection as a model of surgical trauma, we investigated whether substrate availability could ameliorate the changes in muscle glucose uptake induced by trauma. We also studied the effect of preoperative feeding on postoperative insulin-stimulated insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol (PI) 3-kinase activity in both Wistar rats and genetically non-insulin-dependent diabetic Goto-Kakazaki rats (GK rats). Serum glucose, insulin, plasma epinephrine, lactate, and plasma nonesterified free fatty acids (NEFAs) were measured as indicators of the metabolic state and surgical stress. Insulin-stimulated glucose transport was significantly reduced in fed traumatized Wistar rats compared with fed nontraumatized rats (P < .05). Significant increases in in vivo insulin-stimulated IRS-1-associated PI 3-kinase activity were found in fed traumatized Wistar rats compared with fed nontraumatized Wistar rats and fasted traumatized Wistar rats, as well as fed traumatized GK rats compared with fed nontraumatized GK animals (all P < .017). Serum insulin concentrations were significantly reduced in fed traumatized Wistar and GK rats compared with the respective fed nontraumatized groups (both P < .01). Serum glucose levels were significantly elevated in fed traumatized GK rats compared with fed nontraumatized animals (P < .01). In the present study, preoperative feeding did not prevent a postoperative reduction in insulin-stimulated glucose transport in skeletal muscle. The finding that insulin-stimulated PI 3-kinase activity increased after trauma in both Wistar and GK rats indicates that postoperative insulin resistance is not caused by an impairment in the early steps of the insulin signaling pathway. The postoperative decreases in serum insulin despite high blood glucose suggest that trauma impairs the insulin response to hyperglycemia.

Animals↗
PubMed2000

Supervised physical activity in Sweden: in theory and practice.

The aim of this study was to assess to which extent community-run projects including physical activity could be identified, described and analysed in terms of objectives, organisation, evaluation and financing, as a resource in prevention and treatment of common lifestyle-related medical problems. The Swedish database Spriline was used as a main source of information. Identification of ongoing Swedish activities was followed by a mail questionnaire. In total, 151 projects were eventually identified. A semistructured questionnaire containing about 30 questions was mailed to the individual listed as responsible for the project, with a reminder 2 months later. Only 52 projects were viable; a follow-up of nonresponders showed that no relevant activity program had ever existed or that the person responsible had left. Walking, aerobics and water activities were the dominating types of activity. Most projects addressed both sexes, but eight weight reduction programs were designed for women only. Evaluation ranged from 'measuring attendance' to 'scientific evaluation'. Physical activity programs may not be as systematically organised as the Swedish database suggests and cannot generally be relied upon as support in patient care, unless critically evaluated in advance.

Adolescent↗
PubMed2000

Cigarette smoking, oral moist snuff use and glucose intolerance.

OBJECTIVE: To investigate the association between cigarette smoking and use of oral moist snuff and impaired glucose tolerance and type 2 diabetes. DESIGN: We performed a population-based cross-sectional study of glucose intolerance and tobacco use in Stockholm during 1992-94. The sample consisted of 3128 men, aged 35-56 years, of whom 52% had a family history of diabetes. In an oral glucose tolerance test, we detected 55 men with type 2 diabetes and 172 with impaired glucose tolerance. Information on cigarette smoking and oral moist snuff use was collected by a questionnaire. RESULTS: The odds ratio of type 2 diabetes was increased for smokers of 25+ cigarettes day-1 (odds ratio = 2.6, 95% confidence interval = 1.1-5.9) as well as for moist snuff dippers of 3+ boxes week-1 (odds ratio = 2.7, 95% confidence interval = 1.3-5.5). The odds ratio of relatively high (highest tertile) fasting insulin levels in subjects with impaired glucose tolerance associated with cigarette smoking of 25+ cigarettes day-1 was 1.5 (95% confidence interval = 0.7-3.6). The corresponding estimate of a relatively low (lowest tertile) 2 h insulin response was 2.5 (95% confidence interval = 0.9-7.1). CONCLUSIONS: These results indicate that heavy users of cigarettes or moist snuff have an increased risk of type 2 diabetes. The results could suggest that tobacco use is associated with a low insulin response.

Adult↗
PubMed2000

Direct medical costs for patients with type 2 diabetes in Sweden.

OBJECTIVES: To estimate the total direct medical costs to society for patients with type 2 diabetes in Sweden and to investigate how different factors, for example diabetic late complications, affect costs. DESIGN: Cross-sectional data regarding health care utilization, clinical characteristics and quality of life, were collected at a single time-point. Data on resource use cover the 6-month period prior to this time point. SETTING: Patient recruitment and data collection were performed in nine primary care centres in three main regions in Sweden. SUBJECTS: Only patients with an age at diabetes diagnosis >/= 30 years (type 2 diabetes) were included (n = 777). RESULTS: The total annual direct medical costs for the Swedish diabetes type 2 population were estimated at about 7 billion SEK (Swedish Kronor) in 1998 prices, which is about 6% of the total health care expenditures and more than four times higher than the former Swedish estimate obtained when using diabetes as main diagnosis for calculating costs. The annual per patient cost was about 25 000 SEK. The largest share of this cost was hospital inpatient care. Costs increased with diabetes duration and were higher for patients treated with insulin compared to those treated with oral hypoglycaemic drugs or with life style modification only. Patients with both macro- and microvascular complications had more than three times higher costs compared with patients without such complications. CONCLUSIONS: Type 2 diabetes is a serious and expensive disease and the key to reducing costs seems to be intensive management and control in order to prevent and delay the associated late complications.

Adult↗
PubMed2000

Augmented expression of daintain/allograft inflammatory factor-1 is associated with clinical disease: dynamics of daintain/allograft inflammatory factor-1 expression in spleen, peripheral nerves and sera during experimental autoimmune neuritis.

Experimental autoimmune neuritis (EAN) is an animal model of Guillain-Barré syndrome, characterized by inflammation and demyelination of the peripheral nervous system (PNS). Daintain/allograft inflammatory factor-1 (daintain/AIF-1) is a novel interferon-gamma-inducible protein expressed by macrophages during organ specific autoimmune diseases. To study the involvement of daintain/AIF-1 in EAN we induced EAN in Lewis rats by immunizing with bovine PNS myelin (BPM) and complete Freund's adjuvant (CFA). The expression of daintain/AIF-1 was examined in the spleen, peripheral nerves and sera during the course of EAN by immunohistochemistry and radioimunoassay (RIA). The expression of daintain/AIF-1 in the spleen and in the sciatic nerves peaked at the preclinical stage (day 7 post immunization (p.i.)) and at the height (day 15 p.i.) of clinical EAN, consistent with a disease promoting role for daintain/AIF-1. Daintain/AIF-1 expressing cells represented a subset of ED1+ or CD11b/c+ mononuclear cells. A significant increase of daintain/AIF-1-like immunoreactivity in sera occurred at the preclinical stage of EAN. Taken together, these data indicate that daintain/AIF-1 may play a proinflammatory role in the pathogenesis of EAN.

Animals↗
PubMed2000

Alcohol consumption, Type 2 diabetes mellitus and impaired glucose tolerance in middle-aged Swedish men.

AIMS: To investigate the association between alcohol consumption and impaired glucose tolerance and Type 2 diabetes mellitus. METHODS: A population-based cross-sectional study consisting of 3,128 Swedish men, aged 35-56 years. Oral glucose tolerance testing identified 55 cases of Type 2 diabetes and 172 cases of impaired glucose tolerance. Information on alcohol consumption, family history of diabetes, smoking and physical activity was obtained by questionnaire. RESULTS: After adjustment for family history, smoking, physical activity and body mass index, the odds ratio of diabetes was 2.1 (95% confidence interval (CI) 1.0-4.5) in men with high consumption of alcohol (corresponding to over 12 drinks per week) and 0.7 (0.3-1.8) in moderate consumers (7-12 drinks), compared to occasional drinkers. For impaired glucose tolerance, the corresponding odds ratios were 0.7 (0.5-1.1) and 0.6 (0.4-1.0), respectively. Separate analyses for type of beverage indicated that high consumers of beer, spirits and wine had an odds ratio for diabetes of 2.9 (1.2-6.9), 3.3 (1.4-7.8) and 1.2 (0.5-2.7), respectively. CONCLUSIONS: The results indicated that high consumption of alcohol increases the occurrence of Type 2 diabetes and that this may primarily concern consumption of beer and spirits. For impaired glucose tolerance, regular alcohol consumption was associated with a reduced prevalence, particularly at moderate levels.

Adult↗
PubMed2000

Islet amyloid polypeptide regulates multiple steps in stimulus-secretion coupling of beta cells in rat pancreatic islets.

Islet amyloid polypeptide (IAPP) is produced in pancreatic beta cells. Intraislet function of IAPP is still uncertain. In the present study, we investigated effects of IAPP and somatostatin on stimulus-secretion coupling of beta cells in isolated rat pancreatic islets. Insulin secretion induced by 22.2 mM glucose was increased by an IAPP antiserum (0.1%) or an IAPP antagonist (IAPP8-37, 10 microM). Pretreatment of islets with pertussis toxin (PTX) abolished the stimulating effect of IAPP8-37 on glucose-induced insulin secretion. In contrast, IAPP antiserum and IAPP8-37 did not change insulin secretion induced by 30 mM KCl. Somatostatin (1 nM) inhibited insulin secretion induced by 22.2 mM glucose, 10 mM L-arginine, 25 microM forskolin, and 200 microM carbachol. IAPP (10 microM) enhanced the inhibitory effect of somatostatin on insulin secretion induced by L-arginine or forskolin. PTX pretreatment abolished the effects of somatostatin and IAPP on arginine-induced insulin secretion. In conclusion, IAPP regulates multiple steps in signal transductions of beta cells. The effects of IAPP on beta cells are mediated by PTX-sensitive regulatory G proteins.

Amyloid↗
PubMed2000

Peptidergic regulation of maturation of the stimulus-secretion coupling in fetal islet beta cells.

The stimulus-secretion coupling of the insulin-producing pancreatic islet beta cell is subject to functional maturation during fetal life. We studied the maturation of a glucose-responsive insulin release from fetal rat islets and specifically investigated the impact of peptidergic regulation. To this end, islets were isolated from 21-day-old fetal rats and maintained for 7 days in tissue culture at 3.3 or 11.1 mM glucose and various supplements. In islets cultured in low glucose, acutely raising the ambient glucose concentration to 16.7 mM evoked a modest stimulation of short-term insulin release that was more pronounced in islets maintained in high glucose. Moreover, the insulin content was much higher in islets cultured in high than in low glucose. Culture with growth hormone (GH) markedly amplified both basal and stimulated short-term insulin secretion from islets maintained in either low or high glucose. Additionally, GH significantly elevated the insulin content in islets maintained in low glucose. Transforming growth factor alpha (TGF-alpha) increased basal, but not glucose-stimulated, insulin release and insulin content in islets cultured in low glucose. Gastrin, expressed in islets during fetal life, did not affect basal or glucose-stimulated insulin release, or insulin content, in islets maintained in either low or high glucose. The addition of gastrin to TGF-alpha did not affect the results obtained with the latter peptide. Gastrin-releasing peptide failed to influence basal or glucose-responsive insulin secretory rates, and insulin content, at either glucose concentration during culture. The somatostatin analog Sandostatin (octreotide acetate) neither influenced basal nor stimulated short-term insulin release at any glucose concentration present during culture, whereas the hormone significantly decreased the insulin content of islets cultured in high glucose. Pancreastatin, produced by porcine islet beta and delta cells, failed to influence basal or glucose-responsive insulin secretory rates, and islet insulin content, at either glucose concentration during culture. Culture with gastric inhibitory peptide (GIP) or glucagon-like peptide I (GLP-1), two proposed incretins, did not affect short-term insulin secretion in response to 3.3 or 16.7 mM glucose irrespective of the ambient glucose concentration during culture. To the contrary, GLP-1, but not GIP, increased the content of insulin in islets cultured in low glucose. We conclude that islet beta-cell differentiation and functional maturation of the stimulus-secretion coupling can be modulated in vitro in fetal rat pancreatic tissue by peptidergic regulation and glycemic stimulation. We suggest that GH and TGF-alpha stimulate, while somatostatin, through paracrine interaction, may inhibit, these processes. These effectors may be of regulatory significance in the in vivo development of glucose-sensitive beta cells, and defects in these mechanisms may result in glucose intolerance in adult subjects.

Animals↗
PubMed2000

Age-induced changes in pancreatic islet blood flow: evidence for an impaired regulation in diabetic GK rats.

The present study aimed to compare longitudinal variations in islet blood perfusion in rats with different degrees of impairment of glucose metabolism. For this purpose, mildly diabetic Goto-Kakizaki (GK) rats, glucose intolerant F(1) hybrids of GK and Wistar (W) rats (H), and control W rats were examined at 5 wk, 12 wk, or 1 yr of age, using the microsphere technique for blood flow measurements. W rats showed progressively increasing islet blood flow (IBF) throughout the experiment. Both GK and H rats demonstrated increasing IBF between 5 and 12 wk. However, H rats showed no further increment in IBF at 1 yr, whereas GK rats displayed a pronounced decrease in IBF between 12 wk and 1 yr of age. The augmented IBF seen in older W rats may constitute an adaptation to the increasing demand for insulin secretion in aging rats. The inability to adapt to the increased demand for insulin secretion by upregulation of islet blood flow could contribute to the progressive deterioration of glucose metabolism seen in the aging GK rat.

Aging↗
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↗