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Biomedical subjects

J J Meier

Publications and source records attributed to J J Meier.

At least 19 recordsLinked to original sources
PubMed2006

Increased islet beta cell replication adjacent to intrapancreatic gastrinomas in humans.

AIMS/HYPOTHESIS: Type 1 and type 2 diabetes are characterised by a beta cell deficit. Islet hyperplasia has been described in patients with Zollinger-Ellison syndrome secondary to gastrin-producing tumours (gastrinomas), and gastrin therapy has increased beta cell mass in rodents and human islets in vitro. In the present studies we addressed the following questions: (1) In pancreas specimens from gastrinoma cases, is the fractional beta cell area increased? (2) If so, is this restricted to tumour-adjacent islets or also present in tumour-distant islets? (3) Is new beta cell formation (beta cell replication and islet neogenesis) increased and beta cell apoptosis decreased in pancreas specimens from gastrinoma cases? METHODS: Pancreas was obtained at surgery from four patients with Zollinger-Ellison syndrome caused by pancreatic gastrinomas and 15 control subjects at autopsy. RESULTS: Islet fractional beta cell area (p<0.001), islet size (p<0.001) and beta cell replication (Ki67 staining) (p<0.05) were increased in islets adjacent to the tumours, but not in tumour-distant pancreas, compared with control subjects. We did not observe any differences in beta cell apoptosis or in the number of insulin-positive cells in ducts either adjacent to or distant from the tumour. CONCLUSIONS/INTERPRETATION: One or more factors released by human gastrinomas increase beta cell replication in islets immediately adjacent to the tumour, but not in tumour-distant islets. While these findings demonstrate that adult human beta cells can be driven into the cell cycle, they caution against the therapeutic usefulness of gastrin, since islets located >1 cm away from the gastrinomas did not exhibit changes in beta cell turnover, despite markedly elevated systemic gastrin levels sufficient to cause severe gastrointestinal symptoms.

Body Mass Index↗
PubMed2006

Direct evidence of attempted beta cell regeneration in an 89-year-old patient with recent-onset type 1 diabetes.

AIMS/HYPOTHESIS: We investigated whether there was evidence of attempted beta cell regeneration in the pancreas obtained from a patient with recent-onset type 1 diabetes, and if so by what mechanism this occurred. SUBJECTS, MATERIALS AND METHODS: We examined pancreas tissue from a lean 89-year-old patient (BMI 18.0 kg/m(2)) with recent-onset type 1 diabetes who had had a distal pancreatectomy to remove a low-grade pancreatic intraepithelial neoplasia. RESULTS: In the tumour-free tissue, the fractional beta cell area was 0.54+/-0.2% of pancreas area (about one-third of that in non-diabetic humans). CD3-positive T lymphocytes and macrophages had infiltrated the majority of the islets. Subclassification of the T cell population revealed a predominance of CD8-positive cells over CD4-positive cells. Beta cell apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling [TUNEL] staining) was greatly increased, consistent with ongoing immune-mediated beta cell destruction. There was also a marked increase (more than approximately 100-fold) in the frequency of beta cell replication (0.69+/-0.15% Ki67-positive beta cells) in all blocks examined. CONCLUSIONS/INTERPRETATION: The present report provides direct evidence of attempted beta cell regeneration through the mechanism of beta cell replication in a case of newly diagnosed type 1 diabetes, and affirms that beta cell apoptosis is an important mechanism for beta cell loss in type 1 diabetes.

Age of Onset↗
PubMed2006

Glucagon-like peptide 1 abolishes the postprandial rise in triglyceride concentrations and lowers levels of non-esterified fatty acids in humans.

AIMS/HYPOTHESIS: Diabetic dyslipidaemia contributes to the excess morbidity and mortality in patients with type 2 diabetes. Exogenous glucagon-like peptide 1 (GLP-1) lowers postprandial glycaemia predominantly by slowing gastric emptying. Therefore, the effects of GLP-1 on postprandial lipid levels and gastric emptying were assessed. METHODS: 14 healthy male volunteers were studied with an i.v. infusion of GLP-1 (1.2 pmol kg(-1) min(-1)) or placebo over 390 min in the fasting state. A solid test meal was served and gastric emptying was determined using a (13)C-labelled sodium octanoate breath test. Venous blood was drawn frequently for measurement of glucose, insulin, C-peptide, glucagon, GLP-1, triglycerides and NEFA. RESULTS: GLP-1 administration lowered fasting and postprandial glycaemia (p<0.0001). Gastric emptying was delayed by GLP-1 compared with placebo (p<0.0001). During GLP-1 administration, insulin secretory responses were higher in the fasting state but lower after meal ingestion. After meal ingestion, triglyceride plasma levels increased by 0.33+/-0.14 mmol/l in the placebo experiments (p<0.0001). In contrast, the postprandial increase in triglyceride levels was completely abolished by GLP-1 (change in triglycerides, -0.023+/-0.045 mmol/l; p<0.05). During GLP-1 infusion, plasma concentrations of NEFA were suppressed by 39% in the fasting state (p<0.01) and by 31+/-5% after meal ingestion (p<0.01). CONCLUSIONS/INTERPRETATION: GLP-1 improves postprandial lipidaemia, presumably as a result of delayed gastric emptying and insulin-mediated inhibition of lipolysis. Thus, by lowering both glucose and lipid concentrations, GLP-1 administration may reduce the cardiovascular risk in patients with type 2 diabetes.

Adult↗
PubMed2005

Increased vulnerability of newly forming beta cells to cytokine-induced cell death.

AIMS/HYPOTHESIS: Beta cell destruction in type 1 diabetes is apparently mediated by the release of cytokines. We questioned whether cytokine-induced apoptosis preferentially kills replicating beta cells. MATERIALS AND METHODS: In the first experiment, rat insulinoma (RIN) cells were studied for 36 h by time-lapse video microscopy. Cells were exposed to three doses of a cytokine mixture (maximal concentration: IL-1beta 50 U/ml; TNF-alpha 1,000 U/ml; IFN-gamma 1,000 U/ml) or vehicle and analysed for the total cell number (2-h intervals) and timing of each cell death and division. In the second experiment, isolated human islets were incubated with the same cytokine mixture for 24 h and examined for replication and paired (postmitotic) apoptosis. RESULTS: In the first experiment, after application of cytokines, apoptosis occurred most frequently immediately after the next or subsequent cell mitosis (p<0.05). In the second experiment, cytokines caused increased apoptosis in human islets, with an increase in the proportion of postmitotic apoptotic pairs (p<0.001). CONCLUSIONS/INTERPRETATION: Cytokine-induced beta cell death preferentially affects newly forming beta cells, which implies that replicating beta cells might be more vulnerable to cytokine destruction. Efforts to expand beta cell mass in type 1 diabetes by fostering beta cell replication are likely to fail unless cytokine-induced apoptosis is concurrently suppressed.

Apoptosis↗
PubMed2005

Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration?

AIMS/HYPOTHESIS: Type 1 diabetes is widely held to result from an irreversible loss of insulin-secreting beta cells. However, insulin secretion is detectable in some people with long-standing type 1 diabetes, indicating either a small population of surviving beta cells or continued renewal of beta cells subject to ongoing autoimmune destruction. The aim of the present study was to evaluate these possibilities. MATERIALS AND METHODS: Pancreatic sections from 42 individuals with type 1 diabetes and 14 non-diabetic individuals were evaluated for the presence of beta cells, beta cell apoptosis and replication, T lymphocytes and macrophages. The presence and extent of periductal fibrosis was also quantified. RESULTS: Beta cells were identified in 88% of individuals with type 1 diabetes. The number of beta cells was unrelated to duration of disease (range 4-67 years) or age at death (range 14-77 years), but was higher (p<0.05) in individuals with lower mean blood glucose. Beta cell apoptosis was twice as frequent in type 1 diabetes as in control subjects (p<0.001), but beta cell replication was rare in both groups. The increased beta cell apoptosis in type 1 diabetes was accompanied by both increased macrophages and T lymphocytes and a marked increase in periductal fibrosis (p<0.001), implying chronic inflammation over many years, consistent with an ongoing supply of beta cells. CONCLUSIONS/INTERPRETATION: Most people with long-standing type 1 diabetes have beta cells that continue to be destroyed. The mechanisms underlying increased beta cell death may involve both ongoing autoimmunity and glucose toxicity. The presence of beta cells despite ongoing apoptosis implies, by definition, that concomitant new beta cell formation must be occurring, even after long-standing type 1 diabetes. We conclude that type 1 diabetes may be reversed by targeted inhibition of beta cell destruction.

Adolescent↗
PubMed2005

Secretion of incretin hormones and the insulinotropic effect of gastric inhibitory polypeptide in women with a history of gestational diabetes.

AIMS/HYPOTHESIS: The insulinotropic effect of gastric inhibitory polypeptide (GIP) is reduced in patients with type 2 diabetes and around 50% of their first-degree relatives under hyperglycaemic conditions. It is unknown whether this is a result of a specific defect in GIP action or of a general reduction in beta cell function. Moreover, impaired secretion of glucagon-like peptide 1 (GLP-1) has been described in patients with type 2 diabetes. Therefore, we studied the insulinotropic effect of GIP in women with previous gestational diabetes (pGDM) under euglycaemic fasting conditions and during a hyperglycaemic clamp experiment. The secretion of GIP and GLP-1 was assessed following oral glucose ingestion. MATERIALS AND METHODS: On separate occasions we performed an OGTT and administered an i.v. bolus of 20 pmol GIP/kg body weight in 20 women with pGDM and 20 control women. An additional hyperglycaemic clamp experiment (140 mg/dl [7.8 mmol/l] over 120 min) with i.v. infusion of GIP (2 pmol kg(-1) min(-1); 30-90 min) was performed in 14 women in each group. Capillary and venous blood samples were drawn for the measurement of glucose (glucose oxidase), insulin, C-peptide, GIP and GLP-1 (specific immunoassays). Indices of insulin sensitivity and beta cell function were calculated. Statistical analyses were carried out using repeated measures ANOVA. RESULTS: Following oral glucose ingestion, plasma glucose, insulin and C-peptide concentrations increased to higher levels in the women with pGDM than in the control women (p<0.05). The women with pGDM were characterised by a higher degree of insulin resistance than the control women (p=0.007 for the Matsuda index), but showed no overt defects in glucose-stimulated insulin secretion (p=0.40 for the insulinogenic index following i.v. glucose). The secretion of GLP-1 and GIP was not different between the groups (p=0.87 and p=0.57, respectively). The insulin secretory response to GIP administration was similar in the two groups both after GIP bolus administration and during the hyperglycaemic clamp experiment (p=0.99 and p=0.88, respectively). A hyperbola-like relationship was found between the degree of insulin sensitivity (Matsuda index) and the insulin secretory response to GIP and i.v. glucose administration. CONCLUSIONS/INTERPRETATION: These results do not support the hypothesis of an early defect in GIP action as a risk factor for subsequent development of diabetes in women with previous gestational diabetes. The inverse relationship between insulin resistance and the insulin secretory response to glucose or GIP suggests that beta cell secretory function in response to different stimuli increases adaptively when insulin sensitivity is diminished.

Adult↗
PubMed2004

Glucagon-like peptide 2 improves intestinal wound healing through induction of epithelial cell migration in vitro-evidence for a TGF--beta-mediated effect.

BACKGROUND/AIMS: In vitro studies suggest that glucagon-like peptide 2 (GLP-2), secreted from enteroendocrine cells in the gastrointestinal tract after food intake, is able to ameliorate mucosal injury in settings of human disease characterized by injury and dysfunction of the intestinal mucosal epithelium. We evaluated this potential of GLP-2 after epithelial trauma by using two in vitro models measuring intestinal epithelial cell proliferation and cell migration. MATERIALS AND METHODS: Injuries were induced in confluent monolayers of the small intestinal cells lines IEC-6 and IEC-18, as well as in the colonic cell lines Caco-2 and Colo 320. GLP-2 (50-500 nM) or other peptides were added to the media. Wound healing was investigated after 24 h by quantification of the number of cells migrating across the wound edge. Proliferation of cells was assessed by using photometric mitochondrial incorporation measurement of MTT (3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide). Monoclonal TGF-beta antibodies were added to wounded monolayers to examine whether the GLP-2-induced wound healing was TGF-beta-mediated. RESULTS: Migration assessments revealed a significant stimulation of GLP-2-induced migration in IEC-6 and IEC-18 monolayers compared to the placebo group. No effect was observed in the colon cancer cell lines Caco-2 and Colo 320. Results of the proliferation assays show a significant inhibition of proliferation by GLP-2 in small intestinal cell lines whereas a dose-dependent stimulation of proliferation in colonic epithelial cells was observed. Addition of neutralizing TGF-beta1 antibodies to wounded IEC-6 and IEC-18 monolayers incubated with GLP-2 significantly reduced the number of migrating cells to the level of the placebo group. CONCLUSIONS: In our in vitro model, it was shown that the GLP-2-induced improvement of intestinal wound healing is TGF-beta-mediated. These effects were predominant in the epithelium of the small intestine compared to colonic epithelium. Our findings provide further insight into mechanisms leading to GLP-2-induced mucosal wound healing. These results suggest that GLP-2 or analogues of this peptide may potentially be useful for the treatment of intestinal disorders characterized by injury and ineffective repair of the intestinal mucosa.

Animals↗
PubMed2004

Is impairment of ischaemic preconditioning by sulfonylurea drugs clinically important?

In the UGDP study, published in the 1970s, a high incidence of cardiovascular mortality was found in patients treated with the sulfonylurea agent tolbutamide. Impaired ischaemic preconditioning is presumed to be the most important mechanism for the excess cardiovascular mortality observed. However, as tolbutamide has only a low affinity for cardiac sulfonylurea receptors, interference with ischaemic preconditioning seems unlikely to account for this excess mortality. Several smaller studies also failed to establish a definite link between sulfonylurea treatment before acute myocardial infarction and in-hospital mortality. However, when the myocardium becomes exposed to repeated or prolonged periods of ischaemia, ischaemic preconditioning may become clinically important. Myocardial ischaemia can also develop during emergency or elective angioplasty and during coronary bypass surgery. Therefore discontinuation of sulfonylurea treatment should be considered in these circumstances.

Animals↗
PubMed2003

Gastric inhibitory polypeptide (GIP) dose-dependently stimulates glucagon secretion in healthy human subjects at euglycaemia.

AIMS/HYPOTHESIS: In the isolated perfused pancreas, gastric inhibitory polypeptide (GIP) has been shown to enhance glucagon secretion at basal glucose concentrations, but in healthy humans no glucagonotropic effect of GIP has yet been reported. Therefore, we studied the effect of GIP on glucagon secretion under normoglycaemic conditions. METHODS: Ten healthy subjects (9 men, 1 woman; age 33+/-11; BMI 26.8+/-2.2 kg/m(2)) received three different doses of intravenous GIP (7, 20, and 60 pmol/kg body weight) and placebo. Venous blood samples were drawn over 30 min for glucagon and GIP concentrations (specific radioimmunoassays). In addition, 31 healthy subjects (16 men, 15 women; 42+/-11 years; BMI 24.4+/-2.7 kg/m(2)) were studied with 20 pmol GIP/kg. Statistics were done with RM-ANOVA and Duncan's post hoc tests. RESULTS: Gastric inhibitory polypeptide dose-dependently stimulated glucagon secretion ( p=0.019) with a maximal increment after 10 min. Incremental glucagon concentrations (Delta(10-0 min)) were 0.1+/-0.7, 1.4+/-0.5, 2.4+/-0.5, and 3.4+/-0.8 pmol/l (for placebo and for 7, 20, and 60 pmol GIP/kg, respectively; p=0.017). After the injection of 20 pmol GIP/kg b.w. in 31 healthy subjects, glucagon concentrations increased over the baseline from 7.5+/-0.5 to 9.3+/-0.7 pmol/l ( p=0.0082). CONCLUSIONS/INTERPRETATION: Glucagon secretion is dose-dependently stimulated by GIP at basal glucose concentrations. The absence of a glucagonotropic GIP effect in previous studies could be due to the hyperglycaemic conditions used in these experiments. Our results underline differences between GIP and the glucagonostatic incretin GLP-1.

Blood Glucose↗
PubMed2003

A 25-year follow-up study of glucose tolerance in first-degree relatives of type 2 diabetic patients: association of impaired or diabetic glucose tolerance with other components of the metabolic syndrome.

A follow-up study of first-degree relatives of type 2 diabetic patients presented the opportunity to study the association of components of the metabolic syndrome with oral glucose tolerance in these subjects. In 1992, 25 years after the first analysis of the cohort, we performed 75-g oral glucose tolerance tests and measured anthropometric data (body mass index, waist-hip ratio), insulin and C-peptide concentrations, and parameters of lipoprotein metabolism (free fatty acids, triglycerides, cholesterol, HDL cholesterol). Of 135 participants, 71 had normal glucose tolerance (GT), 22 had impaired GT, and 42 had diabetic GT (WHO 1985 criteria). Impaired glucose tolerance and diabetes were significantly (Kruskal-Wallis test) associated with advanced age (p=0.001), higher body mass index (p=0.005) and waist-hip ratio (p=0.027), systolic hypertension (p=0.031), elevated basal insulin concentrations (p<0.001), higher free fatty acids (p<0.001) and triglycerides (p=0.017), and lower HDL cholesterol (p=0.003); no associations were found with total and LDL cholesterol levels (Friedewald's formula, p=0.25). Abnormalities (obesity, hypertriglyceridemia, low HDL cholesterol, hypertension, pathological oral glucose tolerance) were associated with significant deterioriations in all other components of the metabolic syndrome, if their number exceeded three. Disturbances of oral glucose tolerance are present in a high percentage of first-degree relatives after 25 years of follow-up (51% of those tested). Impaired or diabetic glucose tolerance in such a cohort was associated with overweight, hypertension and disturbances of lipoprotein metabolism characteristic of the metabolic syndrome. Hypercholesterolemia (LDL-cholesterol) is not a component of the metabolic syndrome in a German population with a high hereditary burden regarding type 2 diabetes. A metabolic syndrome should certainly be diagnosed if three components are present, although even in the presence of only two components, an elevated risk is evident.

Aged↗
PubMed2003

[Appetite regulation by ghrelin - a novel neuro-endocrine gastric peptide hormone in the gut-brain-axis].

Ghrelin a novel peptide consisting of 28 amino acids was first identified in the stomach in 1999. It is mainly produced in endocrine cells of the human gastric mucosa, but it was also found in several other tissues e. g. in the pituitary, the hypothalamus and the pancreas. The functional receptor belongs to the family of the 7-transmembrane G-protein receptors and is predominantly detected in the pituitary and at lower levels in hypothalamic nuclei, the stomach, heart, lungs, kidneys, gut, the adipose and many other tissues. According to the widespread distribution of the peptide and its receptor, ghrelin has multiple biological effects: it stimulates the release of growth hormone in the pituitary and induces a rise in the serum concentration of ACTH, cortisol, catecholamines and prolactin. Ghrelin causes an increase of food intake and body weight by stimulating the production of neuropeptide Y (NPY) and agouti-related protein (AGP) in the nucleus arcuatus. It further leads to elevated concentrations of plasma glucose. A physiological antagonism between ghrelin and GLP-1 in the hypothalamic regulation of appetite is being discussed. The basic serum level of ghrelin depends on the state of nutrition and is negatively correlated with the body-mass-index. It shows a certain pattern of variation before and after food intake with a preprandial increase and a postprandial decrease. Ghrelin modulates gastric acid secretion and the gastrointestinal motility via vagal cholinergic pathways. The discovery of ghrelin definitely contributes to the understanding of the growth-hormone secretion and of the regulation of appetite and food intake.

Adrenocorticotropic Hormone↗
PubMed2003

Influence of an antidiabetic treatment with sulfonylurea drugs on long-term survival after acute myocardial infarction in patients with type 2 diabetes. The LAngendreer Myocardial infarction and Blood glucose in Diabetic patients Assessment (LAMBDA).

INTRODUCTION: Patients with type 2 diabetes show a significantly higher mortality after acute myocardial infarction than non-diabetic patients. The influence of sulfonylureas on the survival after acute myocardial infarction is still under debate. PATIENTS AND METHODS: Survival of 562 patients, consecutively admitted to an intensive care unit with the diagnosis acute myocardial infarction, was prospectively assessed for > 3 years. At the time of hospital admission, patients were grouped as (a) non-diabetic patients; (b) patients with newly diagnosed type 2 diabetes; (c) patients with known type 2 diabetes not treated with sulfonylureas and (d) patients with known type 2 diabetes treated with sulfonylureas. Survival-analysis was performed according to Kaplan-Meier. RESULTS: 324 patients were non-diabetics, in 86 cases type 2 diabetes was newly diagnosed at the time of hospital admission, 77 patients with known diabetes had taken sulfonylureas (glibenclamide in all cases) prior to the acute myocardial infarction, 75 patients were on any other antidiabetic treatment. Long-term-survival was significantly shorter in patients with type 2 diabetes compared to the non-diabetic patients (p < 0.0001). However, no significant differences were observed between the patients with type 2 diabetes treated with sulfonylurea-drugs and those receiving any other antidiabetic treatment (p = 0.53) CONCLUSIONS: An antidiabetic treatment with sulfonylurea-drugs prior to acute myocardial infarction does not have negative effects on the long-term survival. Larger prospective studies will be necessary to finally clarify this question.

Acute Disease↗
PubMed2002

[Influence of impaired glucose tolerance on long-term survival after acute myocardial infarction].

BACKGROUND AND OBJECTIVE: An impaired glucose tolerance as well as type 2 diabetes are associated with an increased cardiovascular mortality. This study was undertaken to determine whether this is also true for impaired glucose tolerance in immediate temporal relation with an acute myocardial infarction (AMI). PATIENTS AND METHODS: The survival of 562 patients (232 females, 330 males; age 68 +/- 13 years) consecutively admitted to the intensive care unit of a medical department with the diagnosis of AMI, were prospectively evaluated over a span of more than 3 years. Type 2 diabetes had been previously known in 152, while it was newly diagnosed in 83 patients. Oral glucose tolerance tests (OGTT) were performed in 129, but the test was not performed in 222 patients. Survival was analysed with the Kaplan-Meier test. RESULTS: Among the 129 patients who had had an OGTT, it was normal in 60 (47%), 45 (35%) had impaired glucose tolerance and 24 (19%) were found to have previously undiagnosed diabetes (WHO criteria). Survival of all patients with type 2-diabetes was significantly worse than in the remainder of patients (p < 0.0001). In patients with impaired glucose tolerance the survival time was significantly shorter than in those with normal glucose tolerance (p = 0.029). Even after excluding those patients who had died in the acute post-infarction phase, the difference between patients with normal and with impaired glucose tolerance remained significant (p = 0.034). CONCLUSION: Patients with impaired glucose tolerance have a significantly shorter survival after AMI than those with a normal glucose tolerance. Blood glucose concentration 2 hours after oral glucose intake thus seems to be an important predictor of death after AMI.

Aged↗
PubMed2002

[Differences in insulin secretion facilitate the differential diagnosis of insulinoma and factitious hypoglycaemia].

HISTORY: A 33-year-old female nurse (married; two children; BMI 30.9 kg/m2) had recurrent episodes of symptomatic hypoglycaemia over some months. INVESTIGATIONS: Two fasting tests were terminated after 26 hours because the patient became unconscious. Improved insulin/glucose ratio was infinity and 6.1 [mU/l]/[mg/dl] (normal value < 0.5). An hyperinsulinaemic-hypoglycaemic angle "clamp test" produced a C-peptide suppression to minimally 0.26 - 0.38 nmol/l (normal value 0.06 +/- 0.01 nmol). There was no spontaneous or paradoxical burst in insulin or C-peptide concentration after either the fasting or the "clamp test". Serum analysis of sulphonylurea on several occasions documented an increase of glibenclamide above therapeutic range. TREATMENT AND COURSE: The patient denied any intake of oral antidiabetic preparations, but there were no further hypoglycaemia attacks in subsequent months. DIAGNOSIS: The demonstration of sulphonylurea in serum confirmed the diagnosis of factitious hypoglycaemia. CONCLUSION: With regard to insulin or C-peptide suppression, the results of the fasting and clamp tests are the same in factitious hypoglycaemia and insulinoma. However, under the influence of sulphonylurea drugs there are no insulin or C-peptide bursts so typical of insulinoma. In case of doubt, detection of sulphonylurea preparations in serum or urine is the only reliable way of diagnosing factitious hypoglaema due to the ingestion of sulphonylurea.

Adult↗
PubMed2002

The effects of acetylsalicylic acid on proliferation, apoptosis, and invasion of cyclooxygenase-2 negative colon cancer cells.

BACKGROUND: Acetylsalicylic acid (ASA, aspirin), the most common nonsteroidal anti-inflammatory drug (NSAID), has been shown to have a protective effect against the incidence and mortality of colorectal cancer. However, the mechanism of its anticancer function remains unclear. The aim of this study was to determine the effects of acetylsalicylic acid on proliferation, apoptosis, and invasion in human cyclooxygenase-2 (COX-2) negative colorectal cancer cell lines. MATERIALS AND METHODS: After treatment with various concentrations of ASA, cell proliferation was measured in the human colon cancer cell line SW480. Apoptotic cells were identified by transmission electron microscopy, acridine orange staining, and flow cytometry. The invasive potential of SW480 cells was detected using an in vitro invasion assay. The production of carcinoembryonic antigen was measured by microparticle enzyme immunoassay. Expression of Bcl2, Bax, CD44v6, and nm23 were evaluated by immunocytochemistry. RESULTS: ASA significantly inhibited the proliferation of SW480 cells and stimulated apoptosis. Production of carcinoembryonic antigen and the invasive potential of SW480 cells were also inhibited by ASA. After treatment with ASA, down-regulation of Bcl2 and CD44v6 expression and up-regulation of nm23 expression were observed in SW480 cells. No obvious effect of ASA was found on Bax expression. CONCLUSION: Our findings reveal that ASA inhibits the proliferation and promotes apoptosis in the human colon cancer cell line SW480. Down-regulation of Bcl2 expression might represent a potential mechanism by which ASA induces apoptosis in this COX-2 negative colon cancer cell line. Our results also suggest that ASA decreases the invasive potential of these colon cancer cells. Decreased CEA content and CD44v6 expression and elevated nm23 expression may contribute to the effect of ASA on invasive potential of SW480 colon cancer cells.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2002

Combined pancreas and kidney transplantation in a lean type 2 diabetic patient. Effects on insulin secretion and sensitivity.

BACKGROUND/AIMS: Pancreas transplantation is an established method of treating Type 1 diabetes. It was our aim to test the consequences of pancreas transplantation in a Type 2 diabetic patient by determining insulin secretion and sensitivity before and after surgery. PATIENTS AND METHODS: A female patient with Type 2 diabetes and end-stage nephropathy was treated with combined pancreas and kidney transplantation. Before surgery and at 4 weeks, 6 months and 2 years afterwards, insulin sensitivity was measured using hyperinsulinemic euglycemic clamps and insulin secretion was quantified after oral glucose or intravenous glucagon challenges. RESULTS: The patient was insulin resistant before surgery (glucose infusion 4.6 mg. kg (-1). min (-1), normal range 6.4 +/- 0.5 mg.kg( -1). min (-1). Insulin sensitivity declined further after transplantation (1.4 and 3.0 mg. kg -1. min -1 after 4 weeks and 6 months, respectively), but improved to 5.4 mg. kg (-1). min (-1) after 2 years. Insulin secretion was greatly impaired before surgery. Insulin and C-peptide responses after oral glucose and intravenous glucagon increased into the normal range from 6 months after surgery onwards and oral glucose tolerance remained non-diabetic (IGT). CONCLUSIONS: Insulin resistance is first aggravated after pancreas transplantation, probably due to immunosuppressive treatment including glucocorticoids, but improves on the long term. The initially impaired insulin secretion from the transplant may also be explained by the action of glucocorticoids or by transient and reversible organ damage.

Diabetes Mellitus, Type 2↗
PubMed2001

Reduced insulinotropic effect of gastric inhibitory polypeptide in first-degree relatives of patients with type 2 diabetes.

In patients with type 2 diabetes, gastric inhibitory polypeptide (GIP) has lost much of its insulinotropic activity. Whether this is similar in first-degree relatives of patients with type 2 diabetes is unknown. A total of 21 first-degree relatives, 10 patients with type 2 diabetes, and 10 control subjects (normal oral glucose tolerance) were examined. During a hyperglycemic "clamp" (140 mg/dl for 120 min), synthetic human GIP (2 pmol. kg(-1). min(-1)) was infused intravenously (30-90 min). With exogenous GIP, patients with type 2 diabetes responded with a lower increment (Delta) in insulin (P = 0.0003) and C-peptide concentrations (P < 0.0001) than control subjects. The GIP effects in first-degree relatives were diminished compared with control subjects (Delta insulin: P = 0.04; Delta C-peptide: P = 0.016) but significantly higher than in patients with type 2 diabetes (P < or = 0.05). The responses over the time course were below the 95% CI derived from control subjects in 7 (insulin) and 11 (C-peptide) of 21 first-degree relatives of patients with type 2 diabetes. In conclusion, a reduced insulinotropic activity of GIP is typical for a substantial subgroup of normoglycemic first-degree relatives of patients with type 2 diabetes, pointing to an early, possibly genetic defect.

Adult↗