Dystextia - a sign of the times?
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Adult↗
Biomedical subjects
S Sreenan
Publications and source records attributed to S Sreenan.
Effects of type-2 diabetes and troglitazone on the expression patterns of small intestinal sugar transporters and PPAR-gamma in the Zucker diabetic fatty rat.
BACKGROUND/AIMS: We have used the Zucker diabetic fatty (ZDF) rat to study the effects of type-2 diabetes and troglitazone on the small intestinal mucosal mass, sugar transporters and the peroxisomal proliferator-activated receptor, PPAR-gamma. METHODS: Age-matched ZDF and lean control (ZLC) rats were fed a standard chow or a troglitazone-enriched diet for 6 weeks. The mucosa of the small intestines were then extracted, weighed, and SGLT1, GLUT2, GLUT5 and PPAR-gamma mRNA expression levels assessed by Northern blotting. In the same animal groups, Western blotting and immunohistochemistry were used to study SGLT1, GLUT2 and GLUT5 protein expression levels and targeting. RESULTS: The ZDF rat small intestinal mucosal mass was 60% greater than the ZLC rat. However, the expression levels of SGLT1, GLUT2, GLUT5 mRNA and protein, and PPAR-gamma mRNA in the ZDF and ZLC rats were the same. In addition, the targeting of brush-border GLUT5 and basolateral GLUT2 protein in the ZDF and ZLC rats were the same. Troglitazone treatment reduced SGLT1 mRNA and protein expression levels by 50% in ZDF and ZLC rats, but had no effect on mucosal mass or the expression levels of GLUT2 mRNA and protein, GLUT5 mRNA, and PPAR-gamma mRNA. The expression levels of GLUT5 protein in troglitazone-treated ZLC rats were unchanged when compared to untreated ZLC rats. However, GLUT5 protein expression levels in the troglitazone-treated ZDF rats were 50% below the untreated ZDF rats. CONCLUSIONS: Hyperphagia and insulin are the chronic regulators of small intestinal mucosal mass and sugar transporter expression patterns, respectively. Furthermore, troglitazone suppresses SGLT1 expression at the transcriptional level and GLUT5 at the post-translational level, independent of changes in glycemia or PPAR-gamma gene expression.
Analysis of Variance↗
Effects of troglitazone on substrate storage and utilization in insulin-resistant rats.
Elevated serum and tissue lipid stores are associated with skeletal muscle insulin resistance and diminished glucose-stimulated insulin secretion, the hallmarks of type 2 diabetes. We studied the effects of 6-wk treatment with the insulin sensitizer troglitazone on substrate storage and utilization in lean control and Zucker diabetic fatty (ZDF) rats. Troglitazone prevented development of diabetes and lowered serum triglycerides (TG) in ZDF rats. Soleus muscle glycogen and TG content were elevated twofold in untreated ZDF rats, and both were normalized by troglitazone to lean control levels (P < 0.05). Troglitazone also normalized insulin-stimulated glucose uptake as well as basal and insulin-stimulated glycogen synthesis, implying increased skeletal muscle glycogen turnover. The proportion of active pyruvate dehydrogenase (PDH) in soleus muscle was reduced in ZDF relative to lean control rat muscle (16 +/- 2 vs. 21 +/- 2%) but was restored by troglitazone treatment (30 +/- 3%). Increased PDH activation was associated with a 70% increase in glucose oxidation. Muscle lipoprotein lipase activity was decreased by 35% in ZDF compared with lean control rats and was increased twofold by troglitazone. Palmitate oxidation and incorporation into TG were higher in ZDF relative to lean control rats but were unaffected by troglitazone treatment. Troglitazone decreased the incorporation of glucose into the acyl group of TG by 60% in ZDF rats. In summary, ZDF rats demonstrate increased skeletal muscle glycogen and TG stores, both of which were reduced by troglitazone treatment. Troglitazone appears to increase both glycogen and TG turnover in skeletal muscle. Normalization of PDH activity and decreased glucose incorporation into acyl TG may underlie the improvements in intracellular substrate utilization and energy stores, which lead to decreased serum TG and glucose.
Animals↗
Increased beta-cell proliferation and reduced mass before diabetes onset in the nonobese diabetic mouse.
To determine whether loss of beta-cell mass and function in the NOD mouse occurs gradually, beginning after the onset of insulitis, or abruptly, just before the onset of overt diabetes, beta-cell mass and rates of beta-cell proliferation and insulin secretory responses from the perfused pancreas were measured in NOD and control NOD/Scid mice at 8-9, 13, and 18 weeks of age. Of the NOD mice, 11 and 70% had diabetes (fasting blood glucose >8.3 mmol/l) at 13 and 18 weeks of age, respectively. Beta-cell mass in 8-week-old NOD mice was 69% of control mice (P>0.05), but the rate of 5-bromo-2-deoxyuridine uptake was greater, suggesting a compensatory proliferative response to ongoing autoimmune beta-cell destruction. Despite an increase in the rate of beta-cell proliferation, beta-cell mass was significantly reduced by 42% in 13-week-old nondiabetic NOD mice and by 73% in 18-week-old diabetic NOD mice. Insulin secretory responses to glucose and arginine demonstrated reductions of similar magnitude. In 18-week-old diabetic NOD mice, insulin secretion was reduced to a greater degree than beta-cell mass, suggesting the presence of beta-cell dysfunction in addition to reduced mass. These results suggest that in the NOD mouse, beta-cell destruction begins soon after the onset of insulitis. Despite a compensatory beta-cell proliferative response, beta-cell mass progressively falls and is significantly reduced by 13 weeks despite normal blood glucose concentrations. Diabetes may be present when residual beta-cell mass represents 30% of control levels.
Aging↗
Defective pancreatic beta-cell glycolytic signaling in hepatocyte nuclear factor-1alpha-deficient mice.
Mutations in the hepatocyte nuclear factor-1alpha (HNF-1alpha) gene cause maturity onset diabetes of the young type 3, a form of type 2 diabetes mellitus. In mice lacking the HNF-1alpha gene, insulin secretion and intracellular calcium ([Ca2+]i) responses were impaired following stimulation with nutrient secretagogues such as glucose and glyceraldehyde but normal with non-nutrient stimuli such as potassium chloride. Patch clamp recordings revealed ATP-sensitive K+ currents (KATP) in beta-cells that were insensitive to suppression by glucose but normally sensitive to ATP. Exposure to mitochondrial substrates suppressed KATP, elevated [Ca2+]i, and corrected the insulin secretion defect. NAD(P)H responses to glucose were substantially reduced, and inhibitors of glycolytic NADH generation reproduced the mutant phenotype in normal islets. Flux of glucose through glycolysis in islets from mutant mice was reduced, as a result of which ATP generation in response to glucose was impaired. We conclude that hepatocyte nuclear factor-1alpha diabetes results from defective beta-cell glycolytic signaling, which is potentially correctable using substrates that bypass the defect.
Adenosine Triphosphate↗
Defective insulin secretion in hepatocyte nuclear factor 1alpha-deficient mice.
Mutations in the gene for the transcription factor hepatocyte nuclear factor (HNF) 1alpha cause maturity-onset diabetes of the young (MODY) 3, a form of diabetes that results from defects in insulin secretion. Since the nature of these defects has not been defined, we compared insulin secretory function in heterozygous [HNF-1alpha (+/-)] or homozygous [HNF-1alpha (-/-)] mice with null mutations in the HNF-1alpha gene with their wild-type littermates [HNF-1alpha (+/+)]. Blood glucose concentrations were similar in HNF-1alpha (+/+) and (+/-) mice (7.8+/-0.2 and 7.9+/-0.3 mM), but were significantly higher in the HNF-1alpha (-/-) mice (13.1+/-0.7 mM, P < 0.001). Insulin secretory responses to glucose and arginine in the perfused pancreas and perifused islets from HNF-1alpha (-/-) mice were < 15% of the values in the other two groups and were associated with similar reductions in intracellular Ca2+ responses. These defects were not due to a decrease in glucokinase or insulin gene transcription. beta cell mass adjusted for body weight was not reduced in the (-/-) animals, although pancreatic insulin content adjusted for pancreas weight was slightly lower (0.06+/-0.01 vs. 0.10+/-0.01 microg/mg, P < 0.01) than in the (+/+) animals. In summary, a null mutation in the HNF-1alpha gene in homozygous mice leads to diabetes due to alterations in the pathways that regulate beta cell responses to secretagogues including glucose and arginine. These results provide further evidence in support of a key role for HNF-1alpha in the maintenance of normal beta cell function.
Animals↗
Troglitazone action is independent of adipose tissue.
We have investigated the antidiabetic action of troglitazone in aP2/DTA mice, whose white and brown fat was virtually eliminated by fat-specific expression of diphtheria toxin A chain. aP2/DTA mice had markedly suppressed serum leptin levels and were hyperphagic, but did not gain excess weight. aP2/DTA mice fed a control diet were hyperlipidemic, hyperglycemic, and had hyperinsulinemia indicative of insulin-resistant diabetes. Treatment with troglitazone alleviated the hyperglycemia, normalized the tolerance to intraperitoneally injected glucose, and significantly decreased elevated insulin levels. Troglitazone also markedly decreased the serum levels of cholesterol, triglycerides, and free fatty acids both in wild-type and aP2/DTA mice. The decrease in serum triglycerides in aP2/DTA mice was due to a marked reduction in VLDL- and LDL-associated triglyceride. In skeletal muscle, triglyceride levels were decreased in aP2/DTA mice compared with controls, but glycogen levels were increased. Troglitazone treatment decreased skeletal muscle, but not hepatic triglyceride and increased hepatic and muscle glycogen content in wild-type mice. Troglitazone decreased muscle glycogen content in aP2/DTA mice without affecting muscle triglyceride levels. The levels of peroxisomal proliferator-activated receptor gamma mRNA in liver increased slightly in aP2/DTA mice and were not changed by troglitazone treatment. The results demonstrate that insulin resistance and diabetes can occur in animals without significant adipose deposits. Furthermore, troglitazone can alter glucose and lipid metabolism independent of its effects on adipose tissue.
Adipose Tissue↗
Thyroid dysfunction is not associated with alterations in serum leptin levels.
To determine if serum leptin levels are affected by thyroid dysfunction, we measured its concentration in serum samples from 25 euthyroid controls and 25 subjects each with hypothyroidism and thyrotoxicosis collected over a 3-month period. Mean leptin levels in the euthyroid (24.1 +/- 8.3 microg/L), hypothyroid (22.7 +/- 7.0 microg/L) and thyrotoxic (23.3 +/- 4.3 microg/L) groups were not significantly different. Data were available to express leptin in terms of body mass index (BMI) in 11 euthyroid, and 6 untreated hypothyroid and thyrotoxic individuals. There was a significant positive correlation between BMI and leptin level (r = 0.60, p = .0002) for this subgroup, irrespective of their thyroid status. These data suggest that leptin levels are not affected by thyroid dysfunction.
Female↗
Relative effects of inhaled corticosteroids on immunopathology and physiology in asthma: a controlled study.
BACKGROUND: Although corticosteroids are recognised as the most efficacious treatment for bronchial asthma, their mode of action remains unclear. A placebo controlled trial was undertaken of the effect of inhaled corticosteroids on physiological and immmunopathological parameters in asthmatic patients in whom the correlations between these indices were tested after treatment. METHODS: Sixteen patients (two women) with asthma entered a double blind, placebo controlled, parallel study during which they inhaled either budesonide 800 micrograms twice daily or matching placebo for six weeks. Spirometric parameters and bronchial reactivity to histamine and terbutaline were measured and endobronchial biopsy samples were taken before and after treatment. Patients recorded morning and evening flow rates during the treatment period. The biopsy samples were subjected to immunohistological analysis to determine the disposition of inflammatory cells within the bronchial wall. RESULTS: Treatment with budesonide resulted in a significant improvement in the 25-75% forced expiratory flow (FEF25-75) from a mean of 133 l/min before treatment to 169 l/min after treatment, and in the morning peak expiratory flow rate (PEFR) from a mean of 384 l/min before treatment to 415 l/min after treatment. No changes were seen in the placebo group. Comparison between the changes in the immunopathological indices after six weeks of treatment with placebo or budesonide showed a significant reduction in the numbers of mast cells (0.5/unit area to 0.2/ unit area), activated eosinophils, and the expression of HLA-DR antigens (relative density -1.9 before to 1.02 after treatment) on inflammatory cells in response to treatment with budesonide. Although reductions in the numbers of other inflammatory cells within the bronchial wall were recorded using immunohistological analysis, these changes were not statistically significant. Significant correlations were found between changing immunological indices and lung physiology. CONCLUSIONS: This controlled study shows that inhaled corticosteroids cause improvement in physiological and immunopathological parameters in patients with stable asthma that are not seen with placebo, and that cause and effect relationships may exist between these two measures of disease status.
Adolescent↗
Prevention of hyperglycemia in the Zucker diabetic fatty rat by treatment with metformin or troglitazone.
To determine whether metformin or troglitazone can delay the onset of diabetes in the Zucker diabetic fatty (ZDF) rat, lean control, fatty, and ZDF rats received metformin, troglitazone, or no treatment from 6 to 12 wk of age. Glucose, insulin, triglyceride (TG), and free fatty acid (FFA) levels and glucose stimulated insulin secretion by the perfused pancreas were measured. Metformin-treated rats gained significantly less weight. Both drugs prevented hyperglycemia by 12 wk in diabetic rats and significantly reduced TG and FFA levels. Insulin secretion at low glucose was elevated in untreated fatty and diabetic animals, and the increment in diabetic animals produced by glucose perfusion was attenuated compared with lean and fatty rats. Both drugs reduced basal insulin secretion in fatty and diabetic rats and improved glucose responsiveness in diabetic rats. Metformin and troglitazone delay the onset of diabetes in the ZDF rat. The significantly improved insulin secretory response of the pancreas undoubtedly contributes to the improved glucose tolerance.
Age Factors↗
Immunological/physiological relationships in asthma: potential regulation by lung macrophages.
There is now a consensus that T-cell-mediated inflammation and eosinophil activation in the bronchial wall contribute to the pathogenesis of asthma. However, the relationship between these immunopathological mechanisms and the observed physiological aberrations remain unclear. Here, Len Poulter and colleagues identify the links between T-cell-mediated inflammation and bronchial hyperresponsiveness, and propose a hypothesis for asthma pathogenesis in which the combination of immunological and physiological abnormalities may result in the promotion of disease. Furthermore, they suggest that an integral factor in the prevention of this process is the regulation of bronchial T-cell reactivity by a population of immunosuppressive macrophages.
Asthma↗
T-cell and macrophage subsets in the bronchial wall of clinically healthy subjects.
This study was conducted to obtain quantitative data on the numbers of T-cells and macrophage subsets in the normal bronchial wall of man, and, thus, produce a baseline against which the numbers of these cells present in inflamed bronchi may be judged. Bronchial biopsies were obtained from 27 clinically healthy subjects attending hospital for elective orthopaedic operations. Eight of the subjects were smokers (median 3.5 pack-years), and eight were atopic as defined by skin prick test. Three to eight weeks after biopsy, subjects attended the lung function laboratory for spirometric testing and determination of provocative concentration of histamine producing a 20% fall in forced expiratory volume in one second (PC20FEV1). The bronchial biopsies were frozen and cryostat sections prepared. These sections were investigated with immunohistological techniques to reveal the presence and distribution of T-cell and macrophage subsets. Twenty six out of 27 subjects had spirometric values within the normal range, but a wide spectrum of bronchial reactivity was observed (PC20FEV1 range 2-36 mg histamine). Using monoclonal antibodies in immunohistological techniques, only small numbers of T-cells were seen, the majority being CD8+ cells in the epithelium. In the underlying tissue, CD4+ cells predominated (CD4/CD8 ratio, epithelium 1:9; underlying tissue 4:1). In both cases, approx. 50% of T-cells expressed the CD45Ro isotype. Small numbers of macrophages were observed in all samples. The majority of these cells expressed a "suppressor cell" phenotype (RFD1+RFD7+), whilst only a small proportion (median 11% ) exhibited the phenotype of antigen presenting cells (RFD1+RFD7-).(ABSTRACT TRUNCATED AT 250 WORDS)
Biopsy↗
Distribution of immunocompetent cells in the bronchial wall of clinically healthy subjects showing bronchial hyperresponsiveness.
BACKGROUND: Nearly all asthmatic subjects show bronchial hyperresponsiveness, in that the provocative concentration of histamine reducing forced expiratory volume in one second (FEV1) by 20% (PC20FEV1) is < or = 8 mg/ml histamine, and have underlying chronic inflammation of the bronchial wall mediated by T cells. The possible cause and effect relationship between these phenomena remains an enigma. As a proportion of clinically healthy subjects show bronchial hyperresponsiveness, this study was undertaken to determine whether they also show evidence of bronchial inflammation. METHODS: Bronchial biopsy specimens were obtained from 27 clinically healthy subjects with no history of lung disease. Samples were taken perioperatively before elective knee arthroscopy for sports injuries. Specimens were frozen and cryostat sections analysed immunocytochemically with monoclonal antibodies to identify the presence of T lymphocytes, antigen presenting cells, and the expression of HLA-DR. Double immunofluorescence studies were performed with monoclonal antibodies RFD1 and RFD7 to show the relative proportions of RFD1+ RFD7- antigen presenting cells, RFD1- RFD7+ mature phagocytes, and RFD1+ RFD7+ suppressor macrophages. Histological stains were performed to show the presence of eosinophils and mast cells. Three to four weeks after bronchoscopy spirometry was performed on these subjects to record FEV1, forced vital capacity (FVC), FEV1/FVC, and forced expiratory flow between 25% and 75% of vital capacity (FEF25-75). Bronchial hyperreactivity was recorded by determining PC20FEV1 to histamine. RESULTS: Nine of the 27 subjects showed bronchial hyperresponsiveness as defined by a PC20FEV1 of < or = 8 mg/ml histamine. Segregated subjects with and without bronchial hyperresponsiveness showed no difference in spirometric results. Immunohistological analysis showed no evidence of inflammation in either group. Numbers of T cells, eosinophils, and mast cells were the same in both groups as was the expression of HLA-DR antigen. No neutrophils were observed in any tissues. Interestingly, reduced numbers of macrophages with the phenotype of antigen presenting cells (monoclonal antibodies RFD1+ RFD7-) were recorded in the subjects with bronchial hyperresponsiveness, who also had a significant increase in the proportion of RFD1+ RFD7+ suppressor macrophages. CONCLUSIONS: Up to 30% of selected clinically healthy subjects may have a PC20FEV1 of < or = 8 mg/ml histamine. This physiological trait can exist in the absence of bronchial inflammation. This suggests that bronchial hyperresponsiveness as currently defined is not dependent on immunopathological changes in the bronchial wall and does not necessarily promote even subclinical inflammation.
Adult↗
Acromegaly secondary to growth hormone releasing hormone secretion.
BACKGROUND: Acromegaly secondary to growth hormone releasing hormone (GHRH) secretion is exceptionally rare. AIM: To report a case of acromegaly diagnosed in 1984 and assumed to be pituitary in origin. Sixteen years later, the cause was found to be a GHRH secreting neuroendocrine pancreatic tumour. METHOD: A case report. CONCLUSION: Although ectopic GHRH production is very rare, endocrinologists should be aware of this possibility in acromegaly patients if a pituitary tumour was not detected using pituitary imaging.
Acromegaly↗
Target blood pressure for patients with type 2 diabetes is difficult to achieve in the setting of a busy diabetes clinic.
BACKGROUND: Target blood pressure control in patients with type 2 diabetes should be 130/85 mmHg or less; however, it is not clear how achievable this target is in clinical practice. AIM: To assess the adequacy of blood pressure control in patients with type 2 diabetes attending a busy outpatient clinic. METHODS: One hundred and eight patients with type 2 diabetes were assessed for the presence of hypertension using a cut-off value of 130/85 mmHg. Antihypertensive treatment and diabetic complications were evaluated. RESULTS: Hypertension was present in 67% of patients, in whom 90% were receiving anti-hypertensive treatment. Forty-nine per cent of the treated patients achieved target blood pressure. Of the undertreated patients, 55% were on one antihypertensive agent, 30% were on two agents and 15% were on three or more agents. The corresponding figures for the adequately treated patients were 28%, 31% and 41%, respectively (p=0.03). CONCLUSION: Adequate blood pressure control was underachieved in this patient group underlying the difficulty in treating blood pressure to target values in patients with type 2 diabetes in the setting of outpatient diabetes clinics. A more aggressive strategy, in particular the use of multiple antihypertensive agents should be adopted.
Ambulatory Care Facilities↗
Prevalence of anaemia in patients with diabetes mellitus.
BACKGROUND: Anaemia is an increasingly recognised entity in patients with diabetes mellitus. AIMS: We aimed to determine the prevalence of anaemia in our population of patients with diabetes, and to examine the factors associated with anaemia. METHODS: The haemoglobin (Hb) levels in a consecutive series of patients attending for annual review of their diabetes over a three-month period were measured. Patients were classified as anaemic as per the WHO criteria. RESULTS: During the period of study, 270 patients attended for review. Eleven per cent of males and 16% of females were anaemic. Seventy four per cent of anaemic patients had a serum creatinine <110micromol/l and 72% of anaemic patients had a calculated creatinine clearance of >60ml/min. CONCLUSIONS: Anaemia was relatively common in patients attending for routine outpatient diabetes clinic review. The high prevalence of anaemia supports the routine screening for anaemia in the diabetes out-patient clinic, including in those without overt nephropathy.
Anemia↗
A case of Resistance to Thyroid Hormone without mutation in the thyroid hormone receptor beta.
BACKGROUND: Resistance to Thyroid Hormone (RTH) is a condition caused by tissue hyposensitivity to the effects of circulating thyroid hormone, and may be misdiagnosed as hyperthyroidism. AIMS: We report the first case of RTH in an Irish patient highlighting the clinical features and the pathophysiological mechanism underlying the characteristic laboratory abnormalities found in the condition. METHODS: We describe an isolated case of RTH initially misdiagnosed as hyperthyroidism, and detail the investigations which ultimately led to the correct diagnosis. Genetic screening of the thyroid hormone receptor beta gene was performed. RESULTS: Thyroid function tests including T3 suppression test and TRH-stimulation test suggested a diagnosis of RTH. Genetic testing failed to demonstrate a mutation in the thyroid hormone receptor. CONCLUSION: RTH is a rare inherited condition that may be misdiagnosed as hyperthyroidism. The case we describe most likely results from a de novo mutation in an as yet undiscovered gene. RTH should be considered in patients with elevated thyroid hormone levels and normal TSH so that unnecessary and potentially harmful treatment can be avoided.
Adult↗