CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 7 2006
MK Peddyreddy
SUMMARY 1Insulin is the drug of choice in the management of type 1 diabetes mellitus. Approximately 76% of diabetic patients suffer from gastrointestinal disorders. An important area of investigating the inherent effect of insulin on small intestinal transit (SIT) remains unexplored. Hence, the present study was planned to investigate the effects of insulin (2 × 10,6, 2 × 10,3 and 2 U/kg) on small intestinal transit following two different routes of administration in healthy animals. 2Insulin or vehicle was administered subcutaneously or intracerebroventricularly in eight groups of healthy, overnight-fasted mice. Blood glucose (BG) levels were measured 2 min before insulin administration and at the time coinciding with SIT determination. Small intestinal transit was determined 50 min after insulin administration using the charcoal meal method. 3Following subcutaneous administration, the lowest dose of insulin (2 × 10,6 U/kg) produced a significant acceleration in SIT without altering BG levels. However, the highest dose of insulin (2 U/kg) produced an acceleration of SIT that was associated with a significant fall in BG levels. 4Following intracerebroventricular administration, the lowest dose of insulin (2 × 10,6 U/kg) attenuated SIT, without producing any alteration in BG levels, but the highest dose (2 U/kg) mimicked the effects seen following subcutaneous administration. Peripherally administered insulin produced significant acceleration of SIT at lower doses (2 × 10,6 or 2 × 10,3 mU/kg) compared with centrally administered insulin at similar doses. However, at the highest dose of insulin (2 U/kg), both routes (s.c. and i.c.v.) produced acceleration of SIT. 5In the present study, peripherally and centrally administered insulin at 2 × 10,6 U/kg produced contrasting effects on SIT, without any hypoglycaemia. However, 2 U/kg insulin accelerated SIT similarly following both s.c. and i.c.v. administration that was associated with hypoglycaemia in healthy animals. [source]

Imidazoline-induced amplification of glucose- and carbachol-stimulated insulin release includes a marked suppression of islet nitric oxide generation in the mouse

ACTA PHYSIOLOGICA, Issue 3 2009
S. Meidute-Abaraviciene
Abstract Aim:, The role of islet nitric oxide (NO) production in insulin-releasing mechanisms is unclear. We examined whether the beneficial effects of the imidazoline derivative RX 871024 (RX) on ,-cell function might be related to perturbations of islet NO production. Methods:, Experiments were performed with isolated islets or intact mice challenged with glucose or carbachol with or without RX treatment. Insulin was determined with radioimmunoassay, NO generation with high-performance liquid chromatography and expression of inducible NO synthase (iNOS) with confocal microscopy. Results:, RX treatment, in doses lacking effects on basal insulin, greatly amplified insulin release stimulated by the NO-generating secretagogues glucose and carbachol both in vitro and in vivo. RX also improved the glucose tolerance curve. Islets incubated at high glucose levels (20 mmol L,1) displayed increased NO production derived from both neuronal constitutive NO synthase (ncNOS) and iNOS. RX abrogated this glucose-induced NO production concomitant with amplification of insulin release. Confocal microscopy revealed abundant iNOS expression in , cells after incubation of islets at high but not low glucose levels. This was abolished after RX treatment. Similarly, islets cultured for 24 h at high glucose levels showed intense iNOS expression in , cells. This was abrogated with RX and followed by an amplified glucose-induced insulin release. Conclusion:, RX effectively counteracts the negative impact of ,-cell NO generation on insulin release stimulated by glucose and carbachol suggesting imidazoline compounds by virtue of NOS inhibitory properties being of potential therapeutic value for treatment of ,-cell dysfunction in hyperglycaemia and type 2 diabetes. [source]

Insulin as ischaemic preconditioning-mimetic

ACTA PHYSIOLOGICA, Issue 2 2009
Coert J. Zuurbier
No abstract is available for this article. [source]

Cell hydration and mTOR-dependent signalling

ACTA PHYSIOLOGICA, Issue 1-2 2006
F. Schliess
Abstract Insulin- and amino acid-induced signalling by the mammalian target of rapamycin (mTOR) involves hyperphosphorylation of the p70 ribosomal S6 protein kinase (p70S6-kinase) and the eukaryotic initiation factor 4E (eIF4E) binding protein 4E-BP1 and contributes to regulation of protein metabolism. This review considers the impact of cell hydration on mTOR-dependent signalling. Although hypoosmotic hepatocyte swelling in some instances activates p70S6-kinase, the hypoosmolarity-induced proteolysis inhibition in perfused rat liver is insensitive to mTOR inhibition by rapamycin. Likewise, swelling-dependent proteolysis inhibition by insulin and swelling-independent proteolysis inhibition by leucine, a potent activator of p70S6-kinase and 4E-BP1 hyperphosphorylation, in perfused rat liver is insensitive to rapamycin, indicating that at least rapamycin-sensitive mTOR signalling is not involved. Hyperosmotic dehydration in different cell types produces inactivation of signalling components around mTOR, thereby attenuating insulin-induced glucose uptake, glycogen synthesis, and lipogenesis in adipocytes, and MAP-kinase phosphatase MKP-1 expression in hepatoma cells. Direct inactivation of mTOR, stimulation of the AMP-activated protein kinase, and the destabilization of individual proteins may impair mTOR signalling under dehydrating conditions. Further investigation of the crosstalk between the mTOR pathway(s) and hyperosmotic signalling will improve our understanding about the contribution of cell hydration changes in health and disease and will provide further rationale for fluid therapy of insulin-resistant states. [source]

Comparison of the antilipolytic effects of an A1 adenosine receptor partial agonist in normal and diabetic rats

DIABETES OBESITY & METABOLISM, Issue 2 2009
A. K. Dhalla
Introduction and Aims:, Elevated plasma free fatty acid (FFA) concentrations play a role in the pathogenesis of type 2 diabetes (2DM). Antilipolytic agents that reduce FFA concentrations may be potentially useful in the treatment of 2DM. Our previous observation that CVT-3619 lowered plasma FFA and triglyceride concentrations in rats and enhanced insulin sensitivity in rodents with dietary-induced forms of insulin resistance suggested that it might be of use in the treatment of patients with 2DM. The present study was undertaken to compare the antilipolytic effects of CVT-3619 in normal (Sprague Dawley, SD) and Zucker diabetic fatty (ZDF) rats. Results:, ZDF rats had significantly higher fat pad weight, glucose, insulin and FFA concentrations than those of SD rats. EC50 values for forskolin-stimulated FFA release from isolated adipocytes from SD and ZDF rats were 750 and 53 nM, respectively (p < 0.05). Maximal forskolin stimulation of FFA release was significantly (p < 0.01) less in ZDF rats (133 ± 60 ,M) compared with SD rats (332 ± 38 ,M). EC50 values for isoproterenol to increase lipolysis in adipocytes from SD and ZDF rats were 2 and 7 nM respectively. Maximal isoproterenol-stimulated lipolysis was significantly (p < 0.01) lower in adipocytes from ZDF rats (179 ± 23 ,M) compared with SD rats (343 ± 27 ,M). Insulin inhibited lipolysis in adipocytes from SD rats with an IC50 value of 30 pM, whereas adipocytes from ZDF rats were resistant to the antilipolytic actions of insulin. In contrast, IC50 values for CVT-3619 to inhibit the release of FFA from SD and ZDF adipocytes were essentially the same (63 and 123 nM respectively). CVT-3619 inhibited lipolysis more than insulin in both SD (86 vs. 46%, p < 0.001) and ZDF (80 vs. 13%, p < 0.001) adipocytes. In in vivo experiments, CVT-3619 (5 mg/kg, PO) lowered FFA to a similar extent in both groups. Plasma concentrations of CVT-3619 were not different in SD and ZDF rats. There was no significant difference in the messenger RNA expression of the A1 receptors relative to ,-actin expression in adipocytes from SD (0.98 ± 0.2) and ZDF rats (0.99 ± 0.3). Conclusion:, The antilipolytic effects of CVT-3619 appear to be independent of insulin resistance and animal model. [source]

Effects of insulin resistance on endothelial function: possible mechanisms and clinical implications

DIABETES OBESITY & METABOLISM, Issue 10 2008
D Tousoulis
Insulin resistance (IR) is defined as a reduced responsiveness of peripheral tissues to the effects of the hormone, referring to abated ability of insulin in stimulating glucose uptake in peripheral tissues and in inhibiting hepatic glucose output. Insulin has both a vasodilatory effect, which is largely endothelium dependent through the release of nitric oxide, and a vasoconstrictory effect through the stimulation of the sympathetic nervous system and the release of endothelin-1. IR and endothelial dysfunction (ED) are not only linked by common pathogenetic mechanisms, involving deranged insulin signalling pathways, but also by other, indirect to the hormone's actions, mechanisms. Different treatment modalities have been proposed to affect positively both the metabolic effects of insulin and ED. Weight loss has been shown to improve sensitivity to insulin as a result of either altered diet or exercise. Exercise has favourable effects on endothelial function in normal states and in states of disease, in men and women, and throughout the age spectrum and, hence, in IR states. Metformin improves sensitivity to insulin and most likely affects positively ED. Studies have shown that inhibitors of the renin,angiotensin system alter IR favourably, while Angiotensin converting enzyme (ACE) inhibitors and Angiotensin receptor type II (ATII) inhibitors improve ED. Ongoing studies are expected to shed more light on the issue of whether treatment with the thiazolidinediones results in improvement of endothelial function, along with the accepted function of improving insulin sensitivity. Finally, improved endothelial function by such treatments is not in itself proof of reduced risk for atherosclerosis; this remains to be directly tested in clinical trials. [source]

Effects of metformin and oleic acid on adipocyte expression of resistin

DIABETES OBESITY & METABOLISM, Issue 1 2006
R Rea
Aim:, The adipocyte-secreted hormone resistin has been implicated in obesity-induced insulin resistance and type 2 diabetes, but pharmacological and dietary factors that regulate resistin gene expression and the effects of resistin on cellular glucose uptake in muscle have not been clearly defined. Methods:, Expression of resistin mRNA was studied in differentiated 3T3-L1 adipocytes by using real-time semiquantitative reverse transcription-polymerase chain reaction. The effects of resistin on insulin-stimulated and insulin-independent 2-deoxyglucose uptake were evaluated in L6 muscle cells. Results:, Insulin 1 µm and rosiglitazone 10 µm markedly reduced resistin mRNA expression (relative to the control gene TF2D) by 4.7-fold (p < 0.05) and 5.3-fold (p < 0.02), respectively. Similar reductions in resistin mRNA were demonstrated with metformin 100 µm (6.2-fold reduction, p < 0.02) and oleic acid 100 µm (3.9-fold reduction, p < 0.03). Resistin 1 µm significantly reduced maximum insulin-stimulated 2-deoxyglucose uptake in L6 cells from 634 to 383% (relative to 100% for control, p < 0.001), and co-administration of rosiglitazone had no effect on resistin-induced insulin resistance. In the absence of insulin, however, resistin increased glucose uptake dose-dependently (e.g., 1.75-fold at 5 µm, p < 0.001) via a mitogen-activated protein kinase-dependent pathway. Conclusions:, These results demonstrate that various glucose-lowering therapies and oleic acid reduce resistin gene expression in isolated adipocytes, and that resistin impairs insulin-stimulated glucose uptake in skeletal muscle-derived cells. [source]

Insulin therapy and quality of life.

DIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue S1 2009
A review
Abstract Three central goals in the treatment of diabetes mellitus are (1) the avoidance of hyperglycaemia to prevent the development or progression of diabetes complications over time, (2) the avoidance of hypoglycaemia and (3) the maintenance or achievement of good quality of life. Insulin is the most powerful agent that can be used to control blood glucose levels. This article reviews the studies that have investigated the effects of different types of insulin and insulin delivery techniques on quality of life of patients with type 1 or type 2 diabetes. First, the concept of ,quality of life' (QoL) is defined and different ways of measuring QoL are explained. Secondly, the effects of different aspects of insulin therapy on QoL are reviewed: (1) the phenomenon of ,psychological insulin resistance'; (2) the effects of different types of insulin: regular insulin versus short-acting insulin analogues, long-acting insulin analogues or biphasic mixtures; (3) multiple daily injections versus pump therapy. Having multiple complications of diabetes is clearly associated with decreased QoL. Results from large studies such as the Diabetes Control and Complications Trial (DCCT) and United Kingdom Prospective Diabetes Study (UKPDS) suggest that intensive treatment itself does not impair QoL. Recent findings further suggest that pump therapy, compared to multiple daily injections, has beneficial effects on QoL. The fact that multiple tools are used to assess QoL makes it difficult to draw conclusions regarding the effects of different types of insulin on QoL. More work on the standardization of the assessment of QoL in diabetes is urgently needed. Copyright © 2009 John Wiley & Sons, Ltd. [source]

Prevalence and projections of diabetes and pre-diabetes in adults in Sri Lanka,Sri Lanka Diabetes, Cardiovascular Study (SLDCS)

DIABETIC MEDICINE, Issue 9 2008
P. Katulanda
Abstract Aims To determine the prevalence of diabetes mellitus and pre-diabetes (impaired fasting glucose and impaired glucose tolerance) in adults in Sri Lanka. Projections for the year 2030 and factors associated with diabetes and pre-diabetes are also presented. Methods This cross-sectional study was conducted between 2005 and 2006. A nationally representative sample of 5000 adults aged , 18 years was selected by a multi-stage random cluster sampling technique. Fasting plasma glucose was tested in all participants and a 75-g oral glucose tolerance test was performed in non-diabetic subjects. Prevalence was estimated for those > 20 years of age. Results Response rate was 91% (n = 4532), males 40%, age 46.1 ± 15.1 years (mean ± standard deviation). The age,sex standardized prevalence (95% confidence interval) of diabetes for Sri Lankans aged , 20 years was 10.3% (9.4,11.2%) [males 9.8% (8.4,11.2%), females 10.9% (9.7,12.1%), P = 0.129). Thirty-six per cent (31.9,40.1%) of all diabetic subjects were previously undiagnosed. Diabetes prevalence was higher in the urban population compared with rural [16.4% (13.8,19.0%) vs. 8.7% (7.8,9.6%); P < 0.001]. The prevalence of overall, urban and rural pre-diabetes was 11.5% (10.5,12.5%), 13.6% (11.2,16.0%) and 11.0% (10.0,12.0%), respectively. Overall, 21.8% (20.5,23.1%) had some form of dysglycaemia. The projected diabetes prevalence for the year 2030 is 13.9%. Those with diabetes and pre-diabetes compared with normal glucose tolerance were older, physically inactive, frequently lived in urban areas and had a family history of diabetes. They had higher body mass index, waist circumference, waist,hip ratio, systolic/diastolic blood pressure, low-density lipoprotein cholesterol and triglycerides. Insulin was prescribed to 4.4% (2.7,6.1%) of all diabetic subjects. Conclusions One in five adults in Sri Lanka has either diabetes or pre-diabetes and one-third of those with diabetes are undiagnosed. [source]

Insulin and glucose profiles during continuous subcutaneous insulin infusion compared with injection of a long-acting insulin in Type 2 diabetes1

DIABETIC MEDICINE, Issue 5 2008
T. Parkner
Abstract Aims To compare insulin and glucose profiles during basal continuous subcutaneous infusion of a rapid-acting insulin analogue and once daily subcutaneous injection of a long-acting insulin analogue in Type 2 diabetes. Methods Twenty-one patients with Type 2 diabetes treated with oral glucose-lowering agents were randomized in this two-period crossover study to an equivalent 24-h dose of continuous subcutaneous infusion of insulin aspart and subsequently once-daily bedtime subcutaneous injection of insulin glargine, or vice versa, for eight consecutive days. Plasma profiles of insulin and glucose were recorded. Results On the last day of each treatment period, the area under the curve (AUC) for glucose was 10% lower on the continuous subcutaneous infusion regimen compared with the insulin injection regimen (P = 0.002). This was accomplished by a flat exogenous insulin infusion profile compared with a peaking profile with injected insulin (AUC was 74% higher after injection compared with pre-injection levels (P = 0.001)). During the last 6 days in each treatment period, the intra-subject variability of exogenous fasting insulin levels in the mornings was 41% lower during insulin infusion compared with insulin injection (P = 0.012). The corresponding intra-subject variability for fasting glucose only showed a tendency to be lower during infusion as compared to the injection regimen (28%; P = 0.104). Thirteen symptomatic-only or minor hypoglycaemic episodes were recorded during the entire infusion period compared with three episodes during the injection period. Conclusions Basal continuous subcutaneous infusion of a rapid-acting insulin analogue improved plasma insulin (more flat insulin profile with a lower variability) and glucose (lower AUC) profiles compared with once-daily subcutaneous injection of a long-acting insulin analogue in Type 2 diabetes. [source]

Insulin, insulin propeptides and intima-media thickness in the carotid artery in 58-year-old clinically healthy men.

DIABETIC MEDICINE, Issue 2 2002
Insulin Resistance study (AIR), The Atherosclerosis
Abstract Aims To examine the relationship between specific (intact) insulin, insulin propeptides and subclinical atherosclerosis. Methods A cross-sectional study based on a stratified sampling of randomly selected, clinically healthy 58-year-old men (n = 391). Ultrasound examinations of the carotid arteries were performed with measurement of intima-media thickness (IMT) in the common carotid artery and in the carotid artery bulb. Fasting, cross-reacting plasma insulin (RIA), specific (intact) insulin, proinsulin, 32,33 split proinsulin and C-peptide were measured. Results Plasma concentrations of cross-reacting plasma insulin, specific insulin, proinsulin, 32,33 split proinsulin and C-peptide were univariately associated with common carotid artery IMT. Established risk factors such as blood pressure, smoking, apoB, triglycerides, body mass index (BMI), and waist,hip ratio were also related to IMT. After adjustment for smoking, apoB, blood pressure and triglycerides, cross-reacting plasma insulin, proinsulin and C-peptide but not specific insulin and split 32,33 proinsulin remained associated with carotid artery IMT. No associations remained after adjustment for BMI. Conclusions Fasting plasma proinsulin, C-peptide, and insulin by cross-reacting RIA was associated with common carotid artery IMT independent of several conventional risk factors for atherosclerosis. The multicollinearity between the insulin peptides and propeptides makes it difficult to clarify the exact role of each peptide. [source]

Serum Insulin and Leptin Levels and Valproate-associated Obesity

EPILEPSIA, Issue 12 2003
Alberto Verrotti
No abstract is available for this article. [source]

Eating disorders in females with type 1 diabetes: an update of a meta-analysis

EUROPEAN EATING DISORDERS REVIEW, Issue 4 2002
Søren Nielsen
Abstract Objective: Firstly to provide a quantitative summary of existing studies on the occurrence of eating disorders (ED) in females with type 1 diabetes (IDDM), with the focus on retinopathy and insulin misuse for the different eating disorders. Secondly to disseminate knowledge about useful statistical tools. Research Design and Methods: Data were extracted from the relevant case,control and follow-up studies. Odds ratios (OR) and risk differences (RD) were the main effect sizes analysed. Analyses were based on ,exact' methods as many studies are sparse. Data and findings are presented in sufficient detail for re-analysis. Results: An hypothesis of an increase in Anorexia Nervosa (AN) in IDDM is not supported by existing evidence. Bulimia Nervosa is increased (OR,=,2.9 (95%CI: 1.03 to 8.4); pOR,=,0.04) in IDDM. Both ED-NOS and subthreshold ED is increased (OR ,2; pOR,<,0.001) in females with IDDM. Co-existing ED in IDDM increases the overall common OR for retinopathy to 4.8 (95%CI: 3.0 to 7.8); pOR,<,0.00001, and the overall mean RD is 33% (95%CI: 25% to 42%); pRD,<,0.001. Insulin misuse (IM) is increased when ED co-exists with IDDM: OR 12.6 (95%CI: 7.8 to 21.1); pOR,<,0.00001, and mean RD is 40% (95%CI: 29% to 50%); pRD,<,0.001. Conclusions: ED-NOS and subthreshold ED seem to be the quantitatively most important EDs in type 1 diabetic females. Mismanagement of diabetes in the form of IM is frequent in eating disordered IDDM probands. Early occurrence of retinopathy and other complications is an increased risk in concurrent cases, as is premature death. The implications of Binge Eating Disorder (BED) and overweight needs to be elucidated for both type 1 and type 2 diabetes. Copyright © 2002 John Wiley & Sons, Ltd and Eating Disorders Association. [source]

Insulin, blood pressure and elevated Na+/H+ exchange activity , novel therapeutic implications

EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 3 2001
M. Tepel
No abstract is available for this article. [source]

Insulin promotes functional induction of silent synapses in differentiating rat neocortical neurons

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2001
Daniela Plitzko
Abstract Long-term synaptic plasticity is thought to underlie synaptic reorganization phenomena that occur during neocortical development. Recently, it has been proposed, that the functional induction of AMPA receptors at silent glutamatergic synapses is of major importance in activity-dependent, developmental plasticity. To investigate the mechanisms involved in the developmental regulation of silent synapses, we analysed the functional maturation of the thalamocortical projection in culture. A large proportion of the thalamocortical synapses were functionally silent at an early stage in vitro. During further differentiation, the incidence of silent synapses decreased drastically, indicating a conversion of silent into functional synapses. Chronic blockade of spontaneous network activity by addition of tetrodotoxin to the culture medium strongly impaired this developmental maturation. Moreover, the developmental decline in the proportion of silent synapses was dramatically accelerated by chronic addition of the neurotrophic factor, insulin. This effect of insulin was partly dependent on spontaneous activity. Thus, insulin appears to be involved in the modulation of long-term developmental plasticity at immature glutamatergic synapses. [source]

Role of insulin, insulin-like growth factor-1, hyperglycaemic food and milk consumption in the pathogenesis of acne vulgaris

EXPERIMENTAL DERMATOLOGY, Issue 10 2009
Bodo C. Melnik
Abstract:, It is the purpose of this viewpoint article to delineate the regulatory network of growth hormone (GH), insulin, and insulin-like growth factor-1 (IGF-1) signalling during puberty, associated hormonal changes in adrenal and gonadal androgen metabolism, and the impact of dietary factors and smoking involved in the pathogenesis of acne. The key regulator IGF-1 rises during puberty by the action of increased GH secretion and correlates well with the clinical course of acne. In acne patients, associations between serum levels of IGF-1, dehydroepiandrosterone sulphate, dihydrotestosterone, acne lesion counts and facial sebum secretion rate have been reported. IGF-1 stimulates 5,-reductase, adrenal and gonadal androgen synthesis, androgen receptor signal transduction, sebocyte proliferation and lipogenesis. Milk consumption results in a significant increase in insulin and IGF-1 serum levels comparable with high glycaemic food. Insulin induces hepatic IGF-1 secretion, and both hormones amplify the stimulatory effect of GH on sebocytes and augment mitogenic downstream signalling pathways of insulin receptors, IGF-1 receptor and fibroblast growth factor receptor-2b. Acne is proposed to be an IGF-1-mediated disease, modified by diets and smoking increasing insulin/IGF1-signalling. Metformin treatment, and diets low in milk protein content and glycaemic index reduce increased IGF-1 signalling. Persistent acne in adulthood with high IGF-1 levels may be considered as an indicator for increased risk of cancer, which may require appropriate dietary intervention as well as treatment with insulin-sensitizing agents. [source]

Aerobic exercise acutely improves insulin- and insulin-like growth factor-1-mediated vasorelaxation in hypertensive rats

EXPERIMENTAL PHYSIOLOGY, Issue 5 2010
Ai-Lun Yang
Limited information is available concerning the effects of aerobic exercise on vasorelaxation in hypertension. The aim of this study was to investigate the effects of a single bout of aerobic exercise on insulin- and insulin-like growth factor-1 (IGF-1)-induced vasorelaxation in hypertensive rats. Four-month-old spontaneously hypertensive rats were randomly divided into a sedentary group (SHR) and an exercise group (SHR+Ex) subjected to a single bout of aerobic exercise conducted by treadmill running at 21 m min,1 for 1 h. Age-matched Wistar,Kyoto rats were used as a normotensive control group (WKY). Insulin- and IGF-1-induced vasorelaxant responses in the three groups were evaluated by using isolated aortic rings, with or without endothelial denudation, in organ baths. Possible roles of phosphatidylinositol 3-kinase (PI3K) and nitric oxide synthase (NOS) involved in the NO-dependent vasorelaxation were examined by adding selective inhibitors. The role of superoxide was also clarified by adding superoxide dismutase (SOD). In addition, the endothelium-independent vascular responses to sodium nitroprusside (SNP), a NO donor, were examined. The insulin- and IGF-1-induced vasorelaxation was significantly (P < 0.05) decreased in the SHR group compared with the WKY group. This decreased response in SHR was improved by exercise. These vasorelaxant responses among the three groups became similar after endothelial denudation and pretreatment with the PI3K inhibitor, NOS inhibitor or SOD. Also, no difference among groups was found in the SNP-induced vasorelaxation. We concluded that a single bout of aerobic exercise acutely improves insulin- and IGF-1-mediated vasorelaxation in an endothelium-dependent manner in hypertensive rats. [source]

Insulin is a kinetic but not a thermodynamic inhibitor of amylin aggregation

FEBS JOURNAL, Issue 12 2009
Wei Cui
One of the most important pathological features of type 2 diabetes is the formation of islet amyloid, of which the major component is amylin peptide. However, the presence of a natural inhibitor such as insulin may keep amylin stable and physiologically functional in healthy individuals. Some previous studies demonstrated that insulin was a potent inhibitor of amylin fibril formation in vitro, but others obtained contradictory results. Hence, it is necessary to elucidate the effects of insulin on amylin aggregation. Here we report that insulin is a kinetic inhibitor of amylin aggregation, only keeping its inhibitory effect for a limited time period. Actually, insulin promotes amylin aggregation after long-term incubation. Furthermore, we found that this promotional effect could be attributed to the copolymerization of insulin and amylin. We also found that insulin copolymerized with amylin monomer or oligomer rather than preformed amylin fibrils. These results suggest that the interaction between insulin and amylin may contribute not only to the inhibition of amylin aggregation but also to the coaggregation of both peptides in type 2 diabetes. [source]

Chitosan Hydrogel-Capped Porous SiO2 as a pH Responsive Nano-Valve for Triggered Release of Insulin

ADVANCED FUNCTIONAL MATERIALS, Issue 5 2009
Jianmin Wu
Abstract A pH responsive, chitosan-based hydrogel film is used to cap the pores of a porous SiO2 layer. The porous SiO2 layer is prepared by thermal oxidation of an electrochemically etched Si wafer, and the hydrogel film is prepared by reaction of chitosan with glycidoxypropyltrimethoxysilane (GPTMS). Optical reflectivity spectroscopy and scanning electron microscopy (SEM) confirm that the bio-polymer only partially infiltrates the porous SiO2 film, generating a double layer structure. The optical reflectivity spectrum displays Fabry,Pérot interference fringes characteristic of a double layer, which is characterized using reflective interferometric Fourier transform spectroscopy (RIFTS). Monitoring the position of the RIFTS peak corresponding to the hydrogel layer allows direct, real-time observation of the reversible volume phase transition of the hydrogel upon cycling of pH in the range 6.0,7.4. The swelling ratio and response time are controlled by the relative amount of GPTMS in the hydrogel. The pH-dependent volume phase transition can be used to release insulin trapped in the porous SiO2 layer underneath the hydrogel film. At pH 7.4, the gel in the top layer effectively blocks insulin release, while at pH 6.0 insulin penetrates the swollen hydrogel layer, resulting in a steady release into solution. [source]

Autonomic Nervous System, Insulin, and Migraine

HEADACHE, Issue 9 2008
Antonio Perciaccante MD
No abstract is available for this article. [source]

Cardiovascular and Metabolic Effects of High-dose Insulin in a Porcine Septic Shock Model

ACADEMIC EMERGENCY MEDICINE, Issue 4 2010
Joel S. Holger MD
Abstract Objectives:, High-dose insulin (HDI) has inotropic and vasodilatory properties in various clinical conditions associated with myocardial depression. The authors hypothesized that HDI will improve the myocardial depression produced by severe septic shock and have beneficial effects on metabolic parameters. In an animal model of severe septic shock, this study compared the effects of HDI treatment to normal saline (NS) resuscitation alone. Methods:, Ten pigs were randomized to an insulin (HDI) or NS group. All were anesthetized and instrumented to monitor cardiovascular function. In both arms, Escherichia coli endotoxin lipopolysaccharide (LPS) and NS infusions were begun. LPS was titrated to 20 ,g/kg/hour over 30 minutes and continued for 5 hours, and saline was infused at 20 mL/kg/hour throughout the protocol. Dextrose (50%) was infused to maintain glucose in the 60,150 mg/dL range, and potassium was infused to maintain a level greater than 2.8 mmol/L. At 60 minutes, the HDI group received an insulin infusion titrated from 2 to 10 units/kg/hour over 40 minutes and continued at that rate throughout the protocol. Survival, heart rate (HR), mean arterial pressure (MAP), pulmonary artery and central venous pressure, cardiac output, central venous oxygen saturation (SVO2), and lactate were monitored for 5 hours (three pigs each arm) or 7 hours (two pigs each arm) or until death. Cardiac index, systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), O2 delivery, and O2 consumption were derived from measured data. Outcomes from the repeated-measures analysis were modeled using a mixed-effects linear model that assumed normally distributed errors and a random effect at the subject level. Results:, No significant baseline differences existed between arms at time 0 or 60 minutes. Survival was 100% in the HDI arm and 60% in the NS arm. Cardiovascular variables were significantly better in the HDI arm: cardiac index (p < 0.001), SVR (p < 0.003), and PVR (p < 0.01). The metabolic parameters were also significantly better in the HDI arm: SVO2 (p < 0.01), O2 delivery (p < 0.001), and O2 consumption (p < 0.001). No differences in MAP, HR, or lactate were found. Conclusions:, In this animal model of endotoxemic-induced septic shock that results in severe myocardial depression, HDI is associated with improved cardiac function compared to NS resuscitation alone. HDI also demonstrated favorable metabolic, pulmonary, and peripheral vascular effects. Further studies may define a potential role for the use of HDI in the resuscitation of septic shock. ACADEMIC EMERGENCY MEDICINE 2010; 17:429,435 © 2010 by the Society for Academic Emergency Medicine [source]

Central and peripheral autoantigen presentation in immune tolerance

IMMUNOLOGY, Issue 2 2004
Alberto Pugliese
Summary Recent studies in both humans and experimental rodent models provide new insight into key mechanisms regulating tolerance to self-molecules. These recent advances are bringing about a paradigm shift in our views about tolerance to self-molecules with tissue-restricted expression. There is, indeed, mounting evidence that selected antigen-presenting cells (APCs) have the ability to synthesize and express self-molecules, and that such expression is critical for self-tolerance. Insulin is a key hormone produced exclusively by pancreatic ,-cells and a critical autoantigen in type 1 diabetes. It provides an excellent example of a molecule with tissue-restricted expression that is expressed ectopically by APCs. The fact that APCs expressing insulin have been demonstrated in both thymus and peripheral lymphoid tissues suggests that they may play a role in insulin presentation in both the central and peripheral immune system. Experimental mice, in which insulin expression was altered, provide functional data that help to dissect the role of insulin presentation by APCs of the immune system. This review addresses recent literature and emerging concepts about the expression of self-molecules in the thymus and peripheral lymphoid tissues and its relation to self-tolerance. [source]

Insulin, insulin analogues and cancer: no cause for panic

INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 5 2010
G. A. Thomson
No abstract is available for this article. [source]

Primary care physician beliefs about insulin initiation in patients with type 2 diabetes

INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 6 2008
R. P. Hayes
Summary Background:, Insulin is the most effective drug available to achieve glycaemic goals in patients with type 2 diabetes. Yet, there is reluctance among physicians, specifically primary care physicians (PCPs) in the USA, to initiate insulin therapy in these patients. Aims:, To describe PCPs' attitudes about the initiation of insulin in patients with type 2 diabetes and identify areas in which there is a clear lack of consensus. Methods:, Primary care physicians practicing in the USA, seeing 10 or more patients with type 2 diabetes per week, and having > 3 years of clinical practice were surveyed via an internet site. The survey was developed through literature review, qualitative study and expert panel. Results:, Primary care physicians (n = 505, mean age = 46 years, 81% male, 62% with > 10 years practice; 52% internal medicine) showed greatest consensus on attitudes regarding risk/benefits of insulin therapy, positive experiences of patients on insulin and patient fears or concerns about initiating insulin. Clear lack of consensus was seen in attitudes about the metabolic effects of insulin, need for insulin therapy, adequacy of self-monitoring blood glucose, time needed for training and potential for hypoglycaemia in elderly patients. Conclusions:, The beliefs of some PCPs are inconsistent with their diabetes treatment goals (HbA1c , 7%). Continuing medical education programmes that focus on increasing primary care physician knowledge about the progression of diabetes, the physiological effects of insulin, and tools for successfully initiating insulin in patients with type 2 diabetes are needed. [source]

Biphasic insulin aspart 70/30 vs. insulin glargine in insulin naïve type 2 diabetes patients: modelling the long-term health economic implications in a Swedish setting

INTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 6 2008
G. Goodall
Summary Objectives:, To evaluate the long-term clinical and economic outcomes of biphasic insulin aspart 70/30 (BIAsp 70/30) treatment vs. insulin glargine in insulin naïve, type 2 diabetes patients failing oral antidiabetic drugs in a Swedish setting. Methods:, A published and validated computer simulation model (the CORE Diabetes Model) was used to project life expectancy, quality-adjusted life expectancy (QALE) and costs over patient lifetimes. Cohort characteristics [54.5% male, mean age 52.4 years, 9 years mean diabetes duration, mean glycosylated haemoglobin (HbA1c) 9.77%] and treatment effects were based on results from the Initiate Insulin by Aggressive Titration and Education (INITIATE) clinical trial. Direct medical costs were accounted in 2006 Swedish Kronor (SEK) and economic and clinical benefits were discounted at 3% per annum. Results:, Biphasic insulin aspart 70/30 treatment when compared with insulin glargine treatment was associated with improvements in discounted life expectancy of 0.21 years (13.10 vs. 12.89 years) and QALE of 0.21 quality-adjusted life years (QALYs) (9.16 vs. 8.96 QALYs). Reductions in the incidence of diabetes-related complications in the BIAsp 70/30 treatment arm led to reduced total costs of SEK 10,367 when compared with insulin glargine (SEK 396,475 vs. SEK 406,842) over patient lifetimes. BIAsp 70/30 treatment was projected to be dominant (cost and lifesaving) when compared with insulin glargine in the base case analysis. Conclusions:, Biphasic insulin aspart 70/30 treatment was associated with improved clinical outcomes and reduced costs compared with insulin glargine treatment over patient lifetimes. These results were driven by improved HbA1c levels associated with BIAsp 70/30 compared with insulin glargine and the accompanying reduction in diabetes-related complications despite increases in body mass index. [source]

Effects of phorbol ester-sensitive PKC (c/nPKC) activation on the production of adiponectin in 3T3-L1 adipocytes

IUBMB LIFE, Issue 6 2009
Takahide Ikeda
Abstract PPAR, plays a key role in adipocyte specific gene expression. In this study, we assessed the effects of phorbol ester (TPA)-sensitive PKC (c/nPKC) activation on the expression of adipocyte specific genes and inflammation related genes. Treatment with both TPA and TNF, decreased mRNA levels of PPAR,, aP2, LPL and adiponectin. TNF,, but not TPA, increased IL-6 and MCP-1 mRNA levels, Next, we investigated the effects of ligands which activate c/nPKC. Insulin and angiotensin II (AII), but not high glucose, reduced PPAR,, aP2 and adiponectin mRNA levels. AII-induced suppression of these genes was restored in the presence of Go6976, a specific c/nPKC inhibitor, and candesartan, an AII receptor blocker. The effect of reduced insulin was prevented by Go6976 and LY294002, a specific PI 3-kinase inhibitors. Our results indicate that activation of c/nPKC could debilitate and/or might deteriorate insulin sensitivity in vivo, through the reduction of PPAR, and adiponectin expression in adipocyte. © 2009 IUBMB IUBMB Life, 61(6): 644,650, 2009 [source]

Nitric Oxide: The "Second Messenger" of Insulin

IUBMB LIFE, Issue 5 2000
Nighat N. Kahn
Abstract Incubation of various tissues, including heart, liver, kidney, muscle, and intestine from mice and erythrocytes or their membrane fractions from humans, with physiologic concentration of insulin resulted in the activation of a membrane-bound nitric oxide synthase (NOS). Activation of NOS and synthesis of NO were stimulated by the binding of insulin to specific receptors on the cell surface. A Lineweaver-Burk plot of the enzymatic activity demonstrated that the stimulation of NOS by insulin was related to the decrease in the Km for L-arginine, the substrate for NOS, with a simultaneous increase of Vmax. Addition of NG-nitro-L-arginine methyl ester (LNAME), a competitive inhibitor of NOS, to the reaction mixture completely inhibited the hormone-stimulated NO synthesis in all tissues. Furthermore, NO had an insulin-like effect in stimulating glucose transport and glucose oxidation in muscle, a major site for insulin action. Addition of NAME to the reaction mixture completely blocked the stimulatory effect of insulin by inhibiting both NO production and glucose metabolism, without affecting the hormone-stimulated tyrosine or phosphatidylinositol 3-kinases of the membrane preparation. Injection of NO in alloxan-induced diabetic mice mimicked the effect of insulin in the control of hyperglycemia (i.e., lowered the glucose content in plasma). However, injection of NAME before the administration of insulin to diabetic-induced and nondiabetic mice inhibited not only the insulin-stimulated increase of NO in plasma but also the glucose-lowering effect of insulin. [source]

Antidiabetic Drug Therapy of African-American and White Community-Dwelling Elderly Over a 10-Year Period

JOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 12 2003
Catherine I. Lindblad PharmD
Objectives: To determine the prevalence and predictors of antidiabetic medication use over a 10-year period in a general population of African-American and white community-dwelling elderly. Design: Survey. Setting: Five adjacent counties (one urban and four rural) in the Piedmont area of North Carolina. Participants: Those aged 65 and older present at the baseline (n=4,136), second (n=3,234), third (n=2,508), and fourth (n=1,633) in-person waves of the Duke Established Populations for Epidemiologic Studies of the Elderly. Measurements: The use of six discrete categories of antidiabetic medications (insulin, first-generation oral sulfonylureas, second-generation oral sulfonylureas, metformin, oral combination therapy, and insulin combination therapy) was determined. Multivariate analyses, using weighted data adjusted for sampling design, were conducted to assess the association between antidiabetic medication use and race and other sociodemographic, health-status, and access-to-healthcare factors at baseline and 10 years later. Results: Antidiabetic medications were taken by 21.4% of the population at baseline; this increased to 28.1% at the 10-year follow-up (P<.001). Insulin was the most commonly used drug at baseline (7.9%). The use of second-generation sulfonylureas increased, and use of first-generation sulfonylureas decreased over the 10-year time period. Combination antidiabetic therapy and metformin use was infrequent throughout the study. Multivariate analyses revealed that, at baseline, African Americans were nearly twice as likely (adjusted odds ratio (AOR)=1.93, 95% confidence interval (CI)=1.46,2.54) to receive any antidiabetic medication as their white counterparts. Other significant (P<.05) factors were hypertension (AOR=1.38, 95% CI=1.03,1.84), stroke (AOR=1.98, 95% CI=1.43,2.73), one or more mobility difficulties (AOR=1.29, 95% CI=1.01,1.66), continuity of care (AOR=1.74, 95% CI=1.20,2.54), and multiple doctor visits (1,4 visits, AOR=1.69, 95% CI=1.08,2.65; ,5 visits, AOR=3.15, 95% CI=1.95,5.07). Being underweight (AOR=0.45, 95% CI=0.30,0.67) and being cognitively impaired (AOR=0.60, 95% CI=0.41,0.87) were factors significantly (P<.05) associated with a decreased risk of antidiabetic medication use. At the 10-year follow-up, similar trends were seen associating these sociodemographic, health-status, and access-to-healthcare factors with antidiabetic medication use. Conclusion: Antidiabetic medication use is common and increases over time for community-dwelling elderly. Race is significantly associated with antidiabetic medication use, even after controlling for other sociodemographic, health-status, and access-to-healthcare variables. [source]

Dietary amino acids fed in free form and as protein components do not differently affect postprandial plasma insulin, glucagon, growth hormone and corticosterone responses in rats

JOURNAL OF ANIMAL PHYSIOLOGY AND NUTRITION, Issue 7-8 2006
J. A. Nolles
Summary This study examined, whether the postprandial fate of dietary amino acids from different amino acid sources is regulated by the responses of insulin, glucagon, corticosterone and growth hormone (GH). Male Wistar rats were cannulated in the vena jugularis and assigned to dietary groups. The diets contained 21% casein or the same amino acids in free form. In the free amino acid diets, methionine level was varied between the groups. The feed was supplied in two distinct meals. In previous experiments it was established that oxidative amino acid losses of the free amino acid diets and protein diets were different. After 3 weeks on those diets, it appeared that the differences in postprandial oxidative losses had been diminished. GH was measured every 12 min, from 144 min before the start of the experimental meal over the following 144 min. Insulin and corticosterone were measured six times from the start of the meal until 270 min after the meal. No differences have been observed between the hormonal responses to both meals at day 5 and at day 26. In conclusion, it has been found that the differences in the oxidative losses between protein and free amino acid meals are not mediated by the combined action of the insulin, glucagon, corticosterone and GH. Postprandial catabolism of amino acids is most probably regulated by substrate induction. [source]

Effects of rumen-protected methionine in a low protein ration on metabolic traits and performance of early lactating cows as opposed to rations with elevated crude protein content

JOURNAL OF ANIMAL PHYSIOLOGY AND NUTRITION, Issue 5 2000
T. F. Kröber
Summary A 5-week experiment with 24 multiparous early lactating Brown Swiss cows was conducted to investigate the effects of supplementary rumen-protected methionine in conjunction with dietary protein reduction on metabolism and performance after 1 week of control measurement. Three rations containing 175, 150 and 125 g of crude protein/kg feed dry matter were supplemented with methionine. The fourth ration, also only containing 125 g of crude protein/kg dry matter, remained unsupplemented. The four treatment groups had a similar metabolic supply of other essential amino acids, protein and energy, as calculated by various approaches. The two low protein rations were, however, slightly deficient in ruminally degraded protein. Treatment effects remained low on feed intake, forage meal pattern, milk yield and fat as well as lactose content. In contrast, the content and yield of milk protein significantly declined only in the unsupplemented low protein ration relative to the initial value. Compared with this ration, the decline in milk protein yield was clearly delayed in the supplemented low protein ration. Blood plasma methionine tended to be reduced without supplementation and to be increased with additional methionine. Supplementation of methionine reduced other plasma amino acids. Plasma insulin, glucose, lactate, ketone bodies and aspartate amino transferase activity indicated a certain liver stress and a somewhat elevated energy requirement with high and particularly with low protein content (when unsupplemented). Methionine improved metabolic protein utilization, followed by the lowest plasma, urine and milk urea levels in the supplemented low protein diet. In conclusion, no major adverse effects were assessed under the conditions tested. Supplementation of methionine may nevertheless be useful in rations with particularly low protein content fed to early lactating cows in order to prevent negative long-term effects which were only visible here as trends. Zusammenfassung Auswirkungen von pansengeschütztem Methionin in einer Niedrigproteinration im Vergleich zu Rationen mit erhöhtem Rohproteingehalt auf Stoffwechselmerkmale und Leistung von frischlaktierenden Milchkühen In einem fünfwöchigen Experiment mit 24 frischlaktierenden Braunviehkühen wurden die Auswirkungen einer Ergänzung mit pansengeschütztem Methionin bei gleichzeitiger Reduktion der Proteinzufuhr nach einer einwöchigen Kontrollphase geprüft. Drei Rationen mit 175, 150 und 125 g Rohprotein/kg T wurden mit Methionin ergänzt. Eine weitere Variante, ebenfalls nur mit 125 g Rohprotein/kg T, wurde nicht supplementiert. Die vier Varianten stellten gemäß verschiedener Futterbewertungsysteme eine vergleichbare metabolische Versorgung mit den übrigen essentiellen Aminosäuren, Protein und Energie sicher. Die Niedrigproteinvarianten enthielten allerdings etwas zu wenig pansenabbaubares Protein. Futteraufnahme, Muster des Grundfutterverzehrs, Milchleistung sowie Fett-und Laktosegehalt der Milch zeigten nur geringe Reaktion auf die Behandlungen. Milchproteingehalt und -menge waren nur in der nicht ergänzten Niedrigproteinvariante relativ zum Ausgangswert signifikant verringert. Im Vergleich zur unsupplementierten Niedrigproteinration war dagegen der Abfall mit Ergänzung deutlich verzögert. Gegenüber dem Ausgangswert war die Methioninkonzentration im Blutplasma ohne Ergänzung tendenziell erniedrigt, mit Ergänzung erhöht. Es erfolgte eine Verringerung der Plasmakonzentration anderer Aminosäuren durch die Methioninergänzung der Niedrigproteinration. Die Plasmaniveaus von Insulin, Glucose, Laktat, Ketonkörpern und Aspartataminotransferase-Aktivität lassen auf eine gewisse Leberbelastung und einen etwas höheren Energiebedarf mit hohem und besonders mit niedrigem Proteingehalt (unsupplementiert) schließen. Die Zulage an Methionin verbesserte die metabolische Proteinverwertung, so dass die Harnstoffgehalte in Blut, Milch und Harn in dieser Niedrigproteinvariante am niedrigsten waren. Insgesamt ergaben sich keine grösseren ungünstigen Effekte unter den getesteten Bedingungen. Dennoch könnte die Ergänzung von Rationen mit besonders niedrigem Rohproteingehalt mit Methionin beim Einsatz an frischlaktierende Kühe hilfreich sein, um negative Langzeitwirkungen zu verhindern, die sich hier lediglich andeuteten. [source]