Posts Tagged ‘Insulin’

Specific Glucose-Induced Control of Insulin Receptor Substrate-2 Expression Is Mediated via Ca2+-Dependent Calcineurin/NFAT Signaling in Primary Pancreatic Islet {beta}-Cells

September 26th, 2011 admin

OBJECTIVE

Insulin receptor substrate-2 (IRS-2) plays an essential role in pancreatic islet β-cells by promoting growth and survival. IRS-2 turnover is rapid in primary β-cells, but its expression is highly regulated at the transcriptional level, especially by glucose. The aim was to investigate the molecular mechanism on how glucose regulates IRS-2 gene expression in β-cells.

RESEARCH DESIGN AND METHODS

Rat islets were exposed to inhibitors or subjected to adenoviral vector-mediated gene manipulations and then to glucose-induced IRS-2 expression analyzed by real-time PCR and immunoblotting. Transcription factor nuclear factor of activated T cells (NFAT) interaction with IRS-2 promoter was analyzed by chromatin immunoprecipitation assay and glucose-induced NFAT translocation by immunohistochemistry.

RESULTS

Glucose-induced IRS-2 expression occurred in pancreatic islets β-cell in vivo but not in liver. Modulating rat islet β-cell Ca2+ influx with nifedipine or depolarization demonstrated that glucose-induced IRS-2 gene expression was dependent on a rise in intracellular calcium concentration derived from extracellular sources. Calcineurin inhibitors (FK506, cyclosporin A, CAIN) abolished glucose-induced IRS-2 mRNA and protein levels, whereas expression of a constitutively active calcineurin increased them. Specific inhibition of NFAT with VIVIT prevented a glucose-induced IRS-2 transcription. NFATc1 translocation to the nucleus in response to glucose and association of NFATc1 to conserved NFAT binding sites in the IRS-2 promoter were demonstrated.

CONCLUSIONS

The mechanism behind glucose-induced transcriptional control of IRS-2 gene expression specific to the islet β-cell is mediated by the Ca2+/calcineurin/NFAT pathway. This novel insight into the IRS-2 regulation could provide novel therapeutic means in type 2 diabetes to maintain an adequate functional mass.


Diabetes Journal publish ahead of print articles

Posted in Diabetes Signs Tags: , , , , , , , , , , , , , , No Comments »

Role of Lipid Peroxidation and PPAR-{delta} in Amplifying Glucose-Stimulated Insulin Secretion

September 9th, 2011 admin

OBJECTIVE

Previous studies show that polyunsaturated fatty acids (PUFAs) increase the insulin secretory capacity of pancreatic β-cells. We aimed at identifying PUFA-derived mediators and their cellular targets that are involved in the amplification of insulin release from β-cells preexposed to high glucose levels.

RESEARCH DESIGN AND METHODS

The content of fatty acids in phospholipids of INS-1E β-cells was determined by lipidomics analysis. High-performance liquid chromatography was used to identify peroxidation products in β-cell cultures. Static and dynamic glucose-stimulated insulin secretion (GSIS) assays were performed on isolated rat islets and/or INS-1E cells. The function of peroxisome proliferator–activated receptor- (PPAR-) in regulating insulin secretion was investigated using pharmacological agents and gene expression manipulations.

RESULTS

High glucose activated cPLA2 and, subsequently, the hydrolysis of arachidonic and linoleic acid (AA and LA, respectively) from phospholipids in INS-1E cells. Glucose also increased the level of reactive oxygen species, which promoted the peroxidation of these PUFAs to generate 4-hydroxy-2E-nonenal (4-HNE). The latter mimicked the GSIS-amplifying effect of high glucose preexposure and of the PPAR- agonist GW501516 in INS-1E cells and isolated rat islets. These effects were blocked with GSK0660, a selective PPAR- antagonist, and the antioxidant N-acetylcysteine or by silencing PPAR- expression. High glucose, 4-HNE, and GW501516 also induced luciferase expression in a PPAR-–mediated transactivation assay. Cytotoxic effects of 4-HNE were observed only above the physiologically effective concentration range.

CONCLUSIONS

Elevated glucose levels augment the release of AA and LA from phospholipids and their peroxidation to 4-HNE in β-cells. This molecule is an endogenous ligand for PPAR-, which amplifies insulin secretion in β-cells.


Diabetes Journal publish ahead of print articles

Posted in Diabetes Signs Tags: , , , , , , , No Comments »

Brain GLP-1 Signaling Regulates Femoral Artery Blood Flow and Insulin Sensitivity Through Hypothalamic PKC-{delta}

August 8th, 2011 admin

OBJECTIVE

Glucagon-like peptide 1 (GLP-1) is a gut-brain hormone that regulates food intake, energy metabolism, and cardiovascular functions. In the brain, through a currently unknown molecular mechanism, it simultaneously reduces femoral artery blood flow and muscle glucose uptake. By analogy to pancreatic β-cells where GLP-1 activates protein kinase C (PKC) to stimulate insulin secretion, we postulated that PKC enzymes would be molecular targets of brain GLP-1 signaling that regulate metabolic and vascular function.


RESEARCH DESIGN AND METHODS

We used both genetic and pharmacological approaches to investigate the role of PKC isoforms in brain GLP-1 signaling in the conscious, free-moving mouse simultaneous with metabolic and vascular measurements.


RESULTS

In normal wild-type (WT) mouse brain, the GLP-1 receptor (GLP-1R) agonist exendin-4 selectively promotes translocation of PKC- (but not -βII, -α, or -) to the plasma membrane. This translocation is blocked in Glp1r–/– mice and in WT mice infused in the brain with exendin-9, an antagonist of the GLP-1R. This mechanism coordinates both blood flow in the femoral artery and whole-body insulin sensitivity. Consequently, in hyperglycemic, high-fat diet–fed diabetic mice, hypothalamic PKC- activity was increased and its pharmacological inhibition improved both insulin-sensitive metabolic and vascular phenotypes.


CONCLUSIONS

Our studies show that brain GLP-1 signaling activates hypothalamic glucose-dependent PKC- to regulate femoral artery blood flow and insulin sensitivity. This mechanism is attenuated during the development of experimental hyperglycemia and may contribute to the pathophysiology of type 2 diabetes.

Diabetes Journal publish ahead of print articles

Posted in Diabetes Signs Tags: , , , , , , , , , , , , No Comments »

Pumping Insulin Like a Champion

July 10th, 2011 admin

A few Diabetes Signs products I can recommend:

Pumping Insulin Like a Champion
Books for adults and children to improve the lives of type 1 diabetics.
Pumping Insulin Like a Champion

Posted in Diabetes Signs Tags: , , , No Comments »

Sanofi GetGoal Programme On Lyxumia(R) (lixisenatide), As An Add-On To Basal Insulin, Shows Significant Positive Phase III Results

June 2nd, 2011 admin

Sanofi announced today that new results from a Phase III study showed that the investigational product Lyxumia® (lixisenatide), when used as an add-on therapy to basal insulin (in association with or without metformin), achieved its primary efficacy endpoint of significantly reducing HbA1c versus placebo for patients with type 2 diabetes without significantly increasing the…
Diabetes News From Medical News Today

Posted in Diabetes Signs Tags: , , , , , , , , , , , , No Comments »

What Is Diabetes? How Diabetes Works Understanding Insulin What Causes Diabetes? What Are the Symptoms of Diabetes?

May 7th, 2011 admin

What Is Diabetes? How Diabetes Works Understanding Insulin What Causes Diabetes? What Are the Symptoms of Diabetes?

What Is Diabetes?
How Diabetes Works
Type 1 Diabetes
Understanding Insulin and Type 1 Diabetes
Who Gets Type 1 Diabetes?
What Causes Type 1 Diabetes?
What Are the Symptoms of Type 1 Diabetes?
How Is Type 1 Diabetes Diagnosed?
How Is Type 1 Diabetes Managed?
Consequences of Uncontrolled Type 1 Diabetes
Type 2 Diabetes
What Is Type 2 Diabetes?
Type 2 Diabetes in Children
Who Gets Type 2 Diabetes?
What Causes Type 2 Diabetes?
What Are the Symptoms of Typ

List Price: $ 4.37

Price:

Posted in Diabetes Signs Tags: , , , , , No Comments »

Altered Skeletal Muscle Lipase Expression and Activity Contribute to Insulin Resistance in Humans

April 20th, 2011 admin

OBJECTIVE

Insulin resistance is associated with elevated content of skeletal muscle lipids, including triacylglycerols (TAGs) and diacylglycerols (DAGs). DAGs are by-products of lipolysis consecutive to TAG hydrolysis by adipose triglyceride lipase (ATGL) and are subsequently hydrolyzed by hormone-sensitive lipase (HSL). We hypothesized that an imbalance of ATGL relative to HSL (expression or activity) may contribute to DAG accumulation and insulin resistance.


RESEARCH DESIGN AND METHODS

We first measured lipase expression in vastus lateralis biopsies of young lean (n = 9), young obese (n = 9), and obese-matched type 2 diabetic (n = 8) subjects. We next investigated in vitro in human primary myotubes the impact of altered lipase expression/activity on lipid content and insulin signaling.


RESULTS

Muscle ATGL protein was negatively associated with whole-body insulin sensitivity in our population (r = –0.55, P = 0.005), whereas muscle HSL protein was reduced in obese subjects. We next showed that adenovirus-mediated ATGL overexpression in human primary myotubes induced DAG and ceramide accumulation. ATGL overexpression reduced insulin-stimulated glycogen synthesis (–30%, P < 0.05) and disrupted insulin signaling at Ser1101 of the insulin receptor substrate-1 and downstream Akt activation at Ser473. These defects were fully rescued by nonselective protein kinase C inhibition or concomitant HSL overexpression to restore a proper lipolytic balance. We show that selective HSL inhibition induces DAG accumulation and insulin resistance.


CONCLUSIONS

Altogether, the data indicate that altered ATGL and HSL expression in skeletal muscle could promote DAG accumulation and disrupt insulin signaling and action. Targeting skeletal muscle lipases may constitute an interesting strategy to improve insulin sensitivity in obesity and type 2 diabetes.

Diabetes Journal publish ahead of print articles

Posted in Diabetes Signs Tags: , , , , , , , , , No Comments »

Nobiletin Attenuates VLDL Overproduction, Dyslipidemia, and Atherosclerosis in Mice With Diet-Induced Insulin Resistance

April 9th, 2011 admin

OBJECTIVE

Increased plasma concentrations of apolipoprotein B100 often present in patients with insulin resistance and confer increased risk for the development of atherosclerosis. Naturally occurring polyphenolic compounds including flavonoids have antiatherogenic properties. The aim of the current study was to evaluate the effect of the polymethoxylated flavonoid nobiletin on lipoprotein secretion in cultured human hepatoma cells (HepG2) and in a mouse model of insulin resistance and atherosclerosis.


RESEARCH DESIGN AND METHODS

Lipoprotein secretion was determined in HepG2 cells incubated with nobiletin or insulin. mRNA abundance was evaluated by quantitative RT-PCR, and Western blotting was used to demonstrate activation of cell signaling pathways. In LDL receptor–deficient mice (Ldlr–/–) fed a Western diet supplemented with nobiletin, metabolic parameters, gene expression, fatty acid oxidation, glucose homeostasis, and energy expenditure were documented. Atherosclerosis was quantitated by histological analysis.


RESULTS

In HepG2 cells, activation of mitogen-activated protein kinase-extracellular signal–related kinase signaling by nobiletin or insulin increased LDLR and decreased MTP and DGAT1/2 mRNA, resulting in marked inhibition of apoB100 secretion. Nobiletin, unlike insulin, did not induce phosphorylation of the insulin receptor or insulin receptor substrate-1 and did not stimulate lipogenesis. In fat-fed Ldlr–/– mice, nobiletin attenuated dyslipidemia through a reduction in VLDL-triglyceride (TG) secretion. Nobiletin prevented hepatic TG accumulation, increased expression of Pgc1α and Cpt1α, and enhanced fatty acid β-oxidation. Nobiletin did not activate any peroxisome proliferator–activated receptor (PPAR), indicating that the metabolic effects were PPAR independent. Nobiletin increased hepatic and peripheral insulin sensitivity and glucose tolerance and dramatically attenuated atherosclerosis in the aortic sinus.


CONCLUSIONS

Nobiletin provides insight into treatments for dyslipidemia and atherosclerosis associated with insulin-resistant states.

Diabetes Journal publish ahead of print articles

Posted in Diabetes Signs Tags: , , , , , , , , , No Comments »

Metformin Inhibits Nuclear Receptor TR4-Mediated Hepatic Stearoyl-Coenzyme A Desaturase 1 Gene Expression With Altered Insulin Sensitivity

April 9th, 2011 admin

OBJECTIVE

TR4 is a nuclear receptor without clear pathophysiological roles. We investigated the roles of hepatic TR4 in the regulation of lipogenesis and insulin sensitivity in vivo and in vitro.


RESEARCH DESIGN AND METHODS

TR4 activity and phosphorylation assays were carried out using hepatocytes and various TR4 wild-type and mutant constructs. Liver tissues from TR4 knockout, C57BL/6, and db/db mice were examined to investigate TR4 target gene stearoyl-CoA desaturase (SCD) 1 regulation.


RESULTS

TR4 transactivation is inhibited via phosphorylation by metformin-induced AMP–activated protein kinase (AMPK) at the amino acid serine 351, which results in the suppression of SCD1 gene expression. Additional mechanistic dissection finds TR4-transactivated SCD1 promoter activity via direct binding to the TR4-responsive element located at –243 to –255 on the promoter region. The pathophysiological consequences of the metformin->AMPK->TR4->SCD1 pathway are examined via TR4 knockout mice and primary hepatocytes with either knockdown or overexpression of TR4. The results show that the suppression of SCD1 via loss of TR4 resulted in reduced fat mass and increased insulin sensitivity with increased β-oxidation and decreased lipogenic gene expression.


CONCLUSIONS

The pathway from metformin->AMPK->TR4->SCD1->insulin sensitivity suggests that TR4 may function as an important modulator to control lipid metabolism, which sheds light on the use of small molecules to modulate TR4 activity as a new alternative approach to battle the metabolic syndrome.

Diabetes Journal publish ahead of print articles

Posted in Diabetes Signs Tags: , , , , , , , , , , , , No Comments »

Diabetes and Me: Information for Children With Insulin Pumps

February 11th, 2011 admin

Diabetes and Me: Information for Children With Insulin Pumps
The book is filled with helpful hints for children who are using an insulin pump, or who want to know more about them. It is also a great resource for the families of those children. Written by a 21-year-old who has been using a pump for 10 years.
Diabetes and Me: Information for Children With Insulin Pumps

Notary Signing Agent 101…Becoming Mobile
This eBook not only informs of what exactly a Signing Agent is, but it also gives Insider’s Secrets to making money and snagging business from the competition! There is also a Helpful Resource Link Section and a an offer for Specialized Training.
Notary Signing Agent 101…Becoming Mobile

Posted in Diabetes Signs Tags: , , , , No Comments »
« Older Entries
Copyright 2010 DiabetesSigns.org, Inc. All rights reserved. The material in this site is intended to be of general informational use and is not intended to constitute medical advice, probable diagnosis, or recommended treatments. See the Terms of Service for more information. Privacy Policy

Powered by Yahoo! Answers