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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Herbs have been used for medicinal purposes, including the treatment of diabetes, for centuries. Plants containing flavonoids are used to treat diabetes in Indian medicine and the green tea flavonoid, epigallocatechin gallate (EGCG), is reported to have glucose-lowering effects in animals. We show here that the regulation of hepatic glucose production is decreased by EGCG. Furthermore, like insulin, EGCG increases tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1), and it reduces phosphoenolpyruvate carboxykinase gene expression in a phosphoinositide 3-kinase-dependent manner. EGCG also mimics insulin by increasing phosphoinositide 3-kinase, mitogen-activated protein kinase, and p70(s6k) activity. EGCG differs from insulin, however, in that it affects several insulin-activated kinases with slower kinetics. Furthermore, EGCG regulates genes that encode gluconeogenic enzymes and protein-tyrosine phosphorylation by modulating the redox state of the cell. These results demonstrate that changes in the redox state may have beneficial effects for the treatment of diabetes and suggest a potential role for EGCG, or derivatives, as an antidiabetic agent.
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PMID:Epigallocatechin gallate, a constituent of green tea, represses hepatic glucose production. 1211 6

The use of embryonic stem cells for cell-replacement therapy in diseases like diabetes mellitus requires methods to control the development of multipotent cells. We report that treatment of mouse embryonic stem cells with inhibitors of phosphoinositide 3-kinase, an essential intracellular signaling regulator, produced cells that resembled pancreatic beta cells in several ways. These cells aggregated in structures similar, but not identical, to pancreatic islets of Langerhans, produced insulin at levels far greater than previously reported, and displayed glucose-dependent insulin release in vitro. Transplantation of these cell aggregates increased circulating insulin levels, reduced weight loss, improved glycemic control, and completely rescued survival in mice with diabetes mellitus. Graft removal resulted in rapid relapse and death. Graft analysis revealed that transplanted insulin-producing cells remained differentiated, enlarged, and did not form detectable tumors. These results provide evidence that embryonic stem cells can serve as the source of insulin-producing replacement tissue in an experimental model of diabetes mellitus. Strategies for producing cells that can replace islet functions described here can be adapted for similar uses with human cells.
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PMID:Growth inhibitors promote differentiation of insulin-producing tissue from embryonic stem cells. 1244 3

Over the last several years, a great level of interest has rallied behind understanding how the pivotal kinase, 3'-phosphoinositide dependent kinase 1 (PDK1) is regulated. PDK1 phosphorylates and activates members of the AGC kinase family shown to be activated downstream of phosphoinositide 3-kinase (P13K); however, the functional dependency of PDK1 on P13K for activation of its targets is less clear. The P13K signaling pathway mediates numerous cellular responses upon growth factor and hormone stimulation. Specifically, P13K signaling influences many of the metabolic and mitogenic functions of the anabolic hormone, insulin. Thus, the regulation of P13K and its downstream targets by insulin has become an important topic for investigation. Given its central role as the kinase upstream of those signaling pathways linked to P13K, the regulation of PDK1 by insulin and other factors is at the height of many of these investigations. Current theories on PDK1 regulation propose substrate conformation and subcellular localization as the primary mediators of PDK1 function. The array of PDK1 substrates suggests, however, that in cells PDK1 may be more tightly regulated. Recent data support phosphorylation as a potential regulatory mechanism that may play an additional role in directing the specificity of PDK1 towards its physiological substrates. The combination of these regulatory mechanisms along with the potential for multiple PDK1 isoforms with select tissue distribution may contribute to the diversified actions of insulin signaling. The targeting of these various aspects of PDK1 regulation may provide for novel therapeutic treatments for diseases such as diabetes and cancer.
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PMID:A new molecular target of insulin action: regulating the pivotal PDK1. 1247 87

Calpains are a family of non-lysosomal cysteine proteases. Recent studies have identified a member of the calpain family of proteases, calpain 10, as a putative diabetes-susceptibility gene that may be involved in the development of type 2 diabetes. Inhibition of calpain activity has been shown to reduce insulin-stimulated glucose uptake in isolated rat-muscle strips and adipocytes. In this report, we examine the mechanism by which calpain affects insulin-stimulated glucose uptake in 3T3-L1 adipocytes. Inhibition of calpain activity resulted in approx. a 60% decrease in insulin-stimulated glucose uptake. Furthermore, inhibition of calpain activity prevented the translocation of insulin-responsive glucose transporter 4 (GLUT4) vesicles to the plasma membrane, as demonstrated by fluorescent microscopy of whole cells and isolated plasma membranes; it did not, however, alter the total GLUT4 protein content. While inhibition of calpain did not affect the insulin-mediated proximal steps of the phosphoinositide 3-kinase pathway, it did prevent the insulin-stimulated cortical actin reorganization required for GLUT4 translocation. Specific inhibition of calpain 10 by antisense expression reduced insulin-stimulated GLUT4 translocation and actin reorganization. Based on these findings, we propose a role for calpain in the actin reorganization required for insulin-stimulated GLUT4 translocation to the plasma membrane in 3T3-L1 adipocytes. These studies identify calpain as a novel factor involved in GLUT4 vesicle trafficking and suggest a link between calpain activity and the development of type 2 diabetes.
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PMID:Calpain facilitates GLUT4 vesicle translocation during insulin-stimulated glucose uptake in adipocytes. 1297 73

White adipose tissue (WAT) plays a critical role in the development of insulin resistance via secretion of free fatty acids (FFA) and adipocytokines. Muscle-specific insulin receptor knockout (MIRKO) mice do not develop insulin resistance or diabetes under physiological conditions despite a marked increase in adiposity and plasma FFA. On the contrary, WAT of MIRKO is sensitized to insulin action during a euglycemic clamp, and WAT glucose utilization is dramatically increased. To get insight into the potential antidiabetic role of MIRKO adiposity, we have studied insulin action in WAT during a euglycemic, hyperinsulinemic clamp, and we have characterized the morphology and biology of WAT. During the clamp, there is no alteration in the expression or activation in the insulin signaling molecules involved in glucose transport through the phosphoinositide 3-kinase/Akt and CAP/Cbl pathways in WAT from MIRKO. The 53% increase in WAT mass results from a 48% increase in adipocyte number (P < 0.05) without alteration in cell size and contemporary to a 300% increase in mRNA levels of the adipogenic transcription factor CCAAT enhancer binding protein-alpha (C/EBP-alpha) (P < 0.05). There is a 39.5% increase in serum adiponectin (P < 0.01) without modification in serum leptin, resistin, and TNF-alpha. In conclusion, the MIRKO mouse displays muscle insulin resistance, visceral obesity, and dyslipidemia but does not develop hyperinsulinemia or diabetes. There is an accelerated differentiation of small insulin sensitive adipocytes, an increased secretion of the insulin sensitizer adiponectin, and maintenance of leptin sensitivity. The MIRKO mouse confirms the importance of WAT plasticity in the maintenance of whole body insulin sensitivity and represents an interesting model to search for new secreted molecules that positively alter adipose tissue biology.
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PMID:Cellular and molecular mechanisms of adipose tissue plasticity in muscle insulin receptor knockout mice. 1468 12

Hyperglycemia causes glomerular mesangial cell proliferation and increases matrix synthesis, contributing to early diabetic glomerulopathy. Immunohistochemical and functional correlations of renal cyclooxygenase-2 in experimental diabetes have been identified. However, the role of cyclooxygenase-2 in early diabetes-induced mesangial cell proliferation remains unknown. The authors tested the hypothesis that hyperglycemia modulates an intrarenal cyclooxygenase-2 expression, which might mediate the mesangial cell proliferation via a possible phosphoinositide 3-kinase/Akt pathway. Expression of cyclooxygenase-2, but not cyclooxygenase-1, could be induced in mesangial cells cultured under high glucose. Antioxidants (pyrrolidine dithiocarbamate and N-acetyl-l-cysteine) and phosphoinositide 3-kinase inhibitors [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002) and wortmannin] effectively inhibited this high glucose-induced response. Moreover, high glucose markedly triggered the activation of phosphoinositide 3-kinase and Akt in mesangial cells, suggesting that a phosphoinositide 3-kinase/Akt pathway is involved in the high glucose-induced responses. Phosphoinositide 3-kinase inhibitors could also effectively attenuate the high glucose-triggered intracellular reactive oxygen species generation and nuclear factor-kappaB activation. Likewise, blocking the phosphoinositide 3-kinase or Akt activity with the dominant-negative vectors DN-p85 or DN-Akt, respectively, also greatly diminished the high glucose-triggered reactive oxygen species generation and nuclear factor-kappaB activation. Treatment of mesangial cells with LY294002 and cyclooxygenase-2 inhibitors [N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS398) and aspirin] effectively inhibited the high glucose-induced mesangial cell proliferation. These results suggest that high glucose may trigger the reactive oxygen species-regulated nuclear factor-kappaB activation and cyclooxygenase-2 expression and cell proliferation in mesangial cells through a phosphoinositide 3-kinase-dependent pathway.
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PMID:Activation of phosphoinositide 3-kinase in response to high glucose leads to regulation of reactive oxygen species-related nuclear factor-kappaB activation and cyclooxygenase-2 expression in mesangial cells. 1521 11

Increased levels of C-peptide, a cleavage product of proinsulin, circulate in patients with insulin resistance and early type 2 diabetes, a high-risk population for the development of a diffuse and extensive pattern of arteriosclerosis. The present study examined the effect of C-peptide on CD4(+) lymphocyte migration, an important process in early atherogenesis. C-peptide stimulated CD4(+) cell chemotaxis in a concentration-dependent manner. This process involves pertussis toxin-sensitive G-proteins as well as activation of phosphoinositide 3-kinase (PI 3-K). Biochemical analysis showed that C-peptide induced recruitment of PI 3-K to the cell membrane as well as PI 3-K activation in human CD4(+) cells. In addition, antidiabetic peroxisome proliferator-activated receptor gamma-activating thiazolidinediones inhibited C-peptide-induced CD4(+) cell chemotaxis as well as PI 3-Kgamma activation. Finally, immunofluorescence staining of thoracic artery specimen of diabetic patients showed intimal CD4(+) cells in areas with C-peptide deposition. Thus, C-peptide might deposit in the arterial intima in diabetic patients during early atherogenesis and subsequently attract CD4(+) cells to migrate into the vessel wall.
Diabetes 2004 Jul
PMID:C-peptide induces chemotaxis of human CD4-positive cells: involvement of pertussis toxin-sensitive G-proteins and phosphoinositide 3-kinase. 1522 Jan 88

Adiponectin is an anti-diabetic and anti-atherogenic hormone that is exclusively secreted from fat cells. Serum adiponectin levels are reduced in obese patients and obese model mice, despite increased adipose tissue mass. Elucidation of the mechanism(s) by which plasma adiponectin levels are decreased in obese and diabetic patients would provide insight into the cause of obesity-induced diabetes and the development of therapeutic advances. In the present study, the regulation of adiponectin secretion was investigated using 3T3-L1 adipocytes and a diabetic-/obese-mouse model. A novel insulin sensitizer, IkappaB kinase beta (IKKbeta) inhibitor, ameliorated insulin resistance and up-regulated plasma levels of adiponectin without producing a significant change in body weight in KKAy mice that were fed a high-fat diet. The IKKbeta inhibitor cancelled the TNFalpha-mediated down-regulation of adiponectin secretion and simultaneously up-regulated the phosphorylation of Akt in 3T3-L1 adipocytes. Using dominant-negative mutants of Akt or PKClambda (downstream effectors of phosphoinositide 3-kinase), insulin-stimulated Akt activity was found to be important in the regulation of adiponectin secretion by insulin in 3T3-L1 adipocytes. These observations suggest that "insulin-stimulated Akt activity in adipocytes" may play an important role in the regulation of adiponectin secretion.
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PMID:A novel IKKbeta inhibitor stimulates adiponectin levels and ameliorates obesity-linked insulin resistance. 1535 28

Several recent reports claim the generation of insulin-producing cells from embryonic stem cells via the differentiation of progenitors that express nestin. Here, we investigate further the properties of these insulin-containing cells. We find that although differentiated cells contain immunoreactive insulin, they do not contain proinsulin-derived C-peptide. Furthermore, we find variable insulin release from these cells upon glucose addition, but C-peptide release is never detected. In addition, many of the insulin-immunoreactive cells are undergoing apoptosis or necrosis. We further show that cells cultured in the presence of a phosphoinositide 3-kinase inhibitor, which previously was reported to facilitate the differentiation of insulin(+) cells, are not C-peptide immunoreactive but take up fluorescein isothiocyanate-labeled insulin from the culture medium. Together, these data suggest that nestin(+) progenitor cells give rise to a population of cells that contain insulin, not as a result of biosynthesis but from the uptake of exogenous insulin. We conclude that C-peptide biosynthesis and secretion should be demonstrated to claim insulin production from embryonic stem cell progeny.
Diabetes 2004 Oct
PMID:Artifactual insulin release from differentiated embryonic stem cells. 1544 90

Proper regulation of the phosphoinositide 3-kinase-Akt pathway is critical for the prevention of both insulin resistance and tumorigenesis. Many recent studies have characterized a negative feedback loop in which components of one downstream branch of this pathway, composed of the mammalian target of rapamycin and ribosomal S6 kinase, block further activation of the pathway through inhibition of insulin receptor substrate function. These findings form a novel basis for improved understanding of the pathophysiology of metabolic diseases (e.g., diabetes and obesity), tumor syndromes (e.g., tuberous sclerosis complex and Peutz-Jegher's syndrome), and human cancers.
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PMID:Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. 1553 96


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