Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proinsulin C-peptide was for long considered to be without biological activity of its own. New findings demonstrate, however, that it is capable of eliciting both molecular and physiological effects, suggesting that C-peptide is in fact a bioactive peptide. When administered in replacement doses to animal models or to patients with type 1 diabetes, C-peptide ameliorates diabetes-induced functional and structural changes in both the kidneys and the peripheral nerves. It augments blood flow in a number of tissues, notably skeletal muscle, myocardium, skin and nerve. These effects are thought to be mediated via a stimulatory influence on Na+,K(+)-ATPase and on endothelial nitric oxide synthase. Specific binding of C-peptide to cell membranes of intact cells and to detergent-solubilized cellular components has been demonstrated, indicating the existence of cell-surface binding sites for C-peptide. A number of intracellular responses are elicited by C-peptide, including a rise in Ca2+ concentration and activation of MAP-kinase signaling pathways. Many but not all of C-peptide's intracellular effects can be inhibited by pertussis toxin, supporting the notion that C-peptide may interact via a G-protein-coupled receptor. Additional data suggest that C-peptide may interact synergistically also in the insulin signaling pathway. Combined, the available observations show conclusively that C-peptide is biologically active, even though its molecular mechanism of action is not as yet fully understood. The possibility that replacement of C-peptide in patients with type 1 diabetes may serve to retard or prevent the development of long-term complications should be evaluated.
Diabetes Metab Res Rev
PMID:C-peptide makes a comeback. 1295 45

The induction or exacerbation of autoimmune diseases is a potential adverse effect of immunostimulating drugs. Vaccines have been suspected of such actions. Epidemiological studies, however, have so far failed to demonstrate any causal relationship between vaccination and autoimmune diseases, including insulin-dependent diabetes mellitus (IDDM). In this study, autoimmune diabetes-prone non-obese diabetic (NOD) mice were treated with two multivalent diphtheria, tetanus, pertussis, poliomyelitis and haemophilus vaccines (diphtheria, tetanus, acellular pertussis, inactivated polio (DTaP-IVP) or DTaP-IVP/Haemophilus influenza type b (Hib)) intraperitoneally at each of 10, 12 and 14 weeks of age. Although non-statistically significant, the incidence of autoimmune diabetes was slightly reduced by the DTaP-IVP vaccine. Blood glucose levels were actually significantly reduced in the mice treated with the DTaP-IVP vaccine relative to the untreated control mice. A slight decrease in blood glucose levels amongst the mice given the DTaP-IVP/Hib vaccine was also noted. Therefore this study does not support previous claims that children's vaccination might be associated with acceleration or exacerbation of IDDM.
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PMID:Effects of two pediatric vaccines on autoimmune diabetes in NOD female mice. 1461 71

Vaccinations protect to a high degree against infectious diseases, but may cause side effects. In the Netherlands since 1962 the adverse events following immunizations are registered and analysed by the National Institute of Health and Environment (RIVM). Since 1983 a permanent Committee of the Dutch Health Council reviews adverse events reported to the RIVM. With the so-called killed vaccines the side effects are mainly local (redness, swelling, pain) or general (fever, listlessness, irritability, sleep and eating problems). They are seen mainly after DPT-IPV vaccination against diphtheria, pertussis, tetanus and poliomyelitis. Some side effects occur rarely (collapse reactions, discoloured legs, persistent screaming and convulsions) and very rarely serious neurological events are reported. After MMR vaccination against measles, mumps and rubella, cases of arthritis, thrombocytopenia and ataxia are reported sporadically. Usually, they have a spontaneous recovery. During recent years a scala of diseases or symptoms have been associated with vaccination (presumed side effects). Careful and extensive investigations have shown that such hypotheses could not be supported. Examples are allergic diseases as asthma, diabetes mellitus, multiple sclerosis (after hepatitis B vaccination), autism and inflammatory bowel disease (after MMR vaccination) and sudden infant death syndrome. The total number of cases where at least a possible relation between side effects and vaccination is observed--apart from local reactions and moderate general symptoms--is very rare (about 0.25 per 1000 vaccinations) and does not balance the benefits from vaccination. There appears increasing doubt about the use and safety of vaccinations. More research is needed about the motives of people to choose for and against vaccination. The education about vaccination for parents and professionals who are involved with vaccination has to be improved. Internet can play an important role.
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PMID:[Childhood vaccinations anno 2004. II. The real and presumed side effects of vaccination]. 1503 89

In islets of Langerhans, L-glutamate is stored in glucagon-containing secretory granules of alpha-cells and cosecreted with glucagon under low-glucose conditions. The L-glutamate triggers secretion of gamma-aminobutyric acid (GABA) from beta-cells, which in turn inhibits glucagon secretion from alpha-cells through the GABAA receptor. In the present study, we tested the working hypothesis that L-glutamate functions as an autocrine/paracrine modulator and inhibits glucagon secretion through a glutamate receptor(s) on alpha-cells. The addition of L-glutamate at 1 mmol/l; (R,S)-phosphonophenylglycine (PPG) and (S)-3,4-dicarboxyphenylglycine (DCPG), specific agonists for class III metabotropic glutamate receptor (mGluR), at 100 micromol/l; and (1S,3R,4S)-1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I) at 50 micromol/l inhibited the low-glucose-evoked glucagon secretion by 87, 81, 73, and 87%, respectively. This inhibition was dose dependent and was blocked by (R,S)-cyclopropyl-4-phosphonophenylglycine (CPPG), a specific antagonist of class III mGluR. Agonists of other glutamate receptors, including kainate and quisqualate, had little effectiveness. RT-PCR and immunological analyses indicated that mGluR4, a class III mGluR, was expressed and localized with alpha- and F cells, whereas no evidence for expression of other mGluRs, including mGluR8, was obtained. L-Glutamate, PPG, and ACPT-I decreased the cAMP content in isolated islets, which was blocked by CPPG. Dibutylyl-cAMP, a nonhydrolyzable cAMP analog, caused the recovery of secretion of glucagon. Pertussis toxin, which uncouples adenylate cyclase and inhibitory G-protein, caused the recovery of both the cAMP content and secretion of glucagon. These results indicate that alpha- and F cells express functional mGluR4, and its stimulation inhibits secretion of glucagon through an inhibitory cAMP cascade. Thus, L-glutamate may directly interact with alpha-cells and inhibit glucagon secretion.
Diabetes 2004 Apr
PMID:Metabotropic glutamate receptor type 4 is involved in autoinhibitory cascade for glucagon secretion by alpha-cells of islet of Langerhans. 1504 15

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

Ghrelin, isolated from the human and rat stomach, is the endogenous ligand for the growth hormone (GH) secretagogue receptor, which is expressed in a variety of tissues, including the pancreatic islets. It has been shown that low plasma ghrelin levels correlates with elevated fasting insulin levels and type 2 diabetes. Here we show a physiological role of endogenous ghrelin in the regulation of insulin release and blood glucose in rodents. Acylated ghrelin, the active form of the peptide, was detected in the pancreatic islets. Counteraction of endogenous ghrelin by intraperitoneal injection of specific GH secretagogue receptor antagonists markedly lowered fasting glucose concentrations, attenuated plasma glucose elevation, and enhanced insulin responses during the glucose tolerance test (GTT). Conversely, intraperitoneal exogenous ghrelin GH-independently elevated fasting glucose concentrations, enhanced plasma glucose elevation, and attenuated insulin responses during GTT. Neither GH secretagogue receptor antagonist nor ghrelin affected the profiles of the insulin tolerance test. In isolated islets, GH secretagogue receptor blockade and antiserum against acylated ghrelin markedly enhanced glucose-induced increases in insulin release and intracellular Ca2+ concentration ([Ca2+]i), whereas ghrelin at a relatively high concentration (10 nmol/l) suppressed insulin release. In single beta-cells, ghrelin attenuated glucose-induced first-phase and oscillatory [Ca2+]i increases via the GH secretagogue receptor and in a pertussis toxin-sensitive manner. Ghrelin also increased tetraethylammonium-sensitive delayed outward K+ currents in single beta-cells. These findings reveal that endogenous ghrelin in islets acts on beta-cells to restrict glucose-induced insulin release at least partly via attenuation of Ca2+ signaling, and that this insulinostatic action may be implicated in the upward control of blood glucose. This function of ghrelin, together with inducing GH release and feeding, suggests that ghrelin underlies the integrative regulation of energy homeostasis.
Diabetes 2004 Dec
PMID:Endogenous ghrelin in pancreatic islets restricts insulin release by attenuating Ca2+ signaling in beta-cells: implication in the glycemic control in rodents. 1556 44

Glucose-stimulated insulin secretion and beta-cell growth are important facets of pancreatic islet beta-cell biology. As a result, factors that modulate these processes are of great interest for the potential treatment of Type 2 diabetes. Here, we present evidence that the heterotrimeric G protein G(z) and its effectors, including some previously thought to be confined in expression to neuronal cells, are present in pancreatic beta-cells, the largest cellular constituent of the islets of Langerhans. Furthermore, signaling pathways upon which G alpha(z) impacts are intact in beta-cells, and G alpha(z) activation inhibits both cAMP production and glucose-stimulated insulin secretion in the Ins-1(832/13) beta-cell-derived line. Inhibition of glucose-stimulated insulin secretion by prostaglandin E (PGE1) is pertussis-toxin insensitive, indicating that other G alpha(i) family members are not involved in this process in this beta-cell line. Indeed, overexpression of a selective deactivator of G alpha(z), the RGS domain of RGSZ1, blocks the inhibitory effect of PGE1 on glucose-stimulated insulin secretion. Finally, the inhibition of glucose-stimulated insulin secretion by PGE1 is substantially blunted by small interfering RNA-mediated knockdown of G alpha(z) expression. Taken together, these data strongly imply that the endogenous E prostanoid receptor in the Ins-1(832/13) beta-cell line couples to G(z) predominantly and perhaps even exclusively. These data provide the first evidence for G(z) signaling in pancreatic beta-cells, and identify an endogenous receptor-mediated signaling process in beta-cells that is dependent on G alpha(z) function.
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PMID:A role for G(z) in pancreatic islet beta-cell biology. 1615 60

Cell loss by apoptosis occurs in renal injury such as diabetic nephropathy. TNF-alpha is a cytokine that induces apoptosis and has been implicated in the pathogenesis of diabetic nephropathy. The aim was to investigate whether C-peptide or insulin could modulate TNF-alpha-mediated cell death in opossum kidney proximal tubular cells and to examine the mechanism(s) of any effects observed. C-peptide and insulin protect against TNF-alpha-induced proximal tubular cell toxicity and apoptosis. Cell viability was analyzed by methylthiazoletetrazolium assay; cell viability was reduced to 60.8 +/- 2.7% of control after stimulation with 300 ng/ml TNF-alpha. Compromised cell viability was reversed by pretreatment with 5 nM C-peptide or 100 nM insulin. TNF-alpha-induced apoptosis was detected by DNA nick-end labeling and by measuring histone associated DNA fragments using ELISA. By ELISA assay, 300 ng/ml TNF-alpha increased apoptosis by 145.8 +/- 4.9% compared with controls, whereas 5 nM C-peptide and 100 nM insulin reduced apoptosis to 81.6 +/- 4.8 and 77.4 +/- 3.1% of control, respectively. The protective effects of C-peptide and insulin were associated with activation of NF-kappaB. Activation of NF-kappaB by C-peptide was pertussis toxin sensitive and dependent on activation of Galpha(i). Phosphatidylinositol 3-kinase but not extracellular signal regulated mitogen-activated protein kinase mediated C-peptide and insulin activation of NF-kappaB. The cytoprotective effects of both C-peptide and insulin were related to increased expression of TNF receptor-associated factor 2, the product of an NF-kappaB-dependent survival gene. These data suggest that C-peptide and/or insulin activation of NF-kappaB-regulated survival genes protects against TNF-alpha-induced renal tubular injury in diabetes. The data further support the concept of C-peptide as a peptide hormone in its own right and suggest a potential therapeutic role for C-peptide.
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PMID:C-peptide signals via Galpha i to protect against TNF-alpha-mediated apoptosis of opossum kidney proximal tubular cells. 1651 Jul 65

Glucose sensing is essential for the ability of pancreatic beta-cells to produce insulin in sufficient quantities to maintain blood glucose within the normal range. Stress causes the release of adrenergic hormones that increase circulating glucose by promoting glucose production and inhibiting insulin release. We have shown that extracellular signal-regulated kinases 1 and 2 (ERK1/2) are responsive to glucose in pancreatic beta-cells and that glucose activates ERK1/2 by mechanisms independent of insulin. Here we show that glucose-induced activation of ERK1/2 is inhibited by epinephrine through the alpha2-adrenergic receptor. Epinephrine and the selective alpha2-adrenergic agonist UK14304 reduced insulin secretion and glucose-stimulated ERK1/2 activation in a pertussis toxin-sensitive manner, implicating the alpha subunit of a Gi family member. Alpha2-adrenergic agonists also reduced stimulation of ERK1/2 by glucagon-like peptide 1 and KCl, but not by phorbol ester or nerve growth factor. Our findings suggest that alpha2-adrenergic agonists act via a Gi family member on early steps in ERK1/2 activation, supporting the idea that ERK1/2 are regulated in a manner that reflects insulin demand.
Diabetes 2006 Apr
PMID:Inhibition of glucose-stimulated activation of extracellular signal-regulated protein kinases 1 and 2 by epinephrine in pancreatic beta-cells. 1656 30

To determine the state of humoral immunity to pertussis in children with insulin-dependent diabetes, IgG antibodies to pertussis toxin (PT) were determined in blood serum samples by means of EIA. In a group of children aged up to 6 years the highest percentage (100%) received the complete course of vaccination against pertussis with Russian adsorbed DPT vaccine, containing whole-cell pertussis monovaccine, while in a group over 6 years the complete vaccination course (3 vaccinations and 1 revaccination) had 53.4% of children. Pertussis morbidity was considerably higher in nonvaccinated subjects than in children with 4-fold vaccination (p < 0.001). The coefficient of association (Q) was 0.84. Children of all age groups were found to have low and average titers of antibodies to PT. The regressive analysis showed a decrease in antibodies in persons completely immunized against pertussis by the age of 6 years old. The presence of antibodies in nonimmunized persons showed that cases of pertussis or carrier state took place among the population. High titers of antibodies, indicative of recent cases of pertussis, were registered in all age groups, but high titers of antibodies were registered mostly in the group of children over 13 years old (p < 0.05), which confirmed an increase in pertussis morbidity in adolescents. Thus, vaccination against pertussis effectively protected children with diabetes of type 1, aged up to 6 years. For more prolonged protection the vaccination and revaccination of children aged over 4 years old is necessary.
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PMID:[Humoral imunity to pertussis in children with diabetes of type 1]. 1683 May 91


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