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

The proband, a 9-year-old Hispanic female, presented with hair loss, strabismus, and weight gain. On magnetic resonance imaging (MRI) she was found to have severe primary hypothyroidism and a large pituitary mass. In addition, acanthosis nigricans, obesity, and hyperinsulinism were observed. Findings were similar in three of four siblings. Thyroid peroxidase antibodies were detected in the father and three of four siblings. Although all family members were obese, and hyperinsulinemia with high proinsulin and C-peptide was found in all except one sibling, only the mother and one child had overt type 2 diabetes mellitus. Because of the unusual association of autoimmune thyroid disease, insulin resistance and obesity rather than insulin deficiency, we searched for possible genetic abnormalities. The HLA haplotypes did not cosegregate with autoimmune thyroid disease or insulin resistance. Mutational analysis of known obesity genes was done. Leptin was not deficient, and sequencing of the proband's DNA showed no mutations in the perixisome proliferator activated receptor (PPAR)-gamma, PPAR-gamma(2), PPAR-alpha or melanocortin 4 receptor genes. Maternally inherited diabetes and deafness was ruled out since no mutations were found in mitochondria DNA. Insulin receptor antibodies were not detected. In conclusion, the remarkably high incidence of childhood autoimmune hypothyroidism, pituitary enlargement, insulin resistance and obesity in this family is not linked to known HLA types or known gene defects.
 ...
PMID:Familial juvenile autoimmune hypothyroidism, pituitary enlargement, obesity, and insulin resistance. 1514 66

The molecular signaling mechanisms by which insulin leads to increased glucose transport and metabolism and gene expression are not completely elucidated. We have characterized the nature of insulin signaling defects in skeletal muscle from Type 2 diabetic patients. Insulin receptor substrate (IRS-1) phosphorylation, phosphatidylinositol (PI) 3-kinase activity, and glucose transport activity are impaired as a consequence of functional defects, whereas insulin receptor tyrosine phosphorylation, mitogen-activated protein kinase (MAPK) phosphorylation, and glycogen synthase activity are normal. Using biotinylated photoaffinity labeling, we have shown that reduced cell surface GLUT4 levels can explain glucose transport defects in skeletal muscle from Type 2 diabetic patients under insulin-stimulated conditions. Current work is focused on mechanisms behind insulin-dependent and insulin-independent regulation of glucose uptake. We have recently determined the independent effects of insulin and hypoxia/AICAR exposure on glucose transport and cell surface GLUT4 content in skeletal muscle from nondiabetic and Type 2 diabetic subjects. Hypoxia and AICAR increase glucose transport via an insulin-independent mechanism involving activation of 5'-AMP-activated kinase (AMPK). AMPK signaling is intact, because 5-aminoimidazole-4-carboxamide 1-beta-D-ribonucleoside (AICAR) increased AMPK and acetyl-CoA carboxylase (ACC) phosphorylation to a similar extent in Type 2 diabetic and nondiabetic subjects. However, AICAR responses on glucose uptake were impaired. Our studies highlight important AMPK-dependent and independent pathways in the regulation of GLUT4 and glucose transport activity in insulin resistant skeletal muscle. Understanding signaling mechanisms to downstream metabolic responses may provide valuable clues to a future therapy for Type 2 diabetes.
 ...
PMID:Sending the signal: molecular mechanisms regulating glucose uptake. 1523 28

Insulin receptor substrates (Irs-proteins) integrate signals from the insulin and insulin-like growth factor-1 (IGF1) receptors with other processes to control cellular growth, function, and survival. Here, we show that Irs2 promoted the maturation and survival of photoreceptors in the murine retina immediately after birth. Irs2 was mainly localized to the outer plexiform layer as well as to photoreceptor inner segments. It was also seen in ganglion cells and inner plexiform layer but in smaller amounts. Compared with control littermates, Irs2 knock-out mice lose 10% of their photoreceptors 1 week after birth and up to 50% by 2 weeks of age as a result of increased apoptosis. The surviving photoreceptor cells developed short organized segments, which displayed proportionally diminished but otherwise normal electrical function. However, IGF1-stimulated Akt phosphorylation was barely detected, and cleaved/activated caspase-3 was significantly elevated in isolated retinas of Irs2-/- mice. When diabetes was prevented, which allowed the Irs2-/- mice to survive for 2 years, most photoreceptor cells were lost by 16 months of age. Because apoptosis is the final common pathway in photoreceptor degeneration, pharmacological strategies that increase Irs2 expression or function in photoreceptor cells could be a general treatment for blinding diseases such as retinitis pigmentosa.
 ...
PMID:Insulin receptor substrate 2 is essential for maturation and survival of photoreceptor cells. 1568 62

The effect of insulin and growth factor mediated signaling to gene regulation was investigated in cultured fibroblasts of a patient with a premature aging syndrome (metageria) and severe insulin resistance. Insulin receptor structure and function as well as major pathways activated by insulin, i.e. phosphatidyl inositol-3 kinase (PI-3 K) cascade or mitogen-activated protein kinase (MAPK) cascades, were functional. Inducibility of the proto-oncogene cfos, a representative endpoint of signaling pathways related to gene expression, by growth factors or insulin was reduced in patient cells. This reduced induction persisted in cfos promoter reporter gene studies indicating that the post receptor defect is localized proximal to the cfos promoter itself. Abundances of the transcription factors Elk-1 and SRF being major players in coupling of MAPKs to cfos promoter activation were not altered. However, basal and inducible phosphorylation of Elk-1 was impaired. In addition, basal and stimulated transcriptional activity mediated by Elk-1 was almost abolished in patient cells. Therefore these results identify a post receptor defect in cFos induction, which appears to be related to a functional alteration of Elk-1. A possible relation of this signal transduction defect to the specific premature aging syndrome remains to be elucidated.
Exp Clin Endocrinol Diabetes 2005 Feb
PMID:Reduced phosphorylation of transcription factor Elk-1 in cultured fibroblasts of a patient with premature aging syndrome and insulin resistance. 1577 1

Evidence demonstrates that exogenous nitric oxide (NO) and the NO produced by inducible nitric oxide synthase (iNOS) can induce insulin resistance in muscle. Here, we investigated whether this insulin resistance could be mediated by S-nitrosation of proteins involved in early steps of the insulin signal transduction pathway. Exogenous NO donated by S-nitrosoglutathione (GSNO) induced in vitro and in vivo S-nitrosation of the insulin receptor beta subunit (IRbeta) and protein kinase B/Akt (Akt) and reduced their kinase activity in muscle. Insulin receptor substrate (IRS)-1 was also rapidly S-nitrosated, and its expression was reduced after chronic GSNO treatment. In two distinct models of insulin resistance associated with enhanced iNOS expression-diet-induced obesity and the ob/ob diabetic mice-we observed enhanced S-nitrosation of IRbeta/IRS-1 and Akt in muscle. Reversal of S-nitrosation of these proteins by reducing iNOS expression yielded an improvement in insulin action in both animal models. Thus, S-nitrosation of proteins involved in insulin signal transduction is a novel molecular mechanism of iNOS-induced insulin resistance.
Diabetes 2005 Apr
PMID:S-nitrosation of the insulin receptor, insulin receptor substrate 1, and protein kinase B/Akt: a novel mechanism of insulin resistance. 1579 33

Glucagon, secreted from islet alpha-cells, mobilizes liver glucose. During hyperglycemia, glucagon secretion is inhibited by paracrine factors from other islet cells, but in type 1 and type 2 diabetic patients, this suppression is lost. We investigated the effects of beta-cell secretory products zinc and insulin on isolated rat alpha-cells, intact islets, and perfused pancreata. Islet glucagon secretion was markedly zinc sensitive (IC(50) = 2.7 micromol/l) more than insulin release (IC(50) = 10.7 micromol/l). Glucose, the mitochondrial substrate pyruvate, and the ATP-sensitive K(+) channel (K(ATP) channel) inhibitor tolbutamide stimulated isolated alpha-cell electrical activity and glucagon secretion. Zinc opened K(ATP) channels and inhibited both electrical activity and pyruvate (but not arginine)-stimulated glucagon secretion in alpha-cells. Insulin transiently increased K(ATP) channel activity, inhibited electrical activity and glucagon secretion in alpha-cells, and inhibited pancreatic glucagon output. Insulin receptor and K(ATP) channel subunit transcripts were more abundant in alpha- than beta-cells. Transcript for the glucagon-like peptide 1 (GLP-1) receptor was not detected in alpha-cells nor did GLP-1 stimulate alpha-cell glucagon release. beta-Cell secretory products zinc and insulin therefore inhibit glucagon secretion most probably by direct activation of K(ATP) channels, thereby masking an alpha-cell metabolism secretion coupling pathway similar to beta-cells.
Diabetes 2005 Jun
PMID:Beta-cell secretory products activate alpha-cell ATP-dependent potassium channels to inhibit glucagon release. 1591 3

Various plants are used in Caribbean folklore for the treatment of a variety of illnesses including diabetes mellitus. Preliminary investigations of several crude plant extracts have indicated that the annatto (Bixa orellana), among others, does in fact exhibit hypoglycaemic properties. This present investigation sought to isolate the hypoglycaemic principle(s) from the crude extract and to determine the mechanism of action. Purification experiments employing thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) resulted in an oil-soluble, partially purified annatto extract. The latter caused a decrease in blood glucose level of 5.62+/-0.13 (n=34) mmol/dL versus 6.31+/-0.12 (n=34) for the control (p<0.01) 1 h after administration. This hypoglycaemia persisted for an additional hour when the oral glucose tolerance test (OGTT) was performed on dogs treated with annatto and compared with the control. Plasma insulin levels measured at 1.0 h showed that there was an increase in plasma insulin levels of 59.57+/-8.3 microIU/mL for the annatto treated dogs versus 40.95+/-5.46 microIU/mL for the control (p<0.05), this elevation persisted throughout the duration of the OGTT which followed. Insulin receptor studies, using a modification of the method of Gambhir et al. done on mononuclear leucocytes and erythrocytes obtained from blood taken 1 h after administration showed that there was an increase in the percentage receptor binding when compared with the control. Insulin affinity results showed that there was an increase of 1.8+/-0.2x10(8) m-1 (n=12) in mononuclear leucocytes for the annatto treated dogs versus 1.2+/-0.2x10(8) m-1 for the control (p<0.05). In the enythrocytes, there was also an increase in affinity from 1.2+/-0.2x10(8) m-1 to 2.3+/-0.2x10(8) m-1 for the control and treated animals, respectively. In conclusion, it can be stated that annatto is responsible for the hypoglycaemic episodes seen in the dogs which was mediated by an increase in plasma insulin concentration as well as an increase in insulin binding on the insulin receptor due to elevated affinity of the ligand for the receptor.
 ...
PMID:The effect of annatto on insulin binding properties in the dog. 1610 87

Insulin receptor substrate-1 (IRS-1) is an endogenous substrate for the insulin receptor tyrosine kinase, which plays a key role in insulin signaling. Recent studies have identified several polymorphisms in the human IRS-1 gene (Irs-1) that are increased in prevalence among type 2 diabetic patients. To determine whether variation in the Irs-1 contributes to genetic susceptibility to type 2 diabetes in Turkish people, PCR-RFLP and DNA sequencing method were utilized to analyze the coding region of Irs-1 in 70 subject and 116 control patients. Three missense mutations were detected (Gly972Arg, Ala512Pro, Ser892Gly). There was no significant association found with any of these variants and diabetes. The Gly972Arg mutation, however, was relatively more common in with 10/70 diabetic patients and 15/116 non-diabetic controls being heterozygous and 1/70 being and 0/116 non-diabetic controls being homozygous for this variant. As a conclusion, Ala512Pro, Ser892Gly mutations were rare and Met613Val, Ser1043Tyr and Cys1095Tyr mutations were not found in the populations studied. Gly972Arg is more common than other known mutations in our population but may not be a major determinant in genetic susceptibility to type 2 diabetes.
 ...
PMID:Molecular scanning for mutations in the insulin receptor substrate-1 (IRS-1) gene in Turkish with type 2 diabetes mellitus. 1628 38

Insulin receptor substrates, including Irs1 and Irs2, integrate insulin and IGF receptor signals with heterologous pathways to coordinate growth and metabolism. Since Irs2 is thought to be especially important in hepatic nutrient homeostasis, we deleted Irs2 [corrected] from hepatocytes of WT mice (called LKO) or genetically insulin-resistant Irs1-/- mice (called LKO::Irs1-/-). Viable LKO::Irs1-/- mice were 70% smaller than WT or LKO mice, and 40% smaller than Irs1-/- mice. Hepatic insulin receptors were functional in all the mice, but insulin signaling via the Akt-FoxO1 pathway was reduced in Irs1-/- and LKO liver, and undetected in LKO::Irs1-/- liver; however, Gsk3beta phosphorylation (Ser9) and hepatic glycogen stores were nearly normal in all of the mice. LKO and Irs1-/- mice developed insulin resistance and glucose intolerance that never progressed to diabetes, whereas LKO::Irs1-/- mice developed hyperglycemia and hyperinsulinemia immediately after birth. Regardless, few hepatic genes changed expression significantly in Irs1-/- or LKO mice, whereas hundreds of genes changed in LKO::Irs1-/- mice--including elevated levels of Pck1, G6pc, Ppargc1, Pparg, and Igfbp1. Thus, signals delivered by Irs1 or Irs2 regulate hepatic gene expression that coordinates glucose homeostasis and systemic growth.
 ...
PMID:Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth. 1637 20

Diabetes is associated with defective beta cell function and altered beta cell mass. The mechanisms regulating beta cell mass and its adaptation to insulin resistance are unknown. It is unclear whether compensatory beta cell hyperplasia is achieved via proliferation of existing beta cells or neogenesis from progenitor cells embedded in duct epithelia. We have used transgenic mice expressing a mutant form of the forkhead-O1 transcription factor (FoxO1) in both pancreatic ductal and endocrine beta cells to assess the contribution of these 2 compartments to islet expansion. We show that the mutant FoxO1 transgene prevents beta cell replication in 2 models of beta cell hyperplasia, 1 due to peripheral insulin resistance (Insulin receptor transgenic knockouts) and 1 due to ectopic local expression of IGF2 (Elastase-IGF2 transgenics), without affecting insulin secretion. In contrast, we failed to detect a specific effect of the FoxO1 transgene on the number of periductal beta cells. We propose that beta cell compensation to insulin resistance is a proliferative response of existing beta cells to growth factor signaling and requires FoxO1 nuclear exclusion.
 ...
PMID:Role of the forkhead protein FoxO1 in beta cell compensation to insulin resistance. 1648 43


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>