Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Type 1 (insulin-dependent) diabetes occurs worldwide and can appear at any age. The genetic susceptibility is strongly associated with HLA-DQ and DR on chromosome 6, but genetic factors on other chromosomes such as the insulin gene on chromosome 11 and the cytotoxic T-lymphocyte antigen gene on chromosome 2 may modulate disease risk. Numerous studies further support the view that environmental factors are important. Gestational infections may contribute to initiation, whereas later infections may accelerate islet beta-cell autoimmunity. The pathogenesis is strongly related to autoimmunity against the islet beta cells. Markers of autoimmunity include autoantibodies against glutamic acid decarboxylase, insulin, and islet cell antigen-2, a tyrosine phosphatase-like protein. Molecular techniques are used to establish reproducible and precise autoantibody assays, which have been subject to worldwide standardization. The diagnostic sensitivity (40-80%) and specificity (99%) of all three autoantibodies for type 1 diabetes are high, and double or triple positivity among first-degree relatives predicts disease. Combined genetic and antibody testing improved prediction in the general population despite the transient nature of these autoantibodies. Classification of diabetes has also been improved by autoantibody testing and may be used in type 2 diabetes to predict secondary failure and insulin requirement. Islet autoantibodies do not seem to be related to late complications but rather to metabolic control, perhaps because the presence of islet cell autoantibodies marks different residual beta-cell function. Combined genetic and autoantibody screening permit rational approaches to identify subjects for secondary and tertiary intervention trials.
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PMID:Type 1 diabetes. 1043 Aug 15

Protein tyrosine phosphatases (PTPs) are required for the dephosphorylation of the insulin receptor (IR) and its initial cellular substrates, and it has recently been reported that PTP-1B may play a role in the pathogenesis of insulin resistance in obesity and type 2 diabetes mellitus (DM). We therefore determined the amount and activity of PTP-1B in abdominal adipose tissue obtained from lean nondiabetic subjects (lean control (LC)), obese nondiabetic subjects (obese control (OC)), and subjects with both type 2 DM (DM2) and obesity (obese diabetic (OD)). PTP-1B protein levels were 3-fold higher in OC than in LC (1444 +/- 195 U vs 500 +/- 146 U (mean +/- SEM), P < .015), while OD exhibited a 5.5-fold increase (2728 +/- 286 U, P < .01). PTP activity was assayed by measuring the dephosphorylating activity toward a phosphorus 32-labeled synthetic dodecapeptide. In contrast to the increased PTP-1B protein levels, PTP-1B activity per unit of PTP-1B protein was markedly reduced, by 71% and 88% in OC and OD, respectively. Non-PTP-1B tyrosine phosphatase activity was comparable in all three groups. Similar results were obtained when PTP-1B activity was measured against intact human IR. A significant correlation was found between body mass index (BMI) and PTP-1B level (r = 0.672, P < .02), whereas BMI and PTP-1B activity per unit of PTP-1B showed a strong inverse correlation (r = -0.801, P < .002). These data suggest that the insulin resistance of obesity and DM2 is characterized by the increased expression of a catalytically impaired PTP-1B in adipose tissue and that impaired PTP-1B activity may be pathogenic for insulin resistance in these conditions.
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PMID:Marked impairment of protein tyrosine phosphatase 1B activity in adipose tissue of obese subjects with and without type 2 diabetes mellitus. 1044 21

Insulin resistance is known to play a pivotal role in type 2 diabetes. Senile individuals, besides being prone to insulin resistance and, consequently, to type 2 diabetes, manifest diseases of the central nervous system (CNS) that may be influenced by disturbances of insulin signaling in the brain, such as memory impairment, Parkinson disease, and Alzheimer disease. We investigated the expression and response to insulin of elements involved in the insulin-signaling pathway in the forebrain cortex and cerebellum of rats ages 1 d to 60 wk. The protein content of insulin receptors and SRC homology adaptor protein (SHC) did not change significantly along the time frame analyzed. However, insulin-induced tyrosine phosphorylation of the insulin receptor and SHC, and the association of SHC/growth factor receptor binding protein-2 (GRB2) decreased significantly from d 1 to wk 60 of life in both types of tissues. Moreover, the expression of SH protein tyrosine phosphatase-2 (SHP2), a tyrosine phosphatase involved in insulin signal transduction and regulation of the insulin signal, decreased significantly with age progression, in both the forebrain cortex and the cerebellum of rats. Thus, elements involved in the insulin-signaling pathway are regulated at the expression and/or functional level in the CNS, and this regulation may play a role in insulin resistance in the brain.
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PMID:Effects of age on elements of insulin-signaling pathway in central nervous system of rats. 1195 67

Antibodies to tyrosine phosphatase (IA2-Ab) and glutamate decarboxylase 65 (GAD65-Ab) are major markers for IDDM in Caucasians. TTG-Ab is specific for celiac disease. Celiac disease is caused by ingestion of the protein gliadin, a component of wheat gluten, and usually resolves on its withdrawal. Ten to twenty percent of celiac disease patients also have IDDM. The aim of the study was to estimate the prevalence of TTG-Ab in MMDM (n = 71), IDDM (n = 74), and NIDDM (n = 216) and 122 controls from Cuttack in eastern India. MMDM patients are typically young at onset with low body mass index, require insulin for glycemic control, have insulin resistance, and do not develop ketosis on withdrawal of insulin. TTG-Ab was evaluated by radioimmunoassay using in vitro translated recombinant human 35S-TTG. In controls, TTG-Ab was present in 3/122 (2%); in MMDM, TTG-Ab was present in 14/71 (20%); 11/74 (15%) IDDM (P < 0.05 vs. controls) and 23/216 (11%) NIDDM (P < 0.05 vs. controls) were also positive for TTG-Ab. We conclude that MMDM, IDDM, and NIDDM patients from Cuttack have a significantly high proportion of TTG-Ab compared to healthy controls. The highest significance is seen with MMDM patients. It is important to note that subclinical celiac disease must be considered in the differential diagnosis of MMDM.
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PMID:Autoantibodies to tissue transglutaminase in patients from eastern India with malnutrition-modulated diabetes mellitus, insulin-dependent diabetes mellitus, and non-insulin-dependent diabetes mellitus. 1202 Nov 13

Women with gestational diabetes mellitus (GDM) have considerable risk for developing both type 1 and type 2 diabetes in life. Autoantibodies against glutamic acid decarboxylase (GAD65) and tyrosine phosphatase (IA-2) are strongly associated with autoimmune diabetes and can be useful in early identification of the development of type 1 diabetes in women with GDM. On the other hand antibodies against minor islet antigens in adults can be predictors for autoimmune polyendocrine syndrome. The aim of our study was to estimate the prevalence of autoantibodies against minor antigens-tissue transglutaminase (TTG), ICA12, and 21-hydroxylase (21-0H)-in GDM patients from southern India. Eighty-six serum samples from GDM subjects and 114 samples from healthy controls were tested for the presence of GAD65 and IA-2Ab as well as for the presence of 21-OH, TTG, and ICA12Ab by radiobinding assay with in vitro translated recombinant human 35S-GAD65, IA-2, TTG, ICA12, and 21-OH antigens. We observed the presence of GAD65 or IA-2 autoantibodies in 41% (35/86) of GDM patients, while none of the patients tested positive for any of the minor autoantibodies. Our results demonstrate that there is a high prevalence of autoantibodies in GDM subjects that are at higher risk of developing autoimmune diabetes later, but none of the patients carries antibodies against minor antigens, which could predict autoimmune polyendocrine syndrome in adults.
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PMID:Women diagnosed with gestational diabetes mellitus do not carry antibodies against minor islet cell antigens. 1202 Nov 24

The identification of autophosphorylation of the insulin receptor as a pivotal component in the signal transduction induced by insulin, initiated the hunt to identify the tyrosine phosphatase(s) that were responsible for regulating dephosphorylation, and thus inactivation of the receptor. Compelling evidence for the existence of an insulin receptor specific PTP has come from the remarkable phenotype of the PTP1B deficient mouse. PTP1B deficient mice display an insulin sensitive phenotype and are able to maintain glucose homeostasis with about half the level of circulating insulin. In response to insulin administration PTP1B deficient mice have a significant increase in insulin receptor phosphorylation in liver and muscle compared to wild type controls. Unexpectedly these animals were also resistant to diet induced obesity. These observations strongly support PTP1B as a negative regulator of insulin action, thereby making it an ideal therapeutic target for intervention in type 2 diabetes and obesity.
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PMID:Protein tyrosine phosphatase 1B: a novel target for type 2 diabetes and obesity. 1267 42

Right classification of diabetes is important clinical issue. The aim of present study was to compare clinical, biochemical and immunological features, to analyze their practical use and to establish new decision tree which make the distinction between diabetes type 1, LADA, diabetes type 2 and MODY. We studied 97 not obese (mean BMI 26.3 +/- 4.9 kg/m2) patients aged 14 to 70 years, mean age 43 +/- 11.7 years, 53 women, 44 men. Mean duration of diabetes--2.3 +/- 4.3 years. We measured basal and stimulated C-peptide (6 minutes after 1 mg i.v. glucagon) (ELISA) and antibodies titers to glutamic acid decarboxylase--antiGAD65, tyrosine phosphatase-like molecule--IA2 and insulin--IAA (RIA). Autoimmune diabetes (LADA, type 1) was diagnosed with presence of one or more islet antigen antibodies. The highest frequencies had anti-GAD antibodies 33/97 (34%). The most complicated was to sort out group of patients with LADA. Comparison between this group and patients with diabetes type 2 have shown that BMI, co-existence of autoimmune disease, autoimmune markers and basal and stimulated C-peptide level measured at entry for the classification were useful in differentiation. Moreover we observed significantly lower C-peptide basal, stimulated and over basal level in group with MODY diabetes in comparison to diabetes type 2 patients. In the studied group were 5 patients with diabetes type 2 and obesity, in relatively young age. At the end there was one case of ADM (atypical diabetes mellitus). Clinical criteria for the classification of diabetes not always correlated with diagnosis. Autoimmune markers, basal and stimulated C-peptide were useful specially in differentiation between LADA and diabetes type 2 or diabetes type 1. Autoimmune diabetes co-existe with autoimmune disease. Proposed diagnostic scheme take for consideration presence of autoantibodies as well as C-peptide criteria.
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PMID:[Clinical, biochemical and immunological characteristic of diabetes type I, LADA, diabetes type II, and MODY patients]. 1268 30

The findings of the recent HOPE trial strongly suggest that ACE inhibitor therapy may reduce risk for type 2 diabetes in patients who are non-diabetic at baseline. This finding is readily rationalized by previous evidence that bradykinin, acting via B2 receptors, can potentiate the insulin responsiveness of both adipocytes and muscle fibers; this effect may be mediated by a reduction in the activity of a tyrosine phosphatase that targets the insulin receptor. ACE inhibitors, in turn, increase the availability of bradykinin by suppressing its proteolytic degradation. In light of the fact that the development of insulin resistance in adipocytes is responsible for the excessive free fatty acid flux that gives rise to the diabetic syndrome, a favorable impact of ACE inhibition on adipocyte insulin responsiveness - complemented by a potentiation of the direct action of bradykinin on skeletal muscle - offers a satisfying explanation for the prevention of diabetes observed during ACE inhibitor therapy. Since the population at risk for diabetes is huge and increasing dramatically, the recent development of orally absorbable food-derived peptides with clinically significant ACE inhibitory activity - such as 'Katsuobushi oligopeptides' derived from bonito - may make it more logistically feasible to achieve this protection on a widescale basis, while simultaneously promoting blood pressure control and reducing risk for atherothrombotic disease.
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PMID:ACE inhibition may decrease diabetes risk by boosting the impact of bradykinin on adipocytes. 1269 3

Dipeptidyl-peptidase IV/CD26 (DPP IV) is a cell-surface protease belonging to the prolyloligopeptidase family. It selectively removes the N-terminal dipeptide from peptides with proline or alanine in the second position. Apart from its catalytic activity, it interacts with several proteins, for instance, adenosine deaminase, the HIV gp120 protein, fibronectin, collagen, the chemokine receptor CXCR4, and the tyrosine phosphatase CD45. DPP IV is expressed on a specific set of T lymphocytes, where it is up-regulated after activation. It is also expressed in a variety of tissues, primarily on endothelial and epithelial cells. A soluble form is present in plasma and other body fluids. DPP IV has been proposed as a diagnostic or prognostic marker for various tumors, hematological malignancies, immunological, inflammatory, psychoneuroendocrine disorders, and viral infections. DPP IV truncates many bioactive peptides of medical importance. It plays a role in glucose homeostasis through proteolytic inactivation of the incretins. DPP IV inhibitors improve glucose tolerance and pancreatic islet cell function in animal models of type 2 diabetes and in diabetic patients. The role of DPP IV/ CD26 within the immune system is a combination of its exopeptidase activity and its interactions with different molecules. This enables DPP IV/CD26 to serve as a co-stimulatory molecule to influence T cell activity and to modulate chemotaxis. DPP IV is also implicated in HIV-1 entry, malignant transformation, and tumor invasion.
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PMID:Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV. 1289 17

The protein tyrosine phosphatase PTP1B is a negative regulator of insulin signaling and a therapeutic target for type 2 diabetes. Our previous studies have shown that the closely related tyrosine phosphatase TCPTP might also contribute to the regulation of insulin receptor (IR) signaling in vivo (S. Galic, M. Klingler-Hoffmann, M. T. Fodero-Tavoletti, M. A. Puryer, T. C. Meng, N. K. Tonks, and T. Tiganis, Mol. Cell. Biol. 23:2096-2108, 2003). Here we show that PTP1B and TCPTP function in a coordinated and temporally distinct manner to achieve an overall regulation of IR phosphorylation and signaling. Whereas insulin-induced phosphatidylinositol 3-kinase/Akt signaling was prolonged in both TCPTP-/- and PTP1B-/- immortalized mouse embryo fibroblasts (MEFs), mitogen-activated protein kinase ERK1/2 signaling was elevated only in PTP1B-null MEFs. By using phosphorylation-specific antibodies, we demonstrate that both IR beta-subunit Y1162/Y1163 and Y972 phosphorylation are elevated in PTP1B-/- MEFs, whereas Y972 phosphorylation was elevated and Y1162/Y1163 phosphorylation was sustained in TCPTP-/- MEFs, indicating that PTP1B and TCPTP differentially contribute to the regulation of IR phosphorylation and signaling. Consistent with this, suppression of TCPTP protein levels by RNA interference in PTP1B-/- MEFs resulted in no change in ERK1/2 signaling but caused prolonged Akt activation and Y1162/Y1163 phosphorylation. These results demonstrate that PTP1B and TCPTP are not redundant in insulin signaling and that they act to control both common as well as distinct insulin signaling pathways in the same cell.
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PMID:Coordinated regulation of insulin signaling by the protein tyrosine phosphatases PTP1B and TCPTP. 1563 81


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