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)

A diabetic acromegalic man, not cured after surgery and radiosurgery, received lanreotide i.m. with great clinical and biochemical improvement. He required NPH insulin (76 to 84 units/day) to control his diabetes mellitus. Thirty-six hours after changing to LAR-octreotide (20 mg i.m/month) he presented symptomatic hypoglycemia, repeated at 48 and 72 h (50 mg/dL), despite reducing insulin to 26 Units/day. Thereafter, he reduced insulin by 30 to 50% for the first week after each LAR-octreotide injection, and gradually increased it again over the next 3 weeks. This situation persists after every injection 3 years later; this consistent behavior supports a specific effect of LAR-octreotide, and not a by chance phenomenon. No marked changes in circulating GH, IGF-1, immunoreative insulin, C-peptide, testosterone and glucose were observed prior to, and 3, 7, 14, 21, and 28 days after LAR-octreotide; however, there was 28% fall in plasma glucagon after 7 days, which rose thereafter. C-peptide (< 1.8 ng/mL) was indicative of decreased beta-cell function. To our knowledge, this is the first report of such a distinct differential behaviour of blood glucose and insulin requirements with different somatostatin analogs, and is worth recalling when starting an insulin-treated diabetic patient on this treatment. It may be related to a preferential binding of LAR-octreotide to subtype 2 somatostatin receptors in the pancreas, while lanreotide preferentially binds to subtype 5, not expressed in this tissue; this would explain the fall in glucagon, in parallel to the decrease in insulin requirements after LAR-octreotide; however, a contribution of differences in the effect of both somatostatin analogues on postreceptor signalling systems and/or intestinal carbohydrate absorption cannot be entirely ruled out.
 ...
PMID:Decreased insulin requirements after LAR-octreotide but not after lanreotide in an acromegalic patient. 1250 80

Type 2 diabetes is increasing at an alarming rate worldwide, and there has been a considerable effort in several laboratories to identify suitable targets for the design of drugs against the disease. To this end, the protein tyrosine phosphatases that attenuate insulin signaling by dephosphorylating the insulin receptor (IR) have been actively pursued. This is because inhibiting the phosphatases would be expected to prolong insulin signaling and thereby facilitate glucose uptake and, presumably, result in a lowering of blood glucose. Targeting the IR protein tyrosine phosphatase, therefore, has the potential to be a significant disease-modifying strategy. Several protein tyrosine phosphatases (PTPs) have been implicated in the dephosphorylation of the IR. These phosphatases include PTPalpha, LAR, CD45, PTPepsilon, SHP2, and PTP1B. In most cases, there is evidence for and against the involvement of the phosphatases in insulin signaling. The most convincing data, however, support a critical role for PTP1B in insulin action. PTP1B knockout mice are not only insulin sensitive but also maintain euglycemia (in the fed state), with one-half the level of insulin observed in wild-type littermates. Interestingly, these mice are also resistant to diet-induced obesity when fed a high-fat diet. The insulin-sensitive phenotype of the PTP1B knockout mouse is reproduced when the phosphatase is also knocked down with an antisense oligonucleotide in obese mice. Thus PTP1B appears to be a very attractive candidate for the design of drugs for type 2 diabetes and obesity.
 ...
PMID:Protein tyrosine phosphatases: the quest for negative regulators of insulin action. 1262 22

Protein tyrosine phosphatases (PTPases) regulate intracellular signal transduction pathways by controlling the level of tyrosine phosphorylation in cells. These enzymes play an important role in a variety of diseases including type II diabetes and infection by the bacterium Yersinia pestis, which is the causative agent of bubonic plague. This report describes the synthesis, using parallel solution-phase methods, of a library of 104 potential inhibitors of PTPases. The library members are based on the bis(aryl alpha-ketocarboxylic acid) motif that incorporates a carboxylic acid on the central benzene linker. This carboxylic acid was coupled with a variety of different aromatic amines through an amide linkage. The aromatic component of the resulting amides is designed to make contacts with residues that surround the active site of the PTPase. The library was screened against the Yersinia PTPase and PTP1B. Based upon the screening results, four members of the library were selected for further study. These four compounds were evaluated against the Yersinia PTPase, PTP1B, TCPTP, CD45, and LAR. Compound 14 has an IC(50) value of 590nM against PTP1B and is a reversible competitive inhibitor. This affinity represents a greater than 120-fold increase in potency over compound 2, the parent structure upon which the library was based. A second inhibitor, compound 12, has an IC(50) value of 240nM against the Yersinia PTPase. In general, the selectivity of the inhibitors for PTP1B was good compared to LAR, but modest when compared to TCPTP and CD45.
 ...
PMID:Parallel synthesis of a library of bidentate protein tyrosine phosphatase inhibitors based on the alpha-ketoacid motif. 1515 97

Protein tyrosine phosphatases (PTPases) and protein tyrosine kinase (PTKases) regulate the phosphorylation and dephosphorylation of tyrosine residues in proteins, events that are essential for a variety of cellular functions. PTPases such as PTP1B and the Yersinia PTPase play an important role in diseases including type II diabetes and bubonic plague. A library of 67 bidentate PTPase inhibitors that are based on the alpha-ketocarboxylic acid motif has been synthesized using parallel solution-phase methods. Two aryl alpha-ketocarboxylic acids were tethered to a variety of different diamine linkers through amide bonds. The compounds were assayed in crude form against the Yersinia PTPase, PTP1B, and TCPTP. Six compounds were selected for further evaluation, in purified form, against the Yersinia PTPase, PTP1B, TCPTP, LAR, and CD45. These compounds had IC50 values in the low micromolar range against the Yersinia PTPase, PTP1B, and TCPTP, showed good selectivity for PTP1B over LAR, and modest selectivity over CD45. The correlation between linker structure and inhibitor activity shows that aromatic groups in the linker can play an important role in determining binding affinity in this class of inhibitors.
 ...
PMID:Investigations of linker structure on the potency of a series of bidentate protein tyrosine phosphatase inhibitors. 1578 8

The fluorogenic reagent 4-(aminosulfonyl)-7-fluoro-2,1,3-benzoxadiazole (ABDF) attenuates the functional activity of the protein tyrosine phosphatase PTP1B by reacting selectively with a single cysteine residue, leaving other cysteines in the protein unmodified. This modification reduces Vmax without substantially affecting substrate binding (Km), indicative of an allosteric mode of inhibition. Consistent with this, the cysteine residue modified by ABDF, Cys 121, lies outside the catalytic site but makes interactions with residues that contact His 214, which has been shown to be important for catalysis. Cys 121 is highly conserved among phosphatases, and ABDF also inhibits TC-PTP and LAR. These findings illustrate that targeting cysteine residues outside catalytic sites may be exploited in allosterically regulating enzymes. Moreover, these results suggest a new strategy for inhibiting a promising diabetes target.
 ...
PMID:Allosteric inhibition of PTP1B activity by selective modification of a non-active site cysteine residue. 1590 85

Octreotide is the first somatostatin analogue to become available for clinical use in the treatment of acromegaly. To our knowledge, there are no reports describing lipoatrophy in patients treated with octreotide. Here, we report three patients who developed lipoatrophy after treatment with subcutaneous octreotide. Three patients (all women; 36, 43, and 50 years of age) with diagnosis of acromegaly due to pituitary macroadenoma who had undergone transsphenoidal surgery and radiotherapy received subcutaneos octreotide because of uncontrolled disease. The dose of octreotide was increased gradually in all patients. Lipoatrophy was noticed around the injection sites after about 6 years, 30 months, and 4 years of subcutaneous octreotide treatment in all patients. Thereafter, subcutaneous octreotide treatment was changed to intramuscular octreotide-LAR injection in all patients. In two of them, lipoatrophy around all injection sites did not regress after about 8 and 12 months of octreotide-LAR treatment, respectively. In the third patient, lipoatrophy around the injection sites regressed after 12 months of octreotide-LAR treatment. These cases highlight a potential for subcutaneous octreotide to induce lipoatrophy. The underlying mechanism is unknown but an immunological mechanism which is seen in lipoatrophy induced by insulin may be involved in the pathogenesis. Besides; simple trauma, personal susceptibility, mistakes in the administration of the drug, a problem in drug pH, or an idiosyncratic reaction of adipocytes to octreotide or additives in the drug may have caused lipoatrophy in our patients. Lipoatrophy in these cases was observed on long-term subcutaneous octreotide administration. Although intramuscular octreotide-LAR has largely replaced subcutaneous octreotide, we suggest close clinical follow-up for lipoatrophy in patients who are still on subcutaneous octreotide.
Exp Clin Endocrinol Diabetes 2005 Jun
PMID:Lipoatrophy induced by subcutaneous administration of octreotide in the treatment of acromegaly. 1597 2

Cushing's syndrome (CS) due to ectopic ACTH secretion has a high morbidity and mortality. Thus, rapid treatment of ectopic CS is mandatory. Carcinoid tumors associated with ectopic ACTH (CTu-ACTH) syndrome represent a more severe clinical picture, due to the carcinoid symptoms that worsen the hypercortisolism state. Management of patients with CTu-ACTH should include the control of hypercortisolism, as well as the carcinoid disturbance. We report 3 patients (2F, 1M) with CTu-ACTH (2 pancreatic, 1 occult) who presented with clinical manifestations of CS (n= 3) and carcinoid syndrome (2): 2 were initially investigated for CS and 1 carcinoid syndrome. In all hypokalemia, hypertension and diabetes mellitus were associated with severe hypercortisolism and high ACTH levels. Administration of octreotide-LAR reduced ACTH levels from 230,000 to 30,000 pg/ml in patient 1, and controlled symptoms of carcinoid syndrome and neoplasic lesions in patient 2; treatment with subcutaneous octreotide in patient 3 controlled carcinoid syndrome and partially reduced symptoms of hypercortisolism. All 3 patients were submitted to bilateral adrenalectomy to control CS. Our data show that combined anti-neoplastic therapy may contribute to the stabilization and/or definitive control of CTu-ACTH.
 ...
PMID:[Octreotide + bilateral adrenalectomy in the management of ACTH-producing carcinoid tumors]. 1644 62

Relief of symptoms can be achieved following surgery for growth hormone (GH)-secreting adenomas, as well as after pharmacological therapy with somatostatin analogs. Recently, long-acting somatostatin analog depot formulations, octreotide LAR and lanreotide SR have become available. Somatostatin analogs control GH/insulin-like growth factor (IGF)-1 excess, induce tumor shrinkage in a high proportion of patients, improve symptoms of acromegaly with relatively limited side effects and are successfully administered in patients not suitable for surgery. Furthermore, preoperative somatostatin analogs have been suggested to improve outcome for tumors with limited invasiveness, while surgical tumor debulking in cases that are, at least partially, somatostatin resistant, increases the achievement of normal IGF-1 levels by postoperative somatostatin analog treatment. Effective control of hypertension, as well as diabetes, is mandatory in order to reduce the increased vascular morbidity/mortality. Control of GH/IGF-1 excess generally improves glucose metabolism. Somatostatin analogs improve insulin sensitivity, exerting, however, a concomitant direct inhibitory effect on insulin secretion, with a net balance leaning towards a deterioration in glucose homeostasis. As a result, oral insulin secretagogues (and/or insulin) should probably be preferred to insulin sensitizers in acromegalic patients developing diabetes while on somatostatin analogs. Nevertheless, glucose tolerance remains normal in most of the nondiabetic acromegalic patients, while diabetic acromegalic patients on insulin are at risk for hypoglycemia during initiation of somatostatin analog therapy. Although successful management of acromegaly has been associated with improvement in morphological and functional parameters of cardiomyopathy, limited and conflicting information is available regarding the effect on blood pressure control. Contradictory results have also been reported regarding sleep hypopnea or apnea in treated acromegalic patients. As acromegalic skeletal abnormalities are rather irreversible, apneic episodes may persist after normalization of hormonal levels. Aggressive therapy, including surgery, pharmacological treatment and, in some cases, pituitary irradiation, aiming at normalization of IGF-1 levels, is required for arthropathy management. Some improvement in pain, crepitus and range of motion has been observed after treatment with somatostatin analogs. Information on the impact of disease control, either by surgery or somatostatin analog treatment, on gonadal function is limited. Finally, the link between the hormonal/biochemical and the psychiatric/psychological features of acromegaly, as well as a potential basis for positive effects of somatostatin analog therapy remain unclear.
 ...
PMID:Medical treatment of acromegaly: comorbidities and their reversibility by somatostatin analogs. 1704 90

No head-to-head comparisons are available to analyze the efficacy of octreotide (LAR) and lanreotide (LAN) as first-line treatment of acromegaly.We compared the efficacy of these two drugs in 54 newly diagnosed patients (21 women, 33 men), 27 treated with LAR (10-30 mg every 28 days) and 27 with LAN (60-90 mg/28 days), for 12 months. Each LAR-treated patient was matched with one LAN-treated patient as for GH levels, sex, and age (+/-5 yr). Outcome measures were GH and IGF-I levels and tumor shrinkage and secondarily classical cardiovascular risk factors (total/HDL-cholesterol ratio, glucose tolerance), blood pressure and drug tolerability. In LAR- and in LAN-treated patients, respectively: GH and IGF-I were controlled in 21 (77.7%) and in 16 patients (59.3%; p=0.26); tumor shrinkage was absent (<25%) in 4 and 5 patients (p=1), mild (25.1-50%) in 9 and 12 (p=0.57), moderate (50.1-75%) in 10 and 6 (p=0.37) and notable (>75%) in 4 and 4 patients (p=1). The total/HDL-cholesterol ratio and insulin levels significantly decreased while glucose levels significantly increased in both groups. None of the patients with normal glucose tolerance at diagnosis developed diabetes mellitus. Side effects were mostly at the gastrointestinal level and were similar with both drugs. In conclusion, newly diagnosed patients with acromegaly treated with LAR and LAN have no significantly different prevalence of disease control, tumor shrinkage, improvement of cardiovascular risk markers and side effects. Therefore, both drugs can be safely employed as first-line therapy of acromegaly.
 ...
PMID:Octreotide-LAR vs lanreotide-SR as first-line therapy for acromegaly: a retrospective, comparative, head-to-head study. 1916 50

Protein Tyrosine Phosphatases (PTPs) that function as negative regulators of the insulin signaling cascade have been identified as novel targets for the therapeutic enhancement of insulin action in insulin resistant disease states. Reducing Protein Tyrosine Phosphatase1B (PTP1B) abundance not only enhances insulin sensitivity and improves glucose metabolism but also protects against obesity induced by high fat feeding. PTP1B inhibitors such as Formylchromone derivatives, 1, 2-Naphthoquinone derivatives and Oxalyl aryl amino benzoic derivatives may eventually find an important clinical role as insulin sensitizers in the management of Type-II Diabetes and metabolic syndrome. We have carried out docking of modified oxalyl aryl amino benzoic acid derivatives into three dimensional structure of PTP1B using BioMed CAChe 6.1. These compounds exhibit good selectivity for PTP1B over most of phosphatases in selectivity panel such as SHP-2, LAR, CD45 and TCPTP found in literature. This series of compounds identified the amino acid residues such as Gly220 and Arg221 are important for achieving specificity via H-bonding interactions. Lipophilic side chain of methionine in modified oxalyl aryl amino benzoic acid derivative [1b (a2, b2, c1, d)] lies in closer vicinity of hydrophobic region of protein consisted of Meth258 and Phe52 in comparison to active ligand. Docking Score in [1b (a2, b2, c1, d)] is -131.740Kcal/mol much better than active ligand score -98.584Kcal/mol. This information can be exploited to design PTP1B specific inhibitors.
 ...
PMID:Docking of oxalyl aryl amino benzoic acid derivatives into PTP1B. 1923 34


<< Previous 1 2 3 4 Next >>