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)

Growth hormone (GH) is well known to induce in vivo insulin resistance. However, the molecular mechanism of GH-induced cellular insulin resistance is largely unknown. In this study, we demonstrated that chronic GH treatment of differentiated 3T3-L1 adipocytes reduces insulin-stimulated 2-deoxyglucose (DOG) uptake and activation of Akt (also known as protein kinase B), both of which are downstream effects of phosphatidylinositol (PI) 3-kinase, despite enhanced tyrosine phosphorylation of insulin receptor substrate (IRS)-1, association of IRS-1 with the p85 subunit of PI 3-kinase, and IRS-1-associated PI 3-kinase activity. In contrast, chronic GH treatment did not affect 2-DOG uptake and Akt activation induced by overexpression of a membrane-targeted form of the p110 subunit of PI 3-kinase (p110(CAAX)) or Akt activation stimulated by platelet-derived growth factor. Fractionation studies indicated that chronic GH treatment reduces insulin-stimulated translocation of Akt from the cytosol to the plasma membrane. Interestingly, chronic GH treatment increased insulin-stimulated association of IRS-1 with p85 and IRS-1-associated PI 3-kinase activity preferentially in the cytosol. These results indicate that cellular insulin resistance induced by chronic GH treatment in 3T3-L1 adipocytes is caused by uncoupling between activation of PI 3-kinase and its downstream signals, which is specific to the insulin-stimulated PI 3-kinase pathway. This effect of GH might result from the altered subcellular distribution of IRS-1-associated PI 3-kinase.
Diabetes 2001 Aug
PMID:Growth hormone induces cellular insulin resistance by uncoupling phosphatidylinositol 3-kinase and its downstream signals in 3T3-L1 adipocytes. 1147 53

The clinical findings and management of five cats with abnormalities consistent with acromegaly were examined retrospectively. Growth hormone (GH) concentrations were elevated in four cats. In one, a minimal elevation of GH was accompanied by a marked elevation in insulin-like growth factor-1 (IGF-1). Insulin-like growth factor-1 concentrations supported the diagnosis in three of four cats measured, but was not elevated initially in one cat, despite a markedly elevated GH concentration. These findings suggest that elevated IGF-1 concentrations are a reliable indicator of acromegaly, but that values within the reference range do not exclude such a diagnosis. Clinical signs of acromegaly were similar to those previously reported, although upper respiratory stridor occurred in one cat, and insulin-resistant diabetes mellitus was not a consistent feature. Despite the lack of a widely available definitive treatment for acromegaly, good control of the clinical signs of diabetes mellitus can be achieved for long periods despite high doses of insulin often being required.
 ...
PMID:Diagnosis and management of diabetes mellitus in five cats with somatotrophic abnormalities. 1171 17

We tested the hypothesis that increased endogenous cortisol secretion reduces autonomic neuroendocrine and neurogenic symptom responses to subsequent hypoglycemia. Twelve healthy young adults were studied on two separate occasions, once after infusions of a pharmacological dose of alpha-(1-24)-ACTH (100 microg/h) from 0930 to 1200 and 1330 to 1600, which raised plasma cortisol levels to approximately 45 microg/dl on day 1, and once after saline infusions on day 1. Hyperinsulinemic (2.0 mU x kg(-1) x min(-1)) stepped hypoglycemic clamps (90, 75, 65, 55, and 45 mg/dl glucose steps) were performed on the morning of day 2 on both occasions. These markedly elevated antecedent endogenous cortisol levels reduced the adrenomedullary (P = 0.004, final plasma epinephrine levels of 489 +/-64 vs. 816 +/-113 pg/ml), sympathetic neural (P = 0.0022, final plasma norepinephrine levels of 244 +/-15 vs. 342 +/-22 pg/ml), parasympathetic neural (P = 0.0434, final plasma pancreatic polypeptide levels of 312 +/- 37 vs. 424 +/- 56 pg/ml), and neurogenic (autonomic) symptom (P = 0.0097, final symptom score of 7.1 +/-1.5 vs. 10.6 +/- 1.6) responses to subsequent hypoglycemia. Growth hormone, but not glucagon or cortisol, responses were also reduced. The findings that increased endogenous cortisol secretion reduces autonomic neuroendocrine and neurogenic symptom responses to subsequent hypoglycemia are potentially relevant to cortisol mediation of hypoglycemia-associated autonomic failure, and thus a vicious cycle of recurrent iatrogenic hypoglycemia, in people with diabetes mellitus.
 ...
PMID:Elevated endogenous cortisol reduces autonomic neuroendocrine and symptom responses to subsequent hypoglycemia. 1188 96

Standard medical therapy for patients with acromegaly includes somatostatin analogs. Owing to the widespread expression of somatostatin receptors, these may be associated with unwanted effects, such as altered glucose tolerance and impaired gut hormone release. Pegvisomant is a novel pegylated GH analog that competes with wild-type GH for GH-receptor binding sites but contains a position 120, amino acid substitution that prevents functional GH receptor dimerization, a known prerequisite for GH signal transduction and generation of IGF-I. We have studied the short-term effects of these two therapies (pegvisomant 20 mg/d for 7 d and octreotide 50 microg thrice daily for 7 d) on glucose tolerance and stimulated gut hormone release in six healthy male volunteers in an open-label, random-order, cross-over study. Subjects were assessed at baseline (oral glucose tolerance test and standard mixed meal) and on d 6 and 7 of each therapy with a minimum washout of 2 wk between treatments. Area under the curve and peak responses were analyzed using one-way repeated-measures ANOVA (on ranks where appropriate). Pegvisomant had no effect on glucose tolerance or stimulated gut hormone response during an oral glucose tolerance test and a standard meal. In contrast, octreotide significantly increased fasting plasma glucose, lowered fasting plasma insulin, and led to deterioration in glucose tolerance; three subjects developed impaired glucose tolerance and one diabetes mellitus by World Health Organization criteria. Octreotide significantly impaired stimulated release of cholecystokinin, gastrin, insulin, and pancreatic polypeptide. In conclusion, pegvisomant, unlike octreotide, is not associated with deterioration in glucose tolerance and impairment of stimulated gut hormone release in normal males.
 ...
PMID:A comparison of the effects of pegvisomant and octreotide on glucose, insulin, gastrin, cholecystokinin, and pancreatic polypeptide responses to oral glucose and a standard mixed meal. 1193 20

Growth hormone (GH) and IGFs have a long distinguished history in diabetes, with possible participation in the development of renal complications. The implicated effect of GH in diabetic end-stage organ damage may be mediated by growth hormone receptor (GHR) or postreceptor events in GH signal transduction. The present study investigates the effects of diabetes induced by streptozotocin (STZ) on renal GH signaling. Our results demonstrate that JAK2, insulin receptor substrate (IRS)-1, Shc, ERKs, and Akt are widely distributed in the kidney, and after GH treatment, there is a significant increase in phosphorylation of these proteins in STZ-induced diabetic rats compared with controls. Moreover, the GH-induced association of IRS-1/phosphatidylinositol 3-kinase, IRS-1/growth factor receptor bound 2 (Grb2), and Shc/Grb2 are increased in diabetic rats as well. Immunohistochemical studies show that GH-induced p-Akt and p-ERK activation is apparently more pronounced in the kidneys of diabetic rats. Administration of G120K-PEG, a GH antagonist, in diabetic mice shows inhibitory effects on diabetic renal enlargement and reverses the alterations in GH signal transduction observed in diabetic animals. The present study demonstrates a role for GH signaling in the pathogenesis of early diabetic renal changes and suggests that specific GHR blockade may present a new concept in the treatment of diabetic kidney disease.
Diabetes 2002 Jul
PMID:Modulation of growth hormone signal transduction in kidneys of streptozotocin-induced diabetic animals: effect of a growth hormone receptor antagonist. 1208 60

Pegvisomant, a polyethylene glycol (PEG) derivative of human growth hormone (GH) that acts as a highly selective GH receptor antagonist, is under development by Pharmacia (formerly Sensus) as a potential treatment for acromegaly. By February 2001, Sensus had submitted an NDA for the treatment of acromegaly, and an approvable letter indicating outstanding issues had been received by July 2001. Pegvisomant was granted Orphan Drug status by the FDA and was designated for Priority Review. Pegvisomant also received Orphan Drug designation in the EU and Japan. In March 2001, additional regulatory filings were being planned for later in 2001. In October 2001, Pharmacia was preparing an NDA in Japan for the treatment of acromegaly. By September 1998, phase 1 trials of the treatment were underway for diabetic retinopathy, and were planned for diabetic nephropathy in 1999. By September 1997, a phase II trial to test the effects of pegvisonant an insulin sensitivity and secretion in type II diabetes patients was underway. However, no development has been reported for these indications since the dates given. By 1994, Sensus had licensed technology for development of GH receptor antagonists from Genentech and Ohio University. Sensus was to pay Genentech, and Genentech was to receive equity in Sensus and royalties from the commercialization of any product resulting from the agreement. In April 2000, the company entered into a licensing agreement with Shearwater Polymers for the PEGylation of pegvisomant using Shearwater's proprietary technology, which is now used to produce the 20-kDa PEG-derivative of pegvisomant. In June 1999, Pharmacia Corp (formerly Pharmacia & Upjohn) signed an agreement to purchase 19.9% of Sensus and to potentially acquire the remainder of the company at a later date. In March 2001, Pharmacia completed its purchase of Sensus. Analysts at Merrill Lynch predicted in February 2002 that the product would be launched in 2003, with US revenues of $20 million, rising to $115 million in 2006.
 ...
PMID:Pegvisomant. Pharmacia. 1209 May 48

The role of growth hormone releasing hormone (GHRH) and growth hormone releasing peptide-6 (GHRP-6) analogue hexarelin was investigated in the regulation of GH production from lymphocytes. Porcine and bovine blood mononuclear cells were separated using density gradient centrifugation method by layering the whole blood or buffy coat cells on lymphodex. Cells were incubated for 3 or 5 days with or without phytohemagglutinin (PHA-M), GHRH, GHRP-6 analogue hexarelin, somatostatin or GHRH + hexarelin. Growth hormone was fractionated from supernatants by gel chromatography and further concentrated by lyophilization at - 20 degrees C. A nearly two fold increase in basal secretion of GH (porcine: 3.5 +/- 0.1 ng/ml, bovine: 3.2 +/- 0.2 ng/ml) was achieved by GHRH and hexarelin at concentrations of 0.1, 1.0, 10 and 100 nM in both porcine and bovine cells. Lymphocytic GH release was also stimulated in response to PHA-M (10 micro g/well). Neither a dose dependent nor a synergistic nor an additive effect was apparent on GH secretion from lymphocytes. GHRH stimulated lymphocytic GH secretion, whereas, somatostatin had no effect. This study reports for the first time that hexarelin stimulates the secretion of GH from peripheral lymphocytes.
Exp Clin Endocrinol Diabetes 2002 Oct
PMID:Growth hormone secretagogue (GHS) analogue, hexarelin stimulates GH from peripheral lymphocytes. 1239 33

Growth hormone hypersecretion is a known cause of insulin resistance. This change in insulin sensitivity is believed to be mediated directly by growth hormone binding to its receptor. Five subjects ages 28-55 years who were participating in a clinical study that had been designed to assess the effects of a growth hormone receptor antagonist (Pegvisomant) on disease activity in acromegaly were evaluated to determine the role of growth hormone hypersecretion in inducing changes in insulin sensitivity. These subjects were treated with the 15-30 mg/day of Pegvisomant for periods ranging from 14 to 23 months. These doses were adequate to normalize IGF-I in four of the five subjects. The subjects were monitored to ensure that there were no significant changes in diet, exercise, or weight. Mean pretreatment IGF-I was 1104+/-277 ng/ml and decreased to a nadir of 355+/-157 ng/ml on treatment. After a 6-week withdrawal period, mean IGF-I had increased to 549+/-142 ng/ml. Fasting insulin was 35.2+/-16 uU/ml prior to treatment then decreased to a nadir of 19.9+/-14.6 uU/ml on treatment and then increased to 24.5+/-11.3 uU/ml. Fasting glucose decreased from 187+/-68 to 122+/-38 mg/dl and then increased to 159+/-41 mg/dl. Hemoglobin A(1)C decreased from 8.1+/-1.7 to 6.3+/-1.5%. Two subjects with overt type II diabetes had decreases in hemoglobin A(1)C from 8.3 to 5.9% and from 11.4 to 8.6%. These changes were associated with decreases in the amount of medication needed to control blood glucose. Weight remained stable throughout the study. The results show that the Pegvisomant is an effective agent for improving insulin resistance in subjects who have acromegaly and that this effect is independent of weight loss. The results suggest a potential role for Pevisomant in the treatment of insulin resistant states other than acromegaly.
 ...
PMID:Growth hormone receptor antagonist improves insulin resistance in acromegaly. 1242 27

Growth hormone (GH) has profound effects on vertebrate growth and cellular differentiation in diverse tissue types. Sexually dimorphic levels of circulating GH vary during development and throughout the lifespan. The synthesis and secretion of GH by the pituitary gland are precisely controlled. Abnormal levels are pathological; hyposecretion in children results in dwarfism while hypersecretion results in acromegaly. This review provides an overview of GH and the GH/insulin-like growth factor (IGF-1) axis and highlights a GH receptor antagonist (i.e. Somavert(R), pegvisomant). This antagonist competes with endogenous GH for the receptor and results in suppression of serum insulin-like growth factor (IGF-1). Pegvisomant is important for the treatment of acromegaly and may have therapeutic implications for certain types of cancer and end organ damage due to diabetes.
 ...
PMID:Growth hormone receptor antagonists. 1251 51

Acromegaly is a chronic disorder invariably caused by a growth hormone (GH)-secreting pituitary tumour and is characterised by disabling symptoms (sweating, arthralgia, headache, paraesthesiae, fatigue), significant comorbidities (diabetes mellitus, hypertension, sleep apnoea), and premature mortality. Symptomatic control can be achieved by lowering insulin-like growth factor-I (IGF-I) concentrations to within the age-adjusted normal range, and survival can be improved to match that of the general population. However, even with optimal surgery and current medical therapies (dopamine agonists, somatostatin analogues), 30% to 50% of patients do not achieve target concentrations of IGF-I and GH. Pegvisomant is a new GH-receptor antagonist that blocks GH activity by inhibiting functional dimerisation of GH-receptors. Given as subcutaneous injections at dosages of 10 mg, 15 mg, or 20 mg/day for 3 Months, pegvisomant normalised serum IGF-I concentrations in, respectively, 54%, 81%, and 89% of acromegalic patients. Moreover, long-term pegvisomant therapy normalised IGF-I concentrations in 97% of patients treated for 12 Months or longer, with no evidence of tachyphylaxis. Pegvisomant is the most effective medical therapy, reported to date, in terms of normalisation of circulating IGF-I concentrations. In addition, pegvisomant appears to be safe and well tolerated. Although additional long-term studies are required to further assess safety, the introduction of this innovative treatment should allow for optimal disease control in patients with acromegaly.
 ...
PMID:Pegvisomant: an advance in clinical efficacy in acromegaly. 1267 Feb 98


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