Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

KK obese mice exhibit a multigenic syndrome of moderate obesity, hyperinsulinemia and hyperglycemia. Here we show that the syndrome is accompanied by a marked elevation of leptin protein in adipose tissue, as well as leptin levels in serum, which corresponds with the degree of obesity. The cDNA sequence of leptin is normal in KK mice, whereas three nucleotide polymorphisms were found in the cDNA of the leptin receptor, one of them resulting in exchange of an aspartate residue for asparagine (Asp600Asn) in a highly conserved part of the second extracellular cytokine-receptor homology module. In female (but not male) F2 mice of a C57BL/6JxKK intercross, the weight of gonadal, retroperitoneal and mesenteric adipose tissue was positively correlated with the number of alleles inherited from the KK parental strain at a microsatellite marker (D4Mit175) which maps close (0.7 centimorgan proximal) to the leptin receptor gene. It is suggested that the Asp600Asn leptin receptor variant contributes to the obesity syndrome in KK female mice, but that its contribution is only a part of the multigenic syndrome.
J Mol Endocrinol 1998 Dec
PMID:Hyperleptinemia and leptin receptor variant Asp600Asn in the obese, hyperinsulinemic KK mouse strain. 984 74

Dialysis-related amyloidosis is recognized as a serious bone and joint complication in long-term dialysis patients. Beta2-microglobulin has been demonstrated to be a major constituent of the amyloid fibrils. However, the molecular pathogenesis of this disorder remains unknown. Recent biochemical and immunohistological studies have identified a new modification of beta2-microglobulin in the amyloid fibrils, i.e., the advanced glycation end products (AGEs). AGEs are formed by non-enzymatic glycative and oxidative (glycoxidation) reactions. The levels of AGEs, such as pentosidine and carboxymethyllysine (CML), are elevated in both the plasma proteins and skin collagen of non-diabetic dialysis patients several times more than in normal subjects. The AGE accumulation in uremia cannot be attributed to hyperglycemia, nor simply to their decreased renal clearance. Recently, gathered evidence has suggested that, in uremia, an increase in carbonyl compounds, derived from both carbohydrates and lipids, modifies proteins, leading to the augmentation of the production of not only AGEs, but also the advanced lipoxidation end products (ALEs). Uremia might thus be a state of carbonyl overload with potentially damaging proteins ('carbonyl stress'). Immunohistochemical studies, with antibodies specific to AGEs and ALEs, identified carbonyl stress in long-lived beta2-microglobulin amyloid deposits. Furthermore, proteins modified by carbonyl stress exhibit a variety of biological activities towards several types of cells, which might partially account for dialysis arthropathies.
Int J Mol Med 1998 Nov
PMID:Implication of the glycoxidation and lipoxidation reactions in the pathogenesis of dialysis-related amyloidosis (Review). 985 52

Preliminary experiments about the suitability of different commonly used culture media in our laboratory indicated, that prolonged exposure to high glucose concentrations during low temperature culture (LTC) impairs the viability of long term cultured human islets. As a consequence of the heterogeneity of tested media the present study was aimed to evaluate the influence of different glucose concentrations on survival, viability and in-vitro function of cultured human islets in order to optimize islet survival until transplantation and to compare species dependent differences in glucose sensitivity. Quantified aliquots of freshly isolated (digestion-filtration, ficoll gradient purification) islets from consecutively processed human (n=6) and porcine (n=11) pancreata were subjected to different glucose concentrations (human islets: 500, 750, 1000 and 2000 mg/l; porcine islets: 1000 and 2000 mg/l) in CMRL (22 degrees C) for 8-10 days. After LTC survival, viability and glucose-stimulated insulin release of incubated tissue was assessed. A reduction of glucose concentration promotes survival and viability of human islets but impairs in vitro function at the same time, presumably due to a reduced glucose oxidation as expressed by the significantly reduced stimulation index. In contrast to these findings in the human, elevated glucose concentration in porcine islet culture increases survival but reduces the glucose-stimulated insulin release and the viability of cultured islets. The contradiction of the results in regard to islet survival related to islet viability are still unclear in the pig and needs further evaluation.
J Mol Med (Berl) 1999 Jan
PMID:Glucose sensitivity of porcine and human islets in vitro. 993 Sep 36

IDDM patients undergoing islet, segmental pancreas or whole pancreas allotransplantation were studied at regular intervals after surgery (3-6 months, 1, 2, 3 and 4 years) to evaluate glycometabolic control (24 h metabolic profile, OGTT) and serum free insulin response to insulinogenic stimuli (arginine, IVGTT). Patients received the same immunosuppressive therapy, based on cyclosporin, steroids and azathioprine. Islet transplanted patients showed: 1) an early peak of insulin secretion after arginine, that was maintained up to 4 years; 2) an early, but low peak of insulin secretion after IVGTT, which was lost at 3 years, despite evidence that islets were still functioning (insulin independence with normal HbAlc levels); 3) a diabetic-like response to OGTT at 3 months, which improved at 2 years (IGT response); 4) fasting euglycemia with mild and reversible post-prandial hyperglycemia during the 24 h metabolic profile, which was maintained for up to 2 years. Insulin secretory patterns of islet transplanted patients were similar to segmental pancreas transplanted patients, and lower than whole pancreas transplanted patients. The reduced beta cell mass transplanted and the functional denervation of the transplanted islets seem to be the major determinants of this behaviour.
J Mol Med (Berl) 1999 Jan
PMID:Insulin secretory patterns and blood glucose homeostasis after islet allotransplantation in IDDM patients: comparison with segmental- or whole-pancreas transplanted patients through a long term longitudinal study. 993 Sep 48

Ca2+-dependent protein kinase C (cPKC) activity and expression have been studied in livers from hypoinsulinemic streptozotocin (STZ)-induced diabetic and untreated control rats. In diabetic rats, cPKC activity was slightly decreased in liver total particulate and nuclear fractions but was unchanged in mitochondrial-lysosomal, microsomal and cytosolic fractions. On Western immunoblot analysis, PKC alpha was identified as two distinct proteins of 90 and 81 kDa. In diabetic rats, the abundance of the 90 kDa protein was increased in most subcellular fractions with a maximum in the cytosolic and microsomal fractions (180%) but that of the 81 kDa protein was unchanged. PKC beta2 was detected as a single 81 kDa protein in cytosolic and microsomal fractions with unchanged levels in diabetic rats. Liver PKC alpha mRNA levels as measured by reverse transcription and competitive PCR amplification were similar in diabetic and control rats. The increased expression of PKC alpha protein in diabetic rats was reversed by insulin but not by phlorizin, suggesting that it did not result from hyperglycemia. We conclude that STZ-induced diabetes induces the expression of a biologically inactive form of PKC alpha which differs from active PKC alpha by an undefined post-translational modification, possibly an increase in phosphorylation state.
Mol Cell Endocrinol 1998 Nov 25
PMID:Increased expression of liver PKC alpha in hypoinsulinemic diabetic rats: a post-translational effect. 1002 75

The participation of hepatic glycogenolysis and gluconeogenesis to the glycemic changes promoted by exercise was investigated. For this purpose, we employed swimming rats (2.5% body weight extra load attached to the tail, at 24 degrees C) using a favorable condition to measure hepatic glycogenolysis (fed rats) and a favorable condition to measure hepatic gluconeogenesis (fasted rats). This experimental approach permits us to compare the contribution of hepatic glycogenolysis and gluconeogenesis to glucose changes for a specific schedule of exercise. The animals were investigated at rest, after 5 minutes of swimming and after swimming to exhaustion. Our results show that hepatic glycogen has a crucial role to determine hyperglycemia during exercise. In contrast, hypoglycemia developed during exercise when glycogen was depleted. However, the ability of the liver to produce glucose from L-lactate, glycerol and L-glutamine was increased during exercise. Taken together, these findings suggest that the hepatic capacity to produce glucose from gluconeogenic substrates (except for L-alanine) was increased when hepatic glycogen stores were depleted. Thus, the increased capacity to produce glucose shown by livers from exercising rats must to be an important metabolic adaptation to protect against severe hypoglycemia.
Res Commun Mol Pathol Pharmacol 1998 Nov
PMID:Changes in glycemia induced by exercise in rats: contribution of hepatic glycogenolysis and gluconeogenesis. 1010 May 3

We have previously shown that human munc13 (hmunc13) is up-regulated by hyperglycemia under in vitro conditions in human mesangial cell cultures. The purpose of the present study was to determine the cellular function of hmunc13. To do this, we have investigated the subcellular localization of hmunc13 in a transiently transfected renal cell line, opossum kidney cells. We have found that hmunc13 is a cytoplasmic protein and is translocated to the Golgi apparatus after phorbol ester stimulation. In addition, cells transfected with hmunc13 demonstrate apoptosis after treatment with phorbol ester, but cells transfected with an hmunc13 deletion mutant in which the diacylglycerol (C1) binding domain is absent exhibit no change in intracellular distribution and no induction of apoptosis in the presence of phorbol ester stimulation. We conclude that both the diacylglycerol-induced translocation and the apoptosis represent functional activity of hmunc13. We have also demonstrated that munc13-1 and munc13-2 are localized mainly to cortical epithelial cells in rat kidney and both are overexpressed under conditions of hyperglycemia in a streptozotocin-treated diabetic rat model. Taken together, our data suggest that hmunc13 serves as a diacylglycerol-activated, PKC-independent signaling pathway capable of inducing apoptosis and that this pathway may contribute to the renal cell complications of hyperglycemia.
Mol Biol Cell 1999 May
PMID:Human munc13 is a diacylglycerol receptor that induces apoptosis and may contribute to renal cell injury in hyperglycemia. 1023 66

In this work we investigate the possible toxicity of vanadyl sulfate (VOSO4), a compound capable of reducing hyperglycemia, on the following serum enzymes of diabetic young rats: alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LD) and creatine kinase (CK), as well as its effects on serum lipids. We find that at a concentration of 1 mg/mL VOSO4 has no toxic effect on the liver and muscles of diabetics young rats. These findings suggest that VOSO4 may be an alternative to insulin in the near future, due to its low cost, low toxicity and ready availability.
Mol Cell Biochem 1999 Aug
PMID:Effect of oral vanadyl sulfate treatment on serum enzymes and lipids of streptozotocin-diabetic young rats. 1049 91

Troglitazone is an insulin sensitizer which affects a number of target tissues. It is believed to exert these effects primarily by binding to and activating the y-isoform of peroxisome proliferator-activated receptor (PPARgamma), which in turn regulates the expression of specific genes. However, in a number of target organs, such as liver, the levels of PPARgamma are low and other isoforms predominate. In the present study, we examined whether troglitazone induces the expression of PPARgamma, thereby sensitizing cells for the action of this drug. Treatment of isolated rat hepatocytes with troglitazone induced both the mRNA and protein levels of PPARgamma in a dose-dependent fashion, with maximal levels of induction being three- to fourfold. This induction was also observed using the 15-deoxy-delta12,14-prostaglandin J2, a known natural ligand for PPARgamma, whereas ligands specific for PPARalpha were without effect. The induction of PPARgamma expression by troglitazone was also observed in livers from rats fed a diet containing troglitazone. Troglitazone had no effect on the expression of the alpha- or beta-isoforms of PPAR, the more predominant liver isoforms. These results indicate that troglitazone produces a reprogramming of PPAR isoform content in liver, which may in part underlie the mechanism whereby troglitazone sensitizes the liver to the action of insulin and/or ameliorates hyperglycemia.
Mol Cell Biol Res Commun
PMID:Troglitazone induces expression of PPARgamma in liver. 1066 98

Studies of the effects of acute and chronic norepinephrine (NE) infusion into the ventromedial hypothalamus (VMH) of rodents indicate important roles for VMH NE activities in the development of the obese-glucose intolerant state. Moreover, elevated endogenous levels of NE and/or its metabolites have been observed in a variety of obese-glucose intolerant animal models. We therefore investigated the VMH neuronal electrophysiologic responsiveness to iontophoretically applied NE in lean-euglycemic and obese-hyperglycemic mice. Additionally, the effect of dopamine agonist treatment (which reduces obesity and hyperglycemia) on VMH responsiveness to NE was examined in obese-hyperglycemic mice. Obese (ob/ob) mice were treated daily for 14 days with either bromocriptine (BC, D2 agonist) (10 mg/kg) plus SKF38393 (SKF, D1 agonist) (20 mg/kg) or vehicle. Lean mice were also similarly treated with vehicle. Twenty-seven hours following the final treatment, mice were anesthetized to obtain electrophysiologic responses of glutamate activated VMH neurons to local NE administration. In all three study groups, NE administration inhibited glutamate evoked neuronal activity in the majority (90%) of recorded neurons. No response to NE was observed in the remaining 10% of neurons. Also within all three groups there existed two patterns of response to NE; a) long duration (>2 min) and low threshold (<20 nA) and b) short duration and high threshold. Relative to lean mice, obese mice exhibited a significant 70% increase in average duration of response, 3-fold increase in percent neurons with long duration of response, and 2-fold increase in percent neurons with low threshold of response. BC/SKF treatment of obese mice significantly reduced the percent VMH neurons with long duration and low threshold of response to NE to resemble the VMH neuronal responsiveness to NE observed in lean mice. Increased VMH responsiveness to NE is part of the endogenous neurophysiology of obese-hyperglycemic ob/ob mice. Taken together with previous findings mentioned above, the present results suggest that this increased VMH responsiveness to NE contributes to the pathophysiology of the obese-hyperglycemic state.
Int J Mol Med 2000 Apr
PMID:Increased responsiveness of ventromedial hypothalamic neurons to norepinephrine in obese versus lean mice: relation to the metabolic syndrome. 1071 49


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