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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Physiological studies hypothesized that unsuppressed gluconeogenesis by insulin in newborn dogs may be a mechanism responsible for neonatal hyperglycemia. In the present study, we determined the effects of fasting and the infusion of insulin, glucose, and/or epinephrine on the liver cytosolic mRNA levels of the gene for the key regulatory enzyme of gluconeogenesis, phosphoenolpyruvate carboxykinase PEPCK (PEPCK; EC 4.1.1.32), in newborn dogs in vivo to further test the hypothesis. We observed the following: (i) Fasting increased the hepatic PEPCK mRNA level in newborn dogs. The hepatic PEPCK mRNA level was not detectable at birth; the PEPCK mRNA level at 4 h was arbitrarily determined as 100.0 +/- 27.8%, was 108.1 +/- 18.4% at 10 h, and stayed at the same level at 24 h (109.1 +/- 8.2). (ii) Euglycemic hyperinsulinemia did not significantly reduce the hepatic PEPCK mRNA levels in newborn dogs; however, the same treatment resulted in the repression of the liver PEPCK mRNA to undetectable levels in adult dogs. (iii) Under hyperinsulinemia, a moderate hyperglycemia lowered the liver PEPCK mRNA in newborn dogs to undetectable levels. (iv) In newborn dogs, despite the presence of hyperinsulinemia and hyperglycemia, the infused epinephrine was still able to elevate the liver PEPCK mRNA from undetectable levels to 79% of the control levels. We suggest that unsuppressed neonatal gluconeogenesis in the presence of hyperinsulinemia may be evidence of insulin resistance in newborn dogs and that the stimulatory effect of epinephrine on gluconeogenesis overriding insulin and glucose in the liver of the newborn dogs may be a mechanism for inducing neonatal hyperglycemia.
Biochem Mol Med 1996 Oct
PMID:Transcription of hepatic cytosolic phosphoenolpyruvate carboxykinase gene in newborn dogs. 890 88

This study has examined whether elevated glucose can induce lipid peroxidation and contribute to the inhibition of cell growth in human kidney proximal tubule(HPT) cells. HPT cells were cultured in media containing glucose concentrations of 8 mM (control), 25 mM, and 50 mM. Lipid peroxidation was assessed by the thiobarbituric acid reactivity and cell growth was assessed by 3H-thymidine uptake. Results show decreased (59%, p < 0.01) growth of HPT cells cultured in 50 mM glucose. Cells cultured in 50 mM mannitol did not show any growth inhibition, suggesting that the decreased cell growth associated with glucose is not due to osmolarity changes. There was an increase (108%, p < 0.02) in lipid peroxidation in cells cultured with high levels of glucose (50 mM) compared with controls and cells cultured with 50 mM mannitol. To examine if membrane lipid peroxidation or malondialdehyde (MDA, an end product of lipid peroxidation) has any role in the inhibition of cell growth, we examined the effect of tertiary butylhydroperoxide (TBH, known to cause lipid peroxidation and generate MDA) on the growth of HPT cells. TBH decreased cell growth (49, 17 and 3% of controls at 0.1, 0.25, and 0.5 mumole TBH/ml medium). Similarly, a marked reduction in the growth was observed with exogenous MDA (72, 69 and 34% of controls at 0.1, 0.25, and 0.5 mumole MDA/ml medium). This suggests that elevated glucose can induce membrane lipid peroxidation and accumulation of MDA, which in turn can inhibit cellular growth and contribute to the altered structure and function of HPT cells in diabetes.
Mol Cell Biochem 1996 Sep 06
PMID:Effect of elevated glucose concentrations on cellular lipid peroxidation and growth of cultured human kidney proximal tubule cells. 890 20

The inhibitory action of vanadate towards protein tyrosine phosphatase (PTPase) has been considered as a probable mechanism by which it exerts insulin-like effects. In this study, we have examined the in vivo effects of vanadate on PTPases in the liver of obese Zucker rats, a genetic animal model for obesity and type II diabetes. These animals were characterized by hyperinsulinemia and mild hyperglycemia. The number of insulin receptors were significantly (p < 0.01) decreased in liver. After chronic administration of vanadate in obese rats, 80% decrease in the plasma levels of insulin was observed. The insulin receptor numbers were significantly (p < 0.01) higher in vanadate-treated obese rats as compared to the untreated ones. The hepatic PTPase activities in cytosolic and particulate fractions, with phosphorylated poly glu:tyr (4:1) and the insulin receptor peptide (residues 1142-1153) as substrates, increased in obese rats. In vanadate-treated obese rat livers, the PTPase activities in both subcellular fractions with these substrates decreased significantly (p < 0.001). The decreases in PTPase activities from these groups of rats were further supported by chromatography on a Mono Q column. These data support the view that inhibition of PTPases plays a role in the insulin-mimetic action of vanadate.
Mol Cell Biochem
PMID:Decrease in protein tyrosine phosphatase activities in vanadate-treated obese Zucker (fa/fa) rat liver. 892 27

In its vanadate (V5+) or vanadyl (V4+) forms, vanadium has been demonstrated to possess antidiabetic activity. Oral treatment of streptozotocin (STZ)-diabetic animals with either form is associated with correction of hyperglycemia, and prevention of diabetes-induced complications, although weight gain is unaffected. Vanadium treatment of non-diabetic animals lowers plasma insulin levels by reducing insulin demand, as these animals remain normoglycemic. These results suggest that vanadium has in vivo insulin-mimetic or insulin-enhancing effects, in agreement with several in vitro observations. Chronic treatment with vanadium has also been shown to result in sustained antidiabetic effects in STZ-diabetic animals long after treatment has ceased. Thus, at 13 weeks after withdrawal from treatment, corrected animals had normalized glucose and weight gain, and improved basal insulin levels. In addition, near-normal glucose tolerance was found despite an insignificant insulin response. Since vanadium accumulates in several tissue sites (e.g. bone, kidney) when pharmacological doses are administered, it is possible that stored vanadium may be important in maintaining near-normal glucose tolerance at least in the short-term following withdrawal from treatment. Recently, following withdrawal of vanadyl treatment up to 30 weeks, diabetic animals which had remained normoglycemic and had normalized glucose tolerance showed improvements in plasma insulin levels both in the basal state and in response to oral glucose, as compared to those which had reverted to hyperglycemia. The observed significant improvements in insulin capacity over the long-term ( > 3 months) suggests that a restored and/or preserved insulin secretion may be essential for maintained reversal of the diabetic state over a prolonged period after treatment is withdrawn.
Mol Cell Biochem
PMID:Long-term antidiabetic activity of vanadyl after treatment withdrawal: restoration of insulin secretion? 892 38

To determine the effects of insulin-like growth factor-1 (IGF-1) and amylin on glucose homeostasis in vivo in newborn dogs, euglycemic hyper-IGF-1 clamps and hypoglycemic hyper-IGF-1 clamps were performed in newborn dogs. Northern blotting and radioimmunoassays were used to study the effects of the infused IGF-1 and/or hypoglycemia on the mRNA expression of the genes for phosphoenolpyruvate carboxykinase (PEPCK) and on the expression of the amylin gene in newborn dogs. Our results were that (1) Infused IGF-1 (plasma IGF-1 >/=1000 ng/ml) rapidly lowered the plasma glucose level, and 120 +/- 38 mg glucose/pup was co-infused during a 105-min clamp to maintain the plasma glucose at the basal level. (2) The infused IGF-1 rapidly reduced the liver cytosolic mRNA for the PEPCK gene to an almost undetectable level. (3) Hyper-IGF-1 had no effect on mRNA level of the amylin gene in pancreas, 106.7 +/- 14.2% vs 100.0 +/- 5.9% (controls), or on plasma amylin concentration, 56. 0 +/- 5.7 pg/ml vs 52.1 +/- 5.7 pg/ml (basal). (4) The amylin mRNA level, 127.8 +/- 3.9% vs 100.0 +/- 5.9% (controls) (P = 0.017), and the plasma amylin concentration, 132.3 +/- 18.3 pg/ml vs 110.0 +/- 10.8 pg/ml (controls) (P = 0.371), showed a parallel stimulation by hypoglycemia in the presence of hyper-IGF-1. We concluded that (1) IGF-1 acutely suppressed cytosolic PEPCK gene expression in liver of newborn dogs. (2) IGF-1 does not effect the expression of the pancreatic amylin gene. (3) Amylin may be involved in glucose homeostasis in newborn dogs and may play a role as a counterregulatory factor during the neonatal period. Unsuppressed amylin production may contribute to neonatal hyperglycemia.
Biochem Mol Med 1996 Dec
PMID:Differential effects of insulin-like growth factor-1 on neonatal canine gene expression. 898 38

One of the mechanisms of angiotensin-converting enzyme inhibitors in treating diabetic nephropathy is the reversal of renal hypertrophy. Hyperglycemia is the common denominator of all diabetic states. Thus, effects of captopril on high glucose (27.5 mM)-induced alterations in LLC-PK1 cells were studied as related to the facilitative glucose transporters. We found that high glucose (27.5 mM) inhibited mitogenesis and induced hypertrophy in these cells after 48 hours of culture concomitantly with decreased glucose transporter I messenger RNA expression. Captopril (1 mM) reversed the above effects concomitantly with enhancement of glucose transporter I and II messenger RNA expressions. We conclude that decreased expression of glucose transporter I may be associated with increased intracellular glucose and the resultant ill effects. Captopril reversed the above high glucose-induced effects partly by enhancing glucose transporter I and II messenger RNA expressions.
Biochem Mol Biol Int 1997 Mar
PMID:Captopril reverses high glucose-induced effects on LLC-PK1 cells partly by enhancing facilitative glucose transporter messenger RNA expressions. 909 Apr 58

In the present report changes in the mRNA level of glucose-6-phosphatase (G6Pase; EC 3.1.39) in newborn and adult dogs in vivo were studied to further test the hypotheses that neonatal hyperglycemia may be due to unsuppressed gluconeogenesis by insulin and that the antidiabetic role of insulin-like growth factor-1 (IGF-1) may be intact in newborn dogs who have consistently demonstrated insulin resistance. Our results were the following: (i) Both renal and hepatic G6Pase mRNA were expressed at birth and increased with time during a 24-h period of fasting after birth. (ii) The renal G6Pase mRNA levels in newborn dogs did not respond to either insulin or epinephrine. (iii) Hyperinsulinemia lowered the liver G6Pase mRNA by only 16.3% in newborn dogs, but reduced the liver G6Pase mRNA to an undetectable level in adult dogs. (iv) Hyperglycemia decreased the hepatic G6Pase mRNA by 14.3% in newborn dogs under hyperinsulinemia. (v) Infused epinephrine did not elevate the hepatic G6Pase mRNA level in newborn dogs in the presence of hyperglycemia and hyperinsulinemia. (vi) In newborn dogs, hyper-IGF-1 rapidly reduced the hepatic G6Pase mRNA level by 50%, and hypoglycemia was unable to elevate the hepatic G6Pase mRNA level under the hyper-IGF-1. We concluded that the reduced rate of suppression of transcription of the liver G6Pase gene by insulin in newborn dogs may reflect the unsuppressed neonatal hepatic gluconeogenesis due to insulin resistance and that the physiological roles of IGF-1 seemed to be intact in newborn dogs and may be not responsible for neonatal hyperglycemia.
Biochem Mol Med 1997 Apr
PMID:Insulin resistance and the transcription of the glucose-6-phosphatase gene in newborn dogs. 916 94

Our previous investigations demonstrated that unsuppressed gluconeogenesis under hyperinsulinemia in newborn dogs may be a mechanism of neonatal hyperglycemia. In the present study, the transcription of the gene for fructose-1,6-bisphosphatase (fru-1,6-P2ase; E 3.1.3.11) of newborn dogs was studied under various metabolic perturbations (age, suckling, fasting, and hyperinsulinemia). Total RNAs isolated from livers and kidneys were hybridized with a rat fru-1,6-P2ase cDNA probe. We observed that (i) fru-1,6-P2ase mRNA was expressed in both kidney and liver at birth and was about 40 and 80% of those in kidney and liver of adult dog, respectively; (ii) suckling decreased the kidney fru-1,6-P2ase mRNA level to 77.8 +/- 1.7% (24 h) from 100.0 +/- 8.0% (4 h), but increased liver mRNA to 158.6 +/- 11.4% (24 h) from 100.0 +/- 2.3% (4 h); (iii) during a 24-h period of fasting, the kidney fru-1,6-P2ase mRNA level did not change in the first 10 h and then increased 18.5% at 24 h, whereas the liver fru-1,6-P2ase mRNA increased ca. 20% during the first 10 h and then up to 161.1 +/- 18.0% at 24 h compared to that at 100.0 +/- 11.4% (0 h); (iv) euglycemic hyperinsulinemia did not change the renal fru-1,6-P2ase mRNA level, but lowered the hepatic fru-1,6-P2ase mRNA level to 56.0 +/- 8.7 from 100.0 +/- 11.8% (fasted controls) in newborn dogs, which was identical to that in adult dogs. These data suggest that the fru-1,6-P2ase in liver may play a more important role in glucose homeostasis of newborn dogs than that in kidney during the first day of their lives and that the incomplete suppression of transcription of the hepatic fru-1,6-P2ase gene by insulin in newborn dogs may not contribute to neonatal hyperglycemia due to insulin resistance.
Biochem Mol Med 1997 Apr
PMID:Developmental aspects of transcription of fructose-1,6-bisphosphatase in newborn dogs. 916

Type 1 diabetes mellitus is caused by a lack of insulin that results from the autoimmune destruction of the pancreatic beta-cells. Severe diabetes, if not controlled by periodic insulin injections, can lead to ketoacidosis and death. We have previously shown that sustained low level production of insulin in the liver of diabetic rats prevented their death from complications of diabetes. To test the hypothesis that there is a window of serum insulin concentrations that can prevent ketoacidosis without significant risk of hypoglycemia secondary to hyperinsulinemia, rats were infused with various doses of a recombinant retrovirus encoding an engineered rat preproinsulin-1 gene. The gene was engineered to allow processing into mature insulin by the protease furin. At the lower doses tested, fatal ketoacidosis was prevented, but the rats exhibited nonfasting hyperglycemia. At intermediate doses, which resulted in serum insulin concentrations of 1.6 mg/ml, the rats achieved near-normoglycemia and no serum ketones. These rats did not exhibit hypoglycemia even during a 24-h fast. At high virus doses, the animals achieved nonfasting normoglycemia but exhibited hypoglycemia during the fast. In conclusion, we have defined a therapeutic window of hepatic insulin expression that provides protection against ketoacidosis without significant risk of hypoglycemia. This window of sustained hepatic insulin expression might permit its development into a novel treatment modality for the prevention of ketoacidosis in patients with severe insulin-dependent diabetes mellitus.
Mol Endocrinol 1997 Jun
PMID:Hepatic insulin gene expression as treatment for type 1 diabetes mellitus in rats. 917 Dec 46

In order to study the effect of undernutrition on the onset of disturbances in insulin secretion and insulin resistance, we compared the effects of a low protein diet containing 4% of protein (LPD) and a normal diet containing 25% of protein (NPD) supplied to the dams during the first 10 days of lactation when the pups turn into adults (90 days). We studies, in these rats, the insulin secretion, the glucose tolerance test (GTT) and, using the glucose clamp technique, the insulin resistance. The GTT showed a delay of the response of LPD group to the glucose challenge (1 mg/kg body weight) at 10 minutes (NPD = 450 +/- 27 mg/dl; LPD = 650 +/- 32 mg/dl, p < 0.01). The insulin secretion, four minutes after stimulation was found reduced in the LPD group (LPD = 1.1 +/- 0.08 microU/islet/min; NPD = 1.85 +/- 0.02 microU/islet/min, p < 0.01). Using the glucose clamp technique the plasma glucose concentration was raised during the first 20 minutes after the glucose stimulation with 10 mg/Kg-1.min-1 (NPD = 200 +/- 32 mg/dl and; LPD = 160 +/- 14 mg/dl., p < 0.01). Afterwards, the hyperglycemia was subsequently maintained (NPD = 154 +/- 9 mg/dl; LPD = 149 +/- 12 mg/dl) and the insulinemia was unchanged by infusion of glucose in the LPD group. In a similar experiment, the administration of glucose (10 mg/Kg-1. min-1) plus insulin (1.67 mU/Kg-1. min-1), the LPD group when compared with the NPD group, displayed an accentuated decreasing of glucose concentration level (LPD = 90 +/- 7 mg/dl; NPD = 130 +/- mg/dl., p < 0.01), 30 minutes after the infusion. The data suggest that undernutrition induces an adaptive process of insulin sensitivity which occurs together with an insulin secretion first phase blockage.
Res Commun Mol Pathol Pharmacol 1997 May
PMID:Insulin secretion impairment and insulin sensitivity improvement in adult rats undernourished during early lactation. 922 52


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