Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fructose activates glucokinase by releasing the enzyme from its inhibitory protein in liver. To examine the importance of acute activation of glucokinase in regulating hepatic glucose uptake, the effect of intraportal infusion of a small amount of fructose on net hepatic glucose uptake (NHGU) was examined in 42 h-fasted conscious dogs. Isotopic ([3-3H] and [U-14C]glucose) and arteriovenous difference methods were used. Each study consisted of an equilibration period (-90 to -30 min), a control period (-30 to 0 min), and a hyperglycemic/hyperinsulinemic period (0-390 min). During the latter period, somatostatin (489 pmol x kg(-1) x min(-1)) was given, along with intraportal insulin (7.2 pmol x kg(-1) x min(-1)) and glucagon (0.5 ng x kg(-1) x min(-1)). In this way, the liver sinusoidal insulin level was fixed at four times basal (456 +/- 60 pmol/l), and liver sinusoidal glucagon level was kept basal (46 +/- 6 ng/l). Glucose was infused through a peripheral vein to create hyperglycemia (12.5 mmol/l plasma). Hyperglycemic hyperinsulinemia (no fructose) switched net hepatic glucose balance (micromoles per kilogram per minute) from output (11.3 +/- 1.4) to uptake (14.7 +/- 1.7) and net lactate balance (micromoles per kilogram per minute) from uptake (6.5 +/- 2.1) to output (4.4 +/- 1.5). Fructose was infused intraportally at a rate of 1.7, 3.3, or 6.7 micromol x kg(-1) x min(-1), starting at 120, 210, or 300 min, respectively. In the three periods, portal blood fructose increased from <6 to 113 +/- 14, 209 +/- 29, and 426 +/- 62 micromol/l, and net hepatic fructose uptake increased from 0.03 +/- 0.01 to 1.3 +/- 0.4, 2.3 +/- 0.7, and 5.1 +/- 0.6 micromol x kg(-1) x min(-1), respectively. NHGU increased to 41 +/- 3, 54 +/- 5, and 69 +/- 8 micromol x kg(-1) x min(-1), respectively, and net hepatic lactate output increased to 11.0 +/- 3.2, 15.3 +/- 2.7, and 22.4 +/- 2.8 micromol x kg(-1) x min(-1) in the three fructose periods, respectively. The amount of [3H]glucose incorporated into glycogen was equivalent to 69 +/- 3% of [3H]glucose taken up by the liver. These data suggest that glucokinase translocation within the hepatocyte is a major determinant of hepatic glucose uptake by the dog in vivo.
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PMID:Small amounts of fructose markedly augment net hepatic glucose uptake in the conscious dog. 960 61

Transgenic mice containing an upstream glucokinase (betaGK) promoter- simian virus 40 T antigen (Tag) fusion gene develop neuroendocrine tumors primarily in the pancreas, gut, and pituitary. Pancreatic tumors from a line with delayed tumorigenesis were of two different types: insulinomas and noninsulinomas. The noninsulinomas are often periductal in location, express none of the four major islet peptide hormones, Glut-2, Pdx1, tyrosine hydroxylase, Pax4, Pax6, or Nkx6.1, but do express glucokinase, Sur1, Isl1, Hnf3beta, Hnf6, Beta2/NeuroD, and Nkx2.2. Cells from two different noninsulinoma tumors, when adapted to culture, began to express either insulin, glucagon, or somatostatin. Given the partial gene expression repertoire of the noninsulinoma tumors, their apparent periductal origin, and the ability of these cells to partially cytodifferentiate in culture, we suggest that these tumors are derived from islet progenitor cells. Thus, betaGK-Tag transgenic mice provide a new model system for studying the events that occur during both islet cell neogenesis and normal embryonic development.
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PMID:Targeted oncogenesis of hormone-negative pancreatic islet progenitor cells. 967 33

We examined the ability of an equivalent increase in circulating glucose concentrations to inhibit endogenous glucose production (EGP) and to stimulate glucose metabolism in patients with Type 2 diabetes mellitus (DM2). Somatostatin was infused in the presence of basal replacements of glucoregulatory hormones and plasma glucose was maintained either at 90 or 180 mg/dl. Overnight low-dose insulin was used to normalize the plasma glucose levels in DM2 before initiation of the study protocol. In the presence of identical and constant plasma insulin, glucagon, and growth hormone concentrations, a doubling of the plasma glucose levels inhibited EGP by 42% and stimulated peripheral glucose uptake by 69% in nondiabetic subjects. However, the same increment in the plasma glucose concentrations failed to lower EGP, and stimulated glucose uptake by only 49% in patients with DM2. The rate of glucose infusion required to maintain the same hyperglycemic plateau was 58% lower in DM2 than in nondiabetic individuals. Despite diminished rates of total glucose uptake during hyperglycemia, the ability of glucose per se (at basal insulin) to stimulate whole body glycogen synthesis (glucose uptake minus glycolysis) was comparable in DM2 and in nondiabetic subjects. To examine the mechanisms responsible for the lack of inhibition of EGP by hyperglycemia in DM2 we also assessed the rates of total glucose output (TGO), i.e., flux through glucose-6-phosphatase, and the rate of glucose cycling in a subgroup of the study subjects. In the nondiabetic group, hyperglycemia inhibited TGO by 35%, while glucose cycling did not change significantly. In DM2, neither TGO or glucose cycling was affected by hyperglycemia. The lack of increase in glucose cycling in the face of a doubling in circulating glucose concentrations suggested that hyperglycemia at basal insulin inhibits glucose-6-phosphatase activity in vivo. Conversely, the lack of increase in glucose cycling in the presence of hyperglycemia and unchanged TGO suggest that the increase in the plasma glucose concentration failed to enhance the flux through glucokinase in DM2. In summary, both lack of inhibition of EGP and diminished stimulation of glucose uptake contribute to impaired glucose effectiveness in DM2. The abilities of glucose at basal insulin to both increase the flux through glucokinase and to inhibit the flux through glucose-6-phosphatase are impaired in DM2. Conversely, glycogen synthesis is exquisitely sensitive to changes in plasma glucose in patients with DM2.
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PMID:Regulation of endogenous glucose production by glucose per se is impaired in type 2 diabetes mellitus. 971 Apr 43

Insulin-induced stimulation of muscle glucose uptake (MGU) is impaired in people with type 2 diabetes. To determine whether insulin-induced stimulation of splanchnic glucose uptake (SGU) is also impaired, we simultaneously measured leg glucose uptake (LGU) and SGU in 14 nondiabetic subjects and 16 subjects with type 2 diabetes using a combined organ catheterization-tracer infusion technique. Glucose was clamped at approximately 9.3 mmol/l, while insulin concentrations were maintained at approximately 72 pmol/l (low) and approximately 150 pmol/l (high) for 3 h each. Endogenous hormone secretion was inhibited with somatostatin. Total body glucose disappearance was lower (P < 0.01) and glucose production higher (P < 0.01) during both insulin infusions in the diabetic compared with the nondiabetic subjects, indicating insulin resistance. Splanchnic glucose production was higher (P < 0.05) in the diabetic subjects during the low but not the high insulin infusion. SGU was slightly lower in the diabetic than in the nondiabetic subjects during the low insulin infusion and 50-60% lower (P < 0.05) during the high insulin infusion. LGU (P < 0.001), but not SGU, was inversely correlated with the degree of visceral adiposity. The contribution of the indirect pathway to hepatic glycogen synthesis did not differ in the diabetic and nondiabetic subjects. In contrast, both flux through the UDP-glucose pool (P < 0.05) and the contribution of the direct pathway to glycogen synthesis (P < 0.01) were lower in the diabetic than in the nondiabetic subjects, indicating decreased uptake and/or phosphorylation of extracellular glucose. On the other hand, glycogenolysis was equally suppressed in both groups. In summary, type 2 diabetes impairs the ability of insulin to stimulate both MGU and SGU. The defect appears to reside at a proximal (e.g., glucokinase) metabolic step and is not related to the degree of visceral adiposity. These data suggest that impaired hepatic glucose uptake as well as MGU contribute to hyperglycemia in people with type 2 diabetes.
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PMID:Effects of type 2 diabetes on the ability of insulin and glucose to regulate splanchnic and muscle glucose metabolism: evidence for a defect in hepatic glucokinase activity. 1086 44

Fructose has been shown to have a catalytic effect on glucokinase activity in vitro; however, its effects on hepatic glycogen metabolism in humans is unknown. To address this question, we used (13)C nuclear magnetic resonance (NMR) spectroscopy to noninvasively assess rates of hepatic glycogen synthesis and glycogenolysis under euglycemic (approximately 5 mmol/l) hyperinsulinemic conditions (approximately 400 pmol/l) with and without a low-dose infusion of fructose (approximately 3.5 micromol. kg(-1). min(-1)). Six healthy overnight-fasted subjects were infused for 4 h with somatostatin (0.1 micromol. kg(-1). min(-1)) and insulin (240 pmol. m(-2). min(-1)). During the initial 120 min, [1-(13)C]glucose was infused to assess glycogen synthase flux followed by an approximately 120-min infusion of unlabeled glucose to assess rates of glycogen phosphorylase flux. Acetaminophen was given to assess the percent contribution of the direct and indirect (gluconeogenic) pathways of glycogen synthesis by the (13)C enrichment of plasma UDP-glucuronide and C-1 of glucose. In the control studies, the flux through glycogen synthase and glycogen phosphorylase was 0.31 +/- 0.06 and 0.17 +/- 0.04 mmol/l per min, respectively, and the rate of net hepatic glycogen synthesis was 0.14 +/- 0.05 mmol/l per min. In the fructose studies, the glycogen synthase flux increased 2.5-fold to 0.79 +/- 0.16 mmol/l per min (P = 0.018 vs. control), whereas glycogen phosphorylase flux remained unchanged (0.24 +/- 0.06; P = 0.16 vs. control). The infusion of fructose resulted in a threefold increase in rates of net hepatic glycogen synthesis (0.54 +/- 0.12 mmol/l per min; P = 0.008 vs. control) without affecting the pathways of hepatic glycogen synthesis (direct pathway approximately 60% in both groups). We conclude that during euglycemic hyperinsulinemia, a low-dose fructose infusion causes a threefold increase in net hepatic glycogen synthesis exclusively through stimulation of glycogen synthase flux. Because net hepatic glycogen synthesis has been shown to be diminished in patients with poorly controlled type 1 and type 2 diabetes, stimulation of hepatic glycogen synthesis by this mechanism may be of potential therapeutic value.
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PMID:Stimulating effects of low-dose fructose on insulin-stimulated hepatic glycogen synthesis in humans. 1137 25

We have previously reported that splanchnic glucose uptake, hepatic glycogen synthesis, and hepatic glucokinase activity are decreased in people with type 2 diabetes during intravenous glucose infusion. To determine whether these defects are also present during more physiological enteral glucose administration, we studied 11 diabetic and 14 nondiabetic volunteers using a combined organ catheterization-tracer infusion technique. Glucose was infused into the duodenum at a rate of 22 micromol. kg(-1). min(-1) while supplemental glucose was given intravenously to clamp glucose at approximately 10 mmol/l in both groups. Endogenous hormone secretion was inhibited with somatostatin, and insulin was infused to maintain plasma concentrations at approximately 300 pmol/l (i.e., twofold higher than our previous experiments). Total body glucose disappearance, splanchnic, and leg glucose extractions were markedly lower (P < 0.01) in the diabetic subjects than in the nondiabetic subjects. UDP-glucose flux, a measure of glycogen synthesis, was approximately 35% lower (P < 0.02) in the diabetic subjects than in the nondiabetic subjects. This was entirely accounted for by a decrease (P < 0.01) in the contribution of extracellular glucose because the contribution of the indirect pathway to hepatic glycogen synthesis was similar between groups. Neither endogenous and splanchnic glucose productions nor rates of appearance of the intraduodenally infused glucose in the portal vein differed between groups. In summary, both muscle and splanchnic glucose uptake are impaired in type 2 diabetes during enteral glucose administration. The defect in splanchnic glucose uptake appears to be due to decreased uptake of extracellular glucose, implying decreased glucokinase activity. Thus, abnormal hepatic and muscle (but not gut) glucose metabolism are likely to contribute to postprandial hyperglycemia in people with type 2 diabetes.
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PMID:Type 2 diabetes impairs splanchnic uptake of glucose but does not alter intestinal glucose absorption during enteral glucose feeding: additional evidence for a defect in hepatic glucokinase activity. 1137 36

Pancreas duodenum homeobox-1 (PDX-1) (also known as insulin promoter factor-1, islet/duodenum homeobox-1, somatostatin transactivating factor-1, insulin upstream factor-1 and glucose-sensitive factor) is a transcription factor encoded by a Hox-like homeodomain gene. In humans and other animal species, the embryonic development of the pancreas requires PDX-1, as demonstrated by the identification of an individual with pancreatic agenesis resulting from a mutation that impaired the transcription of a functionally active PDX-1 protein. In adult subjects, PDX-1 is essential for normal pancreatic islet function as suggested by its regulatory action on the expression of a number of pancreatic genes, including insulin, somatostatin, islet amyloid polypeptide, the glucose transporter type 2 and glucokinase. Furthermore, heterozygous mutations of PDX-1 have been linked to a type of autosomal dominant form of diabetes mellitus known as maturity onset diabetes of the young type 4. The dual action of PDX-1, as a differentiation factor during embryogenesis and as a regulator of islet cell physiology in mature islet cells, underscores the unique role of PDX-1 in health and disease of the human endocrine pancreas.
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PMID:Pancreas duodenum homeobox-1 regulates pancreas development during embryogenesis and islet cell function in adulthood. 1183 21

The ability of hyperglycemia per se to suppress endogenous glucose production (GP) is blunted in type 2 diabetes. This could be due in part to decreased glucose-induced flux through glucokinase (GK). Because fructose activates hepatic GK, we examined whether catalytic amounts of fructose could restore inhibition of GP by hyperglycemia in humans with type 2 diabetes. Glucose fluxes ([3-(3)H]glucose) were measured during euglycemia (5 mmol/l) and after abrupt onset of hyperglycemia (10 mmol/l; variable dextrose infusion) under fixed hormonal conditions (somatostatin infusion for 6 h with basal insulin/glucagon/growth hormone replacement). A total of 10 subjects with moderately controlled type 2 diabetes and 7 age- and BMI-matched nondiabetic subjects were studied on up to three separate occasions under the following conditions: without fructose (F(-)) or with infusion of fructose at two dosages: 0.6 mg/kg center dot min (low F) and 1.8 mg/kg center dot min (high F). Although GP failed to decrease in response to hyperglycemia in type 2 diabetes, the coinfusion of both doses of fructose was associated with comparable decreases in GP in response to hyperglycemia (low F = -27%, high F = -33%; P < 0.01 vs. F(-) at both dosages), which approached the 44% decline in GP observed without fructose in the nondiabetic subjects. GP responses to hyperglycemia were not altered by the addition of fructose in the nondiabetic group (low F = -47%, high F = -42%; P > 0.05 vs. F(-)). Thus, the administration of small amounts of fructose to type 2 diabetic subjects partially corrected the regulation of GP by hyperglycemia per se, yet did not affect this regulation in the nondiabetic subjects. This suggests that the liver's inability to respond to hyperglycemia in type 2 diabetes, likely caused by impaired GK activity, contributes substantially to the increased GP in these individuals.
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PMID:Fructose improves the ability of hyperglycemia per se to regulate glucose production in type 2 diabetes. 1187 57

To explore induced islet neogenesis in the liver as a strategy for the treatment of diabetes, we used helper-dependent adenovirus (HDAD) to deliver the pancreatic duodenal homeobox-1 gene (Ipf1; also known as Pdx-1) to streptozotocin (STZ)-treated diabetic mice. HDAD is relatively nontoxic as it is devoid of genes encoding viral protein. Mice treated with HDAD-Ipf1 developed fulminant hepatitis, however, because of the exocrine-differentiating activity of Ipf1. The diabetes of STZ mice was partially reversed by HDAD-mediated transfer of NeuroD (Neurod), a factor downstream of Ipf1, and completely reversed by a combination of Neurod and betacellulin (Btc), without producing hepatitis. Treated mice were healthy and normoglycemic for the duration of the experiment (>120 d). We detected in the liver insulin and other islet-specific transcripts, including proinsulin-processing enzymes, beta-cell-specific glucokinase and sulfonylurea receptor. Immunocytochemistry detected the presence of insulin, glucagon, pancreatic polypeptide and somatostatin-producing cells organized into islet clusters; immuno-electron microscopy showed typical insulin-containing granules. Our data suggest that Neurod-Btc gene therapy is a promising regimen to induce islet neogenesis for the treatment of insulin-dependent diabetes.
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PMID:NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. 1272 55

Many transcription factors are critical for ensuring proper embryonic development of the endocrine pancreas and normal islet function. The transcription factor pancreatic duodenal homeobox 1 (PDX-1) is uniformly expressed in early pancreatic buds of embryos as well as the beta and delta cells of the islets of Langerhans. PDX-1 has also been found in dispersed endocrine cells of the duodenum in adults and plays a key role in pancreas formation. It has been reported that null mutation of PDX-1 in mice results in a failure of the pancreatic bud to expand; thus, the mice die 2-3 days after birth from hyperglycemia and dehydration. Heterozygous PDX-1 mice developed a pancreas but were diabetic. It has been shown that PDX-1 is required for maintaining the pancreatic islet functions by activating gene transcriptions including insulin, somatostatin (SST), islet amyloid polypeptide, glucose transporter type 2, and glucokinase. PDX-1 serves a dual role in pancreatic development. It initially contributes to pancreatic formation during embryogenesis and subsequently regulates the pancreatic islet cell physiology in mature islet cells. Understanding the underlying molecular mechanisms of pancreas formation, especially the function of PDX-1, may contribute to the enhanced treatment and prevention of debilitating diseases such as diabetes, insulinomas, and pancreatic carcinomas.
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PMID:PDX-1 and the pancreas. 1502 42


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