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1.  Characterization of the responses of circulating glucagon-like immunoreactivity to intraduodenal and intravenous administration of glucose 
The effects of ingested and infused glucose upon circulating glucagon-like immunoreactivity (GLI) were compared in 14 triply catheterized conscious dogs. Within 60 min after the intraduodenal administration of 2 g/kg of glucose, the mean level of glucagon-like immunoreactivity in the vena caval plasma more than doubled, whereas after intravenous infusion of the same dose over a 90 min period no change in the mean vena caval level was observed; during glucose infusion mean glucagon-like immunoreactivity in the pancreatic venous effluent declined, suggesting that hyperglycemia suppresses rather than stimulates pancreatic glucagon secretion.
To determine if the rise in glucagon-like immunoreactivity that occurs during glucose absorption was of pancreatic origin, the effect of pancreatectomy performed 1 hr after the intraduodenal administration of glucose was determined. Although circulating insulin disappeared after resection of the pancreas, the level of glucagon-like immunoreactivity continued to rise, establishing its extrapancreatic origin. In other experiments, measurements of Glucagon-like immunoreactivity in plasma obtained simultaneously from pancreaticoduodenal and mesenteric veins and from the vena cava revealed the increment after intraduodenal glucose loading to be greatest in the mesenteric vein in 8 of 12 experiments, favoring the gut as the likely source of the rise.
To characterize gut glucagon-like immunoreactivity, acid-alcohol extracts of canine jejunum were compared with similar glucagon-containing extracts of canine pancreas with respect to certain physical and biological properties. On a G-25 Sephadex column the elution volume of the jejunal immunoreactivity was found to be smaller than that of glucagon, which suggested a molecular size at least twice that of pancreatic glucagon. Furthermore, the in vivo and in vitro biological activities of the eluates containing jejunal glucagon-like immunoreactivity appeared to differ from those of eluates containing pancreatic glucagon. The jejunal material lacked hyperglycemic activity when injected endoportally into dogs, was devoid of glycogenolytic activity in the isolated perfused rat liver, and did not increase hepatic 3′,5′ cyclic adenylate in the perfused liver; however, like glucagon it appeared to stimulate insulin release. It seems quite clear the material in intestinal extracts either is a different substance or a different form from that of true pancreatic glucagon, although it crossreacts in the radioimmunoassay with antibodies to glucagon.
It is concluded, (a) that hyperglycemia does not stimulate and probably suppresses the secretion of pancreatic glucagon; (b) that during intestinal absorption of glucose, a rise in glucagon-like immunoreactivity occurs; (c) this immunoreactivity is derived from an extrapancreatic site, probably the gut; (d) that the glucagon-like immunoreactivity extractable from jejunum is not the same as pancreatic glucagon but is a larger molecule devoid of hyperglycemic and glycogenolytic activity, a cross-reactant in radioimmunoassay for glucagon; and (e) that the eluate in which jejunal immunoreactivity is contained can stimulate insulin release in conscious dogs.
PMCID: PMC297147  PMID: 5638120
2.  The Glycogenolytic Activity of Immunoreactive Pancreatic Glucagon in Plasma 
Journal of Clinical Investigation  1971;50(8):1650-1655.
Conclusions concerning the physiologic role of pancreatic glucagon in health and its contribution to disorders of carbohydrate metabolism, such as diabetes mellitus, are based entirely on measurements of plasma glucagon by radioimmunoassay. The changes in plasma immunoreactive glucagon can have the metabolic and clinical significance which has been implied, only if the glucagon detected by immunoassay has biological activity. The present study was designed to determine if a relationship between the immunoassayable glucagon and glycogenolytic activity of plasma could be demonstrated.
Plasma specimens obtained from normal and diabetic subjects under widely varying circumstances of alpha cell activity were extracted by a modification of the Kenny technique and the recovery of immunoreactive glucagon was calculated. Glycogenolytic activity of each extract was determined by perfusion in the Mortimore rat liver system, modified so as to detect as little as 1 ng of crystalline glucagon.
A significant correlation between the calculated quantity of immunoreactive glucagon and the glycogenolytic activity of plasma extracts was observed for both normal and diabetic subjects. Most of the glycogenolytic activity was abolished by incubating the extract with antiglucagon serum.
It was concluded that the glycogenolytic activity of extractable glucagon is proportional to its immunoreactivity as calculated from its original concentration in plasma. This would tend to support the view that all or most of the immunoreactive glucagon of plasma is biologically active.
PMCID: PMC442065  PMID: 5097572
3.  The effect of experimental insulin deficiency on glucagon secretion 
Journal of Clinical Investigation  1971;50(9):1992-1999.
Suppression of pancreatic glucagon secretion by hyperglycemia is a characteristic of normal alpha cell function. However, in diabetic subjects, plasma glucagon is normal or high despite hyperglycemia. It seemed possible that the presence of glucose or its metabolites within the alpha cell might be essential for suppression of glucagon secretion, and that in diabetes an intracellular deficiency of glucose secondary to insulin lack might be responsible for the nonsuppressibility. The present study was designed to determine the effect upon glucagon secretion of blockade of glucose metabolism and of experimental insulin deficiency.
Blockade of glucose metabolism was induced in dogs by administration of 2-deoxyglucose or mannoheptulose. A striking rise in glucagon was observed despite accompanying hyperglycemia and hyperinsulinemia, which, in the case of mannoheptulose, was induced by infusing crystalline insulin.
To determine if insulin lack also causes paradoxical hyperglucagonemia, dogs were made severely diabetic by alloxan. Fasting glucagon levels ranged from 3 to 22 times normal despite severe hyperglycemia, and were quickly restored to normal by infusing insulin. Diabetes induced in rats by anti-insulin serum was also associated with significant elevation in plasma glucagon. However, diazoxide-induced insulin lack did not increase glucagon in dogs.
It is concluded that normal suppression of glucagon secretion by hyperglycemia does not occur when glucose metabolism is blocked or when severe insulin deficiency is produced. It is suggested that normal glucose metabolism within the alpha cell may be an insulin-requiring process without which hyperglycemic suppression of glucagon release cannot occur.
PMCID: PMC292125  PMID: 4935445
4.  Identification of glucagon in the gastrointestinal tract. 
Journal of Clinical Investigation  1975;56(1):135-145.
Gel filtration studies on Bio-Gel P-10 columns of a 50-fold purified porcine duodenal extract revealed a main peak of glucagon-like immunoreactivity (GLI) in the 2,900 mol wt zone and a smaller peak in the 3,500 mol wt zone, the same zone as the pancreatic glucagon marker. Like pancreatic glucagon, samples of 3,500 mol wt material gave essentially identical measurements in radioimmunoassays employing the pancreatic glucagon-specific antiserum 30K and the GLI crossreacting antiserum 78J, whereas the 2,900 mol wt peptide gave 60-fold higher readings in the 78J assay. On disk gel electrophoresis, the 3,500 mol wt fraction, like pancreatic glucagon, migrated at pH 8.3, whereas the 2,900 mol wt peptide remained at the origin; at pH 4.7, the 2,900 mol wt peptide migrated while the 3,500 mol wt immunoreactive peptide and glucagon remained at the origin. Isoelectric focusing revealed the 3,500 mol wt moiety to have an isoelectric point (pI) of 6.2, the same as pancreatic glucagon, whereas the 2,900 mol wt peptide had an pI greater than 10. The glycogenolytic activity of the 3,500 mol wt peptide in the perfused rat liver did not differ significantly from glucagon, and its adenylate cyclase stimulating activity in partially purified liver cell membranes was comparable to that of glucagon; the 2,900 mol wt peptide had less than 20% of these activities. In samples of 3,500 mol wt material subjected to isoelectric focusing, adenylate cyclase-stimulating activity was confirmed to fractions containing 30K immunoreactivity with a pI of 6.2. In samples of 2,900 mol wt material subjected to isoelectric focusing, adenylate cyclase-stimulating activity was confined to fractions containing 78J immunoreactivity with an pI greater than 10. Displacement of [125-I]glucagon from the membranes was limited to these two biologically active fractions. However, the affinity of both pancreatic glucagon and the 3,500 mol wt peptide was an order of magnitude greater than of the 2,900 mol wt peptide. Thus, by all of several biologic, physiocochemical, and immunometric techniques, the 3,500 mol wt gut immunoreactive peptide could not be distinguished from pancreatic glucagon, while the 2,900 mol wt peptide was readily differentiated by all these techniques. "True" A-cells, ultrastructurally indistinguishable from pancreatic A-cells but differing from the A-like cells of the lower bowel, were identified in the gastric fundus of dogs. Their distribution corresponded to that of the 3,500 mol wt immunoreactivity resembling pancreatic glucagon, while the distribution of "A-like cells" in the lower small intestine corresponded to that of GLI.
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PMCID: PMC436564  PMID: 237936
5.  Influence of uremia and hemodialysis on the turnover and metabolic effects of glucagon. 
Journal of Clinical Investigation  1976;57(3):722-731.
To evaluate the mechanism and role of hyperglucagonemia in the carbohydrate intolerance of uremia, 19 patients with chronic renal failure (12 of whom had undergone chronic hemodialysis for at least 11 mo) and 35 healthy control subjects were studied. Plasma glucagon, glucose, and insulin were measured in the basal state, after glucose ingestion (100 g), after intravenous alanine (0.15 g/kg), and during a 3-h continuous infusion of glucagon (3 ng/kg per min) which in normal subjects, raised plasma glucagon levels into the upper physiological range. Basal concentrations of plasma glucagon, the increment in glucagon after infusion of alanine, and post-glucose glucagon levels were three- to fourfold greater in uremic patients than in controls. The plasma glucagon increments after the infusion of exogenous glucagon were also two- to threefold greater in the uremics. The metabolic clearance rate (MCR) of glucagon in uremics was reduced by 58% as compared to controls. In contrast, the basal systemic delivery rate (BSDR) of glucagon in uremics was not significantly different from controls. Comparison of dialyzed and undialyzed uremics showed no differences with respect to plasma concentrations, MCR, or BSDR of glucagon. However, during the infusion of glucagon, the increments in plasma glucose in undialyzed uremics were three- to fourfold greater than in dialyzed uremics or controls. When the glucagon infusion rate was increased in controls to 6 ng/kg per min to produce increments in plasma glucagon comparable to uremics, the glycemic response remained approximately twofold greater in the undialyzed uremics. The plasma glucose response to glucagon in the uremics showed a direct linear correlation with oral glucose tolerance which was also improved with dialysis. The glucagon infusion resulted in 24% reduction in plasma alanine in uremics but had no effect on alanine levels in controls. It is concluded that (a) hyperglucagonemia in uremia is primarily a result of decreased catabolism rather than hypersecretion of this hormone; (b) sensitivity to the hyperglycemic effect of physiological increments in glucagon is increased in undialyzed uremic patients; and (c) dialysis normalizes the glycemic response to glucagon, possibly accounting thereby for improved glucose tolerance despite persistent hyperglucagonemia. These findings thus provide evidence of decreased hormonal catabolism contributing to a hyperglucagonemic state, and of altered tissue sensitivity contributing to the pathophysiological action of this hormone.
PMCID: PMC436707  PMID: 1249205
6.  Glucagon Receptor–Mediated Extracellular Signal–Regulated Kinase 1/2 Phosphorylation in Rat Mesangial Cells 
Hypertension  2006;47(3):580-585.
Glucagon, a major insulin counterregulatory hormone, binds to specific Gs protein–coupled receptors to activate glycogenolytic and gluconeogenic pathways, causing blood glucose levels to increase. Inappropriate increases in serum glucagon play a critical role in the development of insulin resistance and target organ damage in type 2 diabetes. We tested the hypotheses that: (1) glucagon induces proliferation of rat glomerular mesangial cells through glucagon receptor–activated phosphorylation of mitogen-activated protein kinase extracellular signal–regulated kinase 1/2 (p-ERK 1/2); and (2) this phosphorylation involves activation of cAMP-dependent protein kinase A (PKA) and phospholipase C (PLC)/[Ca2+]i signaling pathways. In rat mesangial cells, glucagon (1 nM) stimulated [3H]-thymidine incorporation by 96% (P < 0.01). This proliferative effect was blocked by the specific glucagon receptor antagonist [Des-His1-Glu9] glucagon (1 μmol/L; P < 0.01), a mitogen-activated protein kinase/ERK kinase inhibitor PD98059 (10 μmol/L; P < 0.01), a PLC inhibitor U73122 (1 μmol/L; P < 0.01), or a PKA inhibitor H-89 (1 μmol/L; P < 0.01). The proliferation was associated with a 2-fold increase in p-ERK 1/2 that peaked 5 minutes after glucagon stimulation (P < 0.01) and also was blocked by [Des-His1-Glu9] glucagon. Total ERK 1/2 was not affected by glucagon. Pretreating of mesangial cells with U73122 or H89 significantly attenuated ERK 1/2 phosphorylation induced by glucagon. We believe that these are the first data showing that glucagon activates specific receptors to induce ERK 1/2 phosphorylation and thereby increase mesangial cell proliferation and that this effect of glucagon involves both PLC/[Ca2+]i- and cAMP-dependent PKA-activated signaling cascades.
doi:10.1161/01.HYP.0000197946.81754.0a
PMCID: PMC2367309  PMID: 16391176
kidney; cyclic AMP; calcium; diabetes mellitus; glomerulosclerosis; insulin resistance
7.  Role of KATP Channels in Glucose-Regulated Glucagon Secretion and Impaired Counterregulation in Type 2 Diabetes 
Cell Metabolism  2013;18(6):871-882.
Summary
Glucagon, secreted by pancreatic islet α cells, is the principal hyperglycemic hormone. In diabetes, glucagon secretion is not suppressed at high glucose, exacerbating the consequences of insufficient insulin secretion, and is inadequate at low glucose, potentially leading to fatal hypoglycemia. The causal mechanisms remain unknown. Here we show that α cell KATP-channel activity is very low under hypoglycemic conditions and that hyperglycemia, via elevated intracellular ATP/ADP, leads to complete inhibition. This produces membrane depolarization and voltage-dependent inactivation of the Na+ channels involved in action potential firing that, via reduced action potential height and Ca2+ entry, suppresses glucagon secretion. Maneuvers that increase KATP channel activity, such as metabolic inhibition, mimic the glucagon secretory defects associated with diabetes. Low concentrations of the KATP channel blocker tolbutamide partially restore glucose-regulated glucagon secretion in islets from type 2 diabetic organ donors. These data suggest that impaired metabolic control of the KATP channels underlies the defective glucose regulation of glucagon secretion in type 2 diabetes.
Graphical Abstract
Highlights
•KATP channel closure stimulates insulin secretion but inhibits glucagon release•α cell depolarization reduces voltage-gated Ca2+ entry and glucagon release•An activating KATP channel mutation impairs glucagon release in mice•KATP channel closure corrects glucagon secretion defect in type 2 diabetic islets
doi:10.1016/j.cmet.2013.10.014
PMCID: PMC3851686  PMID: 24315372
8.  The effect of alanine on glucagon secretion 
Journal of Clinical Investigation  1971;50(10):2215-2218.
If glucagon plays a hormonal role in the regulation of gluconeogenesis from endogenous amino acids, its secretion might be stimulated by an increase in the concentration of alanine, which has recently been identified as a principal gluconeogenic precursor. To determine if this is the case, 0.75 mmole of alanine per kilo was infused into conscious dogs immediately after a priming injection of 0.25 mmole per kg for 15 min. A uniform rise in the plasma level of pancreatic glucagon, as determined by a relatively specific radioimmunoassay for pancreatic glucagon, was observed. The rise, which averaged 90 pg per ml, was highly significant at 7½ and 15 min after the start of the infusion. Insulin rose an average of only 8 μU per ml, while glucose rose an average of 10 mg per 100 ml. A lower dose of alanine, 1 mmole per kg, infused over a 1 hr period without an initial priming injection, also elicited a significant rise in glucagon measured in the pancreaticoduodenal venous plasma; glucagon rose from 350 pg per ml to 1066 pg per ml at the end of the infusion. The insulin response was modest and inconsistent, and glucose, again, rose 10 mg per 100 ml.
To determine if the availability of exogenous glucose would abolish the alanine-induced rise in glucagon secretion, dogs were made hyperglycemic by a constant intravenous glucose infusion and were then given the high-dose alanine infusion. Under these circumstances, glucagon did not rise above the mean fasting concentration of 75 pg per ml, whereas mean insulin rose dramatically by more than 100 μU per ml.
It was concluded that, in the fasting state, alanine does stimulate the secretion of glucagon, while having very little stimulatory effect on insulin secretion. Glucagon could, therefore, be a humoral mediator of gluconeogenesis from endogenous alanine, responding to hyperalaninemia in the fasting state, but not when exogenous glucose is available.
PMCID: PMC292156  PMID: 5116210
9.  Glucagon Like Peptide-1-Induced Glucose Metabolism in Differentiated Human Muscle Satellite Cells Is Attenuated by Hyperglycemia 
PLoS ONE  2012;7(8):e44284.
Background
Glucagon like peptide-1 (GLP-1) stimulates insulin secretion from the pancreas but also has extra-pancreatic effects. GLP-1 may stimulate glucose uptake in cultured muscle cells but the mechanism is not clearly defined. Furthermore, while the pancreatic effects of GLP-1 are glucose-dependent, the glucose-dependency of its extra-pancreatic effects has not been examined.
Methods
Skeletal muscle satellite cells isolated from young (22.5±0.97 yr), lean (BMI 22.5±0.6 kg/m2), healthy males were differentiated in media containing either 22.5 mM (high) or 5 mM (normal) glucose for 7 days in the absence or presence of insulin and/or various GLP-1 concentrations. Myocellular effects of GLP-1, insulin and glucose were assessed by western-blot, glucose uptake and glycogen synthesis.
Results
We firstly show that the GLP-1 receptor protein is expressed in differentiated human muscle satellite cells (myocytes). Secondly, we show that in 5 mM glucose media, exposure of myocytes to GLP-1 results in a dose dependent increase in glucose uptake, GLUT4 amount and subsequently glycogen synthesis in a PI3K dependent manner, independent of the insulin signaling cascade. Importantly, we provide evidence that differentiation of human satellite cells in hyperglycemic (22.5 mM glucose) conditions increases GLUT1 expression, and renders the cells insulin resistant and interestingly GLP-1 resistant in terms of glucose uptake and glycogen synthesis. Hyperglycemic conditions did not affect the ability of insulin to phosphorylate downstream targets, PKB or GSK3. Interestingly we show that at 5 mM glucose, GLP-1 increases GLUT4 protein levels and that this effect is abolished by hyperglycemia.
Conclusions
GLP-1 increases glucose uptake and glycogen synthesis into fully-differentiated human satellite cells in a PI3-K dependent mechanism potentially through increased GLUT4 protein levels. The latter occurs independently of the insulin signaling pathway. Attenuation of both GLP-1 and insulin-induced glucose metabolism by hyperglycemia is likely to occur downstream of PI3K.
doi:10.1371/journal.pone.0044284
PMCID: PMC3429413  PMID: 22937169
10.  Hepatic TRAF2 Regulates Glucose Metabolism Through Enhancing Glucagon Responses 
Diabetes  2012;61(3):566-573.
Obesity is associated with intrahepatic inflammation that promotes insulin resistance and type 2 diabetes. Tumor necrosis factor receptor–associated factor (TRAF)2 is a key adaptor molecule that is known to mediate proinflammatory cytokine signaling in immune cells; however, its metabolic function remains unclear. We examined the role of hepatic TRAF2 in the regulation of insulin sensitivity and glucose metabolism. TRAF2 was deleted specifically in hepatocytes using the Cre/loxP system. The mutant mice were fed a high-fat diet (HFD) to induce insulin resistance and hyperglycemia. Hepatic glucose production (HGP) was examined using pyruvate tolerance tests, 2H nuclear magnetic resonance spectroscopy, and in vitro HGP assays. The expression of gluconeogenic genes was measured by quantitative real-time PCR. Insulin sensitivity was analyzed using insulin tolerance tests and insulin-stimulated phosphorylation of insulin receptors and Akt. Glucagon action was examined using glucagon tolerance tests and glucagon-stimulated HGP, cAMP-responsive element–binding (CREB) phosphorylation, and expression of gluconeogenic genes in the liver and primary hepatocytes. Hepatocyte-specific TRAF2 knockout (HKO) mice exhibited normal body weight, blood glucose levels, and insulin sensitivity. Under HFD conditions, blood glucose levels were significantly lower (by >30%) in HKO than in control mice. Both insulin signaling and the hypoglycemic response to insulin were similar between HKO and control mice. In contrast, glucagon signaling and the hyperglycemic response to glucagon were severely impaired in HKO mice. In addition, TRAF2 overexpression significantly increased the ability of glucagon or a cAMP analog to stimulate CREB phosphorylation, gluconeogenic gene expression, and HGP in primary hepatocytes. These results suggest that the hepatic TRAF2 cell autonomously promotes hepatic gluconeogenesis by enhancing the hyperglycemic response to glucagon and other factors that increase cAMP levels, thus contributing to hyperglycemia in obesity.
doi:10.2337/db11-0474
PMCID: PMC3282816  PMID: 22315325
11.  Effects of the naturally‐occurring disaccharides, palatinose and sucrose, on incretin secretion in healthy non‐obese subjects 
Abstract
Aims/Introduction
Incretins might play some pathophysiological role in glucose metabolism in diabetes and obesity; it is not clear whether or not the amount and the pattern of incretin secretion vary with different types of sugars. To evaluate the effect of two types of disaccharides on glucose metabolism and the kinetics of incretin secretion, plasma levels were measured after palatinose or sucrose ingestion in non‐obese healthy participants.
Materials and Methods
The study was carried out on healthy participants who were given a solution containing 50 g of palatinose or sucrose for ingestion. Blood samples were obtained before loading and after ingestion. Insulin, glucagon and incretins hormones were measured by the enzyme‐linked immunosorbent assay method.
Results
When the data were compared between palatinose and sucrose ingestion, both plasma glucose values at 15, 30 and 60 min, and plasma insulin values at 15 and 30 min after palatinose loading were significantly lower than those after sucrose loading. Plasma levels of total glucose‐dependent insulinotropic polypeptide at 15–90 min after palatinose loading were significantly lower than those after sucrose loading. Plasma levels of total and active glucagon‐like peptide‐1 at 90 min and the area under the curve (60–120 min) of the total glucagon‐like peptide‐1 were significantly higher with palatinose‐loading than with sucrose loading.
Conclusion
Compared with sucrose, palatinose appears to have a more favorable effect on glucose metabolism and protection of pancreatic islets as a result of less hyperglycemic and hyperinsulinemic potency.
doi:10.1111/jdi.12045
PMCID: PMC4015665  PMID: 24843667
Incretin; Palatinose; Type 2 diabetes mellitus
12.  Effect of Prostaglandins on Hepatic Cyclic Nucleotide Concentration, Carbohydrate and Lipid Metabolism 
The effects of exogenous prostaglandin E1 (PGE1) or prostaglandin E2 (PGE2) were studied in the isolated perfused rat liver and in the intact canine liver in order to determine the possible physiological role of prostaglandins on hepatic carbohydrate and lipid metabolism. The data indicate that PGE1 and PGE2 did not stimulate cyclic AMP (cAMP) and cyclic GMP (cGMP) concentrations in intact dog liver and PGE1 failed to stimulate cAMP or cGMP in fed or fasted perfused rat liver. PGE1 did not promote hyperglycemia, glycogenolysis, lipolysis, or prevent epinephrine-induced hyperglycemia in the isolated perfused rat liver. Other known glycogenolytic agents including glucagon and epinephrine increased cAMP and glycogenolysis in the same perfusion system. This study does not support a physiologic role for PGE1 on hepatic glycogenolysis or lipolysis. If PGE1 subsequently is found to influence other metabolic parameters such as lipogenesis, gluconeogenesis, ureogenesis or amino acid transport in isolated perfused liver, such alterations would probably occur independent of changes in cyclic nucleotide activity.
PMCID: PMC2595716  PMID: 222076
13.  Regulation of pancreatic PC1 and PC2 associated with increased glucagon-like peptide 1 in diabetic rats 
Journal of Clinical Investigation  2000;105(7):955-965.
The pancreatic processing enzymes, PC1 and PC2, convert proinsulin to insulin and convert proglucagon to glucagon and glucagon-like peptide 1 (GLP-1). We examined the effect of streptozotocin (STZ) treatment on the regulation of these enzymes and the production of insulin, glucagon, and GLP-1 in the rat. Pancreatic PC1 and PC2 mRNA increased >2-fold and >4-fold, respectively, in rats receiving intraperitoneal STZ (50 mg/kg) daily for 5 days. Immunocytochemistry revealed that, although pancreatic islet cells in the STZ-treated rats were sparse and atrophic PC1, PC2, glucagon, and GLP-1 immunoreactivity increased dramatically in the remaining islet cells. Heightened PC1 and PC2 expression was seen in cells expressing glucagon but not in insulin-expressing cells. Furthermore, in STZ-treated rats, bioactive GLP-17–36 amide accumulated in pancreatic extracts and serum 3- and 2.5-fold, respectively, over control animals. This treatment also caused a 2-fold increase in the ratio of amidated forms of GLP-1 immunoreactivity to total glucagon immunoreactivity in the pancreas but did not affect the ratio of proinsulin to insulin. We conclude that hyperglycemic rats have an increased expression of prohormone converting enzymes in islet α cells, leading to an increase in amidated GLP-1, which can then exert an insulinotropic effect on the remaining β cells.
PMCID: PMC377475  PMID: 10749575
14.  The effects of corn silk on glycaemic metabolism 
Background
Corn silk contains proteins, vitamins, carbohydrates, Ca, K, Mg and Na salts, fixed and volatile oils, steroids such as sitosterol and stigmasterol, alkaloids, saponins, tannins, and flavonoids. Base on folk remedies, corn silk has been used as an oral antidiabetic agent in China for decades. However, the hypoglycemic activity of it has not yet been understood in terms of modern pharmacological concepts. The purpose of this study is to investigate the effects of corn silk on glycaemic metabolism.
Methods
Alloxan and adrenalin induced hyperglycemic mice were used in the study. The effects of corn silk on blood glucose, glycohemoglobin (HbA1c), insulin secretion, damaged pancreatic β-cells, hepatic glycogen and gluconeogenesis in hyperglycemic mice were studied respectively.
Results
After the mice were orally administered with corn silk extract, the blood glucose and the HbA1c were significantly decreased in alloxan-induced hyperglycemic mice (p < 0.05, p < 0.01, respectively), while the level of insulin secretionn was markedly elevated in alloxa-induced hyperglycemic mice (p < 0.05). The alloxan-damaged pancreatic β-cells of the mice were partly recovered gradually after the mice were administered with corn silk extract 15 days later. Also, the body weight of the alloxan-induced hyperglycemic mice was increased gradually. However, ascension of blood glucose induced by adrenalin and gluconeogenesis induced by L-alanine were not inhibited by corn silk extract treatment (p > 0.05). Although corn silk extract increased the level of hepatic glycogen in the alloxan-induced hyperglycemic mice, there was no significant difference between them and that of the control group(p > 0.05).
Conclusion
Corn silk extract markedly reduced hyperglycemia in alloxan-induced diabetic mice. The action of corn silk extract on glycaemic metabolism is not via increasing glycogen and inhibiting gluconeogenesis but through increasing insulin level as well as recovering the injured β-cells. The results suggest that corn silk extract may be used as a hypoglycemic food or medicine for hyperglycemic people in terms of this modern pharmacological study.
doi:10.1186/1743-7075-6-47
PMCID: PMC2785813  PMID: 19930631
15.  Effects of Acute Hyperglucagonemia on Hepatic and Intestinal Lipoprotein Production and Clearance in Healthy Humans 
Diabetes  2011;60(2):383-390.
OBJECTIVE
The metabolism of hepatic- and intestinally derived lipoproteins is regulated in a complex fashion by nutrients, hormones, and neurologic and other factors. Recent studies in animal models suggest an important role for glucagon acting via the glucagon receptor in regulating hepatic triglyceride (TG) secretion. Here we examined the direct effects of glucagon on regulation of hepatic and intestinal lipoprotein metabolism in humans.
RESEARCH DESIGN AND METHODS
Eight healthy men underwent two studies each, in random order, 4–6 weeks apart in which de novo lipogenesis, kinetics of larger VLDL1 TG, and kinetics of VLDL1 and smaller VLDL2 apolipoprotein (apo)B100 and B48 were studied using established stable isotope enrichment methods. Subjects were studied in the constant fed state under conditions of a pancreatic clamp (with infusion of somatostatin, insulin, and growth hormone) at either basal glucagon (BG study, 64.5 ± 2.1 pg/mL) or hyperglucagonemia (high glucagon [HG] study, 183.2 ± 5.1 pg/mL).
RESULTS
There were no significant differences in plasma concentration of VLDL1 or VLDL2 TG, apoB100 or apoB48 between BG and HG studies. There was, however, lower (P < 0.05) VLDL1 apoB100 fractional catabolic rate (−39%) and production rate (−30%) in HG versus BG, but no difference in de novo lipogenesis or TG turnover, and glucagon had no effect on intestinal (B48-containing) lipoprotein metabolism.
CONCLUSIONS
Glucagon acutely regulates hepatic but not intestinal lipoprotein particle metabolism in humans both by decreasing hepatic lipoprotein particle production as well as by inhibiting particle clearance, with no net effect on particle concentration.
doi:10.2337/db10-0763
PMCID: PMC3028336  PMID: 20980459
16.  Regulation of glucose homeostasis in humans with denervated livers. 
Journal of Clinical Investigation  1997;100(4):931-941.
The liver plays a major role in regulating glucose metabolism, and since its function is influenced by sympathetic/ parasympathetic innervation, we used liver graft as a model of denervation to study the role of CNS in modulating hepatic glucose metabolism in humans. 22 liver transplant subjects were randomly studied by means of the hyperglycemic/ hyperinsulinemic (study 1), hyperglycemic/isoinsulinemic (study 2), euglycemic/hyperinsulinemic (study 3) as well as insulin-induced hypoglycemic (study 4) clamp, combined with bolus-continuous infusion of [3-3H]glucose and indirect calorimetry to determine the effect of different glycemic/insulinemic levels on endogenous glucose production and on peripheral glucose uptake. In addition, postabsorptive glucose homeostasis was cross-sectionally related to the transplant age (range = 40 d-35 mo) in 4 subgroups of patients 2, 6, 15, and 28 mo after transplantation. 22 subjects with chronic uveitis (CU) undergoing a similar immunosuppressive therapy and 35 normal healthy subjects served as controls. The results showed that successful transplantation was associated with fasting glucose concentration and endogenous glucose production in the lower physiological range within a few weeks after transplantation, and this pattern was maintained throughout the 28-mo follow-up period. Fasting glucose (4. 55+/-0.06 vs. 4.75+/-0.06 mM; P = 0.038) and endogenous glucose production (11.3+/-0.4 vs. 12.9+/-0.5 micromol/[kg.min]; P = 0.029) were lower when compared to CU and normal patients. At different combinations of glycemic/insulinemic levels, liver transplant (LTx) patients showed a comparable inhibition of endogenous glucose production. In contrast, in hypoglycemia, after a temporary fall endogenous glucose production rose to values comparable to those of the basal condition in CU and normal subjects (83+/-5 and 92+/-5% of basal), but it did not in LTx subjects (66+/-7%; P < 0.05 vs. CU and normal subjects). Fasting insulin and C-peptide levels were increased up to 6 mo after transplantation, indicating insulin resistance partially induced by prednisone. In addition, greater C-peptide but similar insulin levels during the hyperglycemic clamp (study 1) suggested an increased hepatic insulin clearance in LTx as compared to normal subjects. Fasting glucagon concentration was higher 6 mo after transplantation and thereafter. During euglycemia/hyperinsulinemia (study 3), the insulin-induced glucagon suppression detectable in CU and normal subjects was lacking in LTx subjects; furthermore, the counterregulatory response during hypoglycemia was blunted. In summary, liver transplant subjects have normal postabsorptive glucose metabolism, and glucose and insulin challenge elicit normal response at both hepatic and peripheral sites. Nevertheless, (a) minimal alteration of endogenous glucose production, (b) increased concentration of insulin and glucagon, and (c) defective counterregulation during hypoglycemia may reflect an alteration of the liver-CNS-islet circuit which is due to denervation of the transplanted graft.
PMCID: PMC508266  PMID: 9259593
17.  A KATP Channel-Dependent Pathway within α Cells Regulates Glucagon Release from Both Rodent and Human Islets of Langerhans  
PLoS Biology  2007;5(6):e143.
Glucagon, secreted from pancreatic islet α cells, stimulates gluconeogenesis and liver glycogen breakdown. The mechanism regulating glucagon release is debated, and variously attributed to neuronal control, paracrine control by neighbouring β cells, or to an intrinsic glucose sensing by the α cells themselves. We examined hormone secretion and Ca2+ responses of α and β cells within intact rodent and human islets. Glucose-dependent suppression of glucagon release persisted when paracrine GABA or Zn2+ signalling was blocked, but was reversed by low concentrations (1–20 μM) of the ATP-sensitive K+ (KATP) channel opener diazoxide, which had no effect on insulin release or β cell responses. This effect was prevented by the KATP channel blocker tolbutamide (100 μM). Higher diazoxide concentrations (≥30 μM) decreased glucagon and insulin secretion, and α- and β-cell Ca2+ responses, in parallel. In the absence of glucose, tolbutamide at low concentrations (<1 μM) stimulated glucagon secretion, whereas high concentrations (>10 μM) were inhibitory. In the presence of a maximally inhibitory concentration of tolbutamide (0.5 mM), glucose had no additional suppressive effect. Downstream of the KATP channel, inhibition of voltage-gated Na+ (TTX) and N-type Ca2+ channels (ω-conotoxin), but not L-type Ca2+ channels (nifedipine), prevented glucagon secretion. Both the N-type Ca2+ channels and α-cell exocytosis were inactivated at depolarised membrane potentials. Rodent and human glucagon secretion is regulated by an α-cell KATP channel-dependent mechanism. We propose that elevated glucose reduces electrical activity and exocytosis via depolarisation-induced inactivation of ion channels involved in action potential firing and secretion.
Author Summary
Glucagon is a critical regulator of glucose homeostasis. Its major action is to mobilize glucose from the liver. Glucagon secretion from α cells of the pancreatic islets of Langerhans is suppressed by elevated blood sugar, a response that is often perturbed in diabetes. Much work has focused on the regulation of α-cell glucagon secretion by neuronal factors and by paracrine factors from neighbouring cells, including the important islet hormone insulin. In contrast, we provide evidence in support of a direct effect of glucose on α cells within intact rodent and human islets. Notably, our work implicates an α-cell glucose-sensing pathway similar to that found in insulin-secreting β cells, involving closure of ATP-dependent K+ channels in the presence of glucose. Furthermore, we find that membrane depolarisation results in inhibition of Na+ and Ca2+ channel activity and α-cell exocytosis. Thus, we propose that elevated blood glucose reduces α-cell electrical activity and glucagon secretion by inactivating the ion channels involved in action potential firing and secretion.
Elevated glucose levels reduce electrical activity and the release of glucagon via inactivation of ion channels in pancreatic islet cells.
doi:10.1371/journal.pbio.0050143
PMCID: PMC1868042  PMID: 17503968
18.  Characterization of a novel protein kinase C response element in the glucagon gene. 
Molecular and Cellular Biology  1997;17(4):1805-1816.
To maintain glucose levels in blood within narrow limits, the synthesis and secretion of pancreatic islet hormones are controlled by a variety of neural, hormonal, and metabolic messengers that act through multiple signal transduction pathways. Glucagon gene transcription is stimulated by cyclic AMP and depolarization-induced calcium influx. In this study, the effect of protein kinase C on glucagon gene transcription was investigated. After transient transfection of a glucagon-reporter fusion gene into the glucagon-producing islet cell line alphaTC2, activation of protein kinase C by 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulated glucagon gene transcription. By 5' deletions, 3' deletions, internal deletion, and oligonucleotide cassette insertion, the TPA-responsive element was mapped to the G2 element (from -165 to -200). Like TPA, overexpression of oncogenic Ras (V-12 Ras) stimulated G2-mediated transcription whereas overexpression of a dominant negative Ras mutant (N-17 Ras) blocked the effect of TPA. A mutational analysis of G2 function and nuclear protein binding indicated that protein kinase C and Ras responsiveness is conferred to the glucagon gene by HNF-3beta functionally interacting with a protein that binds to a closely associated site with sequence similarity to binding sites of Ets family proteins. HNF-3beta belongs to the winged-helix family of transcription factors and has been implicated in the control of cell-specific and developmental gene expression. The results of the present study show that the cell lineage-specific transcription factor HNF-3beta is an essential component of a novel protein kinase C response element in the glucagon gene.
PMCID: PMC232027  PMID: 9121428
19.  Effects of physiologic levels of glucagon and growth hormone on human carbohydrate and lipid metabolism. Studies involving administration of exogenous hormone during suppression of endogenous hormone secretion with somatostatin. 
Journal of Clinical Investigation  1976;57(4):875-884.
To study the individual effects of glucagon and growth hormone on human carbohydrate and lipid metabolism, endogenous secretion of both hormones was simultaneously suppressed with somatostatin and physiologic circulating levels of one or the other hormone were reproduced by exogenous infusion. The interaction of these hormones with insulin was evaluated by performing these studies in juvenile-onset, insulin-deficient diabetic subjects both during infusion of insulin and after its withdrawal. Infusion of glucagon (1 ng/kg-min) during suppression of its endogenous secretion with somatostatin produced circulating hormone levels of approximately 200 pg/ml. When glucagon was infused along with insulin, plasma glucose levels rose from 94 +/- 8 to 126 +/- 12 mg/100 ml over 1 h (P less than 0.01); growth hormone, beta-hydroxy-butyrate, alanine, FFA, and glycerol levels did not change. When insulin was withdrawn, plasma glucose, beta-hydroxybutyrate, FFA, and glycerol all rose to higher levels (P less than 0.01) than those observed under similar conditions when somatostatin alone had been infused to suppress glucagon secretion. Thus, under appropriate conditions, physiologic levels of glucagon can stimulate lipolysis and cause hyperketonemia and hyperglycemia in man; insulin antagonizes the lipolytic and ketogenic effects of glucagon more effectively than the hyperglycemic effect. Infusion of growth hormone (1 mug/kg-h) during suppression of its endogenous secretion with somastostatin produced circulating hormone levels of approximately 6 ng/ml. When growth hormone was administered along with insulin, no effects were observed. After insulin was withdrawn, plasma beta-hydroxybutyrate, glycerol, and FFA all rose to higher levels (P less than 0.01) than those observed during infusion of somatostatin alone when growth hormone secretion was suppressed; no difference in plasma glucose, alanine, and glucagon levels was evident. Thus, under appropriate conditions, physiologic levels of growth hormone can augment lipolysis and ketonemia in man, but these actions are ordinarily not apparent in the presence of physiologic levels of insulin.
Images
PMCID: PMC436731  PMID: 820717
20.  Anti-Diabetic Efficacy and Impact on Amino Acid Metabolism of GRA1, a Novel Small-Molecule Glucagon Receptor Antagonist 
PLoS ONE  2012;7(11):e49572.
Hyperglucagonemia is implicated in the pathophysiology of hyperglycemia. Antagonism of the glucagon receptor (GCGR) thus represents a potential approach to diabetes treatment. Herein we report the characterization of GRA1, a novel small-molecule GCGR antagonist that blocks glucagon binding to the human GCGR (hGCGR) and antagonizes glucagon-induced intracellular accumulation of cAMP with nanomolar potency. GRA1 inhibited glycogenolysis dose-dependently in primary human hepatocytes and in perfused liver from hGCGR mice, a transgenic line of mouse that expresses the hGCGR instead of the murine GCGR. When administered orally to hGCGR mice and rhesus monkeys, GRA1 blocked hyperglycemic responses to exogenous glucagon. In several murine models of diabetes, acute and chronic dosing with GRA1 significantly reduced blood glucose concentrations and moderately increased plasma glucagon and glucagon-like peptide-1. Combination of GRA1 with a dipeptidyl peptidase-4 inhibitor had an additive antihyperglycemic effect in diabetic mice. Hepatic gene-expression profiling in monkeys treated with GRA1 revealed down-regulation of numerous genes involved in amino acid catabolism, an effect that was paralleled by increased amino acid levels in the circulation. In summary, GRA1 is a potent glucagon receptor antagonist with strong antihyperglycemic efficacy in preclinical models and prominent effects on hepatic gene-expression related to amino acid metabolism.
doi:10.1371/journal.pone.0049572
PMCID: PMC3501516  PMID: 23185367
21.  Sprint Training Increases Muscle Oxidative Metabolism During High-Intensity Exercise in Patients With Type 1 Diabetes  
Diabetes Care  2008;31(11):2097-2102.
OBJECTIVE—To investigate sprint-training effects on muscle metabolism during exercise in subjects with (type 1 diabetic group) and without (control group) type 1 diabetes.
RESEARCH DESIGN AND METHODS—Eight subjects with type 1 diabetes and seven control subjects, matched for age, BMI, and maximum oxygen uptake (V̇o2peak), undertook 7 weeks of sprint training. Pretraining, subjects cycled to exhaustion at 130% V̇o2peak. Posttraining subjects performed an identical test. Vastus lateralis biopsies at rest and immediately after exercise were assayed for metabolites, high-energy phosphates, and enzymes. Arterialized venous blood drawn at rest and after exercise was analyzed for lactate and [H+]. Respiratory measures were obtained on separate days during identical tests and during submaximal tests before and after training.
RESULTS—Pretraining, maximal resting activities of hexokinase, citrate synthase, and pyruvate dehydrogenase did not differ between groups. Muscle lactate accumulation with exercise was higher in type 1 diabetic than nondiabetic subjects and corresponded to indexes of glycemia (A1C, fasting plasma glucose); however, glycogenolytic and glycolytic rates were similar. Posttraining, at rest, hexokinase activity increased in type 1 diabetic subjects; in both groups, citrate synthase activity increased and pyruvate dehydrogenase activity decreased; during submaximal exercise, fat oxidation was higher; and during intense exercise, peak ventilation and carbon dioxide output, plasma lactate and [H+], muscle lactate, glycogenolytic and glycolytic rates, and ATP degradation were lower in both groups.
CONCLUSIONS—High-intensity exercise training was well tolerated, reduced metabolic destabilization (of lactate, H+, glycogenolysis/glycolysis, and ATP) during intense exercise, and enhanced muscle oxidative metabolism in young adults with type 1 diabetes. The latter may have clinically important health benefits.
doi:10.2337/dc08-0329
PMCID: PMC2571053  PMID: 18716051
22.  Effect of insulin-glucose infusions on plasma glucagon levels in fasting diabetics and nondiabetics. 
Journal of Clinical Investigation  1975;56(5):1132-1138.
The effect of the intravenous infusion of insulin plus glucose on plasma glucagon levels was studied in hyperglycemic fasting adult-type and juvenile-type diabetics and compared with fasting nondiabetics. Adult-type diabetics were given insulin for 2 h at a rate of 0.03 U/kg-min, raising their mean insulin to between 25 and 36 muU/ml; glucagon declined from a base-line value of 71+/-2 (SEM) to 56+/-1 pg/ml at 120 min (P less than 0.001). In juvenile-type diabetics given the same insulin-glucose infusion, glucagon declined from a base-line level of 74+/-8 to 55+/-5 pg/ml at 120 min (P less than 0.05). The absolute glucagon values in the diabetic groups did not differ significantly at any point from the mean glucagon levels in nondiabetics given insulin at the same rate plus enough glucose to maintain normoglycemia. When glucagon was expressed as percent of baseline, however, the normoglycemic nondiabetics exhibited significantly lower values than adult-type diabetics at 90 and 120 min and juvenile-type diabetics at 60 min. In nondiabetics given insulin plus glucose at a rate that caused hyperglycemia averaging between 134 and 160 mg/dl, glucagon fell to 41+/-7 pg/ml at 120 min, significantly below the adult diabetics at 90 and 120 min (P less than 0.01 and less than 0.05) and the juvenile group at 60 min (P less than 0.01). The mean minimal level of 39+/-2 pg/ml was significantly below the adult (P less than 0.001) and juvenile groups (P less than 0.05). When insulin was infused in the diabetic groups at a rate of 0.4 U/kg-min together with glucose, raising mean plasma insulin to between 300 and 600 muU/ml, differences from the hyperglycemic nondiabetics were no longer statistically significant. It is concluded that, contrary to the previously reported lack of insulin effect in diabetics during carbohydrate meals, intravenous administration for 2 h of physiologic amounts of insulin plus glucose is accompanied in unfed diabetics by a substantial decline in plasma glucagon. These levels are significantly above hyperglycemic nondiabetics at certain points but differ from normoglycemic nondiabetics only when expressed as percent of the baseline. At a supraphysiologic rate of insulin infusion in diabetics, these differences disappear.
PMCID: PMC301975  PMID: 1184740
23.  Hyperinsulinemic hypoglycemia after Roux-en-Y gastric bypass: Unraveling the role of gut hormonal and pancreatic endocrine dysfunction 
The Journal of surgical research  2010;167(2):199-205.
Introduction
Profound hypoglycemia occurs rarely as a late complication after Roux-en-Y gastric bypass (RYGB). We investigated the role of glucagon-like-peptide-1 (GLP-1) in four subjects) who developed recurrent neuro-glycopenia 2-3 years after RYGB.
METHODS
A standardized test meal (STM) was administered to all four subjects. A 2 hr hyperglycemic clamp with GLP-1 infusion during the second hr was performed in one subject, before, during a 4 wk trial of octreotide (Oc) and after 85% distal pancreatectomy. After cessation of both glucose and GLP-1 infusion at the end of the 2 hr clamp, blood glucose levels were monitored for 30 minutes. Responses were compared to a control group (5 subjects 12 mo status post RYGB without hypoglycemic symptoms).
RESULTS
During STM, both GLP-1 and insulin levels were elevated 3-4 fold in all subjects, and plasma glucose-dependent insulinotropic peptide (GIP) levels were elevated 2-fold. Insulin responses to hyperglycemia ± GLP-1 infusion in one subject were comparable to controls, but after cessation of glucose infusion, glucose levels fell to 40 mg/dl. During Oc, the GLP-1 and insulin responses to STM were reduced (>50%). During the clamp, insulin response to hyperglycemia alone was reduced, but remained unchanged during GLP-1. Glucagon levels during hyperglycemia alone were suppressed and further suppressed after the addition of GLP-1. With the substantial drop in glucose during the 30 minute follow-up, glucagon levels failed to rise. Due to persistent symptoms, one subject underwent 85% distal pancreatectomy; post-operatively, the subject remained asymptomatic (blood glucose: 119-220 mg/dl), but a repeat STM showed persistence of elevated levels of GLP-1. Histologically enlarged islets, and beta cell clusters scattered throughout the acinar parenchyma was seen, as well as beta-cells present within pancreatic duct epithelium. An increase in pancreatic and duodenal homeobox-1 protein (PDX-1) expression was observed in the subject compared to control pancreatic tissue.
CONCLUSIONS
A persistent exaggerated hypersecretion of GLP-1, which has been shown to be insulinotropic, insulinomimetic and glucagonostatic, is the likely cause of post-RYGB hypoglycemia. The hypertrophy and ectopic location of beta-cells is likely due to over-expression of the islet cell transcription factor, PDX-1, caused by prolonged hypersecretion of GLP-1.
doi:10.1016/j.jss.2010.09.047
PMCID: PMC3148142  PMID: 21414635
24.  Hyperglycemia limits experimental aortic aneurysm progression 
Objective
Diabetes mellitus (DM) is associated with reduced progression of abdominal aortic aneurysm (AAA) disease. Mechanisms responsible for this negative association remain unknown. We created AAAs in hyperglycemic mice to examine the influence of serum glucose concentration on experimental aneurysm progression.
Methods
Aortic aneurysms were induced in hyperglycemic (DM) and normoglycemic models by using intra-aortic porcine pancreatic elastase (PPE) infusion in C57BL/6 mice or by systemic infusion of angiotensin II (ANG) in apolipoprotein E-deficient (ApoE−/−) mice, respectively. In an additional DM cohort, insulin therapy was initiated after aneurysm induction. Aneurysmal aortic enlargement progression was monitored with serial transabdominal ultrasound measurements. At sacrifice, AAA cellularity and proteolytic activity were evaluated by immunohistochemistry and substrate zymography, respectively. Influences of serum glucose levels on macrophage migration were examined in separate models of thioglycollate-induced murine peritonitis.
Results
At 14 days after PPE infusion, AAA enlargement in hyperglycemic mice (serum glucose ≥ 300 mg/dL) was less than that in euglycemic mice (PPE-DM: 54% ± 19% vs PPE: 84% ± 24%, P < .0001). PPE-DM mice also demonstrated reduced aortic mural macrophage infiltration (145 ± 87 vs 253 ±119 cells/cross-sectional area, P = .0325), elastolysis (% residual elastin: 20% ± 7% vs 12% ± 6%, P = .0209), and neovascularization (12 ± 8 vs 20 ± 6 vessels/high powered field, P = .0229) compared with PPE mice. Hyperglycemia limited AAA enlargement after ANG infusion in ApoE−/− mice (ANG-DM: 38% ± 12% vs ANG: 61% ± 37% at day 28). Peritoneal macrophage production was reduced in response to thioglycollate stimulation in hyperglycemic mice, with limited augmentation noted in response to vascular endothelial growth factor administration. Insulin therapy reduced serum glucose levels and was associated with AAA enlargement rates intermediate between euglycemic and hyperglycemic mice (PPE: 1.21 ± 0.14 mm vs PPE-DM: 1.00 ± 0.04 mm vs PPE-DM + insulin: 1.14 ± 0.05 mm).
Conclusions
Hyperglycemia reduces progression of experimental AAA disease; lowering of serum glucose levels with insulin treatment diminishes this protective effect. Identifying mechanisms of hyperglycemic aneurysm inhibition may accelerate development of novel clinical therapies for AAA disease.
Clinical Relevance
This report provides mechanistic insight into prior population-based clinical studies identifying a negative association between diabetes mellitus and abdominal aortic aneurysm (AAA). The inhibitory effects of hyperglycemia on aneurysm development are examined independent of other AAA risk factors. Further investigations into these or related mechanisms may accelerate the development of effective medical strategies to suppress progression of AAA disease.
doi:10.1016/j.jvs.2010.05.086
PMCID: PMC2987703  PMID: 20678880
25.  The Inactivation of Arx in Pancreatic α-Cells Triggers Their Neogenesis and Conversion into Functional β-Like Cells 
PLoS Genetics  2013;9(10):e1003934.
Recently, it was demonstrated that pancreatic new-born glucagon-producing cells can regenerate and convert into insulin-producing β-like cells through the ectopic expression of a single gene, Pax4. Here, combining conditional loss-of-function and lineage tracing approaches, we show that the selective inhibition of the Arx gene in α-cells is sufficient to promote the conversion of adult α-cells into β-like cells at any age. Interestingly, this conversion induces the continuous mobilization of duct-lining precursor cells to adopt an endocrine cell fate, the glucagon+ cells thereby generated being subsequently converted into β-like cells upon Arx inhibition. Of interest, through the generation and analysis of Arx and Pax4 conditional double-mutants, we provide evidence that Pax4 is dispensable for these regeneration processes, indicating that Arx represents the main trigger of α-cell-mediated β-like cell neogenesis. Importantly, the loss of Arx in α-cells is sufficient to regenerate a functional β-cell mass and thereby reverse diabetes following toxin-induced β-cell depletion. Our data therefore suggest that strategies aiming at inhibiting the expression of Arx, or its molecular targets/co-factors, may pave new avenues for the treatment of diabetes.
Author Summary
Type 1 diabetes is a condition that results from the loss of insulin-producing β-cells. Despite current therapies, diabetic patients are prone to vascular complications. Using the mouse as a model, we previously found that pancreatic glucagon-expressing cells can be regenerated and converted into β-like cells by the forced expression of a single gene, Pax4. Here, we generated transgenic mice allowing both the permanent labeling of α-cells and the inactivation of Arx solely in this cell subtype. Our results indicate that, upon Arx inactivation, α-cells can be continuously regenerated from duct-lining precursors and converted into β-like cells. Importantly, the additional loss of Pax4 does not impact these processes, suggesting that Arx is the main trigger of α-cell-mediated β-like cell neogenesis. Most interestingly, upon chemical induction of diabetes/β-cell loss, while control animals die or remain severely hyperglycemic, a normalization of the glycemia, a clear regeneration of the β-like cell mass, and an extended lifespan are noted in animals with the conditional inactivation of Arx. Our data therefore suggest that strategies aiming at inhibiting the expression of Arx, or its molecular targets/co-factors, may pave new avenues for the treatment of diabetes.
doi:10.1371/journal.pgen.1003934
PMCID: PMC3814322  PMID: 24204325

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