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Background: Ischemic post-conditioning (IPoC) has been shown to improve outcomes in limited pre-clinical models. As down-time is often unknown, this technique needs to be investigated over a range of scenarios. As this tool limits reperfusion injury, there may be limited benefit or even harm after short arrest and limited ischemia-reperfusion injury. Methods: Eighteen male Wistar rats underwent 7 min of asphyxial arrest. Animals randomized to IPoC received a 20 s pause followed by 20 s of compressions, repeated four times, initiated 40 s into cardiopulmonary resuscitation. If return of spontaneous circulation (ROSC) was achieved, epinephrine was titrated to mean arterial pressure (MAP) of 70 mmHg. Data were analyzed using t-test or Mann–Whitney test. Significance set at p ≤ 0.05. Results: The rate of ROSC was equivalent in both groups, 88%. There was no statistically significant difference in time to ROSC, epinephrine required post ROSC, carotid flow, or peak lactate at any timepoint. There was a significantly elevated MAP with IPoC, 90.7 mmHg (SD 13.9), as compared to standard CPR, 76.7 mmHg (8.5), 2 h after ROSC, p = 0.03. Conclusions: IPoC demonstrated no harm in a model of short arrest using a new arrest etiology for CPR based IPoC intervention in a rat model. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is characterized by insulin resistance, hyperglycemia, and progressive β cell dysfunction. Excess glucose and lipid impair β cell function in islet cell lines, cultured rodent and human islets, and in vivo rodent models. Here, we examined the mechanistic consequences of glucotoxic and lipotoxic conditions on human islets in vivo and developed and/or used 3 complementary models that allowed comparison of the effects of hyperglycemic and/or insulin-resistant metabolic stress conditions on human and mouse islets, which responded quite differently to these challenges. Hyperglycemia and/or insulin resistance impaired insulin secretion only from human islets in vivo. In human grafts, chronic insulin resistance decreased antioxidant enzyme expression and increased superoxide and amyloid formation. In human islet grafts, expression of transcription factors NKX6.1 and MAFB was decreased by chronic insulin resistance, but only MAFB decreased under chronic hyperglycemia. Knockdown of NKX6.1 or MAFB expression in a human β cell line recapitulated the insulin secretion defect seen in vivo. Contrary to rodent islet studies, neither insulin resistance nor hyperglycemia led to human β cell proliferation or apoptosis. These results demonstrate profound differences in how excess glucose or lipid influence mouse and human insulin secretion and β cell activity and show that reduced expression of key islet-enriched transcription factors is an important mediator of glucotoxicity and lipotoxicity., Introduction Patients with type 2 diabetes (T2D) have impaired insulin secretion in response to glucose, and this β cell dysfunction is progressive, often requiring exogenous insulin therapy. Physiological levels of [...]

To determine the effect of an acute increase in hepatic glycogen on net hepatic glucose uptake (NHGU) and disposition in response to insulin in vivo, studies were performed on two groups of dogs fasted 18 h. During the first 4 h of the study, somatostatin was infused peripherally, while insulin and glucagon were replaced intraportally in basal amounts. Hyperglycemia was brought about by glucose infusion, and either saline (n = 7) or fructose (n = 7; to stimulate NHGU and glycogen deposition) was infused intraportally. A 2-h control period then followed, during which the portal fructose and saline infusions were stopped, allowing NHGU and glycogen deposition in the fructose-infused animals to return to rates similar to those of the animals that received the saline infusion. This was followed by a 2-h experimental period, during which hyperglycemia was continued but insulin infusion was increased fourfold in both groups. During the initial 4-h glycogen loading period, NHGU averaged 1.18 [+ or -] 0.27 and 5.55 [+ or -] 0.53 mg x [kg.sup.-1] x [min.sup.-1] and glycogen synthesis averaged 0.72 [+ or -] 0.24 and 3.98 [+ or -] 0.57 mg x [kg.sup.-1] x [min.sup.-1] in the saline and fructose groups, respectively (P < 0.05). During the 2-h hyperinsulinemic period, NHGU rose from 1.5 [+ or -] 0.4 and 0.9 [+ or -] 0.2 to 3.1 [+ or -] 0.6 and 2.5 [+ or -] 0.5 mg x [kg.sup.-1] x [min.sup.-1] in the saline and fructose groups, respectively, a change of 1.6 mg x [kg.sup.-1] x [min.sup.-1] in both groups despite a significantly greater liver glycogen level in the fructose-infused group. Likewise, the metabolic fate of the extracted glucose (glycogen, lactate, or carbon dioxide) was not different between groups. These data indicate that an acute physiological increase in the hepatic glycogen content does not alter liver glucose uptake and storage under hyperglycemic/ hyperinsulinemic conditions in the dog. liver glycogen; hyperglycemia; hyperinsulinemia; hepatic insulin signaling

We examined whether intraportal delivery of neuropeptide Y (NPY) affects glucose metabolism in 42-h-fasted conscious dogs using arteriovenous difference methodology. The experimental period was divided into three subperiods (P1, P2, and P3). During all subperiods, the dogs received infusions of somatostatin, intraportal insulin (threefold basal), intraportal glucagon (basal), and peripheral intravenous glucose to increase the hepatic glucose load twofold basal. Following P1, in the NPY group (n = 7), NPY was infused intraportally at 0.2 and 5.1 pmo1*[kg.sup.-1]*[min.sup.-1] during P2 and P3, respectively. The control group (n = 7) received intraportal saline infusion without NPY. There were no significant changes in hepatic blood flow in NPY vs. control. The lower infusion rate of NPY (P2) did not enhance net hepatic glucose uptake. During P3, the increment in net hepatic glucose uptake (compared with P1) was 4 [+ or -] 1 and 10 [+ or -] 2 [micro]mol*[kg.sup.-1]*[min.sup.-1] in control and NPY, respectively (P < 0.05). The increment in net hepatic fractional glucose extraction during P3 was 0.015 [+ or -] 0.005 and 0.039 [+ or -] 0.008 in control and NPY, respectively (P < 0.05). Net hepatic carbon retention was enhanced in NPY vs. control (22 [+ or -] 2 vs. 14 [+ or -] 2 [micro]mol*[kg.sup.-1]*[min.sup.-1], P < 0.05). There were no significant differences between groups in the total glucose infusion rate. Thus, intraportal NPY stimulates net hepatic glucose uptake without significantly altering whole body glucose disposal in dogs. dog; liver; nerves

In this issue of the JCI, Denechaud et al. report studies investigating the role of the liver X receptors (LXRs) LXR[alpha] and LXR[beta] in carbohydrate sensing by the liver (see the related article beginning on page 956). The results of this study, which utilized LXR[alpha]/[beta] double-KO mice, strongly contradict a recent Nature report that proposed that LXR[alpha]/[beta] sense glucose independent of metabolic flux. The reported findings further support a key role for the carbohydrate-responsive element--binding protein (ChREBP) in the regulation of lipogenic genes by glucose and dietary carbohydrates., The liver plays a central and vitally important role in glucose homeostasis by continuously adapting its own metabolism to the availability of nutrients and overall energetic needs of the body. [...]

Effect of stimulation of glucokinase (GK) export from the nucleus by small amounts of sorbitol on hepatic glucose flux in response to elevated plasma glucose was examined in 6-h fasted Zucker diabetic fatty rats at 10 wk of age. Under basal conditions, plasma glucose, insulin, and glucagon were ~8 mM, 2,000 pmol/l, and 60 rig/l, respectively. Endogenous glucose production (EGP) was 44 [+ or -] 4 [micro]mol*[kg.sup.-l]*[min.sup.-1]. When plasma glucose was raised to ~17 raM, GK was still predominantly localized with its inhibitory protein in the nucleus. EGP was not suppressed. When sorbitol was infused at 5.6 and 16.7 [micro]mol*[kg.sup.-l]*[min.sup.-1], along with the increase in plasma glucose, GK was exported to the cytoplasm. EGP (23 [+ or -] 19 and 12 [+ or -] 5 [micro]mol*[kg.sup.-1]*[min.sup.-1]) was suppressed without a decrease in glucose 6-phosphatase flux (145 [+ or -] 23 and 126 [+ or -] 16 vs. 122 [+ or -] 10 [micro]mol*[kg.sup.-l]*[min.sup.-1] without sorbitol) but increased in glucose phosphorylation as indicated by increases in glucose recycling (122 [+ or -] 17 and 114 [+ or -] 19 vs. 71 [+ or -] 11 [micro]mol*[kg.sup.-l]*[min.sup.-1]), glucose-6-phosphate content (254 [+ or -] 32 and 260 [+ or -] 35 vs. 188 [+ or -] 20 nmol/g liver), fractional contribution of plasma glucose to uridine 5'-diphosphateglucose flux (43 [+ or -] 8 and 42 [+ or -] 8 vs. 27 [+ or -] 6%), and glycogen synthesis from plasma glucose (20 [+ or -] 4 and 22 [+ or -] 5 vs. 9 [+ or -] 4 [micro]mol glucose/g liver). The decreased glucose effectiveness to suppress EGP and stimulate hepatic glucose uptake may result from failure of the sugar to activate GK by stimulating the translocation of the enzyme. obese-type 2 diabetes; glucokinase regulatory protein

Pancreatic [alpha]-cells, like [beta]-cells, express ATP-sensitive [K.sup.+] ([K.sub.ATP]) channels. To determine the physiological role of [K.sub.ATP] channels in [alpha]-cells, we examined glucagon secretion in mice lacking the type 1 sulfonylurea receptor (Surl). Plasma glucagon levels, which were increased in wild-type mice after an overnight fast, did not change in Surl null mice. Pancreas perfusion studies showed that Surl null pancreata lacked glucagon secretory responses to hypoglycemia and to synergistic stimulation by arginine. Pancreatic [alpha]-cells isolated from wild-type animals exhibited oscillations of intracellular free [Ca.sup.2+] concentration ([[[Ca.sup.2+]].sub.i]) in the absence of glucose that became quiescent when the glucose concentration was increased. In contrast, Surl null [alpha]-cells showed continuous oscillations in [[[Ca.sup.2+]].sub.i] regardless of the glucose concentration. These findings indicate that [K.sub.ATP] channels in [alpha]-cells play a key role in regulating glucagon secretion, thereby adding to the paradox of how mice that lack [K.sub.ATP] channels maintain euglycemia. pancreatic a-cell; adenosine 5'-triphosphate-sensitive potassium channel; sulfonylurea receptor 1; pancreas perfusion; glucagon

The effect of small amounts of fructose on net hepatic glucose uptake (NHGU) during hyperglycemia was examined in the presence of insulinopenia in conscious 42-h fasted dogs. During the study, somatostatin (0.8 [micro]*g[kg.sup.-1] * [min.sup.-1]) was given along with basal insulin (1.8 pmol*[kg.sup.-1] * [min.sup.-1]) and glucagon (0.5 ng*[kg.sup.-1] * [min.sup.-1]). After a control period, glucose (36.1 [micro]mol*[kg.sup.-l]*[min.sup.-1]) was continuously given intraportally for 4 h with (2.2 [micro]mol*[kg.sup.-l]*[min.sup.-1]) or without fructose. In the fructose group, the sinusoidal blood fructose level (nmol/ml) rose from < 16 to 176 [+ or -] 11. The infusion of glucose alone (the control group) elevated arterial blood glucose ([micro]mol/ml) from 4.3 [+ or -] 0.3 to 11.2 [+ or -] 0.6 during the first 2 h after which it remained at 11.6 [+ or -] 0.8. In the presence of fructose, glucose infusion elevated arterial blood glucose ([micro]mol/ml) from 4.3 [+ or -] 0.2 to 7.4 [+ or -] 0.6 during the first 1 h after which it decreased to 6.1 [+ or -] 0.4 by 180 min. With glucose infusion, net hepatic glucose balance ([micro]mol*[kg.sup.-l]* [min.sup.-1]) switched from output (8.9 [+ or -] 1.7 and 13.3 [+ or -] 2.8) to uptake (12.2 [+ or -] 4.4 and 29.4 [+ or -] 6.7) in the control and fructose groups, respectively. Average NHGU ([micro]mol*[kg.sup.-l] *[min.sup.-1]) and fractional glucose extraction (%) during last 3 h of the test period were higher in the fructose group (30.6 [+ or -] 3.3 and 14.5 [+ or -] 1.4) than in the control group (15.0 [+ or -] 4.4 and 5.9 [+ or -] 1.8). Glucose 6-phosphate and glycogen content ([micro]mol glucose/g) in the liver and glucose incorporation into hepatic glycogen ([micro]mol glucose/g) were higher in the fructose (218 [+ or -] 2, 283 [+ or -] 25, and 109 [+ or -] 26, respectively) than in the control group (80 [+ or -] 8,220 [+ or -] 31, and 41 [+ or -] 5, respectively). In conclusion, small amounts of fructose can markedly reduce hyperglycemia during intraportal glucose infusion by increasing NHGU even when insulin secretion is compromised. diabetes mellitus; hyperglycemia; hyperinsulinemia

In type 2 diabetes mellitus, insulin resistance and an inadequate pancreatic [beta]-cell response to the demands of insulin resistance lead to impaired insulin secretion and hyperglycemia. Pancreatic duodenal homeodomain-1 (PDX-1), a transcription factor required for normal pancreatic development, also plays a key role in normal insulin secretion by islets. To investigate the role of PDX-1 in islet compensation for insulin resistance, we examined glucose disposal, insulin secretion, and islet cell mass in mice of four different genotypes: wild-type mice, mice with one PDX-1 allele inactivated ([PDX-1.sup.+/-], resulting in impaired insulin secretion), mice with one GLUT4 allele inactivated ([GLUT4.sup.+/-], resulting in insulin resistance), and mice heterozygous for both PDX-1 and GLUT4 ([GLUT4.sup.+/-];[PDX-1.sup.+/-]). The combination of PDX-1 and GLUT4 heterozygosity markedly prolonged glucose clearance. [GLUT4.sup.+/-];[PDX-1.sup.+/-] mice developed [beta]-cell hyperplasia but failed to increase their [beta]-cell insulin content. These results indicate that PDX-1 heterozygosity (~60% of normal protein levels) abrogates the [beta]-cell's compensatory response to insulin resistance, impairs glucose homeostasis, and may contribute to the pathogenesis of type 2 diabetes. pancreatic duodenal homeodomain-1; diabetes; pancreatic islets; transcription factors

Hepatic glucose fluxes and intracellular movement of glucokinase (GK) in response to increased plasma glucose and insulin were examined in 10-wk-old, 6-h-fasted, conscious Zucker diabetic fatty (ZDF) rats and lean littermates. Under basal conditions, plasma glucose (mmol/l) and glucose turnover rate (GTR; [micro]mol*[kg.sup.-1]*[min.sup.-1]) were slightly higher in ZDF (8.4 [+ or -] 0.3 and 53 [+ or -] 7, respectively) than in lean rats (6.2 [+ or -] 0.2 and 45 [+ or -] 4, respectively), whereas plasma insulin (pmol/l) was higher in ZDF (1,800 [+ or -] 350) than in lean rats (150 [+ or -] 14). The ratio of hepatic uridine 5'-diphosphate-glucose [sup.3]H specific activity to plasma glucose [sup.3]H specific activity ([[sup.3]H]UDP-G/[[sup.3]H]G; %), total hepatic glucose output ([micro]mol*[kg.sup.-1]*[min.sup.-1]), and hepatic glucose cycling ([micro]mol*[kg.sup.-1]*[min.sup.-1]) were higher in ZDF (35 [+ or -] 5, 87 [+ or -] 16, and 33 [+ or -] 10, respectively) compared with lean rats (18 [+ or -] 3, 56 [+ or -] 6, and 11 [+ or -] 2, respectively). [[sup.3]H]glucose incorporation into glycogen ([micro]mol glucose/g liver) was similar in lean (1.0 [+ or -] 0.7) and ZDF (1.6 [+ or -] 0.8) rats. GK was predominantly located in the nucleus in both rats. With elevated plasma glucose and insulin, GTR ([micro]mol*[kg.sup.-1]*[min.sup.-1]), [[sup.3]H]UDP-G/[[sup.3]H]G (%), and [[sup.3]H]glucose incorporation into glycogen ([micro]mol glucose/g liver) were markedly higher in lean (191 [+ or -] 22, 62 [+ or -] 3, and 5.0 [+ or -] 1.4, respectively) but similar in ZDF rats (100 [+ or -] 6, 37 [+ or -] 3, and 1.4 [+ or -] 0.4, respectively) compared with basal conditions. GK translocation from the nucleus to the cytoplasm occurred in lean but not in ZDF rats. The unresponsiveness of hepatic glucose flux to the rise in plasma glucose and insulin seen in prediabetic ZDF rats was associated with impaired GK translocation. liver; glucose flux; insulin; hyperglycemia

Chu, Chang An, Yuka Fujimoto, Kayano Igawa, Joseph Grimsby, Joseph F. Grippo, Mark A. Magnuson, Alan D. Cherrington, and Masakazu Shiota. Rapid translocation of hepatic glucokinase in response to intraduodenal glucose infusion and changes in plasma glucose and insulin in conscious rats. Am J Physiol Gastrointest Liver Physiol 286: G627-G634, 2004. First published December 4, 2003; 10.1152/ajpgi.00218.2003.--The rate of liver glucokinase (GK) translocation from the nucleus to the cytoplasm in response to intraduodenal glucose infusion and the effect of physiological rises of plasma glucose and/or insulin on GK translocation were examined in 6-h-fasted conscious rats. Intraduodenal glucose infusion (28 [mg.kg.sup.-1.min.sup.-1] after a priming dose at 500 mg/kg) elevated blood glucose levels (mg/dl) in the artery and portal vein from 90 [+ or -] 3 and 87 [+ or -] 3 to 154 [+ or -] 4 and 185 [+ or -] 4, respectively, at 10 min. At 120 min, the levels had decreased to 133 [+ or -] 6 and 156 [+ or -] 5, respectively. Plasma insulin levels (ng/ml) in the artery and the portal vein rose from 0.7 [+ or -] 0.1 and 1.8 [+ or -] 0.3 to 11.8 [+ or -] 1.5 and 20.2 [+ or -] 2.0 at 10 min, respectively, and 12.4 [+ or -] 3.1 and 18.0 [+ or -] 4.8 at 30 min, respectively. GK was rapidly exported from the nucleus as determined by measuring the ratio of the nuclear to the cytoplasmic immunofluorescence (N/C) of GK (2.9 [+ or -] 0.3 at 0 rain to 1.7 [+ or -] 0.2 at 10 min, 1.5 [+ or -] 0.1 at 20 min, 1.3 [+ or -] 0.1 at 30 min, and 1.3 [+ or -] 0.1 at 120 min). When plasma glucose (arterial; mg/dl) and insulin (arterial; ng/ml) levels were clamped for 30 min at 93 [+ or -] 7 and 0.7 [+ or -] 0.1, 81 [+ or -] 5 and 8.9 [+ or -] 1.3, 175 [+ or -] 5 and 0.7 [+ or -] 0.1, or 162 [+ or -] 5 and 9.2 [+ or -] 1.5, the N/C of GK was 3.0 [+ or -] 0.5, 1.8 [+ or -] 0.1, 1.5 [+ or -] 0.1, and 1.2 [+ or -] 0.1, respectively. The N/C of GK regulatory protein (GKRP) did not change in response to the intraduodenal glucose infusion or the rise in plasma glucose and/or insulin levels. The results suggest that GK but not GKRP translocates rapidly in a manner that corresponds with changes in the hepatic glucose balance in response to glucose ingestion in vivo. Additionally, the translocation of GK is induced by the postprandial rise in plasma glucose and insulin. glucokinase regulatory protein

Lipid infusion or ingestion of a high-fat diet results in insulin resistance, but the mechanism underlying this phenomenon remains unclear. Here we show that, in rats fed a high-fat diet, whole-animal, muscle and liver insulin resistance is ameliorated following hepatic overexpression of malonyl-coenzyme A (CoA) decarboxylase (MCD), an enzyme that affects lipid partitioning. MCD overexpression decreased circulating free fatty acid (FFA) and liver triglyceride content. In skeletal muscle, levels of triglyceride and long-chain acyl-CoA (LC-CoA)--two candidate mediators of insulin resistance--were either increased or unchanged. Metabolic profiling of 36 acylcarnitine species by tandem mass spectrometry revealed a unique decrease in the concentration of one lipid-derived metabolite, [beta]-OH-butyrate, in muscle of MCD-overexpressing animals. The best explanation for our findings is that hepatic expression of MCD lowered circulating FFA levels, which led to lowering of muscle [beta]-OH-butyrate levels and improvement of insulin sensitivity., Author(s): Jie An [1]; Deborah M Muoio [1]; Masakazu Shiota [2]; Yuka Fujimoto [2]; Gary W Cline [3]; Gerald I Shulman [3]; Timothy R Koves [1]; Robert Stevens [1]; David [...]

Arteriovenous difference and tracer ([3-[sup.3]H]glucose) techniques were used in 42-h-fasted conscious dogs to identify any insulin-like effects of intraportally administered glucagonlike peptide 1-(7-36)amide (GLP-1). Each study consisted of an equilibration, a basal, and three 90-min test periods (P1, P2, and P3) during which somatostatin, intraportal insulin (3-fold basal) and glucagon (basal), and peripheral glucose were infused. Saline was infused intraportally in P1. During P2 and P3, GLP-1 was infused intraportally at 0.9 and 5.1 pmol*[kg.sup.-1]* [min.sup.-1] in eight dogs, at 10 and 20 pmol*[kg.sup.-1]*[min.sup.-1] in seven dogs, and at 0 pmol*[kg.sup.-1]*[min.sup.-1] in eight dogs (control group). Net hepatic glucose uptake was significantly enhanced during GLP-1 infusion at 20 pmol*[kg.sup.-1]*[min.sup.-1] [21.8 vs. 13.4 [micro]mol* [kg.sup.-1]*[min.sup.-1] (control), P < 0.05]. Glucose utilization was significantly increased during infusion at 10 and 20 pmol*[kg.sup.-1] [min.sup.-1] [87.3 [+ or -] 8.3 and 105.3 [+ or -] 12.8, respectively, vs. 62.2 [+ or -] 5.3 and 74.7 [+ or -] 7.4 [micro]mol*[kg.sup.-1]*[min.sup.-1] (control), P < 0.05]. The glucose infusion rate required to maintain hyperglycemia was increased (P < 0.05) during infusion of GLP-1 at 5.1, 10, and 20 pmol*[kg.sup.-1]*[min.sup.-1] (22, 36, and 32%, respectively, greater than control). Nonhepatic glucose uptake increased significantly during delivery of GLP-1 at 5.1 and 10 pmol*[kg.sup.-1]*[min.sup.-1] (25 and 46% greater than control) and tended (P = 0.1) to increase during GLP-1 infusion at 20 pmol*[kg.sup.-1]*[min.sup.-1] (24% greater than control). Intraportal infusion of GLP-1 at high physiological and pharmacological rates increased glucose disposal primarily in nonhepatic tissues. incretin; net hepatic glucose uptake; muscle glucose uptake; blood glucose