Intraperitoneal Insulin Administration Research Articles

Abstract 12104: Treatment With Exogenous Atrial Natriuretic Peptide Ameliorates Myocardial Insulin Resistance and Protects Against Ischemia-Reperfusion Injury in Diet-Induced Obesity

Increasing evidence suggests natriuretic peptide (NP) coordinate inter-organ metabolic crosstalk in addition to its classical actions on hemodynamic regulation. We recently reported exogenous atrial NP (ANP) treatment ameliorated systemic insulin resistance by inducing adipose tissue browning and by attenuating hepatic steatosis in diet-induced obesity. We herein hypothesized that exogenous ANP treatment also ameliorates insulin resistance of the myocardium in which endogenous NP is produced, leading to the cardioprotection during ischemia-reperfusion injury (IRI) in diet-induced obesity. The mice fed a high fat diet (HFD) or normal fat diet (NFD) for 13 weeks were treated with or without ANP infusion subcutaneously via osmotic pump for another 3 weeks (0.5 μg/kg/min). Intraperitoneal administration of insulin induced Akt phosphorylation in NFD hearts, which was reduced in HFD. ANP treatment restored the impaired insulin-induced Akt phosphorylation in HFD hearts, suggesting that exogenous ANP ameliorated myocardial insulin resistance. To test the functional significance of this, hearts were exposed to IRI using Langendorff model. After IRI, HFD resulted in an impaired left ventricular developed pressure (LVDP) recovery with corresponding increase in infarct size. However, ANP treatment improved functional recovery and reduced injury along with restoration of the impaired IRI-induced Akt phosphorylation in HFD hearts. (% LVDP recovery of baseline: NFD 62.9%±3.6 <n=8>, NFD+ANP 64.5%±4.2% <n=8>, HFD 20.8%±3.3 <n=9>, HFD+ANP 31.4%±2.8% <n=9>, p<0.05) Myocardial ultrastructural analyses by electron microscopy showed number of peri-mitochondrial lipid droplets was increased in HFD treated with ANP, suggesting that ANP protects mitochondria from lipid overload. Of note, ANP treatment substantially attenuated mitochondria cristae disruption after IRI in HFD hearts. In conclusion, exogenous ANP treatment ameliorates myocardial insulin resistance and protects against IRI associated with restoration of disrupted mitochondrial structure in diet-induced obesity. The findings that exogenous NP has significant impact on the NP-rich failing myocardium provide new insight into the biological properties and dynamics of NP.

Modeling Intraperitoneal Insulin Absorption in Patients with Type 1 Diabetes.

Standard insulin therapy to treat type 1 diabetes (T1D) consists of exogenous insulin administration through the subcutaneous (SC) tissue. Despite recent advances in insulin formulations, the SC route still suffers from delays and large inter/intra-subject variability that limiting optimal glucose control. Intraperitoneal (IP) insulin administration, despite its higher invasiveness, was shown to represent a valid alternative to the SC one. To date, no mathematical model describing the absorption and distribution of insulin after IP administration is available. Here, we aim to fill this gap by using data from eight patients with T1D, treated by implanted IP pump, studied in a hospitalized setting, with frequent measurements of plasma insulin and glucose concentration. A battery of models describing insulin kinetics after IP administration were tested. Model comparison and selection were performed based on model ability to predict the data, precision of parameters and parsimony criteria. The selected model assumed that the insulin absorption from the IP space was described by a linear, two-compartment model, coupled with a two-compartment model of whole-body insulin kinetics with hepatic insulin extraction controlled by hepatic insulin. Future developments include model incorporation into the UVa/Padova T1D Simulator for testing open- and closed-loop therapies with IP insulin administration.

Intraperitoneal insulin administration in pigs: effect on circulating insulin and glucose levels

IntroductionThe effect of intraperitoneal insulin infusion has limited evidence in the literature. Therefore, the aim of the study was to investigate the pharmacokinetics and pharmacodynamics of different intraperitoneal insulin boluses....

Regulation of glucose and lipid metabolism by insulin and glucagon in vivo and in vitro in common carp Cyprinus carpio L.

Our objective is to study the low metabolic utilization of dietary carbohydrates in fish. The regulation of key enzymes involved in glucose and lipid metabolism in the common carp (Cyprinus carpio L.), known to be relatively tolerant to dietary carbohydrates, were assessed. We performed intraperitoneal (i.p.) administration of insulin and glucagon to common carp and also subjected common carp primary hepatocytes to insulin or glucagon. The results showed that insulin administration induced hypoglycaemia through up-regulation of the expression of the glycolysis genes glucokinase (GK) and hexose kinase (HK), coupled with increased gene expression of fatty acid synthase (FAS), acetyl-CoA carboxylase-1 (ACC-1), sterol-regulator element-binding protein-1 (SREBP-1). Insulin also limited the expression of the gluconeogenesis genes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), coupled with decreased gene expression of lipoprotein lipase (LPL) and carnitine palmitoyl transferase I (CPT-1). However, glucagon had the opposite effect. The results showed that glucagon induced hyperglycemia with increased expression of PEPCK and G6Pase and increased lipolytic capacity as indicated by lower mRNA levels of SREBP-1. Glucagon (i.p.) significantly increased the activity of PEPCK and LPL in hepatopancreas. In addition, the mRNA expression of HK showed an up-regulated trend and the mRNA expression of PEPCK and G6Pase showed a down-regulated trend in the group of glucose (i.p.). This study demonstrates that insulin and glucagon possess the intrinsic ability to regulate hepatic energy metabolism in common carp, the regulation of which seems to be similar to that of the mammals at least at the molecular level.

Effect of acute insulin therapy on the concentration of vascular endothelial growth factor A (VEGF-A) in the intraocular fluid in an experiment

To study the effect of insulin therapy on the concentration of vascular endothelial growth factor A (VEGF-A) in the intraocular fluid of rats with alloxan model of diabetes mellitus. The experiment was conducted on 80 mongrel rats. In 65 rats, the alloxan model of diabetes mellitus was simulated by a single intraperitoneal injection of 100 mg/kg alloxan hydrate saluted in 0.4 ml of citrate buffer. 72 hours after intraperitoneal administration of alloxan monohydrate, these animals were divided into 2 groups. The main group (group 1) consisted of animals with alloxan model of diabetes mellitus, who started daily single intraperitoneal administration of prolonged-acting insulin at a therapeutic dose of 0.9 U/kg Body weight. The comparison group (group 2) consisted of animals with alloxan model of diabetes mellitus who did not receive specific therapy. 15 healthy rats constituted the control group (group 3). Experimental animals were removed from the study on day 31 of insulin therapy. The concentration of VEGF-A was determined in 80-90 μl of intraocular fluid collected from both eyes of each animal. In the main group, the median of VEGF-A concentration [25th; 75th percentiles] in the intraocular fluid was 140 [136; 210] pg/ml, which is 1.94 times higher than in the comparison group (72 [58; 86] pg/ml) and 1.84 times higher than in the control group (76 [62.5; 88] pg/ml). The concentration of VEGF-A in the intraocular fluid in the main group was statistically significantly higher, as compared with the comparison group (pm-u<0.0004), and compared with the control group (pm-u=0.0045). The comparison group had no statistically significant differences when compared with the control group (pm-u=0.9979). Insulin therapy for 31 days increases the concentration of VEGF-A in the intraocular fluid of rats with alloxan model of diabetes mellitus.

Advantages and feasibility of intraperitoneal insulin delivery

Under normal conditions, insulin secreted by the pancreas enters the liver through the portal vein, forming a difference in insulin concentration above the peripheral circulation. Subcutaneous administration of insulin forms a portal-peripheral concentration gradient of insulin above the liver, which is inconsistent with normal physiological conditions. Intraperitoneal insulin administration has been extensively investigated because that is closer to physiological state. In this paper, the pharmacokinetic and pharmacodynamic studies of insulin intraperitoneal administration were reviewed. Compared with the conventional subcutaneous delivery, intraperitoneal insulin administration can not only reduce the incidence of hypoglycemia, but also has the advantage of correcting abnormal lipid metabolism. This means that intraperitoneal administration of insulin has a positive effect on the prevention and treatment of diabetic complications. Therefore, it is necessary and feasible to develop a safe, low-cost, and easy-to-use percutaneous intraperitoneal insulin delivery device. Key words: Insulin; Intraperitoneal delivery; Lipid metabolism; Diabetes

Liver-Specific Overexpression of Gamma-Glutamyltransferase Ameliorates Insulin Sensitivity of Male C57BL/6 Mice.

In the current study, we developed a liver-specific GGT-overexpressing mice model by rapid injection pLIVE-GGT vector through tail vein and investigated the effects of GGT elevation on glucose metabolism and insulin sensitivity. The serum GGT activity was significantly increased after 7 days of pLIVE-GGT1 vector delivery and lasted for about 3 weeks. GGT overexpression reduced the levels of GSSG and GSH in the liver and serum and had no effects on total antioxidative capacity in the liver, kidney, and skeletal muscle except for the pancreas. Increased GGT activity had no effect on the glucose tolerance but could facilitate blood glucose lowering after intraperitoneal insulin administration. The results of Western blotting showed that increased GGT activity enhanced insulin-induced AKT phosphorylation at Ser473. Furthermore, GGT inhibitor could attenuate the changes of insulin-induced blood glucose uptake and AKT phosphorylation in the liver. In summary, the present study developed a liver-specific GGT-overexpressing mice model and found that GGT elevation in short term had no effects on glucose metabolism but could increase insulin sensitivity through enhancing the activity of insulin signaling pathway.

Phylogenesis and Biological Characterization of a New Glucose Transporter in the Chicken (Gallus gallus), GLUT12.

In mammals, insulin-sensitive GLUTs, including GLUT4, are recruited to the plasma membrane of adipose and muscle tissues in response to insulin. The GLUT4 gene is absent from the chicken genome, and no functional insulin-sensitive GLUTs have been characterized in chicken tissues to date. A nucleotide sequence is predicted to encode a chicken GLUT12 ortholog and, interestingly, GLUT12 has been described to act as an insulin-sensitive GLUT in mammals. It encodes a 596 amino acid protein exhibiting 71% identity with human GLUT12. First, we present the results of a phylogenetic study showing the stability of this gene during evolution of vertebrates. Second, tissue distribution of chicken SLC2A12 mRNA was characterized by RT-PCR. It was predominantly expressed in skeletal muscle and heart. Protein distribution was analysed by Western blotting using an anti-human GLUT12 antibody directed against a highly conserved region (87% of identity). An immuno-reactive band of the expected size (75kDa) was detected in the same tissues. Third a physiological characterization was performed: SLC2A12 mRNA levels were significantly lowered in fed chickens subjected to insulin immuno-neutralization. Finally, recruitment of immuno-reactive GLUT12 to the muscle plasma membrane was increased following 1h of intraperitoneal insulin administration (compared to a control fasted state). Thus insulin administration elicited membrane GLUT12 recruitment. In conclusion, these results suggest that the facilitative glucose transporter protein GLUT12 could act in chicken muscle as an insulin-sensitive transporter that is qualitatively similar to GLUT4 in mammals.

After 6 years of intraperitoneal insulin administration IGF-I concentrations in T1DM patients are at low-normal level

ObjectiveLow concentrations of insulin-like growth factor-I (IGFI) have been reported in type 1 diabetes mellitus (T1DM), suggested to be due to low insulin concentrations in the portal vein. The aim was to describe the long-term course of IGFI concentrations among T1DM subjects treated with continuous intraperitoneal (IP) insulin infusion (CIPII). DesignNineteen patients that participated in a randomized cross-over trial comparing CIPII and subcutaneous (SC) insulin therapy in 2006 were followed until 2012. IGF-I measurements were performed at the start of the 2006 study, after the 6month SC- and CIPII treatment phase in 2006 and during CIPII therapy in 2012. Z-scores were calculated to compare the IGF-I concentrations with age-specific normative range values of a non-DM reference population. ResultsIn 2012, IGF-I Z-scores (−0.7; 95% confidence interval −1.3, −0.2) were significantly higher than at the start of the 2006 study (−2.5; −3.3, −1.8), the end of the SC (−2.0; −2.6, −1.5) and CIPII (−1.6; −2.1, −1.0) treatment phase with a mean difference of: 1.8 (0.9, 2.7), 1.3 (0.5, 2.1) and 0.8 (0.1, 1.6), respectively. ConclusionAfter 6years of treatment with CIPII, IGF-I concentrations among T1DM patients increased to a level that is higher than during prior SC insulin treatment and is in the lower normal range compared to a non-DM reference population. The results of this study suggest that long-term IP insulin administration influences the IGF system in T1DM.

Development of a Transgenic Mouse Model to Study the Immunogenicity of Recombinant Human Insulin

Mouse models are commonly used to assess the immunogenicity of therapeutic proteins and to investigate the immunological processes leading to antidrug antibodies. The aim of this work was to develop a transgenic (TG) Balb/c mouse model for evaluating the immunogenicity of recombinant human insulin (insulin) formulations. Validation of the model was performed by measuring the antibody response against plain and particulate insulin in TG and nontransgenic (NTG) mice. Intraperitoneal administration of insulin (20 μg/dose, 12 doses over a period of 4 weeks) did not break the immune tolerance of the TG mice, whereas it did elicit antibodies in NTG mice. The immune tolerance of TG mice could be circumvented, albeit at low titers, by administering insulin covalently bound to 50-nm polystyrene nanoparticles. The TG mouse model was employed to compare the immunogenicity of oxidized aggregated insulin, oxidized nonaggregated insulin, and three commercially available formulations of insulin variants (i.e., Levemir®, Insulatard®, and Actrapid®). Oxidized insulin, aggregated or nonaggregated, was moderately immunogenic in TG mice (50% and 33% responders, respectively), whereas the immunogenicity of the commercial formulations was low. This model can be used to compare the immunogenicity of insulin formulations and to study immune mechanisms of antibody formation against insulin.

Intraperitoneal insulin delivery to patients with type 1 diabetes results in higher serum IGF‐I bioactivity than continuous subcutaneous insulin infusion

Type 1 diabetes (T1D) is associated with low IGF-I and altered levels of IGF-binding proteins (IGFBPs) in plasma. This may be of importance for insulin sensitivity and the risk of developing diabetic complications. We hypothesized that IGF-I bioactivity is affected by the route of insulin administration and that continuous intraperitoneal insulin infusion (CIPII) has a more pronounced effect than continuous subcutaneous insulin infusion (CSII). We compared 10 patients with T1D on CIPII with 20 age- and sex-matched patients on CSII. Blood sampling was carried out 7-9 am after an overnight fast. All patients were C-peptide negative. IGF-I bioactivity was measured in vitro using a specific IGF-I kinase receptor activation (KIRA) assay. IGF-I was also measured by immunoassay together with IGF-II, IGFBP-1 and IGFBP-2. When compared with subcutaneous insulin, intraperitoneal insulin resulted in (CIPII vs CSII) higher IGF-I bioactivity (1·83 ± 0·76 vs 1·16 ± 0·24 μg/l; P = 0·02), IGF-I (120 ± 35 vs 81 ± 19 μg/l; P = 0·01) and IGF-II (1050 ± 136 vs 879 ± 110 μg/l; P = 0·02). By contrast, log-transformed IGFBP-1 was reduced (P = 0·013), whereas log-transformed IGFBP-2 was not different (P = 0·12). There was a positive correlation between IGF bioactivity and IGF-I (r = 0·69; P < 0·001) and an inverse correlation between IGF-I bioactivity and log10 IGFBP-1 (r = -0·68, P < 0·001). The in vitro IGF-I bioactivity was higher in patients treated with CIPII compared with CSII supporting the theory that the route of insulin administration is of importance for the activity of the IGF system. Intraperitoneal insulin administration may therefore be beneficial by correcting the alterations of the IGF system in T1D.

Differential effects of insulin induced hypoglycaemia upon redox balance in distinct rat brain areas

Insulin induced hypoglycaemia does not generate uniform injuries throughout the brain. We hypothesized that redox balance in different brain regions might respond diversely to hypoglycaemia and aimed to test it in the rat brain model. Blood glucose level, malondialdehyde (MDA), protein carbonyl (PC) adducts and superoxide dismutase (Cu2+-Zn2+- SOD) activity in tissue homogenates of the cortex, cerebellum, basal ganglia and brain stem of rat brain (n = 12) were assayed 2 h after intraperitoneal administration of insulin in subcomatous dosage (6.0 IU/Kg diluted in normal saline) against matched controls (n = 8) that received the vehicle only (10 ml/kg). The cortex, cerebellum, basal ganglia and brain stem areas showed significantly higher mean values for MDA and PC products with lower mean Cu2+-Zn2+-SOD activity in the insulin administered hypoglycaemic rats (p < 0.001). Blood glucose level prevailed to be the chief predictor for the intracellular antioxidant status in all areas of the rat brain as evident from the multiple linear regression study. Post hoc ANOVA confirmed that oxidative stress markers were highest in the basal ganglia region compared to other brain areas (p < 0.001 for both MDA and PC products). Results indicated that hypoglycaemia induced impairment in redox balance were most damaging in the basal ganglia and least in the brain stem and cerebellum. We propose that similar mechanisms may contribute to distinctive neurological complications due to hypoglycaemia in human beings after receiving toxic dosage of insulin or intensive insulin therapy for a substantial period.

Effects of subcutaneous and intraperitoneal administration of insulin to KK mice's oxygen free radicals metaholism

Objective To observe the subcutaneous and intraperitoneal insulin injection's effect of the level of oxygen free radicals of type 2 diabetes model.Methods C57BL/6J mice were chosen as normal control group (C group,n=9).KK mice were randomly divided into intraperitoneal injection of insulin group (i.p.group,n=9),the subcutaneous insulin group (s.c.group,n=9) and untreated group (U group,n =9).The i.p.group and the s.c.groups were given certain amount of insulin (insulin injecta and protamine insulin injecta by volume ratio of 2:1 mixture)for one month,maintained the GLU at normal levels (6±1.5) mmol/L.SOD,GSH-PX activity and MDA content of serum,liver,kidney and heart in each group were detected.Results The liver,kidney,heart and serum's SOD and GSH-PX activity significantly reduced and MDA content significantly increased in the U group.Both kinds of delivery methods could increase serum SOD and GSH-PX activity and reduce the content of MDA to the normal control group level,but the intraperitoneal injection had stronger effect.Two kinds of delivery methods could both reduce the MDA content of liver,and had almost the same effect; but the subcutaneous injection group had better effect on increasing the liver's SOD activity,and the intraperitoneal injection had better effect on increasing liver's GSH-PX activity.Intraperitoneal injection had better effect on reducing kidney' s MDA content and increased SOD activity.Two kinds of delivery methods had the same effect on reducing the heart's MDA content.Conclusion The two delivery methods can both make the MDA levels of KK mice in serum,heart,liver and kidney fall to as normal as that of control group,but the two delivery methods have different ways of improving the antioxidant capacity in different organs.Intraperitoneal injection can reduce MDA content in serum and kidney better. Key words: Diabetes; Insulin; Oxygen free radicals

Coexistence of insulin resistance and increased glucose tolerance in pregnant rats: A physiological mechanism for glucose maintenance

AimThe contribution of insulin resistance (IR) and glucose tolerance to the maintenance of blood glucose levels in non diabetic pregnant Wistar rats (PWR) was investigated. Main methodsPWR were submitted to conventional insulin tolerance test (ITT) and glucose tolerance test (GTT) using blood sample collected 0, 10 and 60min after intraperitoneal insulin (1U/kg) or oral (gavage) glucose (1g/kg) administration. Moreover, ITT, GTT and the kinetics of glucose concentration changes in the fed and fasted states were evaluated with a real-time continuous glucose monitoring system (RT-CGMS) technique. Furthermore, the contribution of the liver glucose production was investigated. Key findingsConventional ITT and GTT at 0, 7, 14 and 20days of pregnancy revealed increased IR and glucose tolerance after 20days of pregnancy. Thus, this period of pregnancy was used to investigate the kinetics of glucose changes with the RT-CGMS technique. PWR (day 20) exhibited a lower (p<0.05) glucose concentration in the fed state. In addition, we observed IR and increased glucose tolerance in the fed state (PWR-day 20 vs. day 0). Furthermore, our data from glycogenolysis and gluconeogenesis suggested that the liver glucose production did not contribute to these changes in insulin sensitivity and/or glucose tolerance during late pregnancy. SignificanceIn contrast to the general view that IR is a pathological process associated with gestational diabetes, a certain degree of IR may represent an important physiological mechanism for blood glucose maintenance during fasting.

Advances in pump technology: insulin patch pumps, combined pumps and glucose sensors, and implanted pumps

This review discusses the most recent developments in insulin pump technology. The benefits of the insulin pump to patients with type 1 diabetes are recognized both for its metabolic effectiveness and its positive effects on quality of life. The current pumps are reliable, small and light, and are becoming more and more sophisticated. Nevertheless, there remain practical and psychological constraints for the patient. However, recent patch-pump advances should simplify the technical aspects of pump treatment and enhance patient comfort. Another advance combines the insulin pump with a glucose sensor. Such a combination is logical for optimizing pump use and, to that end, developing an automated or 'closed-loop'system that permits the delivery of subcutaneous insulin adjusted according to measured levels of subcutaneous glucose. Finally, implanted insulin pumps have proven their worth not only because of their simple use, but also for their contribution in the artificial pancreas project. Indeed, the prompt response with intraperitoneal administration of insulin makes it of interest for use in a closed-loop system.

Neonatal exposure to leptin reduces glucose tolerance in adult mice

The aim of this study was to evaluate the effect of leptin treatment in mouse neonates on glucose metabolism in adulthood. Leptin was administered subcutaneously to normally nourished neonates, from 5.5 to 10.5 days of age, to mimic the premature surge observed in neonates undernourished in utero. At 15-16 weeks of age, we measured blood glucose or insulin levels after the intraperitoneal administration of glucose or insulin. After the intraperitoneal administration of glucose, the levels of blood glucose, but not insulin, in adult mice that received the neonatal leptin treatment were significantly higher than that of those which received vehicle control. After the intraperitoneal administration of insulin, the levels of blood glucose in adult mice that underwent neonatal leptin treatment were significantly higher than that of those which received vehicle control. These findings suggest that the premature leptin surge plays an essential role, as a programming signal during the early neonatal period, as well as in the developmental origins of impaired insulin sensitivity.

Imaging appearance of severe subcapsular hepatic steatosis: mimicking hepatic embolic infarcts

We report a case of severe subcapsular hepatic steatosis in a middle-aged woman with diabetic nephropathy requiring continuous ambulatory peritoneal dialysis (CAPD). The CT appearances of the liver were initially suspected to be due to embolic infarcts. However, an accurate diagnosis was made only after a history of intraperitoneal insulin administration was elicited, and this was confirmed on MRI with chemical shift gradient-echo pulse sequences. Haemodialysis was recommenced, and follow-up imaging 4 years later showed complete resolution of subcapsular hepatic steatosis.

Food intake of infant rats after intraperitoneal administration of insulin.

The effects of intraperitoneal insulin on the food intake have been determined in infant rats up to weaning. It was found that intraperitoneal (IP) insulin reduced the milk intake of 13 and 17 day-old pups for three hours after treatment. In 5, 9 and 24 day-old pups the food intake was not significantly changed after IP insulin administration. Only in 28 day-old rat pups IP insulin induced an increase of food intake. Since subcutaneously (SC) administered insulin gave rise to short-term hyperphagia in 24 day-old rat pups we assessed the effects of SC versus IP insulin on the blood glucose level. Blood glucose was lower 3 hours after SC administration compared to the IP route. Results indicate that IP insulin causes a short lasting hypoglycaemia and consequently IP insulin increases food intake only after the 28th day of life.

Insulin regulates the expression of several metabolism-related genes in the liver and primary hepatocytes of rainbow trout (Oncorhynchus mykiss)

Rainbow trout have a limited ability to use dietary carbohydrates efficiently and are considered to be glucose intolerant. Administration of carbohydrates results in persistent hyperglycemia and impairs post-prandial down regulation of gluconeogenesis despite normal insulin secretion. Since gluconeogenic genes are mainly under insulin control, we put forward the hypothesis that the transcriptional function of insulin as a whole may be impaired in the trout liver. In order to test this hypothesis, we performed intraperitoneal administration of bovine insulin to fasted rainbow trout and also subjected rainbow trout primary hepatocytes to insulin and/or glucose stimulation. We demonstrate that insulin was able to activate Akt, a key element in the insulin signaling pathway, and to regulate hepatic metabolism-related target genes both in vivo and in vitro. In the same way as in mammals, insulin decreased mRNA expression of gluconeogenic genes, including glucose 6-phosphatase (G6Pase), fructose 1,6-bisphosphatase (FBPase) and phosphoenolpyruvate carboxykinase (PEPCK). Insulin also limited the expression of carnitine palmitoyltransferase 1 (CPT1), a limiting enzyme of fatty acid beta-oxidation. In vitro studies revealed that, as in mammals, glucose is an important regulator of some insulin target genes such as the glycolytic enzyme pyruvate kinase (PK) and the lipogenic enzyme fatty acid synthase (FAS). Interestingly, glucose also stimulates expression of glucokinase (GK), which has no equivalent in mammals. This study demonstrates that insulin possesses the intrinsic ability to regulate hepatic gene expression in rainbow trout, suggesting that other hormonal or metabolic factors may counteract some of the post-prandial actions of insulin.

Metabolic effects of sub-chronic ablation of the incretin receptors by daily administration of (Pro3)GIP and exendin(9–39)amide in obese diabetic (ob/ob) mice

Effects of chemical ablation of the GIP and GLP-1 receptors on metabolic aspects of obesity-diabetes were investigated using the stable receptor antagonists (Pro3)GIP and exendin(9-39)amide. Ob/ob mice received a daily i.p. injection of saline vehicle, (Pro3)GIP, exendin(9-39)amide or a combination of both peptides over a 14-day period. Non-fasting plasma glucose levels were significantly (p<0.05) lower in (Pro3)GIP-treated mice compared to control mice after just 9 days of treatment. (Pro3)GIP-treated mice also displayed significantly lower plasma glucose concentrations in response to feeding and intraperitoneal administration of either glucose or insulin (p<0.05 to p<0.001). The (Pro3)GIP-treated group also exhibited significantly (p<0.05) reduced pancreatic insulin content. Acute administration of exendin(9-39)amide immediately prior to re-feeding completely annulled the beneficial effects of sub-chronic (Pro3)GIP treatment, but non-fasting concentrations of active GLP-1 were unchanged. Combined sub-chronic administration of (Pro3GIP) with exendin(9-39)amide revealed no beneficial effects. Similarly, daily administration of exendin(9-39)amide alone had no significant effects on any of the metabolic parameters measured. These studies highlight an important role for GIP in obesity-related forms of diabetes, suggesting the possible involvement of GLP-1 in the beneficial actions of GIP receptor antagonism.