Chronic Administration of the Glucagon-Like Peptide-1 Analog, Liraglutide, Delays the Onset of Diabetes and Lowers Triglycerides in UCD-T2DM Rats

ObjectiveThe efficacy of liraglutide, a human glucagon-like peptide-1 (GLP-1) analog, to prevent or delay diabetes in UCD-T2DM rats, a model of polygenic obese type 2 diabetes, was investigated.Research design and methodsAt 2 months of age, male rats were divided into three groups: control, food-restricted, and liraglutide. Animals received liraglutide (0.2 mg/kg s.c.) or vehicle injections twice daily. Restricted rats were food restricted to equalize body weights to liraglutide-treated rats. Half of the animals were followed until diabetes onset, whereas the other half of the animals were killed at 6.5 months of age for tissue collection.ResultsBefore diabetes onset energy intake, body weight, adiposity, and liver triglyceride content were higher in control animals compared with restricted and liraglutide-treated rats. Energy-restricted animals had lower food intake than liraglutide-treated animals to maintain the same body weights, suggesting that liraglutide increases energy expenditure. Liraglutide treatment delayed diabetes onset by 4.1 ± 0.8 months compared with control (P < 0.0001) and by 1.3 ± 0.8 months compared with restricted animals (P < 0.05). Up to 6 months of age, energy restriction and liraglutide treatment lowered fasting plasma glucose and A1C concentrations compared with control animals. In contrast, liraglutide-treated animals exhibited lower fasting plasma insulin, glucagon, and triglycerides compared with both control and restricted animals. Furthermore, energy-restricted and liraglutide-treated animals exhibited more normal islet morphology.ConclusionsLiraglutide treatment delays the development of diabetes in UCD-T2DM rats by reducing energy intake and body weight, and by improving insulin sensitivity, improving lipid profiles, and maintaining islet morphology

Influence of Lactose on the Maillard Reaction and Dehydroalanine-Mediated Protein Cross-Linking in Casein and Whey

A liquid chromatography–mass spectrometry method based on multiple reaction monitoring (MRM) was developed for the simultaneous quantification of markers representing two potentially competing pathways, the Maillard reaction and the dehydroalanine pathway. The two pathways involve the same residues in the proteins to some extent, namely, the essential amino acid lysine, as well as free-amino terminals available on proteins and polypeptides, competition between the two pathways in food systems may occur. The developed method comprises the following markers of the Maillard reaction: furosine, N-ε-(carboxyethyl)lysine (CEL) and N-ε-(carboxymethyl)lysine (CML), together with the dehydroalanine reaction pathway markers; lanthionine (LAN) and lysinoalanine (LAL), as well as lysine itself. The validated method was then used for the absolute quantification of heat-induced protein modifications in model systems of micellar casein and whey protein isolates (MCI and WPI, respectively) in the presence or absence of lactose. As expected, the Maillard reaction markers furosine, CEL and CML increased during the applied heat treatment in the presence of lactose, whereas the dehydroalanine markers, LAN and LAL increased with heating in both MCI and WPI, both in the presence and absence of lactose, although at lower levels in the presence of lactose, confirming the competing state of the two pathways

Glucagon-like peptide-1 receptor expression in Xenopus oocytes stimulates inositol trisphosphate-dependent intracellular Ca2+ mobilization

AbstractThe signal transduction pathway of the cloned human glucagon-like peptide-1 (GLP-1) receptor was studied in voltage-clamped Xenopus oocytes. Binding of GLP-1(7–36)amide was associated with cAMP production, increased [Ca2+]i and activation of Ca2+-dependent Cl− current. The effect of GLP-1(7–36)amide reflects intracellular Ca2+ mobilization and was suppressed by injection of the Ca2+ chelator BAPTA and the inositol trisphosphate receptor antagonist heparin. The responses were not mimicked by the adenylate cyclase activator forskolin and unaffected by the protein kinase A (PKA) inhibitor Rp-cAMPS. We conclude that GLP-1 receptor expression in Xenopus oocytes evokes inositol trisphosphate-dependent intracellular Ca2+ mobilization independent of the cAMP/PKA signaling pathway

Growth hormone treatment does not augment the anti-diabetic effects of liraglutide in UCD-T2DM rats.

IntroductionThe incretin hormone glucagon-like peptide-1 (GLP-1) slows gastric emptying, increases satiety and enhances insulin secretion. GLP-1 receptor agonists, such as liraglutide, are used therapeutically in humans to improve glycaemic control and delay the onset of type 2 diabetes mellitus (T2DM). In UCD-T2DM rats, a model of polygenic obesity and insulin resistance, we have previously reported that daily liraglutide administration delayed diabetes onset by >4 months. Growth hormone (GH) may exert anti-diabetic effects, including increasing β-cell mass and insulin secretion, while disrupting GH signalling in mice reduces both the size and number of pancreatic islets. We therefore hypothesized that GH supplementation would augment liraglutide's anti-diabetic effects.MethodsMale UCD-T2DM rats were treated daily with GH (0.3 mg/kg) and/or liraglutide (0.2 mg/kg) from 2 months of age. Control (vehicle) and food-restricted (with food intake matched to liraglutide-treated rats) groups were also studied. The effects of treatment on diabetes onset and weight gain were assessed, as well as measures of glucose tolerance, lipids and islet morphology.ResultsLiraglutide treatment significantly reduced food intake and body weight and improved glucose tolerance and insulin sensitivity, relative to controls. After 4.5 months, none of the liraglutide-treated rats had developed T2DM (overall p = .019). Liraglutide-treated rats also displayed lower fasting triglyceride (TG) concentrations and lower hepatic TG content, compared to control rats. Islet morphology was improved in liraglutide-treated rats, with significantly increased pancreatic insulin content (p < .05 vs. controls). Although GH treatment tended to increase body weight (and gastrocnemius muscle weight), there were no obvious effects on diabetes onset or other diabetes-related outcomes.ConclusionGH supplementation did not augment the anti-diabetic effects of liraglutide