u-0126 and Diabetes-Mellitus--Type-1

Type 1 diabetic animal models, generated by injecting streptozotocin (STZ), have been widely used in research. We previously reported that juvenile-onset diabetes mellitus (JDM) rats, which were prepared by administering STZ to 17-day-old rats, developed cognitive impairments and hippocampal synaptic plasticity deficiencies, which were restored by glucagon-like peptide-1 (GLP-1). GLP-1 and GLP-2 are simultaneously derived from proglucagon and act through their own specific receptors. The present study was performed to investigate the potential of GLP-2 in JDM rats. The results obtained demonstrated that GLP-2 restored impairments in spatial working memory and hippocampal long-term depression (LTD) in JDM rats, and that the MEK1/2 inhibitor, U0126, inhibited this recovery. Therefore, GLP-2 has potential in the treatment of cognitive deficits in childhood-onset diabetes.

Topics: Animals; Behavior, Animal; Butadienes; Cognitive Dysfunction; Diabetes Complications; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Glucagon-Like Peptide 2; Hippocampus; Long-Term Synaptic Depression; MAP Kinase Signaling System; Memory, Short-Term; Nitriles; Protein Kinase Inhibitors; Rats; Rats, Wistar; Spatial Memory

The onset of diabetic neuropathy, a complication of diabetes mellitus, has been linked to poor glycemic control. We tested the hypothesis that the mitogen-activated protein kinases (MAPK) form transducers for the damaging effects of high glucose. In cultures of adult rat sensory neurons, high glucose activated JNK and p38 MAPK but did not result in cell damage. However, oxidative stress activated ERK and p38 MAPKs and resulted in cellular damage. In the dorsal root ganglia of streptozotocin-induced diabetic rats (a model of type I diabetes), ERK and p38 were activated at 8 wk duration, followed by activation of JNK at 12 wk duration. We report activation of JNK and increases in total levels of p38 and JNK in sural nerve of type I and II diabetic patients. These data implicate MAPKs in the etiology of diabetic neuropathy both via direct effects of glucose and via glucose-induced oxidative stress.

Topics: Animals; Butadienes; Cell Survival; Cells, Cultured; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Ganglia, Spinal; Glucose; Humans; Hydrogen Peroxide; Imidazoles; JNK Mitogen-Activated Protein Kinases; Male; MAP Kinase Kinase 4; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Neurons, Afferent; Nitriles; p38 Mitogen-Activated Protein Kinases; Pyridines; Rats; Rats, Wistar; Sural Nerve