title: Direct effects of glucose, insulin, GLP-1, and GIP on bulbospinal neurons in the rostral ventrolateral medulla in neonatal wistar rats.
abstract: Although patients with diabetes mellitus (DM) often exhibit hypertension, the mechanisms responsible for this correlation are not well known. We hypothesized that the bulbospinal neurons in the rostral ventrolateral medulla (RVLM) are affected by the levels of glucose, insulin, or incretins (glucagon like peptide-1 [GLP-1] or glucose-dependent insulinotropic peptide [GIP]) in patients with DM. To investigate whether RVLM neurons are activated by glucose, insulin, GLP-1, or GIP, we examined changes in the membrane potentials of bulbospinal RVLM neurons using whole-cell patch-clamp technique during superfusion with various levels of glucose or these hormones in neonatal Wistar rats. A brainstem-spinal cord preparation was used for the experiments. A low level of glucose stimulated bulbospinal RVLM neurons. During insulin superfusion, almost all the RVLM neurons were depolarized, while during GLP-1 or GIP superfusion, almost all the RVLM neurons were hyperpolarized. Next, histological examinations were performed to examine transporters for glucose and receptors for insulin, GLP-1, and GIP on RVLM neurons. Low-level glucose-depolarized RVLM neurons exhibited the presence of glucose transporter 3 (GLUT3). Meanwhile, insulin-depolarized, GLP-1-hyperpolarized, and GIP-hyperpolarized RVLM neurons showed each of the respective specific receptor. These results indicate that a low level of glucose stimulates bulbospinal RVLM neurons via specific transporters on these neurons, inducing hypertension. Furthermore, an increase in insulin or a reduction in incretins may also activate the sympathetic nervous system and induce hypertension by activating RVLM neurons via their own receptors.
authors.affiliation: Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Saitama, Japan. Electronic address: oshima@ndmc.ac.jp.
authors.forename: Naoki
authors.initials: N
authors.lastname: Oshima
authors.affiliation: Department of Physiology, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Onimaru
authors.affiliation: Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Hidehito
authors.initials: H
authors.lastname: Matsubara
authors.affiliation: Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Uchida
authors.affiliation: Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Imakiire
authors.affiliation: Department of Physiology, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nishida
authors.affiliation: Department of Nephrology and Endocrinology, National Defense Medical College, Tokorozawa, Saitama, Japan.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Kumagai
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002491:Central Nervous System Agents / Q000008:administration & dosage; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism*; D051274:Glucose Transporter Type 3 / Q000378:metabolism; D006946:Hyperinsulinism / Q000378:metabolism / Q000473:pathology; D007003:Hypoglycemia / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000008:administration & dosage / Q000378:metabolism*; D008526:Medulla Oblongata / Q000166:cytology / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000008:administration & dosage; D010455:Peptides / Q000008:administration & dosage; D017208:Rats, Wistar; D013779:Tetrodotoxin / Q000008:administration & dosage; D046509:Tissue Culture Techniques
chemical_list: D002491:Central Nervous System Agents; D051274:Glucose Transporter Type 3; D007328:Insulin; D010446:Peptide Fragments; D010455:Peptides; C532752:S961 peptide; C495690:Slc2a3 protein, rat; D013779:Tetrodotoxin; C083773:exendin (9-39); D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D005947:Glucose
keywords: GIP; GLP-1; RVLM neurons; glucose; hypertension; insulin