Senescence marker protein-30/gluconolactonase deletion worsens glucose tolerance through impairment of acute insulin secretion.
Senescence marker protein-30 (SMP30) is an androgen-independent factor that decreases with age. We recently identified SMP30 as the lactone-hydrolyzing enzyme gluconolactonase (GNL), which is involved in vitamin C biosynthesis in animal species. To examine whether the age-related decrease in SMP30/GNL has effects on glucose homeostasis, we used SMP30/GNL knockout (KO) mice treated with L-ascorbic acid. In an ip glucose tolerance test at 15 wk of age, blood glucose levels in SMP30/GNL KO mice were significantly increased by 25% at 30 min after glucose administration compared with wild-type (WT) mice. Insulin levels in SMP30/GNL KO mice were significantly decreased by 37% at 30 min after glucose compared with WT mice. Interestingly, an insulin tolerance test showed a greater glucose-lowering effect in SMP30/GNL KO mice. High-fat diet feeding severely worsened glucose tolerance in both WT and SMP30/GNL KO mice. Morphometric analysis revealed no differences in the degree of high-fat diet-induced compensatory increase in beta-cell mass and proliferation. In the static incubation study of islets, insulin secretion in response to 20 mm glucose or KCl was significantly decreased in SMP30/GNL KO mice. On the other hand, islet ATP content at 20 mm in SMP30/GNL KO mice was similar to that in WT mice. Collectively, these data indicate that impairment of the early phase of insulin secretion due to dysfunction of the distal portion of the secretion pathway underlies glucose intolerance in SMP30/GNL KO mice. Decreased SMP30/GNL may contribute to the worsening of glucose tolerance that occurs in normal aging.
Hasegawa
Goji
G
Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine Graduate School of Medical Science, 465 Kajii-cho, Hirokoji, Kawaramachi-dori, Kamikyo-ku, Kyoto 602-8566, Japan. goji@koto.kpu-m.ac.jp
Yamasaki
Masahiro
M
Kadono
Mayuko
M
Tanaka
Muhei
M
Asano
Mai
M
Senmaru
Takafumi
T
Kondo
Yoshitaka
Y
Fukui
Michiaki
M
Obayashi
Hiroshi
H
Maruyama
Naoki
N
Nakamura
Naoto
N
Ishigami
Akihito
A
D000273:Adipose Tissue / Q000187:drug effects / Q000502:physiology; D000375:Aging / Q000235:genetics / Q000502:physiology; D000821:Animal Feed; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000172:deficiency*; D002265:Carboxylic Ester Hydrolases / Q000172:deficiency* / Q000235:genetics*; D002455:Cell Division / Q000187:drug effects; D004822:Epididymis / Q000033:anatomy & histology; D005951:Glucose Tolerance Test; D007328:Insulin / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D000078790:Insulin Secretion; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency*; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D008168:Lung / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011650:Pulmonary Alveoli / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015430:Weight Gain; D019014:fas Receptor / Q000494:pharmacology
D001786:Blood Glucose; D002135:Calcium-Binding Proteins; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; C513324:Rgn protein, mouse; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D002265:Carboxylic Ester Hydrolases; C020579:gluconolactonase