インスリン非依存型糖尿病合併高血圧モデルの開発

Streptozotocin (STZ) treatment on neonatal rats produces a non-insulin-dependent diabetes mellitus (NIDDM) model in adulthood. Applying this model to spontaneously hypertensive rats (SHR), we designed the present study to develop a new model of NIDDM with genetic hypertension. Two-day-old male and female SHR were intraperitoneally injected with 25. 0-75. Omg/kg STZ, and two-day-old Wistar Kyoto rats (WKY) of both sexes, which are a normotensive control strain for SHR, were similarly injected with 75. 0-150. Omg/kg STZ. Control rats received vehicle alone. The relationships between the doses of the STZ injected and the changes of the metabolic variable and blood pressure were examined for 12 weeks following the treatment. Plasma glucose levels in male SHR increased in a dose-dependent manner at 12 weeks, control 122±8(SEM) mg/ di, 25. Omg/kg STZ 139±13mg/dl (ns), 37. 5mg/kg STZ 240±5lmg/dl (ns), 50. Omg/kg STZ 359±39mg/dl (p<0.01), 62.5mg/kg STZ 419±33mg/dl(p<0.001) and 75. Omg/kg STZ 513±lOmg/dl(p<0.001), whereas in male WKY, only mild hyperglycemia developed in case of the higher doses of STZ given, control 112±4mg/dl,75.0mg/kg STZ 136±18mg/ di (ns), 100.0mg/kg STZ 204エ40mg/dl (ns), 125. Omg/kg STZ 219エ37mg/dl(p<0.05), and 150. Omg/kg STZ 177±12mg/dl(p<O.01). The development of hypertension was not affected by the neonatal STZ treatment in male SHR at 11 weeks, systolic blood pressure being control 210± 7mmHg, 25.0mg/kg STZ 217±5mmHg(ns), 37. 5mg/kg STZ 202±3mmHg(ns), 50. Omg/kg STZ 216±6mmHg(ns), 62. 5mg/kg STZ 210±6mmHg(ns), and 75. Omg/kg STZ 209±5mmHg(ns). / For the long-term observation, STZ-treated male SHR were divided into mild diabetes group (plasma glucose at 12 weeks<300mg/dl, mean 195±21mg/dl)and severe diabetes group(≧300mg/dl, mean 445±18mg/dl). Hyperglycemia in both groups was maintained until 28 weeks, plasma glucose being control 112±4mg/dl,mild diabetes group 161±lOmg/dl(p<0.01), and severe diabetes group 419±25mg/dl(p<O.001) but it later gradually ameliorated, plasma glucose at 52 weeks being control 120±3mg/dl,mild diabetes group 131±7mg/dl(ns), and severe diabetes group 220±43mg/dl (ns). However, hypertension persisted in both diabetes groups until 52 weeks, systolic blood pressure being control 209±6mmHg,mild diabetes group 199±9mmHg (ns), and severe diabetes group 221±6mmHg(ns)．Urinary protein excretion in the severe diabetes group was increased at 12 weeks as compared with the other two groups, control 21.5± 1. 7mg/ day, mild diabetes group 21. 9±2. Omg/ day (ns), and severe diabetes group 34. 5±4.0mg/ day (p < 0. 01), and its difference became larger at 28 weeks, control 15. 3±2.3mg/day,mild diabetes group 19.5±2.4mg/ day (ns), and severe diabetes group 50. 7±12.8mg/ day (p < 0. 001). Thereafter, however, urinary protein excretion was rapidly increased in both control and mild diabetes groups and did not significantly differ among the three groups at 52 weeks, control 64. 2±10.6mg/day,mild diabetes group 95.7±20.Omg/ day (ns), and severe diabetes group 103.1±20. 8mg/ day (ns). Histologically, the glomerular lesion was accelerated in the severe diabetes group at 24 weeks as compared with the control, whereas this difference was not apparent at 52 weeks. Insulinoma was found in 57% of the mild diabetes group, and tumors other than insulinoma were evident in the liver and kidney in 29% of the mild diabetes group and 50% of the severe diabetes group. Neonatally STZ-treated SHR may be a useful model for studying early renal complications caused by the combination of hyperglycemia and hypertension.