Characterizing the induction of diabetes in juvenile cynomolgus monkeys with different doses of streptozotocin

Abstract

Juvenile (23 years old) cynomolgus monkeys are frequently used as recipients in non-human primate islet transplantation studies. The aim of this study was to examine the effects of different doses of streptozotocin (STZ), and find the optimal dose for inducing diabetes in these monkeys. Fifteen juvenile (23 years old) cynomolgus monkeys were separated into three groups and administered with different doses of STZ (100, 68 or 60 mg kg 1 ). Basal and glucose-stimulated blood glucose, insulin, and C-peptide levels, as well as body weights were monitored. Hepatic and renal function tests and pancreatic immunohistochemistry were performed before and after STZ treatment. Monkeys treated with both 100 and 68 mg kg 1 of STZ exhibited continuous hyperglycemia, which coincided with a nearly complete loss of islet -cells. Two monkeys received 60 mg kg 1 of STZ, but only one became completely diabetic. During the first week following STZ treatment, hepatic and renal function slightly increased in these three groups. However, 24 hours post-STZ, serum total bile acid levels were significantly increased in monkeys treated with 100 mg kg 1 than those treated with 68 mg kg 1 of STZ (P<0.05). These data suggest that 100 mg kg 1 and 68 mg kg 1 of STZ can safely induce diabetes in cynomolgus monkeys aged 23 years, but 68 mg kg 1 of STZ, rather than 100 mg kg 1 of STZ, may be more appropriate for inducing diabetes in these monkeys. Furthermore, body surface area, rather than body weight, was a more reliable determinant of dosage, where 700 mg m 2 of STZ should be the lower limit for inducing diabetes in juvenile monkeys. cynomolgus monkeys, diabetes, streptozotocinCitation:

Dynamic Changes of Betatrophin and Its Potential Effect on β-cells in Spontaneously Developed or Streptozocin-induced Diabetes Monkeys

“…Therefore, in order to investigate the dynamic changes of betatrophin and β-cells, a STZ-induced diabetes model was conducted in rhesus monkeys ( Table 2). Seven of eight normoglycemic rhesus monkeys were administered with 35 mg/ kg STZ, because one study showed that monkeys treated with both 100 and 68 mg/kg of STZ exhibited continuous hyperglycemia, which coincided with a nearly complete loss of islet β-cells [28]. In order to preserve some β-cells, a relatively low dose of STZ was thus applied in our study.…”

“…It has been known that diabetic pancreas pathophysiology differs in rodents from in humans greatly, but nonhuman primates (NHPs) are more close to humans [25][26][27]. Numerous studies have used spontaneously developed or streptozocin (STZ)-induced diabetic monkeys to investigate diabetes progression and therapy [28][29][30][31][32].…”

Liken Ekstrelerinin Sağlıklı Ratlar Üzerindeki Etkileri ve Bu Ekstrelerin Diyabete Bağlı Çoklu Organ Yetmezliğinin Önlenmesinde Medikal Kullanımı

“…Additionally, the insulin-induced the weight loss was observed after induction of STZ into the animals in present investigation. Animals treated with STZ exhibite continuous hyperglycemia, which coincided with a nearly complete loss of islet β-cells [44,45] Two explanations for weight loss may be presented; firstly, due to polyuria and dehydration the body weight may be declined and, secondly, as the blood glucose level is high there is possibility of muscle breakdown in hyperglycemic rats [46] . Only, the treatment with the C. islandica enhanced pancreas function by improving glucose tolerance and increasing β-cell insulin reserve in rats.…”

Nonhuman Primate Models of Type 1 Diabetes Mellitus for Islet Transplantation

“…Higher doses of STZ (80–150 mg/kg body weight) were found to be effective and sufficient [13, 81, 84, 87, 91–93] but were associated with more systemic side effects (e.g., transient vomiting, severe hypoglycemia) and serious complications (e.g., hepatic and renal function/tissue injury), as well as higher morbidity and mortality (approximately 28.6%–100%) [69, 87, 92–94]. Koulmanda et al [78], Tal et al [95], Dufrane et al [94], and Zou et al [96] demonstrated that STZ dose of 50–70 mg/kg could induce stable IDDM in all macaques for up to 0.5–1 y without any evidence of regeneration of β -cell, as well as liver and kidney toxicity. On the contrary, Theriault and colleagues reported the safe and consistent induction of IDDM with a single high-dose of STZ (150 mg/kg body weight) in young cynomolgus monkeys (6–8-month-old).…”

“…Moreover, Wijkstrom et al [87] recommended that the STZ dose should depend on body surface area (BSA) (1250 mg/m 2 ) rather than body weight (BW). Zou et al [96] further demonstrated that a dose > 760 mg/m 2 of STZ might reliably induce IDDM in juvenile cynomolgus monkeys (2-3-year-old), whereas a dose < 700 mg/m 2 was not effective. One reason for these discrepancies is that the β -cells of younger monkeys may be more resistant to the toxic effect of STZ than that of older ones, and this may account for the varying SZT dosages to induce DM.…”