Differential responses of the growth hormone axis in two rat models of streptozotocin-induced insulinopenic diabetes

Abstract

The impact of streptozotocin (STZ)-induced, insulinopenic diabetes on the GH axis of rats and mice differs from study to study, where this variation may be related to the induction scheme, severity of the diabetes and/or the genetic background of the animal model used. In order to begin differentiate between these possibilities, we compared the effects of two different STZ induction schemes on the GH axis of male Sprague-Dawley rats: (1) a single high-dose injection of STZ (HI STZ, 80 mg/kg, i.p.), which results in rapid chemical destruction of the pancreatic -cells, and (2) multiple low-dose injections of STZ (LO STZ, 20 mg/kg for 5 consecutive days, i.p.), which results in a gradual, autoimmune destruction of -cells. STZ-treated animals were killed after 3 weeks of hyperglycemia (>400 mg/dl), and in both paradigms circulating insulin levels were reduced to <40% of vehicle-treated controls. HI STZ-treated rats lost weight, while body weights of LO STZ-treated animals gradually increased over time, similar to vehicle-treated controls. As previously reported, HI STZ resulted in a decrease in circulating GH and IGF-I levels which was associated with a rise in hypothalamic neuropeptide Y (NPY) mRNA (355% of vehicle-treated controls) and a fall in GH-releasing hormone (GHRH) mRNA (45% of vehicle-treated controls) levels. Changes in hypothalamic neuropeptide expression were reflected by an increase in immunoreactive NPY within the arcuate and paraventricular nuclei and a decrease in GHRH immunoreactivity in the arcuate nucleus, as assessed by immunohistochemistry. Consistent with the decline in circulating GH and hypothalamic GHRH, pituitary GH mRNA levels of HI STZ-treated rats were 58% of controls. However, pituitary receptor mRNA levels for GHRH and ghrelin increased and those for somatostatin (sst2, sst3 and sst5) decreased following HI STZ treatment. The impact of LO STZ treatment on the GH axis differed from that observed following HI STZ treatment, despite comparable changes in circulating glucose and insulin. Specifically, LO STZ treatment did suppress circulating IGF-I levels to the same extent as HI STZ treatment; however, the impact on hypothalamic NPY mRNA levels was less dramatic (158% of vehicle-treated controls) where NPY immunoreactivity was increased only within the paraventricular nucleus. Also, there were no changes in circulating GH, hypothalamic GHRH or pituitary receptor expression following LO STZ treatment, with the exception that pituitary sst3 mRNA levels were suppressed compared with vehicle-treated controls. Taken together these results clearly demonstrate that insulinopenia, hyperglycemia and reduced circulating IGF-I levels are not the primary mediators of hypothalamic and pituitary changes in the GH axis of rats following HI STZ treatment. Changes in the GH axis of HI STZ-treated rats were accompanied by weight loss, and these changes are strikingly similar to those observed in the fasted rat, which suggests that factors associated with the catabolic state are critical in modify...

Ileal apical Na+-dependent bile acid transporter ASBT is upregulated in rats with diabetes mellitus induced by low doses of streptozotocin

“…To avoid confounding toxicity inflicted by the high dose of STZ, we used the recently described model of inducing diabetes mellitus with multiple injections of low doses of STZ (21). Our findings demonstrated an increase in ASBT function and expression in the distal ileum of diabetic rats.…”

“…STZ is an antibiotic that destroys ␤-cells in the pancreas, causing insulinopenia, hyperglycemia, and a disease process similar to type 1 diabetes mellitus (23,37). Conventionally, diabetes mellitus in rats is induced by a single intraperitoneal injection of a high dose of STZ (60 -80 mg/kg body wt) (21,37). A high dose of STZ, however, has been shown to cause rapid and severe weight loss with other toxic effects influencing gastric motility and the function of gastrointestinal neuroendocrine cells (5,21).…”

“…Conventionally, diabetes mellitus in rats is induced by a single intraperitoneal injection of a high dose of STZ (60 -80 mg/kg body wt) (21,37). A high dose of STZ, however, has been shown to cause rapid and severe weight loss with other toxic effects influencing gastric motility and the function of gastrointestinal neuroendocrine cells (5,21). Therefore, observations pertaining to the gastrointestinal tract obtained from the high-dose model of STZ-induced diabetes mellitus should be interpreted with caution.…”

“…Recent studies, however, indicated that high toxicity and severe weight loss caused by the high dose of STZ might confound the results obtained from this model (21). An alternative approach that uses multiple injections of low doses of STZ (20 mg/kg body wt) has been shown to be equally effective and less toxic (21). To investigate alterations in ASBT expression in diabetes mellitus, we used the rat model with multiple low doses of STZ.…”

“…previously reported weight loss caused by the high-dose model (21). To further characterize the model of diabetes mellitus induced by multiple low doses of STZ, we measured the levels of plasma cholesterol in control and experimental rats.…”