Altered Pituitary Growth Hormone (GH) Regulation in Streptozotocin-Diabetic Rats: A Combined Defect of Hypothalamic Somatostatin and GH-Releasing Factor*

Abstract

Diabetes mellitus in the rat is associated with loss of pulsatile GH secretion. An interplay between hypothalamic GH-releasing factor (GRF) and inhibitory factor [somatostatin (SRIF)] secretion is thought to account for episodic pituitary GH release. An increase in SRIF tone/action or a decrease in GRF release/response in diabetic rats could account for the suppressed GH levels. Pituitaries from streptozotocin-diabetic rats contained less GH than controls (15.9 +/- 2.5 vs. 29.5 +/- 4.6 micrograms/mg; P less than 0.05) despite normal somatotrope representation, as demonstrated using immunofluorescence studies. Basal GH secretion from monolayer culture of dispersed anterior pituitary (AP) cells from diabetic rats was proportionately decreased (150 +/- 10 vs. 103 +/- 10 ng/10(5) cells; P less than 0.005). GRF (10(-11)-10(-8) M)-induced release of GH from AP cells was decreased in diabetic rats (maximum response to 10(-8) M GRF, 401 +/- 60 vs. 618 +/- 41 ng/10(5) cells; P less than 0.01); however, sensitivity to GRF was unchanged (EC50, 79 +/- 41 vs. 128 +/- 67 pM). By contrast, SRIF (10(-7)-10(-10)-induced inhibition of GRF (10(-8) M)-mediated GH release was impaired in AP cells of diabetic rats compared to that in controls (IC50, 112 +/- 33 vs. 55 +/- 31 pM; P less than 0.05) associated with a decrease in AP plasma membrane SRIF receptor concentration (63.4 +/- 15.6 vs. 160.3 +/- 13.7 fmol/mg protein; P less than 0.05), with no change in affinity. These findings are consistent with chronic exposure to increased hypothalamic SRIF influence. GH synthesis has been shown to be independent of SRIF regulation; however, insulin-like growth factor-I and GRF inhibit and stimulate GH synthesis, respectively. In diabetic rats insulin-like growth factor-I levels were decreased, appropriate to low GH status, in serum (290 +/- 66 vs. 1662 +/- 92 ng/ml; P less than 0.001) and hypothalamus (6.8 +/- 1.0 vs. 13.0 +/- 0.4 pg/mg wet wt; P less than 0.001) and, thus, did not seem to account for the low AP GH content. Hypothalamic GRF content in diabetic rats (1.11 +/- 0.10 ng/hypothalamus) did not differ from that in controls (1.16 +/- 0.17 ng/hypothalamus). GRF mRNA levels, however, were reduced by 80% in diabetic rats compared to controls. Taken together these data support a combined role for decreased hypothalamic GRF and increased SRIF in mediating alterations of GH synthesis and secretion in streptozotocin-induced diabetes.

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

“…HI STZ treatment resulted in hyperglycemia, hypoinsulinemia and significant weight loss ( 27·4%), consistent with previous reports (Busiguina et al 2000b, Marks et al 1993, Olchovsky et al 1990; Fig. 1).…”

“…HI STZ-induced insulinopenia is typically associated with rapid weight loss, due to a decrease in fat stores, leading to a fall in circulating leptin (Havel et al 1998, Sindelar et al 1999 and a compensatory rise in hypothalamic neuropeptide Y (NPY), an orexigenic signal (Ishii et al 2002, Marks et al 1993, White et al 1990. In rats (Sprague-Dawley and Wistar), these metabolic changes have been associated with suppression of the growth hormone (GH) axis, which includes a decrease in hypothalamic GH-releasing hormone (GHRH) and pituitary GH mRNA levels and a reduction in pulsatile GH release, and mean circulating insulin-like growth factor (IGF)-I levels (Busiguina et al 2000b, Olchovsky et al 1990. Despite these changes, the pituitary of the HI STZ-treated rat is more sensitive to the stimulatory actions of GHRH (Sheppard et al 1989a(Sheppard et al , 1989b and GH secretagogue (GHS) receptor (GHS-R) agonists (ipamorelin; Johansen et al 2003) and less sensitive to the inhibitory actions of somatostatin (SRIH; Bruno et al 1994, Sheppard et al 1989b.…”

Differential effects of casein versus whey on fasting plasma levels of insulin, IGF-1 and IGF-1/IGFBP-3: results from a randomized 7-day supplementation study in prepubertal boys

“…This might be indicative of the fact that an association between adiposity and insulin resistance exists even among nonobese, healthy children, as seen in other studies (Hoppe et al, 2004a). In addition, the fact that fasting insulin and IGF-1 were closely correlated might be explained by the relative hyperinsulinemia, as some data suggest that insulin stimulates the hepatic IGF-1 production in young subjects with T1DM (Amiel et al, 1984) in diabetic rats (Olchovsky et al, 1990) and in rat hepatocytes (Johnson et al, 1989). Also, in short-statured normal 9-year-old children, IGF-1 and IGFBP-3 were associated with insulin resistance (Bleicher et al, 2002).…”

High intakes of milk, but not meat, increase s-insulin and insulin resistance in 8-year-old boys

“…Some data suggest that insulin stimulates the hepatic IGF-I production in young subjects with type I diabetes (Amiel et al, 1984), in diabetic rats (Olchovsky et al, 1990) and in rat hepatocytes (Johnson et al, 1989), whereas plasma concentration of IGF-I decreased slightly during an intravenous glucose tolerance test (Nyomba et al, 1997). Also, in short-statured normal 9-yold children, IGF-I and IGFBP-3 were associated with insulin resistance, as calculated by HOMA (Bleicher et al, 2002).…”