Fundamental Research in Oncology and Thrombosis 2 (FRONTLINE 2): A Follow-Up Survey
Ajay K. KakkarRupert BauersachsAnna FalangaJohn WongGloria KayaniAlex KahneyRodney HughesMark N. Levine
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Fundamental Research in Oncology and Thrombosis (FRONTLINE) is a global survey of physicians' perceptions and practice in the management of venous thromboembolism (VTE) in patients with cancer.To study the influence of different blood glucose (BG) concentrations on the release of pituitary hormones, the effect of the simultaneous iv administration of LRH (200 micrograms), TRH (400 micrograms), and arginine (30 g/30 min) upon the serum concentrations of LH, FSH, TSH, PRL, and GH was determined in six male insulin-dependent diabetics. BG concentration was clamped by feedback control and an automated glucose-controlled insulin infusion system at euglycemic (BG 4-5 mmol/liter) or hyperglycemic (BG, 14-18 mmol/liter) levels. Increments in serum concentrations of LH, FSH, TSH, and PRL were similar in the euglycemic and hyperglycemic steady states, whereas the GH response to arginine was suppressed during the hyperglycemic clamp (P less than 0.01). Omission of exogenous insulin during hyperglycemia did not modify the observed hormonal responses. Thus, the release of LH, FSH, TSH, and PRL in response to adequate acute stimuli at the pituitary level is not modulated by hyperglycemia in insulin-dependent diabetes, while arginine-induced GH release is suppressed. Since the effect of arginine on GH is most likely mediated by an action on the hypothalamus, the data suggest that elevated glucose concentrations may exert their modulatory influence on GH secretion at the hypothalamic rather than at the pituitary level.
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Corticosterone (CORT) and other glucocorticoids cause peripheral insulin resistance and compensatory increases in β-cell mass. A prolonged high-fat diet (HFD) induces insulin resistance and impairs β-cell insulin secretion. This study examined islet adaptive capacity in rats treated with CORT and a HFD. Male Sprague-Dawley rats (age ∼6 weeks) were given exogenous CORT (400 mg/rat) or wax (placebo) implants and placed on a HFD (60% calories from fat) or standard diet (SD) for 2 weeks (N = 10 per group). CORT-HFD rats developed fasting hyperglycemia (>11 mM) and hyperinsulinemia (∼5-fold higher than controls) and were 15-fold more insulin resistant than placebo-SD rats by the end of ∼2 weeks (Homeostatic Model Assessment for Insulin Resistance [HOMA-IR] levels, 15.08 ± 1.64 vs 1.0 ± 0.12, P < .05). Pancreatic β-cell function, as measured by HOMA-β, was lower in the CORT-HFD group as compared to the CORT-SD group (1.64 ± 0.22 vs 3.72 ± 0.64, P < .001) as well as acute insulin response (0.25 ± 0.22 vs 1.68 ± 0.41, P < .05). Moreover, β- and α-cell mass were 2.6- and 1.6-fold higher, respectively, in CORT-HFD animals compared to controls (both P < .05). CORT treatment increased p-protein kinase C-α content in SD but not HFD-fed rats, suggesting that a HFD may lower insulin secretory capacity via impaired glucose sensing. Isolated islets from CORT-HFD animals secreted more insulin in both low and high glucose conditions; however, total insulin content was relatively depleted after glucose challenge. Thus, CORT and HFD, synergistically not independently, act to promote severe insulin resistance, which overwhelms islet adaptive capacity, thereby resulting in overt hyperglycemia.
Hyperinsulinemia
Corticosterone
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The effect of 48 h of fasting in C57B1/6J-ob/ob and +/+ mice on body weight (BW), blood glucose (BG), serum immunreactive insulin (IRI), plasma immunoreactive glucagon (IRG) and on tissue levels of cyclic adenosine monophosphate (cAMP) were studied. Both groups of mice lost weight and demonstrated a decrease in BG and IRI with fasting. However, the BG and IRI of the ob/ob animals were initially highter and remained higher than those of the 2% of their initial weight while the +/+ lost 14 %. The +/+ mice exhibited an increase in cAMP levels in skeletal muscle, fat and liver with fasting, while the ob/ob mice had increased levels of cAMP in fat, but not in muscle. They also had a paradoxical decrease in liver cAMP levels with fasting, and associated with this was the lack of stimulation of glycogenolysis. Glycogenolysis was significant in the livers of fasted +/+ mice. The plasma IRG levels of the fed ob/ob mice were significantly higher (1.8) times) than those of the fed +/+ mice. Islet cAMP levels were decreased with fasting in ob/ob mice. However, the levels were significantly higher in 48-h faster ob/ob mice compared to the fasted +/+ group. The apparent paradoxical response to fasting observed in the livers of the ob/ob mice remains unexplained.
Glycogenolysis
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Cortistatin (CORT) shares high structural and functional similarities with somatostatin (SST) but displays unique sex-dependent pituitary actions. Indeed, although female CORT-knockout (CORT-KO) mice exhibit enhanced GH expression/secretion, Proopiomelanocortin expression, and circulating ACTH/corticosterone/ghrelin levels, male CORT-KO mice only display increased plasma GH/corticosterone levels. Changes in peripheral ghrelin and SST (rather than hypothalamic levels) seem to regulate GH/ACTH axes in CORT-KOs under fed conditions. Because changes in GH/ACTH axes during fasting provide important adaptive mechanisms, we sought to determine whether CORT absence influences GH/ACTH axes during fasting. Accordingly, fed and fasted male/female CORT-KO were compared with littermate controls. Fasting increased circulating GH levels in male/female controls but not in CORT-KO, suggesting that CORT can be a relevant regulator of GH secretion during fasting. However, GH levels were already higher in CORT-KO than in controls in fed state, which might preclude a further elevation in GH levels. Interestingly, although fasting-induced pituitary GH expression was elevated in both male/female controls, GH expression only increased in fasted female CORT-KOs, likely owing to specific changes observed in key factors controlling somatotrope responsiveness (ie, circulating ghrelin and IGF-1, and pituitary GHRH and ghrelin receptor expression). Fasting increased corticosterone levels in control and, most prominently, in CORT-KO mice, which might be associated with a desensitization to SST signaling and to an augmentation in CRH and ghrelin-signaling regulating corticotrope function. Altogether, these results provide compelling evidence that CORT plays a key, sex-dependent role in the regulation of the GH/ACTH axes in response to fasting.
Corticosterone
Proopiomelanocortin
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Bilateral destruction of the hypothalamic paraventricular nuclei (PVN) produced a profound depression of plasma TSH and the median eminence TRH concentration in hypothyroid rats. Anterior pituitary type II iodothyronine 5′- deiodinase (5′-D) activity was consistently lower but not significantly different in sham- and PVN-lesioned rats. Treatment with suboptimal replacement doses of 0.15 and 0.75 ng T4/100 g BW-day produced a graded depression of plasma TSH in the PVN (P < 0.02), but not in the sham (P > 0.8) groups. Adenohypophyseal 5′-D was depressed in both sham and PVN groups by the highest T4 dose. Plasma T4 was much lower in PVN than in sham rats given comparable doses of T4 (P < 0.001), but plasma T3 was not significantly different. This suggests that an increase in peripheral T4 metabolism was produced by PVN lesions. Our data indicate that changes in adenohypophyseal 5′- D activity are not responsible for the decrease in plasma TSH in PVN-lesioned rats and that neither the PVN nor endogenous TRH plays a significant role in the regulation of anterior pituitary 5′-D activity. (Endocrinology123: 1676–1681, 1988)
Median eminence
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Abstract Dysregulation of the adipoinsular axis in male obese Zucker diabetic fatty (ZDF; fa/fa) rats, a model of type 2 diabetes, results in chronic hyperinsulinemia and increased de novo lipogenesis in islets, leading to β-cell failure and diabetes. Diazoxide (DZ; 150 mg/kg·d), an inhibitor of insulin secretion, was administered to prediabetic ZDF animals for 8 wk as a strategy for prevention of diabetes. DZ reduced food intake (P < 0.02) and rate of weight gain only in ZDF rats (P < 0.01). Plasma insulin response to glucose load was attenuated in DZ-Zucker lean rats (ZL; P < 0.01), whereas DZ-ZDF had higher insulin response to glucose than controls (P < 0.001). DZ improved hemoglobin A1c (P < 0.001) and glucose tolerance in ZDF (P < 0.001), but deteriorated hemoglobin A1c in ZL rats (P < 0.02) despite normal tolerance in the fasted state. DZ lowered plasma leptin (P < 0.001), free fatty acid, and triglyceride (P < 0.001) levels, but increased adiponectin levels (P < 0.02) only in ZDF rats. DZ enhanced β3-adrenoreceptor mRNA (P < 0.005) and adenylate cyclase activity (P < 0.01) in adipose tissue from ZDF rats only, whereas it enhanced islet β3- adrenergic receptor mRNA (P < 0.005) but paradoxically decreased islet adenylate cyclase activity (P < 0.005) in these animals. Islet fatty acid synthase mRNA (P < 0.03), acyl coenzyme A carboxylase mRNA (P < 0.01), uncoupling protein-2 mRNA (P < 0.01), and triglyceride content (P < 0.005) were only decreased in DZ-ZDF rats, whereas islet insulin mRNA and insulin content were increased in DZ-ZDF (P < 0.01) and DZ-ZL rats (P < 0.03). DZ-induced β-cell rest improved the lipid profile, enhanced the metabolic efficiency of insulin, and prevented β-cell dysfunction and diabetes in diabetes-prone animals. This therapeutic strategy may be beneficial in preventing β-cell failure and progression to diabetes in humans.
Hyperinsulinemia
Lipogenesis
Diazoxide
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In normal rats, females have higher circulating GH-binding protein (GHBP) levels than males, whereas in the GH-deficient dwarf (Dw) rat, there is no sexual dimorphism in plasma GHBP, suggesting that GH secretion may be involved in this difference. In order to study the relationship between gonadal steroids and GH on GHBP and GH receptor regulation, the levels of plasma GHBP, hepatic bovine GH, and human GH (hGH) binding as well as GHBP and GH receptor messenger RNA (mRNA) have now been studied in normal, Dw, hypophysectomized (Hx), or ovariectomized (Ovx) rats, subjected to different GH and gonadal steroid exposure. In normal male rats, estradiol (E2, 12.5-25 micrograms/day for 1 or 2 weeks) markedly increased plasma GHBP and hepatic hGH, and bGH binding. These effects of E2 were diminished in Dw rats, absent in Hx rats, but restored in Hx rats given exogenous hGH. Plasma GHBP rose in female rats given E2, and fell in females given the anti-estrogen tamoxifen. Ovx animals had lower plasma GHBP and hepatic GH binding which was reversed by E2, but not testosterone treatment. Continuous hGH infusions in Ovx rats restored hepatic GH binding, and increased plasma GHBP. In Dw males, hGH increased plasma GHBP and hepatic GH binding, whereas testosterone had no effect on GHBP or GH receptors and did not affect their up-regulation by hGH. Hepatic levels of GHBP-, and GH receptor mRNA transcripts showed the same trends in response to steroid or GH treatment, but the differences were rarely significant, except in Ovx animals which had higher GHBP mRNA transcripts after GH or E2 treatment. Thus E2 and GH increase both plasma GHBP and hepatic GH receptor binding. GH up-regulates GHBP in the absence of E2, whereas E2 treatment does not raise GHBP in the absence of GH. Whereas some of the effects of estrogen could be mediated via alterations in GH secretion, estrogen may also directly influence GHBP production at the liver, but only in the presence of GH.
Growth hormone-binding protein
Sexual dimorphism
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Plasma glucose, insulin, and FFA concentrations were determined in 15 normal subjects and 15 patients with noninsulin-dependent diabetes mellitus (NIDDM) from 0800 to 1600 h. Breakfast and lunch were consumed at 0800 and 1200 h, respectively, and plasma concentrations were measured at hourly intervals from 0800-1600 h. Plasma glucose concentrations between 0800 and 1600 h were significantly elevated in patients with NIDDM, and the higher the fasting glucose level, the greater the postprandial hyperglycemia. Hyperglycemia in patients with NIDDM was associated with plasma insulin levels that were significantly higher (P less than 0.001) than those in normal subjects, and substantial hyperinsulinemia occurred between 0800 and 1600 h in patients with mild NIDDM (fasting plasma glucose concentrations, less than 140 mg/dl). Both fasting and postprandial FFA levels were also increased in patients with NIDDM (P less than 0.001), and the greater the plasma glucose response, the higher the FFA response (r = 0.70; P less than 0.001). However, there was no significant correlation between plasma insulin and FFA concentrations. More specifically, hyperinsulinemic patients with mild diabetes (fasting plasma glucose, less than 140 mg/dl) maintained normal ambient FFA levels, while FFA concentrations were significantly elevated in patients with severe NIDDM (fasting plasma glucose, greater than 250 mg/dl), with insulin concentrations comparable to those in normal subjects. These results demonstrate that patients with NIDDM are not capable of maintaining normal plasma FFA concentrations. This defect in FFA metabolism is proportionate to the magnitude of hyperglycemia and occurs despite the presence of elevated levels of plasma insulin. These results are consistent with the view that insulin resistance in NIDDM also involves the ability of insulin to regulate FFA metabolism.
Hyperinsulinemia
Carbohydrate Metabolism
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Glucagon-like peptide-1 augments nutrient-stimulated insulin secretion. Chow-fed mice lacking the glucagon-like peptide-1 receptor (Glp1r) exhibit enhanced insulin-stimulated muscle glucose uptake but impaired suppression of endogenous glucose appearance (endoRa). This proposes a novel role for the Glp1r to regulate the balance of glucose disposal in muscle and liver by modulating insulin action. Whether this is maintained in an insulin-resistant state is unknown. The present studies tested the hypothesis that disruption of Glp1r expression overcomes high-fat (HF) diet-induced muscle insulin resistance and exacerbates HF diet-induced hepatic insulin resistance. Mice with a functional disruption of the Glp1r (Glp1r−/−) were compared with wild-type littermates (Glp1r+/+) after12 wk on a regular chow diet or a HF diet. Arterial and venous catheters were implanted for sampling and infusions. Hyperinsulinemic-euglycemic clamps were performed on weight-matched male mice. [3-3H]glucose was used to determine glucose turnover, and 2[14C]deoxyglucose was used to measure the glucose metabolic index, an indicator of glucose uptake. Glp1r−/− mice exhibited increased glucose disappearance and muscle glucose metabolic index on either diet. This was associated with enhanced activation of muscle Akt and AMP-activated protein kinase and reduced muscle triglycerides in HF-fed Glp1r−/− mice. Chow-fed Glp1r−/− mice exhibited impaired suppression of endoRa and hepatic insulin signaling. In contrast, HF-fed Glp1r−/− mice exhibited improved suppression of endoRa and hepatic Akt activation. This was associated with decreased hepatic triglycerides and impaired activation of sterol regulatory element-binding protein-1. These results show that mice lacking the Glp1r are protected from HF diet-induced muscle and hepatic insulin resistance independent of effects on total fat mass.
Glucose clamp technique
Carbohydrate Metabolism
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The role of the hypothalamic paraventricular nucleus (PVN) in thyroid hormone regulation of TSH synthesis during hypothyroidism was studied in adult male rats that were normal (n = 10), had primary hypothyroidism with sham lesions in the hypothalamus (n = 17), and had primary hypothyroidism with PVN lesions (n = 14). Two and 4 weeks after initiation of treatment, plasma levels of thyroid hormones (TSH, corticosterone and PRL) and pituitary content of TSH beta and alpha-subunit mRNA were measured. TRH mRNA levels in the PVN were determined by in situ hybridization histochemistry. At 2 weeks, despite a decrease in plasma free T4 in both hypothyroid groups, plasma TSH levels increased, but to a lesser degree, in the hypothyroid PVN lesioned compared to hypothyroid sham-lesioned group (7.8 +/- 1.3 vs. 20.5 +/- 1.1 ng/dl; P less than 0.05). Similarly, at 4 weeks, the hypothyroid PVN-lesioned group demonstrated a blunted TSH response compared to the hypothyroid sham-lesioned group (6.8 +/- 0.7 vs. 24.0 +/- 1.3 ng/dl; P less than 0.05). Plasma corticosterone and PRL did not significantly differ between sham-lesioned and PVN-lesioned groups. TSH beta mRNA levels markedly increased in hypothyroid sham-lesioned rats compared to those in euthyroid controls at 2 weeks (476 +/- 21% vs. 100 +/- 39%; P less than 0.05) and 4 weeks (1680 +/- 270% vs. 100 +/- 35%; P less than 0.05). In contrast, TSH beta mRNA levels did not increase with hypothyroidism in the PVN-lesioned group compared to those in euthyroid controls at 2 weeks (140 +/- 16%, P = NS) and only partially increased at 4 weeks (507 +/- 135; P less than 0.05). alpha mRNA levels at 4 weeks markedly increased in hypothyroid sham-lesioned rats compared to those in euthyroid controls (1121 +/- 226% vs. 100 +/- 48%; P less than 0.05), but did not increase in the hypothyroid PVN-lesioned rats (61 +/- 15%; P = NS). TRH mRNA in the PVN increased in the hypothyroid sham-lesioned rats compared to those in euthyroid controls (16.6 +/- 1.3 vs. 4.8 +/- 1.2 arbitrary densitometric units; P less than 0.05), and TRH mRNA was not detectable in the PVN of hypothyroid-lesioned rats at 2 weeks. In summary, lesions in rat PVN prevented the full increase in plasma TSH, pituitary TSH beta mRNA, and alpha mRNA levels in response to hypothyroidism. Thus, factors in the PVN are important in thyroid hormone feedback regulation of both TSH synthesis and secretion.
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