Insulin action in adipose tissue and muscle in hypothyroidism.

BACKGROUND: Although insulin resistance in thyroid hormone excess is well documented, information on insulin action in hypothyroidism is limited. METHODS: To investigate this, a meal was given to 11 hypothyroid (HO; aged 45 +/- 3 yr) and 10 euthyroid subjects (EU; aged 42 +/- 4 yr). Blood was withdrawn for 360 min from veins (V) draining the anterior abdominal sc adipose tissue and the forearm and from the radial artery (A). Blood flow (BF) in adipose tissue was measured with 133Xe and in forearm with strain-gauge plethysmography. Tissue glucose uptake was calculated as (A-V)glucose(BF), lipoprotein lipase as (A-V)Triglycerides(BF), and lipolysis as [(V-A)glycerol(BF)]-lipoprotein lipase. RESULTS: The HO group had higher glucose and insulin levels than the EU group (P < 0.05). In HO vs. EU after meal ingestion (area under curve 0-360 min): 1) BF (1290 +/- 79 vs. 1579 +/- 106 ml per 100 ml tissue in forearm and 706 +/- 105 vs. 1340 +/- 144 ml per 100 ml tissue in adipose tissue) and glucose uptake (464 +/- 74 vs. 850 +/- 155 micromol per 100 ml tissue in forearm and 208 +/- 42 vs. 406 +/- 47 micromol per 100 ml tissue in adipose tissue) were decreased (P < 0.05), but fractional glucose uptake was similar (28 +/- 6 vs. 33 +/- 6% per minute in forearm and 17 +/- 4 vs. 14 +/- 3% per minute in adipose tissue); 2) suppression of lipolysis by insulin was similar; and 3) plasma triglycerides were elevated (489 +/- 91 vs. 264 +/- 36 nmol/liter.min, P < 0.05), whereas adipose tissue lipoprotein lipase (42 +/- 11 vs. 80 +/- 21 micromol per 100 ml tissue) and triglyceride clearance (45 +/- 10 vs. 109 +/- 21 ml per 100 ml tissue) were decreased in HO (P < 0.05). CONCLUSIONS: In hypothyroidism: 1) glucose uptake in muscle and adipose tissue is resistant to insulin; 2) suppression of lipolysis by insulin is not impaired; and 3) hypertriglyceridemia is due to decreased clearance by the adipose tissue.

The unexpected anabolic phenotype and extended longevity of skin fibroblasts after chronic glucocorticoid excess.

Intense stress can challenge tissue homeostasis and accelerate the ageing process. However, several lines of evidence indicate that repeated mild stresses can have beneficial and even life-prolonging effects. Hypersecretion of glucocorticoids (GC) represents the major hormonal response to stress. Besides its life-sustaining role, GC excess, usually due to several side-effects that promote a "catabolic" phenotype, can be detrimental for several tissues. Cushing's syndrome patients are characterized by chronic endogenous GC excess and consequently at the time of diagnosis they have an atrophic elderly-like skin. Interestingly, when Cushing's syndrome fibroblasts were removed from the high-GC milieu in vivo and cultured in vitro under standard conditions they express an "anabolic" phenotype, i.e. they restore their ability for collagen synthesis, they secrete reduced levels of metalloproteases (MMP-1 and MMP-2) and have an increased proliferative capacity and contractility. Furthermore, these cells exhibit a significant extension of their proliferative lifespan, while they respond better to exogenous stress by producing significantly higher levels of heat-shock protein-70 (HSP70). These results imply that long-term hypercortisolism in vivo can have beneficial consequences on fibroblast physiology in vitro.

The impact of chronic in vivo glucocorticoid excess on the functional characteristics of human skin fibroblasts obtained from patients with endogenous Cushing's syndrome.

OBJECTIVE: Chronic exposure to elevated glucocorticoid (GC) concentrations induces detrimental effects in several tissues. In the skin, GCs provoke intense alterations on various parameters of the physiology of fibroblasts, cumulatively leading to skin atrophy and impaired wound healing. As there are concerns that GCs may generate permanent adverse functional changes, we have investigated whether chronic in vivo exposure to GC excess results in persisting defects in skin fibroblasts. DESIGN AND METHODS: We have studied in vitro primary skin fibroblast cultures obtained from patients suffering from endogenous Cushing's syndrome (CF), as well as from sex- and age-matched normal donors (NF). The following functional parameters were investigated: cell proliferation, secretion of collagen, matrix metalloproteinases (MMPs) and their inhibitors (tissue inhibitors of metalloproteinases; TIMPs) and contractile capacity. RESULTS: CFs, grown under standard culture conditions in the absence of a hypercortisolemic milieu, exhibited an increased proliferative capacity and a higher final cell culture density compared with NFs. Collagen synthesis, in the absence or presence of transforming growth factor-beta, was equal to that of NFs. However, CFs secreted comparatively lower levels of MMP-1, MMP-2 and TIMP-1, and nearly equal levels of TIMP-2. CFs also exhibited an increased ability to contract gels of polymerized collagen. CONCLUSIONS: Collectively, these functional characteristics of CFs are in contrast to the known catabolic effects of GCs, and suggest that prior exposure to GC excess is not associated with a persisting adverse outcome in the functional phenotype of the fibroblasts.

Growth hormone binding protein and acid labile subunit levels in the assessment of acromegaly treatment.

OBJECTIVE: Post-treatment monitoring of acromegalic patients is a matter of controversy, as discrepancies between GH and IGF-I levels have been reported. The aim of our study was to evaluate the role of acid-labile subunit (ALS), a component of the 150 kD IGF-I/IGFBP-3/ALS complex, and the growth hormone binding protein (GHBP) in the follow-up of patients with acromegaly after therapeutic intervention. DESIGN: Forty-one patients with acromegaly, 10 at the time of diagnosis and 31 post therapeutic intervention, were studied. Patients were evaluated by the determination of baseline (fasting) IGF-I, ALS and GHBP and of glucose and GH during OGTT. RESULTS: Significantly lower ALS and higher GHBP levels were detected in successfully treated acromegalics compared to patients before treatment (34.1+/-1.6 vs. 52.8+/-2 mg/L and 0.9+/-0.08 vs 0.4+/-0.1 ìg/L, respectively P<0.05). Furthermore, no difference was noted in ALS and GHBP values between patients successfully treated with either somatostatin analogues or another type of treatment. CONCLUSIONS: a) Successfully treated acromegalic patients demonstrate lower ALS and higher GHBP levels than patients before treatment, and b) somatostatin analogue treatment does not have a direct effect on GHBP and ALS concentration in acromegaly. Studies in larger groups of patients are needed to disclose whether these alterations will be useful in the post-treatment assessment of acromegalic patients.

Assessment of GH reserve before and after successful treatment of adult patients with Cushing's syndrome.

OBJECTIVE: Several studies have demonstrated impaired GH secretion in patients with active Cushing's syndrome (CS). It has been suggested that persistence of GH deficiency, despite treatment of cortisol excess, may delay the recovery of these patients and therefore temporary treatment with GH may have some benefit. However, the time course of restoration of GH secretion after successful treatment of CS has only been investigated in a limited number of mostly paediatric reports. The aim of the present study was the evaluation of GH reserve in adult patients with CS before and after correction of cortisol excess. DESIGN AND PATIENTS: Sixteen patients (12 females, four males) with CS aged 44.7 +/- 5.05 years were recruited. These included seven patients with Cushing's disease, four patients with ectopic ACTH secretion and five patients with adrenal adenoma. All patients were evaluated before any therapeutic intervention. Twelve patients were successfully treated following appropriate surgery and these were further studied. The combined pyridostigmine/GHRH test was used to assess GH reserve in these patients. In a proportion of cases an insulin tolerance test (ITT) was also used. RESULTS: Before any therapeutic intervention, an impaired GH response to PD/GHRH was noted in all patients. Restoration of GH response at 6 months was observed in six patients (50%); at 12 months in two; at 18 months in one patient. Two of the patients with no restoration of GH response at 12 months did not accept further investigation. Only one patient did not achieve an adequate GH response even when tested 30 months following cure of CS. Restoration of GH reserve was more commonly observed in those patients in whom there was recovery of the HPA axis. There was a good correlation between peak GH levels to PD + GHRH and ITT. No statistically significant difference was revealed in IGF-I levels between pre- and post-treatment evaluation. CONCLUSIONS: Adult patients with active Cushing's syndrome demonstrate a profound suppression of stimulated GH secretion. In the majority of these patients the disruption of GH secretion is normalized within a year after successful treatment of endogenous cortisol excess.

Chronic in vivo exposure to glucocorticoids prolongs cellular lifespan: the case of Cushing's syndrome-patients' fibroblasts.

Glucocorticoid (GC) hypersecretion constitutes the major hormonal response to stress. In an effort to investigate the impact of a long-lasting exposure to high GC levels in vivo on cellular longevity, we have studied the lifespan of skin fibroblasts from patients suffering from Cushing's syndrome, who are characterised by chronic endogenous GC excess. Interestingly, we have observed that these cells exhibit a significant increase in their proliferative lifespan when cultured in vitro, under standard conditions, compared to fibroblasts from normal donors. In parallel, these cells secrete lower levels of transforming growth factor-beta, known to be implicated in stress-induced premature senescence. Furthermore, they also exhibit an intense stress reaction (near 2-fold, compared to normal cells) in terms of heat-shock protein-70 induction. These results support the hypothesis that stress response may have beneficial consequences in cellular longevity, as well as in tissue homeostasis.