Background:
Treatment for acromegaly patients with long-acting somatotropin release-inhibiting factor (LA-SRIF) often does not result in complete normalization of IGF-1. Addition of pegvisomant ...(PEGV), a GH receptor antagonist, could improve this; however, the literature has not described long-term follow-up.
Objective:
To assess long-term efficacy and safety of this combined treatment in the largest current single-center cohort of patients, from 2004–2013.
Design:
Acromegaly patients were treated for at least 6 months with a high-dose LA-SRIF. To patients with persistently elevated IGF-1 levels (>1.2 × upper limit of normal) or poor quality of life, PEGV was added as one weekly injection.
Results:
The patients (n = 141) were treated with PEGV and LA-SRIFs for a median period of 4.9 years (range, 0.5–9.2). Efficacy, defined as the lowest measured IGF-1 level during treatment, was 97.0%. The median PEGV dose to achieve this efficacy was 80 mg weekly (interquartile range, 60–120 mg). Combination treatment-related adverse events were recorded in 26 subjects (18.4%). Pituitary tumor size increase was observed in one patient. Injection-site reactions were observed in four subjects. In 19 patients (13.5%), transiently elevated liver transaminases of more than three times the upper limit of normal were observed, of which 83% occurred within the first year of combination treatment. Eight patients died, at a mean age of 71 years; none of them were considered treatment-related.
Conclusions:
The combination treatment with LA-SRIFs and PEGV was effective in 97% of the patients, it appears to be a safe medical treatment and it reduces the required dose of PEGV.
The ability of growth hormone (GH) to induce adipose tissue lipolysis has been known for over five decades; however, the molecular mechanisms that mediate this effect and the ability of GH to inhibit ...insulin-stimulated glucose uptake have scarcely been documented. In this same time frame, our understanding of adipose tissue has evolved to reveal a complex structure with distinct types of adipocyte, depot-specific differences, a biologically significant extracellular matrix and important endocrine properties mediated by adipokines. All these aforementioned features, in turn, can influence lipolysis. In this Review, we provide a historical and current overview of the lipolytic effect of GH in humans, mice and cultured cells. More globally, we explain lipolysis in terms of GH-induced intracellular signalling and its effect on obesity, insulin resistance and lipotoxicity. In this regard, findings that define molecular mechanisms by which GH induces lipolysis are described. Finally, data are presented for the differential effect of GH on specific adipose tissue depots and on distinct classes of metabolically active adipocytes. Together, these cellular, animal and human studies reveal novel cellular phenotypes and molecular pathways regulating the metabolic effects of GH on adipose tissue.
Purpose
Although quality of life (QoL) is improved in patients with acromegaly after disease control, QoL correlates only weakly with traditional biomarkers. Our objective is to investigate a ...potential relation between the new serum biomarker soluble Klotho (sKlotho), GH and insulin-like growth factor 1 (IGF-1) levels, and QoL.
Methods
In this prospective cohort study, we investigated 54 acromegaly patients biochemically well-controlled on combination treatment with first-generation somatostatin receptor ligands (SRLs) and pegvisomant (PEGV) at baseline and 9 months after switching to pasireotide LAR (PAS-LAR; either as monotherapy,
n
= 28; or in combination with PEGV,
n
= 26). QoL was measured by the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) and Acromegaly Quality of Life (AcroQoL) questionnaire.
Results
Switching to PAS-LAR treatment significantly improved QoL without altering IGF-1 levels. QoL did not correlate with GH or IGF-1 levels, but sKlotho correlated with the observed improvements in QoL by the AcroQoL global (
r
= −0.35,
p
= 0.012) and physical subdimension (
r
= −0.34,
p
= 0.017), and with PASQ headache (
r
= 0.28,
p
= 0.048), osteoarthralgia (
r
= 0.46,
p
= 0.00080) and soft tissue swelling score (
r
= 0.29,
p
= 0.041). Parallel changes in serum sKlotho and IGF-1 (
r
= 0.31,
p
= 0.023) suggest sKlotho and IGF-1 to be similarly dependent on GH. Comparing the PAS-LAR combination therapy and the monotherapy group we did not observe a significant difference in improvement of QoL.
Conclusions
Patients experienced improved QoL during PAS-LAR, either as monotherapy or in combination with PEGV. Soluble Klotho concentrations appear to be a useful marker of QoL in acromegaly patients but the underlying mechanisms remain to be investigated.
phosphorylation of AS160 and TBC1D1 plays an important role for GLUT4 mobilization to the cell surface. The phosphorylation of AS160 and TBC1D1 in humans in response to acute exercise is not fully ...characterized.
to study AS160 and TBC1D1 phosphorylation in human skeletal muscle after aerobic exercise followed by a hyperinsulinemic euglycemic clamp.
eight healthy men were studied on two occasions: 1) in the resting state and 2) in the hours after a 1-h bout of ergometer cycling. A hyperinsulinemic euglycemic clamp was initiated 240 min after exercise and in a time-matched nonexercised control condition. We obtained muscle biopsies 30 min after exercise and in a time-matched nonexercised control condition (t = 30) and after 30 min of insulin stimulation (t = 270) and investigated site-specific phosphorylation of AS160 and TBC1D1.
phosphorylation on AS160 and TBC1D1 was increased 30 min after the exercise bout, whereas phosphorylation of the putative upstream kinases, Akt and AMPK, was unchanged compared with resting control condition. Exercise augmented insulin-stimulated phosphorylation on AS160 at Ser(341) and Ser(704) 270 min after exercise. No additional exercise effects were observed on insulin-stimulated phosphorylation of Thr(642) and Ser(588) on AS160 or Ser(237) and Thr(596) on TBC1D1.
AS160 and TBC1D1 phosphorylations were evident 30 min after exercise without simultaneously increased Akt and AMPK phosphorylation. Unlike TBC1D1, insulin-stimulated site-specific AS160 phosphorylation is modified by prior exercise, but these sites do not include Thr(642) and Ser(588). Together, these data provide new insights into phosphorylation of key regulators of glucose transport in human skeletal muscle.
Background: Low IGF-I levels may be associated with the development of stroke; however, prospective data appear to be unavailable.
Methods: This was a nested case-control study within a Danish ...follow-up study, including 57,053 men and women. Baseline data included circulating IGF-I, IGF-II, and IGF binding protein (IGFBP)-3 concentrations as well as lifestyle factors and medical history. We identified 254 cases with incident ischemic stroke and 254 gender- and age-matched controls.
Results: Participants in the bottom quartiles of IGF-I and IGFBP-3 levels (median concentrations, 72 and 2937 ng/ml, respectively) were at increased risk of ischemic stroke, e.g. adjusted odds ratios (ORs) of 2.06 95% confidence interval (CI), 1.05–4.03 and 2.29 (95% CI, 1.17–4.49), respectively, when compared with participants in the top quartiles (median concentrations, 125 and 4835 ng/ml, respectively). A negative, although weaker, association was also found for IGF-II (adjusted OR 1.44, 95% CI 0.79–2.64) when comparing the bottom quartile with the top quartile. No substantial associations were seen for IGF-I and IGF-II when also adjusting for IGFBP-3; adjusting IGFBP-3 for IGF-I and -II had only a minor impact on the risk estimates.
Conclusion: These findings give some support to the hypothesis that the IGF axis is involved in the pathogenesis of ischemic stroke.
Aims
To evaluate the performances of commercially available glucagon‐like peptide‐1 (GLP‐1) assays and the implications for clinical studies.
Methods
Known concentrations (5–300 pmol/l) of synthetic ...GLP‐1 isoforms (GLP‐1 1‐36NH2, 7‐36NH2, 9‐36NH2, 1‐37, 7‐37 and 9‐37) were added to the matrix (assay buffer) supplied with 10 different kits and to human plasma, and recoveries were determined. Assays yielding meaningful results were analysed for precision and sensitivity by repeated analysis and ability to discriminate low concentrations. Endogenous GLP‐1 levels in clinical samples were assessed using three commercial kits.
Results
The USCN LIFE assay detected none of the GLP‐1 isoforms. The active GLP‐1 enzyme‐linked immunosorbent assays (ELISAs) from Millipore and DRG appeared identical and were specific for intact GLP‐1 in buffer and plasma. The Meso Scale Discovery (MSD) total GLP‐1 kit detected all six GLP‐1 isoforms, although recovery of non‐active forms was incomplete, especially in plasma. Millipore total GLP‐1 ELISA kit detected all isoforms in buffer, but mainly amidated forms in plasma. The Alpco, Phoenix and Bio‐Rad kits detected only amidated GLP‐1, but the Alpco kit had a limited measurement range (30 pmol/l), the Phoenix kit had incomplete recovery in plasma and the Bio‐Rad kit was insensitive (detection limit in plasma 40 pmol/l). The pattern of postprandial GLP‐1 responses in clinical samples was similar between the kits tested, but the absolute concentrations measured varied.
Conclusions
The specificity and sensitivity of commercially available kits for the analysis of GLP‐1 levels vary considerably. This should be taken into account when selecting which assay to use and when comparing data from different studies.
Aims/hypothesis
Growth hormone (GH) causes insulin resistance that is linked to lipolysis, but the underlying mechanisms are unclear. We investigated if GH-induced insulin resistance in skeletal ...muscle involves accumulation of diacylglycerol (DAG) and ceramide as well as impaired insulin signalling, or substrate competition between fatty acids and glucose.
Methods
Nine GH-deficient male participants were randomised and examined in a 2 × 2 factorial design with and without administration of GH and acipimox (an anti-lipolytic compound). As-treated analyses were performed, wherefore data from three visits from two patients were excluded due to incorrect GH administration. The primary outcome was insulin sensitivity, expressed as the AUC of the glucose infusion rate (GIR
AUC
), and furthermore, the levels of DAGs and ceramides, insulin signalling and the activity of the active form of pyruvate dehydrogenase (PDHa) were assessed in skeletal muscle biopsies obtained in the basal state and during a hyperinsulinaemic–euglycaemic clamp (HEC).
Results
Co-administration of acipimox completely suppressed the GH-induced elevation in serum levels of NEFA (GH versus GH+acipimox,
p
< 0.0001) and abrogated GH-induced insulin resistance (mean GIR
AUC
95% CI mg min
−1
kg
−1
during the HEC: control, 595 493, 718; GH, 468 382, 573; GH+acipimox, 654 539, 794; acipimox, 754 618, 921; GH vs GH+acipimox:
p
= 0.004). GH did not significantly change either the accumulation of DAGs and ceramides or insulin signalling in skeletal muscle, but GH antagonised the insulin-stimulated increase in PDHa activity (mean ± SEM % from the basal state to the HEC: control, 47 ± 19; GH, −15 ± 21; GH+acipimox, 3 ± 21; acipimox, 57 ± 22; main effect:
p
= 0.02).
Conclusions/interpretation
GH-induced insulin resistance in skeletal muscle is: (1) causally linked to lipolysis; (2) not associated with either accumulation of DAGs and ceramides or impaired insulin signalling; (3) likely to involve substrate competition between glucose and lipid intermediates.
Trial registration
ClinicalTrials.gov
NCT02782208
Funding
The work was supported by the Grant for Growth Innovation (GGI), which was funded by Merck KGaA, Darmstadt, Germany.
Graphical abstract
The main purpose was to assess the incidence and late outcome of Cushing's syndrome, particularly in Cushing's disease. Information for all patients diagnosed with Cushing's syndrome during an 11-yr ...period in Denmark was retrieved. The incidence was 1.2-1.7/million.yr (Cushing's disease), 0.6/million.yr (adrenal adenoma) and 0.2/million.yr (adrenal carcinoma). Other types of Cushing's syndrome were rare. In 139 patients with nonmalignant disease, 11.1% had died during follow-up (median, 8.1 yr; range, 3.1-14.0), yielding a standard mortality ratio (SMR) of 3.68 95% confidence interval (CI), 2.34-5.33. The SMR was partly attributable to an increased mortality within the first year after diagnosis. Eight patients died before treatment could be undertaken. The prognosis in patients with malignant disease was very poor. Patients in whom more than 5 yr had elapsed since initial surgery were studied separately, including a questionnaire on their perceived quality of health. In 45 patients with Cushing's disease who had been cured through transsphenoidal neurosurgery, only 1 had died (SMR, 0.31; CI, 0.01-1.72) compared with 6 of 20 patients with persistent hypercortisolism after initial neurosurgery (SMR, 5.06; CI, 1.86-11.0). In patients with adrenal adenoma, SMR was 3.95 (CI, 0.81-11.5). The perceived quality of health was significantly impaired only in patients with Cushing's disease and appeared independent of disease control or presence of hypopituitarism. It is concluded that 1) Cushing's syndrome is rare and is associated with increased mortality, in patients with no concurrent malignancy also; 2) the excess mortality was mainly observed during the first year of disease; and 3) the impaired quality of health in long-term survivors of Cushing's disease is not fully explained.
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