Agatha A. van der Klaauw

Disease-specific impairments in quality of life during long-term follow-up of patients with different pituitary adenomas

Objective  Quality of life (QoL) is impaired in patients treated for pituitary adenomas. However, differences in age and gender distributions hamper a proper comparison of QoL. Therefore, we compared age‐ and gender‐specific standard deviations (SD) scores (Z‐scores) of QoL parameters in patients treated for pituitary adenomas.

The Hunger Genes: Pathways to Obesity

The global rise in the prevalence of obesity and associated co-morbidities such as type 2 diabetes, cardiovascular disease, and cancer represents a major public health concern. The biological response to increased consumption of palatable foods or a reduction in energy expenditure is highly variable between individuals. A more detailed mechanistic understanding of the molecular, physiological, and behavioral pathways involved in the development of obesity in susceptible individuals is critical for identifying effective mechanism-based preventative and therapeutic interventions.

KSR2 Mutations Are Associated with Obesity, Insulin Resistance, and Impaired Cellular Fuel Oxidation

Summary Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEK-ERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes. PaperFlick

Obesity due to Melanocortin 4 Receptor (MC4R) Deficiency Is Associated with Increased Linear Growth and Final Height, Fasting Hyperinsulinemia, and Incompletely Suppressed Growth Hormone Secretion

CONTEXT Melanocortin receptor 4 (MC4R) deficiency is characterized by increased linear growth greater than expected for the degree of obesity. OBJECTIVE The objective of the investigation was to study the somatotroph axis in obese MC4R-deficient patients and equally obese controls. PATIENTS AND METHODS We obtained anthropometric measurements and insulin concentrations in 153 MC4R-deficient subjects and 1392 controls matched for age and severity of obesity. We measured fasting IGF-I, IGF-II, IGF binding protein (IGFBP)-1, IGFBP-3, and acid-labile subunit levels in a subset of 33 MC4R-deficient patients and 36 control subjects. We examined pulsatile GH secretion in six adult MC4R-deficient subjects and six obese controls. RESULTS Height sd score was significantly greater in MC4R-deficient children under 5 yr of age compared with controls (mean ± SEM: 2.3 ± 0.06 vs. 1.8 ± 0.04, P < 0.001), an effect that persisted throughout childhood. Final height (cm) was greater in MC4R-deficient men (mean ± SEM 173 ± 2.5 vs. 168 ± 2.1, P < 0.001) and women (mean 165 ± 2.1 vs. 158 ± 1.9, P < 0.001). Fasting IGF-I, IGF-II, acid-labile subunit, and IGFBP-3 concentrations were similar in the two groups. GH levels were markedly suppressed in obese controls, but pulsatile GH secretion was retained in MC4R deficiency. The mean maximal GH secretion rate per burst (P < 0.05) and mass per burst (P < 0.05) were increased in MC4R deficiency, consistent with increased pulsatile and total GH secretion. Fasting insulin levels were markedly elevated in MC4R-deficient children. CONCLUSIONS In MC4R deficiency, increased linear growth in childhood leads to increased adult final height, greater than predicted by obesity alone. GH pulsatility is maintained in MC4R deficiency, a finding consistent with animal studies, suggesting a role for MC4R in controlling hypothalamic somatostatinergic tone. Fasting insulin levels are significantly higher in children carrying MC4R mutations. Both of these factors may contribute to the accelerated growth phenotype characteristic of MC4R deficiency.

The prevalence of the metabolic syndrome is increased in patients with GH deficiency, irrespective of long-term substitution with recombinant human GH

OBJECTIVES Many reports demonstrate improvements in cardiovascular risk factors during GH replacement (rhGH) in adult GH deficiency (GHD). However, it remains to be determined to what extent these changes translate into a reduction of increased cardiovascular morbidity and mortality. The aim of this study was to evaluate the effects of long-term rhGH replacement on the prevalence of the metabolic syndrome (MS). Design, settings, main outcome measures: The MS was scored by the National Cholesterol Education Program-Adult Treatment Panel III definition in 50 consecutive GHD patients (45 +/- 9 years of age), before and after 2 and 5 years of rhGH replacement, and the data of untreated patients were compared with the general population using data from a Dutch population-based study (n=1062, 44 +/- 8 years of age). RESULTS Hypertriglyceridaemia (46.0 vs 18.5%, P<0.0001), hypertension (66.0 vs 35.5%, P<0.0001) and abdominal obesity (38.0 vs 23.4%, P=0.0178) were more prevalent in untreated patients when compared with controls, resulting in a higher prevalence of the MS in patients (38.0 vs 15.7%, P<0.0001). During rhGH replacement at a mean dose of 0.5 +/- 0.2 mg/day resulting in IGF-I concentrations in the normal age-adjusted reference range, mean high-density lipoprotein cholesterol level increased compared with baseline (P<0.001). However, the prevalence of (components of) the MS did not change after 2 or 5 years of treatment with rhGH. CONCLUSION In this study, the prevalence of the MS in patients with GHD is increased compared with healthy controls, irrespective of rhGH replacement.

High protein intake stimulates postprandial GLP1 and PYY release

Meals high in protein induce greater intermeal satiety than meals high in fat and carbohydrates. We studied the gut hormone response and subsequent food intake after breakfasts high in protein, carbohydrate or high in fat controlled for volume, calories and appearance.

Influence of the d3-Growth Hormone (GH) Receptor Isoform on Short-Term and Long-Term Treatment Response to GH Replacement in GH-Deficient Adults

OBJECTIVE Recombinant human GH (rhGH) replacement in adults is aimed at improving signs and symptoms of the adult GH deficiency (GHD) syndrome. In children, a common polymorphism of the GH receptor (exon-3 deletion, d3GHR) increases the response to rhGH replacement. The aim of this study was to assess the effects of this polymorphism on the response to rhGH replacement in adults. DESIGN Prospective intervention with rhGH during 1 yr (n = 99) and in a subset during 5 yr (n = 53). PATIENTS AND METHODS The presence of the d3GHR variant was established in GHD patients and linked to short-term and long-term effects of rhGH replacement on IGF-I, lipid metabolism, anthropometric parameters, and bone mineral density. RESULTS Fifty-five patients had two wild-type alleles (56%), whereas 38 patients (38%) had one allele and six patients (6%) had two alleles coding the d3GHR isoform. During short-term rhGH replacement, the increase in IGF-I was higher in patients bearing at least one d3GHR allele, compared with those with two wild-type alleles (at an identical mean dose of rhGH). The decrease in total cholesterol and low-density lipoprotein cholesterol was lower in the group bearing at least one d3GHR allele, whereas the increase in high-density lipoprotein cholesterol was higher, compared with patients with the wild-type genotype. In contrast, these differential responses of GHR genotype could not be demonstrated during long-term rhGH replacement. CONCLUSION The d3GHR genotype contributes, at least for some parameters, to the interindividual differences in efficacy of short-term, but not long-term, rhGH replacement in adults with GHD.

Type 2 iodothyronine deiodinase in skeletal muscle: Effects of hypothyroidism and fasting

CONTEXT The iodothyronine deiodinases D1, D2, and D3 enable tissue-specific adaptation of thyroid hormone levels in response to various conditions, such as hypothyroidism or fasting. The possible expression of D2 mRNA in skeletal muscle is intriguing because this enzyme could play a role in systemic as well as local T3 production. OBJECTIVE We determined D2 activity and D2 mRNA expression in human skeletal muscle biopsies under control conditions and during hypothyroidism, fasting, and hyperinsulinemia. DESIGN This was a prospective study. SETTING The study was conducted at a university hospital. PATIENTS We studied 11 thyroidectomized patients with differentiated thyroid carcinoma (DTC) on and after 4 wk off T4( replacement and six healthy lean subjects in the fasting state and during hyperinsulinemia after both 14 and 62 h of fasting. MEAN OUTCOME MEASURES D2 activity and D2 mRNA levels were measured in skeletal muscle samples. RESULTS No differences were observed in muscle D2 mRNA levels in DTC patients on and off T4 replacement therapy. In healthy subjects, muscle D2 mRNA levels were lower after 62 h compared to 14 h of fasting. Insulin increased mRNA expression after 62 h, but not after 14 h of fasting. Skeletal muscle D2 activities were very low and not influenced by hypothyroidism and fasting. CONCLUSION Human skeletal muscle D2 mRNA expression is modulated by fasting and insulin, but not by hypothyroidism. The lack of a clear effect of D2 mRNA modulation on the observed low D2 activities questions the physiological relevance of D2 activity in human skeletal muscle.

Previous radiotherapy negatively influences quality of life during 4 years of follow‐up in patients cured from acromegaly

Objective  Cross‐sectional studies have shown impaired quality of life (QoL) in patients in biochemical control of acromegaly. The aim of this study was to assess longitudinal changes in QoL in a homogenous cohort of patients with sustained biochemical control of acromegaly.

Increased aortic root diameters in patients with acromegaly

OBJECTIVE The clinical manifestations of acromegalic cardiomyopathy include arrhythmias, valvular regurgitation, concentric left ventricular (LV) hypertrophy, and LV systolic and diastolic dysfunction. At present, it is unknown whether acromegaly also affects the aortic root. DESIGN Aortic root diameters were prospectively assessed in 37 acromegalic patients (18 patients with active disease and 19 with controlled disease) by conventional two-dimensional and Doppler echocardiography before, and after, an observation period of 1.9 years (range 1.5-3.0 years). Baseline parameters were compared with healthy controls. RESULTS The diameters of the aortic root at the sino-tubular junction and the ascending aorta were increased in patients with acromegaly: 30+/-4 vs 26+/-3 mm (P=0.0001) and 33+/-5 vs 30+/-4 mm (P=0.006) respectively. The diameter of the aortic root at the aortic annulus and aortic sinus were not different from controls. During follow-up, the aortic root diameters increased at the levels of the annulus and the sinotubular junction (P=0.025 and P=0.024 respectively), whereas there was no change in the diameters at the levels of the sinus and the ascending aorta during follow-up. Baseline aortic root diameters were not influenced by disease duration, current disease activity, or blood pressure. When patients with active and inactive disease were analyzed separately, only the diameter of the sinotubular junction increased in patients with inactive acromegaly during follow-up (P=0.031). CONCLUSION Aortic root diameters are increased in patients with acromegaly compared with healthy controls.