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GLP-1 analogues as a new treatment option for hypothalamic obesity in adults: report of nine cases

Flavius Zoicas, Michael Droste, Bernhard Mayr, Michael Buchfelder, and Christof Schöfl

Background

Patients with hypothalamic pathology often develop morbid obesity, causing severe metabolic alterations resulting in increased morbidity and mortality. Glucagon-like peptide-1 (GLP-1) analogues improve glycaemic control in type 2 diabetic patients and cause weight loss in obese patients by yet unknown mechanisms. Here we tested whether GLP-1 analogues were also effective in the treatment of obesity and associated metabolic alterations in patients with hypothalamic disease.

Methods

Nine patients (eight with type 2 diabetes mellitus) with moderate to severe hypothalamic obesity were treated with GLP-1 analogues for up to 51 months. Body weight, homeostasis model assessment - insulin resistance (HOMA-IR), HbA1c and lipids were assessed.

Results

Eight patients experienced substantial weight loss (−13.1±5.1 kg (range −9 to −22)). Insulin resistance (HOMA-IR −3.2±3.5 (range −9.1 to 0.8)) and HbA1c values (−1.3±1.4% (range −4.5 to 0.0)) improved under treatment (24.3±18.9 months (range 6 to 51)). Five patients reported increased satiation in response to the treatment. Two of the eight patients complained about nausea and vomiting and one of them abandoned therapy because of sustained gastrointestinal discomfort after 6 months. One patient suffered from intolerable nausea and vomiting and discontinued treatment within 2 weeks.

Conclusion

GLP-1 analogues can cause substantial and sustained weight loss in obese patients with hypothalamic disease. This offers a new approach for medical treatment of moderate to severe hypothalamic obesity and associated metabolic alterations.

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GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts

Bernhard Mayr, Dirk Schnabel, Helmuth-Günther Dörr, and Christof Schöfl

The calcium-sensing receptor (CASR) is the main calcium sensor in the maintenance of calcium metabolism. Mutations of the CASR, the G protein alpha 11 (GNA11) and the adaptor-related protein complex 2 sigma 1 subunit (AP2S1) genes can shift the set point for calcium sensing causing hyper- or hypo-calcemic disorders. Therapeutic concepts for these rare diseases range from general therapies of hyper- and hypo-calcemic conditions to more pathophysiology oriented approaches such as parathyroid hormone (PTH) substitution and allosteric CASR modulators. Cinacalcet is a calcimimetic that enhances receptor function and has gained approval for the treatment of hyperparathyroidism. Calcilytics in turn attenuate CASR activity and are currently under investigation for the treatment of various diseases. We conducted a literature search for reports about treatment of patients harboring inactivating or activating CASR, GNA11 or AP2S1 mutants and about in vitro effects of allosteric CASR modulators on mutated CASR. The therapeutic concepts for patients with familial hypocalciuric hypercalcemia (FHH), neonatal hyperparathyroidism (NHPT), neonatal severe hyperparathyroidism (NSHPT) and autosomal dominant hypocalcemia (ADH) are reviewed. FHH is usually benign, but symptomatic patients benefit from cinacalcet. In NSHPT patients pamidronate effectively lowers serum calcium, but most patients require parathyroidectomy. In some patients cinacalcet can obviate the need for surgery, particularly in heterozygous NHPT. Symptomatic ADH patients respond to vitamin D and calcium supplementation but this may increase calciuria and renal complications. PTH treatment can reduce relative hypercalciuria. None of the currently available therapies for ADH, however, prevent tissue calcifications and complications, which may become possible with calcilytics that correct the underlying pathophysiologic defect.

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Molecular and functional properties of densely and sparsely granulated GH-producing pituitary adenomas

Bernhard Mayr, Rolf Buslei, Marily Theodoropoulou, Günter K Stalla, Michael Buchfelder, and Christof Schöfl

Objective

GH-producing pituitary adenomas display two distinct morphological patterns of cytoplasmic GH-containing secretory granules, namely the densely and sparsely granulated somatotroph adenoma subtype. It is unknown whether these morphological variants reflect distinct pathophysiological entities at the molecular level.

Methods

In 28 GH-producing adenoma tissues from a consecutive set of patients undergoing pituitary surgery for acromegaly, we studied the GH granulation pattern, the expression of somatostatin receptor subtypes (SSTR) as well as the calcium, cAMP and ZAC1 pathways in primary adenoma cell cultures.

Results

The expression of GSP oncogene was similar between densely and sparsely granulated somatotroph adenoma cells. There were no differences in the calcium, cAMP and ZAC1 pathways as well as in their regulation by SSTR agonists. SSTR2 was exclusively expressed in densely but not in sparsely granulated tumours (membrane expression 86 vs 0%; cytoplasmic expression 67 vs 0%). By contrast, expression of SSTR5 was only found in sparsely but not in densely granulated somatotroph adenomas (membrane expression 29 vs 0%; cytoplasmic expression 57 vs 0%).

Conclusions

Our results indicate that different granulation patterns in GH-producing adenomas do not reflect differences in pathways and factors pivotal for somatotroph differentiation and function. In vitro, the vast majority of both densely and sparsely granulated tumour cells were responsive to SSTR activation at the molecular level. Sparsely granulated adenomas lacking SSTR2, but expressing SSTR5, might be responsive to novel SSTR agonists with increased affinity to SSTR5.

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Adipocyte fatty acid-binding protein is associated with markers of obesity, but is an unlikely link between obesity, insulin resistance, and hyperandrogenism in polycystic ovary syndrome women

Matthias Möhlig, Martin O Weickert, Elham Ghadamgadai, Andrea Machlitt, Bettina Pfüller, Ayman M Arafat, Andreas F H Pfeiffer, and Christof Schöfl

Objective: Many polycystic ovary syndrome (PCOS) women suffer from adiposity and insulin resistance (IR), which play an important role in the development and maintenance of PCOS. Adipocyte fatty acid-binding protein (A-FABP) is mainly expressed in adipocytes, and circulating A-FABP has been associated with markers of obesity and IR. Thus, as observed with other adipose tissue derived factors, secreted A-FABP might be involved in the pathogenesis of obesity-associated disorders such as PCOS.

Design: Plasma A-FABP concentrations were measured in 102 non-diabetic PCOS women, and associations with markers of obesity, IR, inflammation, and hyperandrogenism were investigated by correlation and multiple linear regression analyses. The effect of lifestyle intervention on A-FABP was studied in a second cohort of 17 obese PCOS women.

Results: A-FABP correlated with body mass index (BMI; R = 0.694, P < 0.001), dual-energy X-ray-absorptiometry (DEXA) fat mass (R = 0.729, P < 0.001), DEXA lean body mass (R = 0.399, P = 0.001), HOMA %S (R = −0.435, P < 0.001), hsCRP (R = 0.355, P = 0.001), and free testosterone (fT; R = 0.230, P = 0.02). Adjusted for age, smoking, and glucose metabolism the association of A-FABP with HOMA %S was still significant (P < 0.001), whereas the associations with fT (P = 0.09) and hsCRP (P = 0.25) were not. Inclusion of BMI into the model abolished the impact of A-FABP on HOMA %S. In BMI-matched PCOS women (n = 20 pairs), neither HOMA %S (P = 0.3) nor fT (P = 0.6) were different despite different A-FABP levels (P < 0.001), and in 17 obese PCOS women undergoing a lifestyle intervention, changes in IR were not paralleled by changes in A-FABP.

Conclusions: Circulating A-FABP was correlated with markers of obesity, but had no major impact on IR, inflammation, or hyperandrogenemia in PCOS women.

Free access

Retinol-binding protein 4 is associated with insulin resistance, but appears unsuited for metabolic screening in women with polycystic ovary syndrome.

Matthias Möhlig, Martin O Weickert, Elham Ghadamgahi, Ayman M Arafat, Joachim Spranger, Andreas F H Pfeiffer, and Christof Schöfl

Objective

Adiposity, insulin resistance (IR), and hyperandrogenism are features of polycystic ovary syndrome (PCOS). Retinol-binding protein 4 (RBP4) secreted from adipose and liver tissues has been linked to IR. The impact of RBP4 on IR in PCOS and its usability to identify women with metabolic syndrome (MS) or impaired glucose tolerance ((IGT) or diabetes) were investigated.

Design

Plasma RBP4 was determined in 115 consecutive PCOS women. Associations with IR, body composition, and hyperandrogenemia were investigated by correlation and multiple linear regression analyses in 110 non-diabetics. Receiver operating characteristic curve analysis was used to evaluate RBP4 as a parameter for identifying MS and IGT or diabetes.

Results

RBP4 increased over tertiles of IR (P=0.009). RBP4 correlated with HOMA %S (R=−0.286, P= 0.002), waist-to-hip ratio (WHR) (R=0.233, P=0.034), and dual energy X-ray absorptiometry (DEXA)-lean body mass (R=0.282, P=0.016) but not with body mass index (BMI), DEXA-total or -trunk fat mass, hsCRP, free testosterone, DHEAS, androstenedione, and 17β-estradiol. Adjusted for age, BMI, smoking, and IGT, the association between RBP4 and HOMA %S remained significant (P=0.032). RBP4 explained 4.6% of the variation in HOMA %S. RBP4 was higher in MS and IGT or diabetes, but its ability to identify these women was low (area under the curve, AUC=0.631, P=0.041 or AUC=0.660, P=0.016).

Conclusions

In PCOS, RBP4 has a small independent impact on IR. It is not correlated with hyperandrogenemia, 17β-estradiol, other adrenal steroids, or with markers of adiposity in general. Furthermore, RBP4 does not appear suitable for screening MS or impaired glucose metabolism (IGT or diabetes).

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Acromegaly per se does not increase the risk for coronary artery disease

Hiroyoshi Akutsu, Jürgen Kreutzer, Gerald Wasmeier, Dieter Ropers, Christian Rost, Matthias Möhlig, Henri Wallaschofski, Michael Buchfelder, and Christof Schöfl

Context

Information about the risk and course of coronary artery disease (CAD) in acromegaly is limited.

Objective

To evaluate CAD risk in acromegalic patients at diagnosis and after successful treatment during follow-up.

Subjects and methods

Twenty-five consecutive patients (age 45.1±10.6 years, 15 women) were studied at the time of diagnosis, and 19 patients were re-evaluated after 4.6±1.1 years. The European Society of Cardiology (ESC) risk score was calculated, and a cardiac computed tomography was performed for detection and quantification (Agatston score (AS)) of coronary artery calcium (CACs). Fifty age-, sex-, and CAD risk-matched subjects and CAC data from the population-based Heinz Nixdorf Recall (HNR) study served as controls.

Results

In 21 of the 25 patients, the 10-year risk of developing CAD according to the ESC risk score was low (<10%) and high (>20%) in four patients. The AS was lower than in controls (2.6±7.9 vs 66±182; P=0.014) and less patients had a positive CAC (AS>0) (20 vs 48%, P=0.024), which in the acromegalic patients was less than expected from the HNR study. The AS did not correlate with GH excess or disease duration. In 19 acromegalic patients, who were in remission and re-evaluated after 4.6±1.1 years, the ESC risk (P=0.102) and the AS (P=0.173) did not change significantly and no symptomatic CAD event occurred.

Conclusion

CAD risk in newly diagnosed acromegalic patients was low and remained stable after successful treatment. CAC was lower than in controls suggesting that GH excess per se does not carry an additional CAD risk.

Free access

The androgen receptor CAG repeat modifies the impact of testosterone on insulin resistance in women with polycystic ovary syndrome

Matthias Möhlig, Annette Jürgens, Joachim Spranger, Kurt Hoffmann, Martin O Weickert, Hans W Schlösser, Thilo Schill, Georg Brabant, Andreas Schüring, Andreas F H Pfeiffer, Jörg Gromoll, and Christof Schöfl

Objective: Hyperandrogenism is a central feature of the polycystic ovary syndrome (PCOS) and might worsen insulin resistance (IR) often seen in PCOS. Androgens act through the androgen receptor (AR). A polymorphic CAG repeat sequence within the AR gene was reported to modulate its transactivation activity. Therefore, we investigated a putative interaction between testosterone and the CAG repeat length polymorphism with respect to IR.

Design: In 63 PCOS women with normal glucose tolerance free testosterone, the biallelic CAG repeat length and a multiplicative interaction term were investigated by multiple linear regression analysis for an association with IR as indicated by the homeostasis model assessment of IR (HOMA-IR).

Results: Free testosterone was correlated with HOMA-IR. The impact of testosterone on HOMA-IR was modified by the AR CAG length as indicated by an interaction term. This interaction remained significant after adjustment for smoking, age and body mass index. While there was a positive association of free testosterone with HOMA-IR, the interaction term was inversely associated. The model, which explained 42.5% of the variation of HOMA-IR predicted that in carriers of short CAG lengths, an increase in testosterone increased IR. This effect attenuated with rising biallelic CAG length until it turns into the opposite at a CAG length longer than 23. The results were confirmed by using CIGMA as another measure of IR.

Conclusions: The association between testosterone and IR is modified by the CAG repeat polymorphism within the AR. Therefore, the evaluation of testosterone effects on IR seems to require consideration of the AR CAG repeat polymorphism in PCOS women.

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Androgen receptor CAG repeat length polymorphism modifies the impact of testosterone on insulin sensitivity in men

Matthias Möhlig, Ayman M Arafat, Martin A Osterhoff, Frank Isken, Martin O Weickert, Joachim Spranger, Andreas F H Pfeiffer, and Christof Schöfl

Objective

Low circulating testosterone concentrations have been associated with insulin resistance (IR). Androgen action is mediated by the androgen receptor (AR) whose activity is modulated by a polymorphic CAG repeat sequence within exon 1. An interaction between testosterone and CAG repeat length (CAG length) with respect to IR has been described in women.

Objective

We investigated such a putative interaction between testosterone and the CAG length with respect to IR in men with normal glucose tolerance.

Design

Cross-sectional study.

Methods

In 113 non-diabetic men calculated free testosterone, the CAG length, and a multiplicative interaction term were investigated by multiple linear regression analysis for an association with IR, as indicated by homeostasis model assessment (HOMA %S).

Results

In a multivariate regression analysis adjusted for age and body mass index, free testosterone, CAG length, and a multiplicative interaction term were significantly associated with IR (P=0.001, P=0.001, P=0.01 respectively). The model explained 36.6% of the variation of IR and predicted that in carriers with a CAG length of 23, changes in testosterone would only minimally affect IR. For CAG lengths longer than 23, however, an increase in testosterone would improve IR, namely the longer the CAG length, the greater the effect. In contrast, in the case of CAG lengths shorter than 23, the effect of increasing testosterone would be the opposite.

Conclusions

In men, testosterone and the AR CAG repeat length polymorphism interacted with respect to IR. The interpretation of the association between testosterone and IR seems to require consideration of the AR CAG repeat polymorphism.

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Predictors of abnormal glucose metabolism in women with polycystic ovary syndrome

Matthias Möhlig, Joachim Spranger, Michael Ristow, Andreas F H Pfeiffer, Thilo Schill, Hans W Schlösser, Lothar Moltz, Georg Brabant, and Christof Schöfl

Objective: Polycystic ovary syndrome (PCOS) is a risk factor for type 2 diabetes mellitus and screening for abnormal glucose metabolism has been recommended by an oral glucose tolerance test (OGTT). This procedure is time-consuming and inconvenient, limiting its general use. Therefore, an easy method is wanted to separate PCOS women with normal from those with potentially abnormal glucose metabolism.

Design: Simple parameters obtained from 101 consecutive PCOS patients were assessed by receiver operating curve analysis for their ability to predict abnormal glucose metabolism.

Results: Comparing discriminating parameters at defined sensitivities revealed that, assessed by homeostasis model assessment (HOMA), insulin resistance (HOMA%S) had the highest specificitiy. At a cut-off point of 73.1%, HOMA%S had a sensitivity of 95.5% and a specificity of 51.9%. Applying this cut-off separated 59 women who had a high probability of abnormal glucose metabolism from 42 women who were at low risk (less than 2.5%). Fasting insulin was the second-best parameter and had a similar specificity. A screening strategy which applies HOMA%S or fasting insulin could almost halve the number of OGTTs by directing them to those PCOS women most likely to be suffering from abnormal glucose metabolism. The negative predictive value of this strategy was 97%. The strategy was tested and confirmed in a second and independent cohort of 264 PCOS women.

Conclusions: HOMA%S, or to a lesser extent fasting insulin, appears to allow for stratified metabolic screening of PCOS women with OGTT.

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Long-term outcome in patients with acromegaly: analysis of 1344 patients from the German Acromegaly Register

Christof Schöfl, Holger Franz, Martin Grussendorf, Jürgen Honegger, Cornelia Jaursch-Hancke, Bernhard Mayr, Jochen Schopohl, and the participants of the German Acromegaly Register

Background

Acromegaly is a rare disease with significant morbidity and increased mortality. Epidemiological data about therapeutic outcome under ‘real life’ conditions are scarce.

Objective

To describe biochemical long-term outcome of acromegaly patients in Germany.

Design and methods

Retrospective data analysis from 1344 patients followed in 42 centers of the German Acromegaly Register. Patients' data were collected 8.6 (range 0–52.6) years after diagnosis. Controlled disease was defined by an IGF1 within the center-specific reference range.

Results

Nine hundred and seventeen patients showed a normalized IGF1 (157 (range 25–443) ng/ml). In patients with a diagnosis dated back >2 years (n=1013), IGF1 was normalized in 76.9%. Of the patients, 19.5% had an elevated IGF1 and a random GH ≥1 ng/ml, 89% of the patients had at least one surgical intervention, 22% underwent radiotherapy, and 43% received medical treatment. After surgery 38.8% of the patients were controlled without any further therapy. The control rates were higher in surgical centers with a higher caseload (P=0.034). Of the patients with adjunctive radiotherapy 34.8% had a normal IGF1 8.86 (0–44.9) years post irradiation, 65.2% of the medically treated patients were controlled, and 47.2% of the patients with an elevated IGF1 received no medical therapy.

Conclusion

The majority of acromegaly patients were controlled according to their IGF1 status. Long-term outcome could be improved by exploiting medical treatment options especially in patients who are not controlled by surgery and/or radiotherapy.