Jens Peter Kroustrup

Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients: a randomised, double-blind, placebo-controlled trial.

BACKGROUND Weight-loss drugs produce an additional mean weight loss of only 3-5 kg above that of diet and placebo over 6 months, and more effective pharmacotherapy of obesity is needed. We assessed the efficacy and safety of tesofensine-an inhibitor of the presynaptic uptake of noradrenaline, dopamine, and serotonin-in patients with obesity. METHODS We undertook a phase II, randomised, double-blind, placebo-controlled trial in five Danish obesity management centres. After a 2 week run-in phase, 203 obese patients (body-mass index 30-</=40 kg/m(2)) were prescribed an energy restricted diet and randomly assigned with a list of randomisation numbers to treatment with tesofensine 0.25 mg (n=52), 0.5 mg (n=50), or 1.0 mg (n=49), or placebo (n=52) once daily for 24 weeks. The primary outcome was percentage change in bodyweight. Analysis was by modified intention to treat (all randomised patients with measurement after at least one dose of study drug or placebo). The study is registered with ClinicalTrials.gov, number NCT00394667. FINDINGS 161 (79%) participants completed the study. After 24 weeks, the mean weight loss produced by diet and placebo was 2.0% (SE 0.60). Tesofensine 0.25 mg, 0.5 mg, and 1.0 mg and diet induced a mean weight loss of 4.5% (0.87), 9.2% (0.91), and 10.6% (0.84), respectively, greater than diet and placebo (p<0.0001). The most common adverse events caused by tesofensine were dry mouth, nausea, constipation, hard stools, diarrhoea, and insomnia. After 24 weeks, tesofensine 0.25 mg and 0.5 mg showed no significant increases in systolic or diastolic blood pressure compared with placebo, whereas heart rate was increased by 7.4 beats per min in the tesofensine 0.5 mg group (p=0.0001). INTERPRETATION Our results suggest that tesofensine 0.5 mg might have the potential to produce a weight loss twice that of currently approved drugs. However, these findings of efficacy and safety need confirmation in phase III trials.

Comparison of gene expression in intra-abdominal and subcutaneous fat: a study of men with morbid obesity and nonobese men using microarray and proteomics.

Abstract: Extent of intra‐abdominal fat had significant linear relations with six metabolic coronary risk factors: systolic and diastolic blood pressure, fasting blood concentrations of glucose, high density lipoprotein (HDL) cholesterol, triglyceride, and plasminogen activator inhibitor‐1. Tumor necrosis factor‐α and adiponectin can be biological mediators from the intra‐abdominal fat to the metabolic coronary risk factors. Complementarily, we describe a new study that will analyze the gene expression in intra‐abdominal and subcutaneous fat on mRNA and protein level using high throughput methods. The study will elucidate further whether intra‐abdominal obesity is the common denominator for the different components of the metabolic syndrome.

Circulating levels of insulin-like growth factor-II/mannose-6-phosphate receptor in obesity and type 2 diabetes

OBJECTIVE The extracellular domain of the insulin-like growth factor II/mannose-6-phosphate receptor (IGF-II/M6P-R) is present in the circulation, but its relationship with plasma IGF-II is largely unknown. As IGF-II appears to be nutritionally regulated, we studied the impact of obesity, type 2 diabetes (T2D) and weight loss on circulating levels of IGF-II and its soluble receptor. METHODS Twenty-three morbidly obese non-diabetic subjects were studied before and after gastric banding (GB), reducing their BMI from 59.3+/-1.8 to 52.7+/-1.6 kg/m(2). Lean controls (n=10, BMI 24.2+/-0.5 kg/m(2)), moderately obese controls (n=21, BMI 31.8+/-1.0 kg/m(2)) and obese T2D patients (n=20, BMI 32.3+/-0.8 kg/m(2)) were studied before and after a hyperinsulinaemic euglycaemic clamp. RESULTS Morbidly obese subjects had elevated IGF-II/M6P-R and IGF-II levels, which both decreased following GB (IGF-II/M6P-R: from 0.97+/-0.038 to 0.87+/-0.030 nmol/l, P=0.001; IGF-II: from 134+/-7 to 125+/-6 nmol/l, P=0.01), as did fasting plasma glucose and insulin (P<0.05). However, the metabolic parameters correlated with neither IGF-II nor IGF-II/M6P-R. Obese diabetics had increased IGF-II/M6P-R as compared with lean and obese controls (0.82+/-0.031 vs. 0.70+/-0.033 vs. 0.74+/-0.026 nmol/l; P<0.03) and levels were unaffected by clamp. In the latter cohort, IGF-II/M6P-R but not IGF-II correlated with HbA1c, and fasting plasma C-peptide, insulin and glucose (0.34<r<0.45; P<0.05). In all subjects, BMI correlated with IGF-II/M6P-R (r=0.57; P<0.001) and IGF-II (r=0.39; P<0.005). IGF-II/M6P-R and IGF-II were not associated. CONCLUSION Serum IGF-II/M6P-R is up-regulated in morbid obesity, down-regulated by weight loss and elevated in moderately obese T2D. However, although plasma IGF-II was also reduced following GB, the two peptides were not statistically correlated. No acute effect of insulin was seen. These findings indicate that the IGF-II/M6P-R is nutritionally regulated, independently of IGF-II.

Characteristics of the Danish families with multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 (MEN1) is caused by autosomal dominantly inherited mutations in the MEN1 gene. Here, we report 25 MEN1 mutations - of which 12 are novel - found in 36 Danish families with MEN1 or variant MEN1 disease. Furthermore, one FIHP family was found to have an earlier reported mutation. The mutations were predominantly found in exons 9 and 10 encoding the C-terminal part of menin. Seven of the mutations were missense mutations, changing conserved residues. Furthermore screening of 93 out of 153 consecutive patients with primary hyperparathyroidism (pHPT) identified five mutation carriers. Two of these belonged to known MEN1 families, whereas the only MEN1-related disease in the other three was pHPT. Screening of 96 consecutive patients with fore-/midgut endocrine tumours revealed five mutation carries out of 28 patients with sporadic gastrinomas, whereas no mutations were found in 68 patients with other fore-/midgut endocrine tumours. Moreover, screening of 60 consecutive patients with primary prolactinoma did not identify any mutation carriers. Our data indicate that MEN1 mutation screening is efficient in patients with familial MEN1. Screening should also be offered to patients with pHPT or gastrinomas after thorough investigation into the family history. In contrast, sporadic carcinoid tumours or primary prolactinomas are rarely associated with germ-line MEN1 mutations.

Distribution of RET mutations in multiple endocrine neoplasia 2 in Denmark 1994-2014: a nationwide study

Background: Germline mutations of the REarranged during Transfection (RET) proto-oncogene cause multiple endocrine neoplasia 2 (MEN2). It is unclear whether the distribution of RET mutations varies among populations. The first nationwide study of the distribution of RET mutations was conducted, and the results were compared to those of other populations. Methods: This retrospective cohort study included 1583 patients who underwent RET gene testing in one of three centers covering all of Denmark between September 1994 and December 2014. Primary testing method was Sanger sequencing, which included exons 8–11 and 13–16. Mutations were defined according to the ARUP database July 1, 2016. Results: RET mutations were identified in 163 patients from 36 apparently unrelated families. Among the 36 families 13 (36.1%) carried mutations in codon 611, four (11.1%) in codon 618, three (8.3%) in codon 620, one (2.8%) in codon 631, six (16.7%) in codon 634, one (2.8%) in codon 790, one (2.8%) in codon 804, one (2.8%) in codon 852, one (2.8%) in codon 883, and five (13.9%) in codon 918. Among the 13 families with codon 611 mutations, 12 had the p.C611Y mutation. Conclusions: The distribution of RET mutations in Denmark appears to differ from that of other populations. Mutations in codon 611 were the most prevalent, followed by more frequently reported mutations. This might be due to a possible founder effect for the p.C611Y mutation. However, further studies are needed to find possible explanations for the skewed mutational spectrum in Denmark.

Incidence and prevalence of multiple endocrine neoplasia 2B in Denmark: a nationwide study

Multiple endocrine neoplasia 2B (MEN2B) is an autosomal dominant inherited cancer syndrome associating medullary thyroid carcinoma (MTC), pheochromocytoma (PHEO), ganglioneuromatosis of the aerodigestive tract and facial, ophthalmologic and skeletal abnormalities. MEN2B is caused by the M918T and A883F mutation of the REarranged during Transfection (RET) proto-oncogene in approximately 95% and <5% of cases, respectively. Only very few other mutations have been reported to cause MEN2B. In approximately 75% of MEN2B patients, mutations occur as de novo (Wells et al. 2015). The epidemiology of MEN2B is poorly defined. A nationwide study from Northern Ireland reported of three MEN2B patients and 1,824,000 inhabitants alive at April 21, 2012, yielding a point prevalence of 1.65 per million (Znaczko et al. 2014). However, it is unclear if this is representative of larger populations. A German study reported an MEN2B incidence (M918T carriers only) of 1.4 per million live births per year from 1991 to 2000 and estimated that at least half of all German RET carriers were captured (Machens et al. 2013). Meanwhile, the incidence of MEN2B and M918T carriers in a complete population is undisclosed. We conducted a nationwide study of the incidence and prevalence of MEN2B in Denmark from 1941 to 2014. This retrospective cohort study included 12 unique MEN2B patients identified through the following sources:

Founder Effect of the RETC611Y Mutation in Multiple Endocrine Neoplasia 2A in Denmark: A Nationwide Study

BACKGROUND Multiple endocrine neoplasia (MEN) 2A and 2B are caused by REarranged during Transfection (RET) germline mutations. In a recent nationwide study, an unusually high prevalence (33%) of families with the C611Y mutation was reported, and it was hypothesized that this might be due to a founder effect. The first nationwide study of haplotypes in MEN2A families was conducted, with the aim of investigating the relatedness and occurrence of de novo mutations among Danish families carrying similar mutations. METHODS The study included 21 apparently unrelated MEN2A families identified from a nationwide Danish RET cohort from 1994 to 2014. Twelve, two, two, three, and two families carried the C611Y, C618F, C618Y, C620R, and C634R mutations, respectively. Single nucleotide polymorphism chip data and identity by descent analysis were used to assess relatedness. RESULTS A common founder mutation was found among all 12 C611Y families and between both C618Y families. No relatedness was identified in the remaining families. CONCLUSION The data suggest that all families with the C611Y germline mutation in Denmark originate from a recent common ancestor, probably explaining the unusually high prevalence of this mutation. Additionally, the results indicate that the C611Y mutation rarely arises de novo, thus underlining the need for thorough multigenerational genetic work up in carriers of this mutation.

Incidence and prevalence of multiple endocrine neoplasia 2A in Denmark 1901–2014: a nationwide study

Background The incidence and prevalence of multiple endocrine neoplasia 2A (MEN2A) have only been reported once in a nationwide setting. However, it is unclear whether the figures are representative of other populations, as the major component of the syndrome, hereditary medullary thyroid carcinoma (MTC), has been reported as rare in the same country. We conducted a nationwide retrospective cohort study of MEN2A in Denmark from 1901 to 2014, aiming to describe the incidence and prevalence. Methods This study included 250 unique MEN2A patients born or resident in Denmark before December 31, 2014. Patients were identified through the Danish REarranged during Transfection (RET) cohort, linkage of MEN2A pedigrees, the Danish MTC cohort, a nationwide collaboration of MEN2 centers, cross-checking of other relevant cohorts, and a systematic literature search. Results The incidence from 1971 to 2000 was 28 (95% CI: 21–37) per million live births per year. Incidence for the specific mutations or for the overall MEN2A group did not change significantly from 1901 to 2014 (P>0.05). Point prevalence at January 1, 2015, was 24 per million (95% CI: 20–28). Conclusion The incidence and prevalence of MEN2A in Denmark seem higher than those reported in other countries. This is likely explained by the Danish C611Y founder effect. Also, our data indicate no significant change in MEN2A incidence during the last century.

Neuromas in Multiple Endocrine Neoplasia Type 2A with a RET Codon 611 Mutation

A large kindred with autosomal dominantly inherited multiple endocrine neoplasia type 2 (MEN 2) was followed for clinical and biochemical signs of the disease. A family-specific germline mutation in the RET proto-oncogene was found in exon 10 at codon 611, altering a cysteine (TGC) to a tyrosine (TAC). All five family members who are RET mutation positive had medullary thyroid carcinoma (MTC) or Ccell hyperplasia. In addition, two had phaeochromocytoma and another hyperparathyroidism. These comprise the classical signs of MEN 2A. Of interest, one family member with MTC and phaeochromocytoma also had neuromas on the lip, a feature often associated with MEN 2B. A female member with papillary thyroid carcinoma did not carry the codon 611 mutation. It is possible that overlap may exist between the clinical presentations of MEN 2A and MEN 2B.