The Transatlantic HbA1c gap: differences in glycaemic control across the lifespan between people included in the US T1D Exchange Registry and those included in the German/Austrian DPV registry.

AIM: To compare HbA1c levels across the lifespan in people with type 1 diabetes in the USA with those in Germany/Austria, and to examine potential differences in HbA1c levels between sexes, insulin delivery methods and minority status. METHODS: Data were extracted from the US T1D Exchange Registry (n=18 381 participants from 73 sites) and from the German/Austrian Prospective Diabetes Follow-up Registry, the DPV (n=32 643 participants from 362 sites). Mean HbA1c was calculated for each year of age for individuals aged ≤25 years, and at 2-year age intervals for individuals aged >25 years. Curves for mean HbA1c by age were estimated using locally weighted scatterplot smoothing. HbA1c differences between registries, sexes, insulin delivery methods, and minority status were assessed by age group using multiple linear regression. RESULTS: In both registries, mean HbA1c increased by ~11 mmol/mol (1.0%) between the ages of 9 and 18 years, although at quite different absolute levels: from 66 mmol/mol (8.2%) to 77 mmol/mol (9.2%) in the T1D Exchange Registry, and from 56 mmol/mol (7.3%) to 66 mmol/mol (8.2%) in the DPV. Sex differences were observed in the DPV only. In the T1D Exchange Registry, injection users had higher mean HbA1c than pump users across the lifespan, whereas in the DPV higher HbA1c levels in injection users were observed in the age groups 6 to <12 years, 12 to <18 years, and 30 to <50 years (P < 0.001). Minority status was significantly associated with higher HbA1c in most age groups in both registries. CONCLUSIONS: Significant differences in HbA1c were noted between the USA and Germany/Austria, with disparities more pronounced in early childhood through to young adulthood. Further studies should identify causes for these disparities.

In a sweet mood? Effects of experimental modulation of blood glucose levels on mood-induction during fMRI.

Glucose is the primary source of energy for the human brain. Previous literature has shown that varying blood glucose levels may have a strong impact on behaviour, subjective mood, and the intensity of the BOLD signal measured in fMRI. Therefore, blood glucose levels varying even within the normal range may interact with cognitive and emotional processing as well as BOLD signal. Here, in a placebo-controlled, double-blind crossover study on 20 healthy women, we show that overnight fasting, compared to an elevated glucose condition, influences brain activation and the affective state during mood induction. Results indicate that our brain may compensate for low glucose levels during fasting by stronger recruitment of the brain areas relevant to the task at hand. Additionally, we systematically tested the effect of prior cognitive effort on behavioural and neural patterns and found that elevated activation is only associated with maintained performance as long as no prior cognitively challenging task is administered. Prior cognitive effort leads to deteriorated performance and a further increase in emotion-associated brain activation in the pregenual anterior and posterior cingulate, the superior frontal gyrus, and the pre-SMA. These results are in line with the strength model of self-regulation. Our results corroborate the strength model of self-regulation and extend it to affect regulation processes. Additionally, our observations suggest that experimentally controlling for fasting state or glucose levels may be beneficial, especially when studying processes that involve self-regulation.

Gender-specific co-activation of arginine vasopressin and the hypothalamic-pituitary-adrenal axis during stress.

OBJECTIVE: To study the interaction between copeptin and hypothalamic-pituitary-adrenal (HPA) activation in men and women during hypoglycaemic stress. DESIGN AND PATIENTS: A prospective study in 118 patients (mean age 47·7 ± 13·6 years, n = 52 women) undergoing insulin tolerance testing for suspected pituitary dysfunction. MEASUREMENTS: Serum copeptin was measured in serially collected blood samples and assessed in relation to ACTH, cortisol and other endocrine parameters. RESULTS: Symptomatic hypoglycaemia (mean glucose nadir, 1·6 ± 0·5 mmol/l) resulted in a rapid significant increase of serum copeptin. Individuals with impaired pituitary function had lower stress-induced copeptin levels (median, 6·26 pmol/l) than patients with intact pituitary (8·46 pmol/l, P < 0·001). A weak overall correlation between stress-induced copeptin and cortisol levels was observed (rs  = 0·31, P < 0·001). In female individuals, there was a positive correlation between stress-induced copeptin and ACTH (rs  = 0·47, P < 0·001) or cortisol levels (rs  = 0·42, P = 0·002), while in males, no correlation with ACTH levels (rs  = 0·03, P = 0·75) and poor correlation with cortisol levels (rs  = 0·24, P = 0·045) was observed. Patients with central diabetes insipidus showed lowest baseline (2·20 pmol/l) and stimulated copeptin levels (3·68 pmol/l). CONCLUSIONS: The data from this study indicate that stress-induced release of AVP in women, but not in men, is linked to the co-activation of the hypothalamic-pituitary-adrenal system.

Glycaemic control of Type 1 diabetes in clinical practice early in the 21st century: an international comparison.

AIMS: Improving glycaemic control in people with Type 1 diabetes is known to reduce complications. Our aim was to compare glycaemic control among people with Type 1 diabetes using data gathered in regional or national registries. METHODS: Data were obtained for children and/or adults with Type 1 diabetes from the following countries (or regions): Western Australia, Austria, Denmark, England, Champagne-Ardenne (France), Germany, Epirus, Thessaly and Thessaloniki (Greece), Galway (Ireland), several Italian regions, Latvia, Rotterdam (The Netherlands), Otago (New Zealand), Norway, Northern Ireland, Scotland, Sweden, Volyn (Ukraine), USA and Wales) from population or clinic-based registries. The sample size with available data varied from 355 to 173 880. Proportions with HbA1c < 58 mmol/mol (< 7.5%) and ≥ 75 mmol/mol (≥ 9.0%) were compared by age and sex. RESULTS: Data were available for 324 501 people. The proportions with HbA1c 58 mmol/mol (< 7.5%) varied from 15.7% to 46.4% among 44 058 people aged < 15 years, from 8.9% to 49.5% among 50 766 people aged 15-24 years and from 20.5% to 53.6% among 229 677 people aged ≥ 25 years. Sex differences in glycaemic control were small. Proportions of people using insulin pumps varied between the 12 sources with data available. CONCLUSION: These results suggest that there are substantial variations in glycaemic control among people with Type 1 diabetes between the data sources and that there is room for improvement in all populations, especially in young adults.

Elevation of plasma 1-deoxy-sphingolipids in type 2 diabetes mellitus: a susceptibility to neuropathy?

BACKGROUND AND PURPOSE: Diabetic distal sensorimotor polyneuropathy (DSPN) is a frequent, disabling complication of diabetes mellitus. There is increasing evidence that sphingolipids play a role in insulin resistance and type 2 diabetes (T2DM). Whether neurotoxic 1-deoxy-sphingolipids are elevated in DSPN patients' plasma and whether levels correlate to the DSPN stage were examined. METHODS: The plasma profile of 12 sphingoid bases in patients with DSPN and T2DM(n = 39) were cross-sectionally compared to other nerve disorders including chronic inflammatory demyelinating polyneuropathy (CIDP) (n = 13), transthyretin-related familial amyloid polyneuropathy (FAP) (n = 10), amyotrophic lateral sclerosis (ALS) (n = 13) and small fibre neuropathy (n = 12) by liquid chromatography mass spectrometry. Correlations to the DSPN stage were additionally performed. Furthermore, the sphingoid base distribution in sural nerve specimens was measured in patients with DSPN (n = 6) compared to CIDP (n = 3). RESULTS: A significantly increased amount of 1-deoxy-sphingolipids [1-deoxy-sphinganine (0.11 ± 0.06 µmol/l), 1-deoxy-sphingosine (0.24 ± 0.16 µmol/l)] in patients with DSPN was observed compared to age-matched healthy controls (0.06 ± 0.03 µmol/l; 0.12 ± 0.05 µmol/l) and to the other groups. (Para)clinical parameters including sensory loss, neuropathic pain, weakness, vibration perception, nerve conduction velocity, sensory nerve action potentials (sural nerve) and duration of T2DM did not correlate with plasma 1-deoxy-sphingolipid levels, neither did the clinical stage according to the Dyck classification for DSPN. Sphingolipid levels in sural nerve biopsies showed no differences between DSPN and CIDP. Contrarily, patients with a small fibre neuropathy had decreased C20-sphingosine plasma levels. CONCLUSION: 1-deoxy-sphingolipid plasma levels are significantly elevated in DSPN. They are already detectable in early disease stages but do not correlate with the clinical course. Further knowledge on 1-deoxy-sphingolipids might lead to a better pathophysiological understanding and future treatment options in DSPN.

Daily insulin doses and injection frequencies of neutral protamine hagedorn (NPH) insulin, insulin detemir and insulin glargine in type 1 and type 2 diabetes: a multicenter analysis of 51 964 patients from the German/Austrian DPV-wiss database.

BACKGROUND: We performed a comparative analysis of the use of long-acting insulin (analogues) neutral protamine hagedorn (NPH), detemir (Det) and glargine (Gla), and quantified injection frequencies and daily insulin doses in patients with type 1 and 2 diabetes in daily practice. METHODS: A total number of 51 964 patients from 336 centres in Germany and Austria with type 1 and 2 diabetes with exclusive insulin therapy were retrospectively analysed. RESULTS: A total number of 42.1%/75.9% (type 1/type 2) of patients used NPH, 19.9%/6.7% Det and 38.0%/17.4% Gla, with similar glycaemic control and proportion of severe hypoglycaemia for NPH/Det/Gla in type 1 (Mean HbA(1c) 7.98%/7.98%/8.07%; mean proportion of severe hypoglycaemia 11.06%/11.93%/10.86%) and type 2 diabetes (Mean HbA(1c) 7.61%/7.78%/7.61%; mean proportion of severe hypoglycaemia 5.66%/4.48%/5.03%). In type 1 diabetes, the mean daily injection frequencies of NPH versus Det versus Gla were 1.9 vs 1.8 vs 1.1, and total daily insulin injections were 5.3 vs 5.6 vs 5.0. The adjusted mean daily basal insulin doses were 0.36, 0.39 and 0.31 IU/kg, mean daily total insulin dose was lowest for Gla (0.74 IU/kg), followed by NPH (0.76 IU/kg) and Det (0.81 IU/kg). In type 2 diabetes patients, mean daily injection frequencies were 1.6 for NPH, 1.4 for Det and 1.1 for Gla, total daily insulin injections were 4.0 vs 4.1 vs 3.6. The mean daily basal insulin dosages were 0.30 IU/kg (NPH), 0.33 IU/kg (Det) and 0.29 IU/kg (Gla), mean total insulin doses per day were 0.63 IU/kg (NPH), 0.77 IU/kg (Det) and 0.67 IU/kg (Gla). CONCLUSIONS: In a 'real-world' setting, the injection frequencies and doses of basal and total insulin per day are lowest with the use of insulin glargine compared with NPH-insulin or insulin detemir at similar glycaemic control and rates of severe hypoglycaemia.

[Update of the S2k guidelines : Surgical treatment of benign thyroid diseases]. / Aktualisierung der S2k-Leitlinie : Operative Therapie benigner Schilddrüsenerkrankungen.

Thyroid resections represent one of the most common operations with 76,140 interventions in the year 2016 in Germany (source Destatis). These are predominantly benign thyroid gland diseases. Recommendations for the operative treatment of benign thyroid diseases were last published by the CAEK in 2010 as S2k guidelines (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V. [AWMF] 003/002) against the background of increasingly more radical resection procedures. Hemithyroidectomy and thyroidectomy are routinely performed for benign thyroid disease in practice. The operation-specific risks show a clear increase with the extent of the resection. Therefore, weighing-up of the risk-indications ratio between unilateral lobectomy or thyroidectomy necessitates an independent evaluation of the indications for both sides. This principle in particular has been used to update the guidelines. In addition, the previously published recommendations of the CAEK for correct execution and consequences of intraoperative neuromonitoring were included into the guidelines, which in particular serve the aim to avoid bilateral recurrent laryngeal nerve paralysis. Moreover, the recommendations for the treatment of postoperative complications, such as hypoparathyroidism and postoperative infections were revised. The updated guidelines therefore represent the current state of the science as well as the resulting surgical practice.

Developing effective screening strategies in multiple endocrine neoplasia type 1 (MEN 1) on the basis of clinical and sequencing data of German patients with MEN 1.

BACKGROUND: Multiple-endocrine-neoplasia-type-1 (MEN1) is an autosomal-dominant inherited disorder characterized by the combined occurrence of primary hyperparathyroidism (pHPT), gastroenteropancreatic neuroendocrine tumors (GEP), adenomas of the pituitary gland (APA), adrenal cortical tumors (ADR) and other tumors. As the tumors appear in an unpredictable schedule, uncertainty about screening programs is persisting. OBJECTIVE: To optimize screening and to analyze possible differences in sporadic versus familial cases. METHODS: We analyzed data of 419 individuals including 306 MEN-1 patients (138 isolated and168 familial cases out of 102 unrelated families). RESULTS: A total of 683 tumors occurred consisting of 273 pHPT, 138 APA, 166 GEP, 57 ADR, 24 thymic- and bronchial-carcinoids as well as 25 neoplasms of other tissues. The age-related penetrance was determined as 10%, 35%, 67%, 81% and 100% at 20, 30, 40, 50 and 65 years respectively. Although pHPT being the most frequent first manifestation (41%), also GEP (22%) or APA (21%) were found to be the first presentation. APA occurred significantly more frequent (p<0,05) in isolated (n=138) than in familial (n=168) cases, whereas GEP showed a tendency to occur more often in familial cases. Genotype/phenotype correlation in 140 clinically affected MEN-1 cases showed a tendency for truncating mutations, especially nonsense mutations to be associated to GEP and carcinoids of the lungs and thymus. CONCLUSION: In view of the morbidity and frequency in familial cases an effective screening programme should aim at an early diagnosis of GEP particularly when truncating, especially nonsense mutations are found.

Prolonged fasting impairs neural reactivity to visual stimulation.

Previous literature has shown that hypoglycemia influences the intensity of the BOLD signal. A similar but smaller effect may also be elicited by low normal blood glucose levels in healthy individuals. This may not only confound the BOLD signal measured in fMRI, but also more generally interact with cognitive processing, and thus indirectly influence fMRI results. Here we show in a placebo-controlled, crossover, double-blind study on 40 healthy subjects, that overnight fasting and low normal levels of glucose contrasted to an activated, elevated glucose condition have an impact on brain activation during basal visual stimulation. Additionally, functional connectivity of the visual cortex shows a strengthened association with higher-order attention-related brain areas in an elevated blood glucose condition compared to the fasting condition. In a fasting state visual brain areas show stronger coupling to the inferior temporal gyrus. Results demonstrate that prolonged overnight fasting leads to a diminished BOLD signal in higher-order occipital processing areas when compared to an elevated blood glucose condition. Additionally, functional connectivity patterns underscore the modulatory influence of fasting on visual brain networks. Patterns of brain activation and functional connectivity associated with a broad range of attentional processes are affected by maturation and aging and associated with psychiatric disease and intoxication. Thus, we conclude that prolonged fasting may decrease fMRI design sensitivity in any task involving attentional processes when fasting status or blood glucose is not controlled.

Molecular cloning of murine ICA69: diabetes-prone mice recognize the human autoimmune-epitope, Tep69, conserved in splice variants from both species.

The islet cell antigen ICA69 is an autoimmune target in most patients with insulin-dependent diabetes. Understanding its role in diabetic autoimmunity would be facilitated by an animal model. We therefore cloned mouse ICA69. The different splice variants now identified conserve Tep69, the single T cell epitope recognized by patient T cells. We show that diabetes-prone NOD mice had Tep69-specific, autoreactive T cell repertoires and thus provide a relevant model for the study of ICA69's role in diabetic autoimmunity.

Primary structure, gene expression and chromosomal mapping of rodent homologs of the MEN1 tumor suppressor gene.

Mutations of the MEN1 tumor suppressor gene cause the multiple endocrine neoplasia type 1 (MEN1) syndrome in humans, and they are involved in a variety of sporadic human endocrine tumors. We here characterize the MEN1 gene homologs of the mouse and rat. cDNA was isolated from a mouse phage library, and two alternative MEN1 mRNA transcripts containing variant 5' untranslated regions were identified by RT-PCR in several mouse and rat tissues. When compared to the human molecule, mouse and rat MEN1 (611 and 610 amino acids, respectively) show an overall identity of 96.5% and 97.0% at the protein level, delimiting four conservational domains (A-D). Mouse and rat MEN1 mRNA, as studied by template-calibrated quantitative RT-PCR, is non-exclusively expressed in hematopoietic and endocrine cells, with similar expression patterns found in fetal and adult tissues. Fluorescent in situ hybridization maps the single murine MEN1 locus to chromosome 19, region B. No MEN1 gene mutations were identified in endocrine islet tumor cell lines RIN 5AH (rat) and NIT-1 (mouse) as compared to wild type cDNA. Our data define mouse and rat MEN1 as widely expressed and highly conserved homologs of the human MEN1 tumor suppressor gene whose role in biology and endocrine tumorigenesis is due for experimental study.

Gene expression of islet cell antigen p69 in human, mouse, and rat.

Based on the detection of specific antibodies and T-cell sensitization in patients with IDDM, islet cell antigen p69 (ICAp69) has been suggested to be a target antigen of diabetic autoimmunity. The biological function, tissue expression, and developmental kinetics of ICAp69 are largely unknown. We analyzed ICAp69 expression at the gene transcription and protein level in human and rodent tissues. By using template-calibrated quantitative reverse transcriptase polymerase chain reaction (RT-PCR), high levels of ICAp69 mRNA were found in human pancreatic islets and brain. In mouse and rat, ICAp69 gene expression peaked in islet cell lines followed by testis, islets, and brain. ICAp69 mRNA was found at low levels in other organs by RT-PCR but not by Northern blot analysis. In mice, ICAp69 transcription becomes detectable in fetal life, and fetal and adult gene expression patterns are similar. Western blot analysis of human and mouse tissues showed high expression of ICAp69 in brain, testis, pancreatic tissue, and islet cell lines. In these organs, ICAp69 immunoreactivity is predominately localized at the blood brain barrier (capillary endothelium), at the blood testis barrier (Sertoli cells and spermatids), and in pancreatic islets (beta-cells). The subcellular localization of ICAp69 to endoplasmic reticulum, Golgi complex, and vesicles by immune electron microscopy suggests a role of this neuroendocrine molecule in cellular protein traffic and processing.off

Loss of self-tolerance to ICA69 in nonobese diabetic mice.

Islet cell antigen p69 (ICA69) is a target autoantigen in IDDM. Studies of T-cells from newly diabetic children suggested possible antigenic mimicry between human ICA69 (in particular the Tep69 T-cell epitope, aa 36-47) and the ABBOS region in bovine serum albumin (BSA; aa 152-169), one of several cow's milk proteins that evoke abnormal immunity in diabetes-prone hosts. We recently found the sequence of Tep69 regions to be identical in the four alternatively spliced human and rodent ICA69 isoforms. Immunization of nonobese diabetic (NOD) mice with BSA or ICA69 generates fully cross-reactive T-cell responses to both Tep69 and ABBOS as the immunodominant, naturally generated, and presented T-cell mimicry epitopes. Such responses are absent or weak in healthy strains of mice. NOD mouse recipients of adoptive spleen cell grafts from diabetic donors spontaneously generate easily detectable pools of T-cells specific for ICA69/BSA, as well as the unrelated GAD65. NOD mice injected neonatally with ABBOS or Tep69 show cross-tolerance, but ABBOS-induced tolerance is transient. Neonatal injection of Tep69 reduces disease incidence (23 vs. 68% IDDM, P < 0.02), while neonatal injection of ABBOS has little effect. In contrast, systemic immunization of young NOD females with ABBOS (but not Tep69) reduces the diabetes incidence and delays disease expression, with protected mice generating ABBOS-specific T-cell repertoires unable to recognize the Tep69 mimicry antigen. Our observations demonstrate a loss of self-tolerance to ICA69 in NOD mice, and they establish antigenic mimicry between the two T-cell epitopes in ICA69 and BSA. Further studies are necessary to understand the molecular basis of this mimicry and how either T-cell peptide can modify the disease course.

Immunological aspects of nutritional diabetes prevention in NOD mice: a pilot study for the cow's milk-based IDDM prevention trial.

Human epidemiological studies delineated early exposure to intact dietary protein (e.g., most infant formulas) as an environmental risk factor for the development of IDDM. The Trial to Reduce IDDM in the Genetically at Risk (TRIGR), an international IDDM prevention trial, has been designed to determine if avoidance of intact dairy protein in high-risk infants < or =6 months of age can reduce the subsequent diabetes incidence. We here studied the casein hydrolysate-based trial diet (Nutramigen) in NOD mice. When given either continuously or for 10 weeks after weaning, the test diet was highly effective in preventing autoimmune diabetes (32-week incidence: 4.6 vs. 58.8%) and in preserving pancreatic insulin levels, with little effect on islet inflammation. Spleen cells from protected NOD mice failed to adoptively transfer diabetes into irradiated syngeneic recipients. When co-transferred with splenocytes from diabetic donors, cells from diet-protected mice inhibited adoptive diabetes transfer (incidence 50 vs. 94%, P < 0.001). T-cell reactivity to the islet cell autoantigens ICA69 (islet cell antigen 69) and GAD65 developed only in diabetic recipients of spleen cell grafts, indicating that diabetes protection extends to more than one autoantigen. In protected mice, ICA69 T-cell reactivity was not detectable spontaneously nor after priming with this autoantigen; however, priming with the cross-reactive non-self-antigen bovine serum albumin recruited T-cells responsive to ICA69. Thus, diabetes prevention with the clinical trial diet is effective in NOD mice, where it affects some T-cell repertoires and allows development of regulatory cells that interfere with destructive autoimmunity.

Antibodies against bovine albumin and other diabetes markers in French children.

OBJECTIVE: Findings in epidemiology and animal experimentation suggest that autoimmunity in insulin-dependent diabetes mellitus (IDDM) may be triggered by dietary cow-milk protein, particularly bovine serum albumin (BSA). Elevated IgG anti-BSA antibodies were found in children from Finland with newly onset diabetes; Finland has the highest incidence of diabetes and cow's milk consumption in the world. We now analyze BSA serology and other diabetes markers in school-age children from France, where diabetes incidence and cow's milk consumption are low. RESEARCH DESIGN: Sera were obtained from three groups: newly diagnosed diabetic (n = 43), islet cell antibody-positive (ICA+) nondiabetic (n = 98), and ICA- healthy control children (n = 267). IgG anti-BSA antibody levels were measured blindly using particle concentration fluoroimmunoassays and analyzed in comparison with ICA titers and human leukocyte antigen-DQB genotypes. RESULTS: There were highly significant differences in BSA antibody levels between all three groups (P < 0.0001). Diabetic patients had elevated anti-BSA levels in 74.4% of cases, compared with 5.5% of control children. In the group of ICA+ non-diabetic children, 20% were anti-BSA-positive. Neither ICA nor BSA antibody titers were significantly related to DQB genotype or sex. ICA titers ( > or = 4 Juvenile Diabetes Foundation units) were present in 84% of diabetic children. Two-thirds of diabetic children were positive for both ICA and anti-BSA antibodies, and none were negative for both markers. CONCLUSIONS: Elevated IgG anti-BSA levels are associated with IDDM in the low-incidence French population. In newly diagnosed diabetic children, these antibodies have similar specificity (95 vs. 98%) and slightly lower sensitivity for IDDM than ICA (74.4 vs. 83.7%). Our results may support an immunological role of BSA in diabetic autoimmunity.

Self and non-self antigen in diabetic autoimmunity: molecules and mechanisms.

In this article, we have summarized current facts, models and views of the autoimmunity that leads to destruction of insulin-producing beta-cells and consequent Type 1 (insulin-dependent) diabetes mellitus. The presence of strong susceptibility and resistance gene loci distinguishes this condition from other autoimmune disorders, but environmental disease factors must conspire to produce disease. The mapping of most of the genetic risk (or disease resistance) to specific alleles in the major histocompatibility locus (MHC class II) has direct functional implications for our understanding of autoimmunity in diabetes and directly implies that presentation of a likely narrow set of peptides is critical to the development of diabetic autoimmunity. While many core scientific questions remain to be answered, current insight into the disease process is beginning to have direct clinical impact with concerted efforts towards disease prevention or intervention by immunological means. In this process, identification of the critical antigenic epitopes recognized by diabetes-associated T cells has achieved highest priority.

Role of the MEN1 tumour suppressor gene in human ductal pancreatic cancer.

MEN1 is a novel tumour suppressor gene involved in the etiology of sporadic endocrine pancreatic tumours. Based on common ontogenetic features of both tissues, we analyzed the role of MEN1 in ductal pancreatic cancer. Wild type MEN1 mRNA expression, but no mutations within the MEN1 coding sequence or MEN1 promoter region were detected in human pancreatic adenocarcinoma tissues and carcinoma cell lines, using sensitive single-strand conformational polymorphism-heteroduplex and sequencing analyses. Thus, human pancreatic cancer does not seem to require inactivation of the MEN1 tumour suppressor pathway.

Multiple endocrine neoplasia type 1 (MEN1) gene mutations in a subset of patients with sporadic and familial primary hyperparathyroidism target the coding sequence but spare the promoter region.

Germ line mutations of the multiple endocrine neoplasia type 1 (MEN1) tumour suppressor gene cause MEN1, a rare familial tumour syndrome associated with parathyroid hyperplasia, adenoma and hyperparathyroidism (HP). Here we investigated the role of the MEN1 gene in isolated sporadic and familial HP. Using RT-PCR single-strand conformational polymorphism screening, somatic (but not germ line) mutations of the MEN1 coding sequence were identified in 6 of 31 (19.3%) adenomas from patients with sporadic primary HP, but none in patients (n=16) with secondary HP due to chronic renal failure. MEN1 mutations were accompanied by a loss of heterozygosity (LOH) for the MEN1 locus on chromosome 11q13 in the adenomas as detected by microsatellite analysis. No DNA sequence divergence within the 5' region of the MEN1 gene, containing the putative MEN1 promoter, was detectable in HP adenomas. Clinical characteristics were not different in HP patients with or without MEN1 mutation. Heterozygous MEN1 gene polymorphisms were identified in 9.6% and 25% of patients with primary and secondary HP respectively. In a large kindred with familial isolated familial HP, MEN1 germ line mutation 249 del4 and LOH was associated with the HP phenotype and a predisposition to non-endocrine malignancies. We suggest that the bi-allelic somatic loss of MEN1 wild-type gene expression is involved in the pathogenesis of a clinically yet undefined subset of sporadic primary HP adenomas. MEN1 genotyping may further help define the familial hyperparathyroidism-MEN1 disease complex, but it seems dispensable in sporadic primary HP.

Concepts for screening and diagnostic follow-up in multiple endocrine neoplasia type 1 (MEN1).

The recent identification of MEN1 gene mutations as the molecular cause of familial multiple endocrine neoplasia type 1 syndrome (MEN1) has had a significant impact on clinical patient care. In the following consensus statement we will present recommendations for clinical screening and follow-up in patients and relatives with suspected or established MEN1 syndrome. MEN1 mutational analysis should be performed in individuals with newly diagnosed MEN1-typical endocrine neoplasia (e.g., primary hyperparathyroidism, gastroenteropancreatic tumor, pituitary adenoma) if additional diagnostic criteria are met (e.g., age <40 years; positive family history; multifocal or recurrent neoplasia; two or more organ systems affected). Genetic family screening is advisable in first degree relatives of MEN1 patients during early adolescence to reliably assess future MEN1 disease risk. In symptomatic individuals carrying MEN1 germ line mutations, annual clinical and biochemical (calcium, PTH, gastrin, prolactin) follow-up as well as routine pancreatic and pituitary imaging may be complemented as individually needed. In contrast, relatives without family-specific MEN1 mutation do not require routine follow-up. Diagnostic procedures and treatment in symptomatic MEN1 mutation carriers and patients may differ from that in sporadic endocrine neoplasia, calling for individual management. Genetic counselling and dedicated endocrine surgery should be integral parts of current medical care in MEN1 syndrome.