Ingrid Nermoen
Akershus University Hospital, Department of Endocrinology, Department Member
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Studies of monogenic diabetes are particularly useful because we can gain insight into the molecular events of pancreatic β-cell failure. Maturity-onset diabetes of the young 1 (MODY1) is a form of monogenic diabetes caused by a mutation... more
Studies of monogenic diabetes are particularly useful because we can gain insight into the molecular events of pancreatic β-cell failure. Maturity-onset diabetes of the young 1 (MODY1) is a form of monogenic diabetes caused by a mutation in the HNF4A gene. Human-induced pluripotent stem cells (hiPSCs) provide an excellent tool for disease modeling by subsequently directing differentiation toward desired pancreatic islet cells, but cellular phenotypes in terminally differentiated cells are notoriously difficult to detect. Re-creating a spatial (three-dimensional [3D]) environment may facilitate phenotype detection. We studied MODY1 by using hiPSC-derived pancreatic β-like patient and isogenic control cell lines in two different 3D contexts. Using size-adjusted cell aggregates and alginate capsules, we show that the 3D context is critical to facilitating the detection of mutation-specific phenotypes. In 3D cell aggregates, we identified irregular cell clusters and lower levels of structural proteins by proteome analysis, whereas in 3D alginate capsules, we identified altered levels of glycolytic proteins in the glucose sensing apparatus by proteome analysis. Our study provides novel knowledge on normal and abnormal function of HNF4A, paving the way for translational studies of new drug targets that can be used in precision diabetes medicine in MODY.
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The type 2 diabetes risk following gestational diabetes mellitus (GDM) is high, particularly among South Asian women in Western countries. Our study aimed to advance the knowledge regarding the mechanisms behind suboptimal follow‐up in... more
The type 2 diabetes risk following gestational diabetes mellitus (GDM) is high, particularly among South Asian women in Western countries. Our study aimed to advance the knowledge regarding the mechanisms behind suboptimal follow‐up in the Nordic and South Asian women with previous GDM by comparing (1) their experiences, (2) health and disease perceptions and (3) barriers to and facilitators of health‐promoting behaviours.
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Summary We present a young woman with treatment resistant insulin autoimmune syndrome (IAS) with a protracted course. Her serum insulin level was 6945 pmol/l (<160), C-peptide 4042 pmol/L (<1480), anti-insulin antibodies 5305 U/mL... more
Summary We present a young woman with treatment resistant insulin autoimmune syndrome (IAS) with a protracted course. Her serum insulin level was 6945 pmol/l (<160), C-peptide 4042 pmol/L (<1480), anti-insulin antibodies 5305 U/mL (<0.4) were monoclonal IgG kappa. After 12 h of fasting, her blood glucose fell to 1.2 mmol/L. Post-meal blood glucose peaked at 12.2 mmol/L with reactive hypoglycaemia below 2 mmol/L. Frequent meals and continuous blood glucose monitoring were helpful, but further treatments advocated in the literature with prednisolone, rituximab, plasmapheresis, cyclophosphamide and ciclosporin were without beneficial effect. Based on this case and a review of the literature, we propose that IAS is not one but two different diseases with different therapeutic strategies. The first disease, polyclonal IAS, predominates in Asia and is characterized by polyclonal anti-insulin antibodies, association with certain HLA genotypes and other autoimmune conditions, medic...
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Purpose: Residual adrenocortical function, RAF, has recently been demonstrated in one-third of patients with autoimmune Addison’s disease (AAD). Here, we set out to explore any influence of RAF on the levels of plasma metanephrines and... more
Purpose: Residual adrenocortical function, RAF, has recently been demonstrated in one-third of patients with autoimmune Addison’s disease (AAD). Here, we set out to explore any influence of RAF on the levels of plasma metanephrines and any changes following stimulation with cosyntropin. Methods: We included 50 patients with verified RAF and 20 patients without RAF who served as controls upon cosyntropin stimulation testing. The patients had abstained from glucocorticoid and fludrocortisone replacement > 18 and 24 h, respectively, prior to morning blood sampling. The samples were obtained before and 30 and 60 min after cosyntropin stimulation and analyzed for serum cortisol, plasma metanephrine (MN), and normetanephrine (NMN) by liquid-chromatography tandem-mass pectrometry (LC-MS/MS). Results: Among the 70 patients with AAD, MN was detectable in 33%, 25%, and 26% at baseline, 30 min, and 60 min after cosyntropin stimulation, respectively. Patients with RAF were more likely to hav...
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Background The type 2 diabetes risk after gestational diabetes mellitus (GDM) is twice as high in South Asian compared to European women. Current guidelines differ regarding which test to use as a screening-tool post-GDM. We aimed to... more
Background The type 2 diabetes risk after gestational diabetes mellitus (GDM) is twice as high in South Asian compared to European women. Current guidelines differ regarding which test to use as a screening-tool post-GDM. We aimed to identify ethnic differences in the prevalence rates and early predictors for actionable HbA1c (defined as prediabetes and diabetes) short time after GDM. Methods This cross-sectional study, enrolling South Asian and Nordic women 1–3 years after a diagnosis of GDM, was undertaken at three hospitals in Norway. We performed a clinical and laboratory evaluation including an oral glucose tolerance test (OGTT). Medical records were used to retrieve data during pregnancy. Prediabetes was classified with HbA1c alone or combined with OGTT glucose measurements according to the WHO, WHO-IEC, and ADA criteria (fasting plasma glucose (FPG) 6.1–6.9 mmol/L, FPG 6.1–6.9 mmol/L and/or HbA1c 42-47 mmol/mol (6.0-6.4%), and FPG 5.6–6.9 mmol/L and/or HbA1c 39-47 mmol/mol (5...
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South Asians have higher risk of type 2 diabetes after gestational diabetes mellitus (GDM) than Nordic women; however the mechanisms behind this difference remain unclear. We investigated insulin sensitivity, beta cell function, and... more
South Asians have higher risk of type 2 diabetes after gestational diabetes mellitus (GDM) than Nordic women; however the mechanisms behind this difference remain unclear. We investigated insulin sensitivity, beta cell function, and hepatic insulin clearance, in 179 South Asian and 108 Nordic women ~17 months after GDM (mean age 35.3 years and BMI 29.1 kg/m2), via an oral glucose tolerance test using deconvolution of C-peptide kinetics. 31% of South Asian and 53% of Nordic participants were normoglycemic at the time of measurement. South Asian women had higher area under the curve (AUC) for glucose, pre-hepatic insulin, peripheral insulin, and lower levels of insulin sensitivity, disposition index, and fasting hepatic insulin clearance compared with Nordic women. In the group with prediabetes or diabetes, South Asian women displayed similar AUC for glucose and pre-hepatic insulin, but higher AUC for peripheral insulin, and lower levels of disposition index, and fasting hepatic insul...
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Studies of monogenic diabetes are particularly useful as we can gain insight into the molecular events of pancreatic β-cell failure. Maturity-onset diabetes of the young 1 (MODY1) is a monogenic diabetes form, caused by a mutation in the... more
Studies of monogenic diabetes are particularly useful as we can gain insight into the molecular events of pancreatic β-cell failure. Maturity-onset diabetes of the young 1 (MODY1) is a monogenic diabetes form, caused by a mutation in the HNF4A gene. Human induced pluripotent stem cells (hiPSC) provide an excellent tool for disease modelling by subsequent directed differentiation toward desired pancreatic islet cells, but cellular phenotypes in terminally differentiated cells are notoriously difficult to detect. Re-creating a spatial (3D) environment may facilitate phenotype detection. In this study, we studied MODY1 using hiPSC-derived pancreatic β-like patient and isogenic control cell lines in two different 3D contexts. Using size-adjusted cell aggregates and alginate capsules we showed that the 3D context was critical to facilitate the detection of mutation-specific phenotypes. In 3D cell aggregates we identified irregular cell clusters and lower levels of structural proteins by ...
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The type 2 diabetes risk following gestational diabetes mellitus (GDM) is high, particularly among South Asian women in Western countries. Our study aimed to advance the knowledge regarding the mechanisms behind suboptimal follow‐up in... more
The type 2 diabetes risk following gestational diabetes mellitus (GDM) is high, particularly among South Asian women in Western countries. Our study aimed to advance the knowledge regarding the mechanisms behind suboptimal follow‐up in the Nordic and South Asian women with previous GDM by comparing (1) their experiences, (2) health and disease perceptions and (3) barriers to and facilitators of health‐promoting behaviours.
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Immunoassays of steroid hormones are still used in the diagnosis and monitoring of patients with congenital adrenal hyperplasia. However, cross-reactivity between steroids can give rise to falsely elevated steroid levels. Here, we compare... more
Immunoassays of steroid hormones are still used in the diagnosis and monitoring of patients with congenital adrenal hyperplasia. However, cross-reactivity between steroids can give rise to falsely elevated steroid levels. Here, we compare the use of immunoassays and liquid chromatography–tandem mass spectrometry (LC–MS/MS) in the monitoring of patients with classic 21-hydroxylase deficiency (21OHD). Steroid profiles in different mutation groups (genotypes) were also compared. Fifty-five patients with classic 21OHD (38 women) were studied. Blood samples were collected in the morning after an overnight medication fast. LC–MS/MS and immunoassays were employed to assay 17-hydroxyprogesterone (17OHP), testosterone and androstenedione. In addition, 21-deoxycortisol (21DF), 11-deoxycortisol (11DF), corticosterone, deoxycorticosterone, cortisone and cortisol were analyzed by LC–MS/MS. Testosterone, androstenedione and 17OHP levels were consistently lower (by about 30–50%) when measured by L...
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In spite of increased vigilance of undiagnosed type 2 diabetes (DM2), the prevalence of unknown DM2 in subjects with morbid obesity is not known. To assess the prevalence of undiagnosed DM2 and compare the performance of glycated A1c... more
In spite of increased vigilance of undiagnosed type 2 diabetes (DM2), the prevalence of unknown DM2 in subjects with morbid obesity is not known. To assess the prevalence of undiagnosed DM2 and compare the performance of glycated A1c (HbA1c) and fasting glucose (FG) for the diagnosis of DM2 and prediabetes (preDM) in patients with morbid obesity. We measured fasting glucose and HbA1c in 537 consecutive patients with morbid obesity without previously known DM2. A total of 49 (9%) patients with morbid obesity had unknown DM2 out of which 16 (33%) fulfilled both the criteria for HbA1c and FG. Out of 284 (53%) subjects with preDM, 133 (47%) fulfilled both the criteria for HbA1c and FG. Measurements of agreement for FG and HbA1c were moderate for DM2 (κ = 0.461, p < .001) and fair for preDM (κ = 0.317, p < .001). Areas under the curve for FG and HbA1c in predicting unknown DM2 were 0.970 (95% CI 0.942, 0.998) and 0.894 (95% CI 0.837, 0.951) respectively. The optimal thresholds to i...
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In about 95% of cases, congenital adrenal hyperplasia (CAH) is caused by mutations in CYP21A2 gene encoding steroid 21-hydroxylase (21OH). Recently, we have reported four novel CYP21A2 variants in the Norwegian population of patients with... more
In about 95% of cases, congenital adrenal hyperplasia (CAH) is caused by mutations in CYP21A2 gene encoding steroid 21-hydroxylase (21OH). Recently, we have reported four novel CYP21A2 variants in the Norwegian population of patients with CAH, of which p.L388R and p.E140K were associated with salt wasting (SW), p.P45L with simple virilising (SV) and p.V211M+p.V281L with SV to non-classical (NC) phenotypes. We aimed to characterise the novel variants functionally utilising a newly designed in vitro assay of 21OH enzyme activity and structural simulations and compare the results with clinical phenotypes. CYP21A2 mutations and variants were expressed in vitro. Enzyme activity was assayed by assessing the conversion of 17-hydroxyprogesterone to 11-deoxycortisol by liquid chromatography tandem mass spectroscopy. PyMOL 1.3 was used for structural simulations, and PolyPhen2 and PROVEAN for predicting the severity of the mutants. The CYP21A2 mutants, p.L388R and p.E140K, exhibited 1.1 and 1...
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ObjectiveThe aim of this study was to determine the genetic, anthropometric and metabolic features in an unselected population of adult Norwegian patients with 21-hydroxylase deficiency (21OHD).Patients, methods and designSixty-four 21OHD... more
ObjectiveThe aim of this study was to determine the genetic, anthropometric and metabolic features in an unselected population of adult Norwegian patients with 21-hydroxylase deficiency (21OHD).Patients, methods and designSixty-four 21OHD patients participated (23 men and 41 women; median age 38.5 years; range 19–72 years) in a cross-sectional study including DNA sequencing ofCYP21A2, anthropometric measurements including dual X-ray absorptiometry scanning and biochemical analyses. The results were compared with reference cohorts from the general population.ResultsWe identified four novel and plausibly disease-causingCYP21A2mutations. Gene deletions/conversions (42.1% of alleles), the splice mutation I2 splice (23.0%) and point mutation I172 N (22.2%) were common. The genotype corresponded to clinical phenotype in 92% of the patients. The prevalence of osteopenia was 48% in males and 34% in females. Both men and women had normal BMI but markedly increased fat mass compared with the ...
Research Interests: Endocrinology, Anthropometry, Medicine, Norway, Humans, and 15 moreInternal Medicine, Mutation, Blood Pressure, Female, Male, Genetic Association Studies, Bone Density, Clinical Sciences, Aged, Middle Aged, Genotype, Adult, Congenital Adrenal Hyperplasia, Cross Sectional Studies, and Paediatrics and reproductive medicine
Autoimmune Addison’s disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. Low prevalence and complex inheritance have long hindered successful genetic studies. We here report the first genome-wide... more
Autoimmune Addison’s disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. Low prevalence and complex inheritance have long hindered successful genetic studies. We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P < 5 × 10−8). In addition to loci implicated in lymphocyte function and development shared with other autoimmune diseases such as HLA, BACH2, PTPN22 and CTLA4, we associate two protein-coding alterations in Autoimmune Regulator (AIRE) with AAD. The strongest, p.R471C (rs74203920, OR = 3.4 (2.7–4.3), P = 9.0 × 10−25) introduces an additional cysteine residue in the zinc-finger motif of the second PHD domain of the AIRE protein. This unbiased elucidation of the genetic contribution to development of AAD points to the importance of central immunological tolerance, and explains 35–41% of heritability (h2).
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Adrenocortical carcinoma is a highly malignant tumour with a poor prognosis. Surgery is the treatment of choice, with repeated procedures if necessary. A 39-year-old woman presented with a pronounced Cushing's syndrome with... more
Adrenocortical carcinoma is a highly malignant tumour with a poor prognosis. Surgery is the treatment of choice, with repeated procedures if necessary. A 39-year-old woman presented with a pronounced Cushing's syndrome with virilizsation. Investigations showed an adrenocortical carcinoma with a diameter of 12 cm and two large metastases in the liver. She was admitted for palliative surgery. The primary tumour and one liver metastasis were resected. Three months later a right hepatectomy was performed, with excision of the remaining liver metastasis. Mitotane tablets were given all the time. After the first operation the patient's clinical condition improved radically. Two years later she was clinically healthy without any tumours and normal hormone levels. After 27 months a relapse in the liver was found by computed tomography, and after 33 months steroid hormone precursors again increased. Radiotherapy to the liver metastasis was given, and at 48 months the patient is still...
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Congenital adrenal hyperplasia (CAH) has been shown to potentially affect psychological adjustment. However, most research has focused on females, and knowledge about psychological challenges in males remains sparse. The aim of this... more
Congenital adrenal hyperplasia (CAH) has been shown to potentially affect psychological adjustment. However, most research has focused on females, and knowledge about psychological challenges in males remains sparse. The aim of this systematic review was therefore to assess these in males with CAH. We systematically searched the OVID Medline, PsycINFO, CINAHL, and Web of Science databases, for articles published up to April 20, 2018, investigating psychological adjustment in males with CAH. Eleven studies were included in the review. Three main health domains were identified: psychological and psychiatric health, quality of life (QoL), and self-perceptions of reproductive health. Some studies covered more than one health domain. Seven studies explored psychological adjustment and/or the presence of psychiatric symptoms or disorders. Results indicated that males with CAH had more problems related to internalizing behaviors (negative behaviors directed toward the self) and more negati...
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Context Contrary to current dogma, growing evidence suggests that some patients with autoimmune Addison disease (AAD) produce corticosteroids even years after diagnosis. Objective To determine frequencies and clinical features of residual... more
Context Contrary to current dogma, growing evidence suggests that some patients with autoimmune Addison disease (AAD) produce corticosteroids even years after diagnosis. Objective To determine frequencies and clinical features of residual corticosteroid production in patients with AAD. Design Two-staged, cross-sectional clinical study in 17 centers (Norway, Sweden, and Germany). Residual glucocorticoid (GC) production was defined as quantifiable serum cortisol and 11-deoxycortisol and residual mineralocorticoid (MC) production as quantifiable serum aldosterone and corticosterone after > 18 hours of medication fasting. Corticosteroids were analyzed by liquid chromatography–tandem mass spectrometry. Clinical variables included frequency of adrenal crises and quality of life. Peak cortisol response was evaluated by a standard 250 µg cosyntropin test. Results Fifty-eight (30.2%) of 192 patients had residual GC production, more common in men (n = 33; P < 0.002) and in shorter disea...
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Summary Primary adrenal lymphoma (PAL) is a rare cause of adrenal insufficiency. More than 90% is of B-cell origin. The condition is bilateral in up to 75% of cases, with adrenal insufficiency in two of three patients. We report two cases... more
Summary Primary adrenal lymphoma (PAL) is a rare cause of adrenal insufficiency. More than 90% is of B-cell origin. The condition is bilateral in up to 75% of cases, with adrenal insufficiency in two of three patients. We report two cases of adrenal insufficiency presenting at the age of 70 and 79 years, respectively. Both patients had negative 21-hydroxylase antibodies with bilateral adrenal lesions on CT. Biopsy showed B-cell lymphoma. One of the patients experienced intermittent disease regression on replacement dosage of glucocorticoids. Learning points: Primary adrenal lymphoma (PAL) is a rare cause of adrenal insufficiency. Bilateral adrenal masses of unknown origin or in individuals with suspected extra-adrenal malignancy should be biopsied quickly when pheochromocytoma is excluded biochemically. Steroid treatment before biopsy may affect diagnosis. Adrenal insufficiency with negative 21-hydroxylase antibodies should be evaluated radiologically.
This study sought to determine whether moderate exercise influences hypoglycaemic responses in insulin-dependent diabetes mellitus (IDDM). Ten patients with IDDM and no history of hypoglycaemia unawareness or autonomic neuropathy were... more
This study sought to determine whether moderate exercise influences hypoglycaemic responses in insulin-dependent diabetes mellitus (IDDM). Ten patients with IDDM and no history of hypoglycaemia unawareness or autonomic neuropathy were included. The patients were studied in random order on 4 occasions: twice during euglycaemia (once at rest and once on a treadmill) and twice during a gradual drop in blood glucose from 5 to 2 mmol/l (once at rest and once on a treadmill). Blood samples for hormones and glucose were drawn, and a symptom questionnaire was filled out every 5 min. Cognitive tests were performed at the start and end of each study. Glucose thresholds for hormones and symptoms are reported as the plasma glucose level at which responses were more than two standard deviations above basal level and continued to increase. The thresholds for adrenaline and noradrenaline release came at a significantly higher blood glucose level during exercise than at rest: 2.7 +/- 0.2 vs 2.1 +/-...