Impact of Lean Body Mass and Insulin Sensitivity on the IGF-1-Bone Mass Axis in Adolescence: the EPICOM Study.

CONTEXT: Insulin-like growth factor-1 (IGF-1) is involved in the growth of muscle and bone mass and contributes to glucose homeostasis. The offspring of mothers with diabetes during pregnancy have an increased risk of insulin resistance (IR). OBJECTIVE: We hypothesized that bone mass was decreased in the offspring of mothers with type 1 diabetes (T1D), and that the IGF-1-bone mass relationship would be negatively influenced by IR. DESIGN: Data from the Epigenetic, Genetic and Environmental Effects on Growth, Metabolism and Cognitive Functions in Offspring of Women with Type 1 Diabetes (EPICOM) study performed from 2012 to 2013 were included. SETTING: This work is a follow-up study of a nationwide register study. PATIENTS: A total of 278 adolescent index offspring whose mothers had T1D and 303 matched controls were studied. MAIN OUTCOME MEASURE: Bone mineral content (BMC) determined by a dual-energy x-ray absorptiometry scan and the interaction with IGF-1 and insulin sensitivity were measured. RESULTS: There was no difference in BMC, bone mineral density, height (SD score [SDS]), or BMC/height between index and control offspring. IGF-1 (SDS) did not differ between the groups but insulin-like growth factor-binding protein 3 (SDS) was higher in index boys compared to controls (B = .31 [95% CI, 0.06-0.57], P = .02). The statistical path analysis showed that IGF-1 predicted BMC/height (B = .24 [95% CI, 0.02-0.45], P = .03), but lean mass was a mediator of this. IGF-1 and the homeostatic model assessment of IR were positively associated (B = .75 [95% CI, 0.37-1.12], P < .001). There was no moderating effect of the interaction between IR and IGF-1 on lean mass in the entire cohort (B = .005 [95% CI, -0.03 to 0.04], P = .81) or when analyzing index cases and controls separately. CONCLUSION: We found that lean mass was an intermediary factor in the IGF-1-bone mass relationship in a large cohort of adolescents, and this relationship was not moderated by IR.

Variability in Medullary Thyroid Carcinoma in RET L790F Carriers: A Case Comparison Study of Index Patients.

Background: Previous studies have suggested that the variability in age of onset and aggressiveness of medullary thyroid carcinoma (MTC) in patients with multiple endocrine neoplasia type 2A (MEN 2A) carrying the same REarranged during Transfection (RET) mutation may be caused by additional RET germline variants or somatic variants. Methods: This study was a retrospective case comparison study of all MEN 2A index patients (n = 2) with the RET L790F germline mutation in Denmark. Whole blood and MTC tissue were analyzed for RET germline variants and other somatic variants (>500), respectively. Results: Patient 1 presented with MTC (T1aN1bM0) at age 14 years, while patient 2 presented with MTC (T1bN0M0) at age 70 years. No germline RET germline variants nor other variants were found to explain this MTC variability. Conclusions: We could not confirm the previously reported finding of a somatic RET variant as likely responsible for the early onset and aggressiveness of MTC in a RET germline mutation carrier. Also, we found no RET germline variants that could explain the MTC variability among our index patients. We did, however, identify a somatic FLT3 R387Q variant with an unknown potential as genetic modifier. Further large-scale studies are needed to investigate genetic modifiers in RET L790F carriers.

The impact of an orthogeriatric intervention in patients with fragility fractures: a cohort study.

BACKGROUND: While orthogeriatric care to patients with hip fractures is established, the impact of similar intervention in patients with fragility fractures in general is lacking. Therefore, we aimed to assess the impact of an orthogeriatric intervention on postoperative complications and readmissions among patients admitted due to and surgically treated for fragility fractures. METHODS: A prospective observational cohort study with a retrospective control was designed. A new orthogeriatric unit for acute patients of sixty-five years or older with fragility fractures in terms of hip, vertebral or appendicular fractures was opened on March 1, 2014. Patients were excluded if the fracture was cancer-related or caused by high-energy trauma, if the patient was operated on at another hospital, treated conservatively with no operation, or had been readmitted within the last month due to fracture-related complications. RESULTS: We included 591 patients; 170 in the historical cohort and 421 in the orthogeriatric cohort. No significant differences were found between the two cohorts with regard to the proportion of participants experiencing complications (24.5% versus 28.3%, p = 0.36) or readmission within 30 days after discharge (14.1% vs 12.1%, p = 0.5). With both cohorts collapsed and adjusting for age, gender and CCI, the odds of having postoperative complications as a hip fracture patient was 4.45, compared to patients with an appendicular fracture (p <  0.001). Furthermore, patients with complications during admission were at a higher risk of readmission within 30 days than were patients without complications (22.3% vs 9.5%, p <  0.001). CONCLUSIONS: In older patients admitted with fragility fractures, our model of orthogeriatric care showed no significant differences regarding postoperative complications or readmissions compared to the traditional care. However, we found significantly higher odds of having postoperative complications among patients admitted with a hip fracture compared to other fragility fractures. Additionally, our study reveals an increased risk of being readmitted within 30 days for patients with postoperative complications.

Asymptomatic parental mosaicism for osteogenesis imperfecta associated with a new splice site mutation in COL1A2.

Recurrent lethal perinatal osteogenesis imperfecta may result from asymptomatic parental mosaicism. A previously unreported mutation in COL1A2 leads to recurrent cases of fetal osteogenesis imperfecta Sillence type IIA, which emphasizes the importance of clinical and genetic evaluation of mosaicism in asymptomatic parents as verified mosaicism highly increases recurrence risk.

Normal hematopoiesis and lack of ß-catenin activation in osteoblasts of patients and mice harboring Lrp5 gain-of-function mutations.

Osteoblasts are emerging regulators of myeloid malignancies since genetic alterations in them, such as constitutive activation of ß-catenin, instigate their appearance. The LDL receptor-related protein 5 (LRP5), initially proposed to be a co-receptor for Wnt proteins, in fact favors bone formation by suppressing gut-serotonin synthesis. This function of Lrp5 occurring in the gut is independent of ß-catenin activation in osteoblasts. However, it is unknown whether Lrp5 can act directly in osteoblast to influence other functions that require ß-catenin signaling, particularly, the deregulation of hematopoiesis and leukemogenic properties of ß-catenin activation in osteoblasts, that lead to development of acute myeloid leukemia (AML). Using mice with gain-of-function (GOF) Lrp5 alleles (Lrp5(A214V)) that recapitulate the human high bone mass (HBM) phenotype, as well as patients with the T253I HBM Lrp5 mutation, we show here that Lrp5 GOF mutations in both humans and mice do not activate ß-catenin signaling in osteoblasts. Consistent with a lack of ß-catenin activation in their osteoblasts, Lrp5(A214V) mice have normal trilinear hematopoiesis. In contrast to leukemic mice with constitutive activation of ß-catenin in osteoblasts (Ctnnb1(CAosb)), accumulation of early myeloid progenitors, a characteristic of AML, myeloid-blasts in blood, and segmented neutrophils or dysplastic megakaryocytes in the bone marrow, are not observed in Lrp5(A214V) mice. Likewise, peripheral blood count analysis in HBM patients showed normal hematopoiesis, normal percentage of myeloid cells, and lack of anemia. We conclude that Lrp5 GOF mutations do not activate ß-catenin signaling in osteoblasts. As a result, myeloid lineage differentiation is normal in HBM patients and mice. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.

[The complex clinical presentation of hereditary mitochondrial diseases].

Mitochondria produce cellular energy, which is of vital importance for cellular metabolism. The organelles contain their own genetic material (i.e. mitochondrial DNA (mtDNA)) with a matrilineal inheritance. Mutations in the mtDNA may cause mitochondrial disease affecting multiple organs leading to diabetes, hearing impairment, muscle fatigue, ptosis and stroke-like episodes in varying combinations and severity. The variable phenotypic presentations make it a challenge to recognize mitochondrial diseases and, consequently, the correct diagnosis is often delayed.

[Diabetes and hearing impairment due to mitochondrial mutation].

Mutations in the mitochondrial genome can cause mitochondrial diabetes. We present two cases in which the same mutation, mtDNA3243A>G, caused two different phenotypes: maternally inherited diabetes and deafness and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. Mitochondrial disease can imitate a variety of common con-ditions and should be considered in the case of multisystem disease, complex neurological symptoms or neurological symptoms combined with symptoms of other organ systems.

Autosomal dominant osteopetrosis revisited: lessons from recent studies.

Systematic studies of autosomal dominant osteopetrosis (ADO) were followed by the identification of underlying mutations giving unique possibilities to perform translational studies. What was previously designated ADO1 turned out to be a high bone mass phenotype caused by a missense mutation in the first propeller of LRP5, a region of importance for binding inhibitory proteins. Thereby, ADO1 cannot be regarded as a classical form of osteopetrosis but must now be considered a disease of LRP5 activation. ADO (Albers-Schönberg disease, or previously ADO2) is characterized by increased number of osteoclasts and a defect in the chloride transport system (ClC-7) of importance for acidification of the resorption lacuna (a form of Chloride Channel 7 Deficiency Osteopetrosis). Ex vivo studies of osteoclasts from ADO have shown that cells do form normally but have reduced resorption capacity and an expanded life span. Bone formation seems normal despite decreased osteoclast function. Uncoupling of formation from resorption makes ADO of interest for new strategies for treatment of osteoporosis. Recent studies have integrated bone metabolism in whole-body energy homeostasis. Patients with ADO may have decreased insulin levels indicating importance beyond bone metabolism. There seems to be a paradigm shift in the treatment of osteoporosis. Targeting ClC-7 might introduce a new principle of dual action. Drugs affecting ClC-7 could be antiresorptive, still allowing ongoing bone formation. Inversely, drugs affecting the inhibitory site of LRP5 might stimulate bone formation and inhibit resorption. Thereby, these studies have highlighted several intriguing treatment possibilities, employing novel modes of action, which could provide benefits to the treatment of osteoporosis.

[Gut microbiota may have influence on glucose and lipid metabolism]. / Tarmbakterieflora kan have betydning for glukose- og fedtmetabolisme.

New gene sequencing-based techniques and the large worldwide sequencing capacity have introduced a new era within the field of gut microbiota. Animal and human studies have shown that obesity and type 2 diabetes are associated with changes in the composition of the gut microbiota and that prebiotics, antibiotics or faecal transplantation can alter glucose and lipid metabolism. This paper summarizes the latest research regarding the association between gut microbiota, diabetes and obesity and some of the mechanisms by which gut bacteria may influence host metabolism.