High bone mass due to novel LRP5 and AMER1 mutations.

WNT signaling is a key regulator of bone metabolism and its increased or decreased activity leads to skeletal disorders. Here we describe two patients with high bone mass (HBM) caused by novel mutations in two different WNT pathway components. The first patient is a 53-year-old male with HBM. He was diagnosed at adult age based on significantly increased bone mineral density (BMD). He has undergone several surgeries due to excessive bone in ear canals, bilateral jaw exostoses and mandibular tori. Radiographs show severe cortical thickening of cranial and long bones. Sanger sequencing identified a novel heterozygous mutation c.592A>T (p.N198Y) in LRP5 (Low-density lipoprotein receptor-related protein 5). The second patient, an adolescent female, was diagnosed with skeletal dysplasia in early childhood. She had macrocephaly (head circumference +6.0 SD), facial dysmorphism, delayed motor development, laryngomalasia and epilepsy. Radiographic findings were consistent with osteopathia striata with cranial sclerosis. A novel heterozygous frameshift mutation c.655del (p.E219Rfs*63) in AMER1 (APC Membrane Recruiting Protein 1) was identified. Although both mutations are predicted to lead to increased WNT signaling with a consequent increase in bone formation, the resulting phenotypes are different; cranial sclerosis versus macrocephaly, long bone cortical thickening versus vertical striations and discordant neurological development. This report underscores the diversity of genotypes and phenotypes of HBM and facilitates their differential diagnosis.

A nationwide study on parathyroid carcinoma.

BACKGROUND: Parathyroid carcinoma (PC) is rare and diagnostically challenging. Reported outcomes are rather poor and the incidence might be increasing. MATERIAL AND METHODS: We performed a nationwide study on all cases (n= 32) diagnosed in 2000-2011 in Finland, and compared clinical and histopathological characteristics and outcome to atypical parathyroid (APA; n= 28) and parathyroid adenomas (PA; n= 72). The incidence in years 1955-1999 was compared to that in 2000-2013. RESULTS: Preoperatively, calcium and parathyroid hormone concentrations were higher in PC compared to APA and PA (1.76, 1.56 and 1.44 mmol/l, p < .001; and 989, 355 and 160 µmol/l, p < .001, respectively). Calcium was ≤1.77 mmol/l for all PAs. Hospitalization (44% vs. 22% and 3%, respectively, p = .01), renal (50% vs. 48% vs. 22%, respectively, p = .01) and bone (47% vs. 15% vs. 38%, respectively p = .002) manifestations were more common. PC and APA tumors were larger than PA (p < .001). Histopathological characteristics of PC compared to PA are increased mitotic activity (p= .001), chief cells (p = .003), diffuse growth pattern (p < .001), higher Ki67 (p< .001) and negative parafibromin (p < .001). One PC (1/18) and one APA (1/16) patient had a CDC73 mutation. After 6.7 (2-13.9) years of follow-up, 9.4% of PC had residual, 21% recurrent disease and 12.5% died of disease. Overall mortality did not differ between subgroups (p = .094). Recurrent PC was characterized by vascular invasion, lymph node metastases, high mitotic activity, necrosis and negative parafibromin. Incidence increased from 1.42 (range 0.52-2.14) to 7.14 (range 3.42-10.38)/10.000.000/years; (p < .001). CONCLUSIONS: PC associates with severe primary hyperparathyroidism and must be suspected if calcium ≥1.77 mmol/l. The prevalence of CDC73 germline mutations in PC and APA in Finland is 6%. PC has distinct histopathological characteristics and its incidence has increased over the past decades.

How are metabolic control targets of patients with Type 1 diabetes mellitus achieved in daily practice in the area with high diabetes prevalence?

AIMS: We assessed the prevalence of Type 1 diabetes mellitus and determined how the targets established in the guidelines for patients with Type 1 diabetes mellitus were achieved in clinical practice in North Karelia, Finland. METHODS: All adult Type 1 diabetes mellitus patients (n=1075) were identified from the regional electronic patient database. The data for HbA1c and LDL cholesterol measurements during the years 2013 and 2014 were obtained from medical records. RESULTS: The prevalence of Type 1 diabetes mellitus in the adult population in North Karelia was 0.8%, which is among the highest worldwide. HbA1c and LDL cholesterol were measured in 93% and 90% of participants, respectively. Nineteen percent of patients reached the HbA1c target of <7.0% (53mmol/mol) and 45% attained LDL cholesterol <2.5mmol/l. Overall, 26% of patients over 60 years old with diabetes achieved glycaemic control targets compared with 13-16% of younger patients with diabetes. CONCLUSIONS: Glycaemic control was in line with the recommendations in only one-fifth of Type 1 diabetes mellitus patients and less than half of them had LDL cholesterol levels within the target range. Interestingly, older Type 1 diabetes mellitus patients met the glycaemic control target more often than younger patients with diabetes. The targets established for patients with Type 1 diabetes mellitus are not achieved satisfactorily in daily practice.

Continuous Subcutaneous Insulin Infusion During Pregnancy in Women with Complicated Type 1 Diabetes Is Associated with Better Glycemic Control but Not with Improvement in Pregnancy Outcomes.

BACKGROUND: The aim of this study was to evaluate maternal and fetal pregnancy outcomes of women with type 1 diabetes managed on continuous subcutaneous insulin infusion (CSII) compared with multiple daily insulin injections (MDI). SUBJECTS AND METHODS: Pregnancy outcomes were assessed retrospectively in women with type 1 diabetes who were patients of the Diabetes Clinic of North Karelia Hospital (Joensuu, Finland) between 2000 and 2012. The medical records of 72 women experiencing 135 pregnancies and data of their infants were retrospectively reviewed. RESULTS: In total, 48 pregnancies were treated with CSII and 87 with MDI. Women on CSII treatment were older and had more diabetes complications compared with women on MDI. No significant differences in glycated hemoglobin (HbA1c) levels were observed between the CSII and MDI groups before or during pregnancy. Maternal or fetal outcomes did not differ between the treatment groups. However, among women with complicated diabetes, HbA1c levels were significantly lower in the CSII group until the second trimester (prepregnancy, 7.22% vs. 8.14%, respectively [P = 0.034]; first trimester, 6.85% vs. 7.87% [P < 0.001]; second trimester, 6.41% vs. 7.03% [P = 0.029]) without an increased rate of maternal hypoglycemia. CONCLUSIONS: Pregnancy outcomes were similar regardless of insulin treatment modality. Although using an insulin pump did not result in improvement of pregnancy outcomes, it allowed for better glycemic control in pregnancies of women with complicated diabetes. Therefore, it is worth considering in high-risk T1DM pregnancies, especially if good glycemic control is not achieved otherwise.

Pregnancy planning in type 1 diabetic women improves glycemic control and pregnancy outcomes.

OBJECTIVE: Pregnancy in women with type 1 diabetes is associated with increased risks. The aim of this study was to evaluate the effect of pregnancy planning on outcomes of type 1 diabetic pregnancies. METHODS: We retrospectively assessed pregnancy outcomes of type 1 diabetic women who were patients of Diabetes Clinic of North Karelia hospital between 2000 and 2012. We evaluated the medical records of 73 women experiencing 145 pregnancies and data of their infants. RESULTS: Altogether 96 (66.2%) pregnancies were planned. HbA1c levels were significantly lower before and during the whole pregnancy when pregnancy was planned than if it was not planned (all p <0.001). Planned pregnancies resulted in significantly fewer congenital anomalies (p <0.001). Pregnancy planning reduced the age-adjusted risk of Cesarean sections (OR 0.25, p = 0.021). Pregnancy planning was associated with a reduced risk of adverse pregnancy outcomes (including miscarriages and congenital anomalies). This association was independent of age, HbA1c before pregnancy, smoking, hypertension, microvascular complications, and thyroid disease (OR 0.26; 95% CI 0.09, 0.76). CONCLUSIONS: Pregnancy planning is beneficial for glycemic control and pregnancy outcomes of type 1 diabetic women. The benefit of pregnancy planning was independent of other risk factors for adverse pregnancy outcomes.

Type 2 diabetes care in North Karelia Finland: do area-level socio-economic factors affect processes and outcomes?

AIMS: This research assessed the impact of area-level socio-economic factors on the prevalence and outcomes of type 2 diabetes in North Karelia, Finland. METHODS: All type 2 diabetes patients (n=10,204) were analyzed from the regional electronic patient database during the years 2011 and 2012. The patient's individual laboratory data was used to assess whether hemoglobin A1c (HbA1c) was measured and whether the recommended level of HbA1c <7% (<53 mmol/l) was achieved. The variables describing socio-economic characteristics of postal code areas were retrieved from the database of Statistics Finland. Linear and logistic regression analyses were used to determine associations. RESULTS: HbA1c had been measured in 83% of patients. Over 70% of those with HbA1c measured reached the recommended level of HbA1c. The worse the area-level socio-economic status, the more probably HbA1c was not measured. Achieving the recommended HbA1c level was associated with being female and having a better area-level socio-economic status. The age-adjusted prevalence of type 2 diabetes was not linearly dependent on the socio-economic circumstances of the postal code areas. CONCLUSIONS: This study shows that socio-economic factors at the small area-level are associated with treatment outcomes. The information from the regional electronic patient database linked with area-level socio-economic information could be effectively utilized to improve diabetes care.

Health-related quality of life in elderly patients with familial hypercholesterolemia.

OBJECTIVES: There are very few descriptions on how familial hypercholesterolemia (FH), a genetic disorder with an increased risk of coronary heart disease (CHD), affects older patients. The aim of this study was to analyze the health-related quality of life (HRQoL) of elderly patients with FH. METHODS: All FH patients with the same FH North Karelia-mutation aged 65 and over living in North Karelia province in Eastern Finland were asked to participate in the study in 2003. They were compared with age-standardized controls from the Finnish general population. A total of forty-three elderly FH patients were identified and thirty-seven of them (aged 65 to 84 years, M/F 10/27) agreed to participate. Most of them (27/37) had been diagnosed with CHD. All but one of these FH patients had been using statins for approximately 15 years. HRQoL was assessed with the RAND-36 (SF-36) and 15D instruments. RESULTS: Despite the clear cardiovascular morbidity and low socioeconomic status, these FH patients enjoyed a similar HRQoL as the age-standardized controls in the general population. CONCLUSIONS: Lifelong hypercholesterolemia was not associated with poorer HRQoL in elderly survivors of FH. These elderly FH individuals were characterized by their healthy lifestyle and long-term statin treatment.

The Leu7Pro polymorphism of the neuropeptide Y gene regulates free fatty acid metabolism.

The Leu7Pro polymorphism in the signal peptide of the preproneuropeptide Y (NPY) has been associated with dyslipidemias and free fatty acid (FFA) levels during exercise. The association of this polymorphism with insulin sensitivity has not been studied. In this study, the Leu7Pro polymorphism was determined in 2 groups of nondiabetic middle-aged subjects (n = 266 and n = 295). Insulin sensitivity was measured with the hyperinsulinemic euglycemic clamp (n = 266) or with an intravenous glucose tolerance test (IVGTT, n = 295). First-phase insulin secretion was determined as insulin area under the curve (AUC) during the first 10 minutes of the IVGTT. FFAs were measured both in the fasting state and during the hyperinsulinemic clamp. The Leu7Pro polymorphism of the NPY gene was not associated with the rates of whole body glucose uptake, insulin sensitivity index, insulin secretion during the IVGTT, or insulin AUC during the oral glucose tolerance test. However, the Pro7 allele was associated with low FFA levels both in the fasting state (P =.043) and during the hyperinsulinemic clamp (P =.003). In conclusion, the Leu7Pro polymorphism of the NPY gene associates with alterations in FFA metabolism but does not have an impact on insulin sensitivity, insulin secretion, or glucose metabolism.

Promoter polymorphisms -359T/C and -303A/G of the catalytic subunit p110beta gene of human phosphatidylinositol 3-kinase are not associated with insulin secretion or insulin sensitivity in finnish subjects.

OBJECTIVE: Phosphatidylinositol (PI) 3-kinase activity is required for insulin-stimulated translocation of GLUT4 transporters and glucose uptake and utilization. Therefore, genes encoding the subunits of PI 3-kinase are promising candidate genes for insulin resistance and type 2 diabetes. We recently cloned the catalytic subunit p110beta gene of human PI 3-kinase and reported two nucleotide polymorphisms, -359T/C and -303A/G, in the promoter region of this gene. In this study, we determined the effects of these polymorphisms on insulin secretion and insulin sensitivity. RESEARCH DESIGN AND METHODS: We studied two separate groups of Finnish nondiabetic subjects. Insulin secretion was evaluated by intravenous glucose tolerance test and insulin sensitivity by hyperinsulinemic-euglycemic clamp. RESULTS: Our results showed that the -359T/C and -303A/G polymorphisms did not have a significant effect on fasting plasma insulin levels, insulin secretion, or insulin sensitivity. CONCLUSIONS: It is unlikely that the promoter polymorphisms -359T/C and -303A/G of the catalytic subunit p110beta gene of human PI 3-kinase have a major impact on insulin secretion, insulin sensitivity, or the risk of type 2 diabetes in Finnish subjects.