In sickness and in health: pivotal role of vitamin D.

Within the last several years, frequency of vitamin D testing has multiplied substantially all over the world, since it has been shown to have an important role in many diseases and conditions. Even though liquid chromatography - tandem mass spectrometry (LC-MS/MS) has been identified as "gold standard" method for vitamin D measurement, most laboratories still use immunochemistry methods. Besides analytical problems (hydrophobicity, low circulating concentrations, ability to bind to lipids, albumins and vitamin D binding protein, presence of multiple vitamin D metabolites and variable ratios of 25(OH)D2 and 25(OH)D3 in the blood), vitamin D shows great preanalytical variability, since its concentration is drastically influenced by seasonal changes, exposure to sun, type of clothes or sun block creams. Vitamin D is mostly measured in serum or plasma, but new studies are showing importance of measuring vitamin D in pleural effusions, breast milk, urine, synovial fluid and saliva. Besides the main role in calcium homeostasis and bone metabolism, many studies linked vitamin D deficiency with cancer, cardiovascular diseases, diabetes, fertility and many other conditions. However, even though initial observational studies indicated that supplementation with vitamin D might be beneficial in disease development and progression; first results of well-designed randomized controlled prospective studies did not find differences in frequency of cardiovascular events or invasive cancer between patients taking vitamin D supplementation compared to placebo. In the light of these recent findings, validity of excessive vitamin D testing remains an open question.

Hypothyroidism and pregnancy: still a controversial issue.

Subclinical hypothyroidism (SCH) in pregnancy is common, according to literature, affecting up to 15% of pregnancies. It still represents a controversy weather levothyroxine has beneficial effects on pregnancy outcomes. In this retrospective and prospective cohort study, we assessed fetal and maternal outcomes in women with known thyroid status pre-pregnancy, and hypothyroidism during pregnancy. We included 393 pregnant women, 90 (22.9%) diagnosed with overt and 303 with SCH (77.1%). A total of 94 (56%) had positive anti-TPO antibodies. Levothyroxine substitution across all observational periods was suboptimal, mostly during first trimester in both groups of patients (85.4%). There was a difference in the number of live births in favor of group with SCH (p = .004). Women with overt hypothyroidism were more likely to develop complications during pregnancy (RR = 1.153, 95%CI = 0.775 - 1.714) and had positive TPO-antibodies more often (p = .022). The only significant association was found between fetal outcomes in women with SCH and positive TPO-antibodies (p = .018), while positive Tg-antibodies did not affect the pregnancy outcomes of women with SCH. Moreover, no correlation was observed between outcomes and adequacy of levothyroxine substitution. These results indicate that TPO-antibody positivity could be the most important factor of pregnancy outcomes independent of the TSH levels or adequacy of levothyroxine therapy.

Inflammation-related cytokines and their roles in gastroenteropancreatic neuroendocrine neoplasms.

Proinflammatory counterworks are important at different stages of tumor development, particularly during invasion and metastasis. Immune cells and their signal molecules can influence all stages of tumor progression, as well as therapeutic intervention. Proinflammatory cytokines are known triggers of growth in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). In this study, we explored the immunohistochemical expression of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1ß), IL-2, and IL-6 in tissues from 43 GEP-NEN patients with tumors of gastric, duodenal, ileal, appendiceal, and colonic origin. The immunohistochemical expression of TNF-α was increased in tumor groups with high proliferation rates (Ki-67; p = 0.034), as well as in those with higher tumor grades (p = 0.05). Moreover, the immunohistochemical expression of TNF-α positively correlated with death outcomes (p = 0.016). Expression of IL-6, IL-1ß, and IL-2 displayed similar immunohistochemical expression patterns regardless of Ki-67, although the expression between the ILs differed. Most GEP-NENs had high levels of IL-6 and lower levels of IL-1ß and IL-2. Although further comprehensive studies are required for a complete understanding of activated mechanisms in proinflammatory protumoral microenvironment of GEP-NENs, TNF-α is a potential marker in the prognosis of those tumors.

Long-Term Effectiveness of Liraglutide in Association with Patients' Baseline Characteristics in Real-Life Setting in Croatia: An Observational, Retrospective, Multicenter Study.

INTRODUCTION: Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are recommended therapy for type 2 diabetes (T2DM) and liraglutide is the most used worldwide. We assessed the glycemic efficacy and extra-glycemic effects of liraglutide during 36 months' follow-up of individuals with poorly regulated T2DM under routine clinical practice and sought to identify the phenotype of treatment responders. METHODS: A total of 207 individuals were included. The primary endpoint was the proportion of participants with HbA1c < 7.0% and/or weight reduction. Secondary endpoints included changes in lipids, blood pressure, fasting c-peptide, and antidiabetic treatment during follow-up of 3 years. RESULTS: Liraglutide was prescribed to 89.8% of participants already on at least two antidiabetic medications and 18% on insulin. Subject's mean age was 53.28 ± 9.42 years with duration of diabetes 8.29 ± 4.89 years. Baseline HbA1c was 8.5 ± 1.3% and body mass index (BMI) was 39 ± 4.5 kg/m2. Reduction of HbA1c was observed in 84.4% of participants, and 89.2% experienced average weight reduction of 5 kg. A composite outcome (reduction of HbA1c with any weight loss) was achieved in 76.2% of patients. After 6 months on liraglutide treatment, 38.1% of participants achieved target HbA1c level < 7%. This effect was maintained for 36 months in 50.8% of subjects. Increase in c-peptide was evident after 24 months (p = 0.030). Participants experienced a significant reduction in systolic blood pressure (BP) (p = 0.003), while there was no effect on diastolic BP, lipid profile, or liver enzymes. The number of participants treated with sulfonylurea decreased from 60.8% to 17.5%, while the number treated with insulin and sodium-glucose co-transporter-2 (SGLT-2) inhibitor increased (17.6% to 24.6% and 2.5% to 36.8%, respectively). Independent predictors of durability of HbA1c reduction were initial BMI (p = 0.004), HbA1c (p < 0.001), systolic BP (p = 0.007), and cholesterol (p = 0.020). Moreover, female gender and shorter duration of diabetes were independent predictors for HbA1c reduction. CONCLUSION: Liraglutide shows sustained glycemic and extra-glycemic effects when used for treatment of obese poorly regulated individuals with T2DM.

Impact of health policy and practice on finding the best fit for patients with type 2 diabetes after metformin failure: Croatian pilot study.

AIM: We assessed the impact of clinical practice and health policy on the choice and efficacy of different second-line therapies for the treatment of type 2 diabetes (T2DM) after failure of metformin. METHODS: This retrospective database analysis included 200 patients with a follow-up period of 6 months. The primary end-point was achievement of HbA1c <7% and fasting (FBG) and postprandial glucose levels (PPG) <7.2mmol/L and <10mmol/L, respectively after three and six months of different add-on treatments. Secondary end-points were weight change during treatment and incidence of hypoglycemia. RESULTS: All second-line therapeutic options, except human basal insulin (BHI) and thiazolidendions (TZD) significantly increased the proportion of patients reaching target HbA1c after 6 months (p<0.01). Only sulfonylurea (SU) and dipeptidyl peptidase-4 (DPP-4) inhibitors significantly reduced all monitored parameters of glucoregulation without changing body weight and BMI after 3 and 6 months as opposed to insulin agents. However, there were no statistically significant differences between the groups when adjusting for starting HbA1c, FBG and PPG (F=1.16, p=NS), although a statistically significant difference in HbA1c levels (F=3.35, p<0.01) persisted in DPP-4 inhibitor users. The incidence of hypoglycemia was significantly higher in patients treated with NPH insulin and premixed insulin than in patients treated with other agents. CONCLUSION: A more aggressive approach is needed with early treatment intensification using available agents.

Are We Compensating for the Lack of Physical Activity in Our Diabetic Patients with Treatment Intensification?

BACKGROUND: We studied the association between leisure time physical activity (LTPA) and glycemic control, body mass index (BMI), and hypoglycemic incidents in type 1 (T1DM) and type 2 diabetes patients (T2DM). METHODS: This is a cross-sectional study of 198 diabetic patients (60 with type 1 diabetes, 138 with type 2 diabetes). LTPA was assessed by a validated 12-month questionnaire. Patients were grouped as sedentary and moderately to vigorously active. Outcome measures were Hemoglobin A1c (HbA1c), BMI, and hypoglycemic episodes. RESULTS: LTPA effect on the HbA1c reduction was present in diabetes type 1 patients. Patients who were involved in the moderate to vigorous-intensity physical activity had a greater decrease in the HbA1c (p = 0.048) than patients with low physical activity (p = 0.085). Level of LTPA was neither associated with increased number of hypoglycemic episodes, nor BMI. After an average of 4 years of diabetes, the number of patients requiring more than one antidiabetic agent increased, although the observed difference did not correlate with LTPA level. CONCLUSIONS: LTPA has an influence on the regulation of diabetes type 1, and intensification of medical treatment is compensating for the lack of lifestyle change-especially in type 2 diabetics.