Mice with a Targeted Deletion of the Type 2 Deiodinase Are Insulin Resistant and Susceptible to Diet Induced Obesity

The type 2 iodothyronine deiodinase (D2) converts the pro-hormone thyroxine into T3 within target tissues. D2 is essential for a full thermogenic response of brown adipose tissue (BAT), and mice with a disrupted Dio2 gene (D2KO) have an impaired response to cold. BAT is also activated by overfeeding.After 6-weeks of HFD feeding D2KO mice gained 5.6% more body weight and had 28% more adipose tissue. Oxygen consumption (V0(2)) was not different between genotypes, but D2KO mice had an increased respiratory exchange ratio (RER), suggesting preferential use of carbohydrates. Consistent with this, serum free fatty acids and β-hydroxybutyrate were lower in D2KO mice on a HFD, while hepatic triglycerides were increased and glycogen content decreased. Neither genotype showed glucose intolerance, but D2KO mice had significantly higher insulin levels during GTT independent of diet. Accordingly, during ITT testing D2KO mice had a significantly reduced glucose uptake, consistent with insulin resistance. Gene expression levels in liver, muscle, and brown and white adipose tissue showed no differences that could account for the increased weight gain in D2KO mice. However, D2KO mice have higher PEPCK mRNA in liver suggesting increased gluconeogenesis, which could also contribute to their apparent insulin resistance.We conclude that the loss of the Dio2 gene has significant metabolic consequences. D2KO mice gain more weight on a HFD, suggesting a role for D2 in protection from diet-induced obesity. Further, D2KO mice appear to have a greater reliance on carbohydrates as a fuel source, and limited ability to mobilize and to burn fat. This results in increased fat storage in adipose tissue, hepatic steatosis, and depletion of liver glycogen in spite of increased gluconeogenesis. D2KO mice are also less responsive to insulin, independent of diet-induced obesity

Iodine Intake, Thyroid Function and Pregnancy Outcome in a Tuscan Cohort of Women Living in an Area with Moderate Iodine Deficiency

Thyroid hormones are crucial for fetal development. Pregnancy leads to multiple changes in thyroid function. Aim of the study was to evaluate iodine intake, thyroid function and thyroid autoimmunity impact on pregnancy outcome. Thyroid function, anti-thyroid antibodies, thyroid ultrasound, urinary iodine [UI], and pregnancy complications were analyzed at 10th, 15th, 20th, 25th and 35th weeks of pregnancy and 3-6 months after delivery in 902 women living in Tuscany, an area of moderate iodine deficiency. Chronic autoimmune thyroiditis [CAT] was found in 414 women (45.9%). Of these, only 261 (63%) were aware of their disease before our evaluation. Similarly, a nodular disease was found in 138 women (15.3%), but only 89 (64%) knew about that before pregnancy. At the first evaluation, iodized salt alone [S] was assumed by 31% of women, multivitamins containing iodine [M] by 20%, both [B] by 24% and none [N] by 25%. While a significantly higher UI and a higher number of women with UI over the desirable 150 µg/L value was measured in M and B groups, median UI was below 150 µg/L in all groups, both considering all women and only women not assuming any thyroid therapy. A significant correlation between FT4, FT3 or TSH and UI was not found in either healthy women or women affected by a thyroid disease, but women with UI below 50 µg/L had a significantly lower FT3/FT4 ratio. Thyroid volume significantly increased throughout pregnancy, this increase depending on both TSH and UI. In women affected by autoimmune thyroiditis, both anti-thyroglobulin and anti-thyroperoxidase antibodies decreased during pregnancy and rebounded 3 months after delivery. Analyzing the previous pregnancy history of recruited women (n=492 pregnancies), a miscarriage was reported in 51.4% of cases, without differences between healthy women and women affected by CAT (miscarriage prevalence being 53.9% and 49.9% respectively). No difference between women affected by CAT and healthy ones was found when considering the 902 pregnancies included in this study, although the prevalence in both groups was about 10%. LT4 dose in women already treated at the beginning of pregnancy required an increase in 57% of women under suppressive therapy (mean increase 52%), 72% of women with autoimmune hypothyroidism (mean increase 33%) and 92% of thyroidectomized women (mean increase 34%). Moreover, 50 women affected by CAT and 5 with thyroid nodules initiated LT4 therapy during pregnancy, mean final dose being 64.2±31.1 µg/die and 55.0±27.4 µg/die respectively. In conclusion, almost a half of women affected by a thyroid disease were not aware of their disease at the beginning of pregnancy, suggesting that a universal screening could be useful. While S seems to be not enough a supplementation during pregnancy, M are able to increase UI but the majority of women continue to have an insufficient iodine uptake. Moreover, M are assumed by a minority of women, suggesting an improvement in supplementation programs is needed. This is crucial when considering that FT3/FT4 ratio increased in women with very low UI, suggesting a role of UI in isolated hypothyroxinemia, which has been previously correlated with children cognitive abilities. While an increase in LT4 therapy is often required, this is not true for all women and varies in different thyroid diseases, so that any change in the dose should follow an early, frequent and personalized thyroid function evaluation

Iodine nutrition status, thyroid function in the first trimester of pregnancy and pregnancy progression in women residing in an area of know moderate iodine deficiency

BACKGROUND: 1) To assess thyroid function in a group of women in the first trimester of pregnancy who reside in a geographic area of moderate iodine deficiency. 2) To assess the usefulness of early pregnancy screening. METHODS: The study population included 240 women in the first trimester of pregnancy residing in the same valley in the Appenine Mountains (Casentino, Tuscany) characterized by a known moderate iodine deficiency. TSH, FT3, FT4, urinary iodine level, and anti-thyroid peroxidase autoantibodies (anti-TPO antibodies) were added to the tests included in the regional prescription pad for the first blood draw and data on thyroid disease and the use of iodized salt was also recorded. RESULTS: Of the 240 women examined, 55 (23%) had a TSH value over 2.5 mUI/L (NV= 2.51-9.89). A urinary iodine level of under 150µg/L was found in 170 women (70%). The median urinary iodine level in women using iodized salt was 103 µg/L, while that in women not using it was 110µg/L (not a significant statistical difference). None of the women included in the study were taking iodine-containing supplements. CONCLUSIONS: In an area of known moderate iodine deficiency 23% of the women presented TSH values over 2.5 mUI/L and 70% of the women presented urinary iodine deficiency in the first trimester of pregnancy. This makes the case for thyroid function screening and strengthening of iodine supplementation at the beginning of pregnancy

Subcapsular Renal Hematoma in Simultaneous Pancreas Kidney Transplantation

Subcapsular renal hematoma (SRH) is a challenging condition, which may jeopardize kidney function or constitute a life-threatening event. This is particularly true in single-kidney patients, such as kidney-transplant recipients. SRH may exert an excessive pressure on the surrounding parenchyma, thus resulting in hypoperfusion and ischemia, with high risk of acute kidney failure and graft loss. Moreover, SRH may precede an overt renal rupture with subsequent hemorrhage and hemodynamic instability. The indication to an interventional management for this condition is still a matter of debate, with some authors advocating the high possibilities of spontaneous resolution and others advocating the high-risk of graft loss and even internal bleeding in case of overt renal rupture. Herein, we report the case of a 51-year-old simultaneous pancreas-kidney transplantation recipient who presented a SRH following a mild trauma. The therapeutic choices were carefully balanced on the specific case, and the conservative management proved successful

Treating Type 1 Diabetes by Pancreas Transplant Alone: a Cohort Study on Actual Long-Term (10 Years) Efficacy and Safety

Background: Physiologically regulated insulin secretion and euglycemia are achievable in type 1 diabetes (T1D) by islet or pancreas transplantation. However, pancreas transplant alone (PTA) remains a debated approach, with uncertainties on its relative benefits and risks. We determined the actual long-term (10 years) efficacy and safety of PTA in carefully characterized T1D subjects. Methods: This is a single-centre, cohort study in 66 consecutive T1D subjects who received a PTA between April 2001 and December 2007, and were then all followed until 10 years since transplant. Main features evaluated were patient survival, pancreas graft function, C-peptide levels, glycemic parameters, and the function of the native kidneys. Results: Ten-year actual patient survival was 92.4%. Optimal (insulin-independence) or good (minimal insulin requirement) graft function was observed in 57.4 and 3.2% of patients, respectively. Six (9.0%) patients developed stage 5 or 4 chronic kidney disease. In the remaining individuals bearing a successful PTA, eGFR decline per year was -2.29±2.69 ml/min/1.73m. Reduction of eGFR at 1 year post-PTA was higher in those with pre-PTA hyperfiltration and higher HbA1c concentrations; eGFR changes afterwards significantly correlated with diabetes duration. In recipients with normoglycemia at 10 years, 74% of normo- or micro-albuminuric subjects pre-PTA remained stable, and 26% progressed towards a worse stage; conversely, in 62.5% of the macro-albuminuric individuals albuminuria severity regressed. Conclusions: These long-term effects of PTA on patient survival, graft function and the native kidneys support PTA as a suitable approach to treat diabetes in selected T1D patients

When genetic load does not correlate with phenotypic spectrum: lessons from the GnRH receptor (GNRHR)

CONTEXT: A broad spectrum of GnRH-deficient phenotypes has been identified in individuals with both mono- and biallelic GNRHR mutations. OBJECTIVE: The objective of the study was to determine the correlation between the severity of the reproductive phenotype(s) and the number and functional severity of rare sequence variants in GNRHR. SUBJECTS: Eight hundred sixty-three probands with different forms of GnRH deficiency, 46 family members and 422 controls were screened for GNRHR mutations. The 70 subjects (32 patients and 38 family members) harboring mutations were divided into four groups (G1-G4) based on the functional severity of the mutations (complete or partial loss of function) and the number of affected alleles (monoallelic or biallelic) with mutations, and these classes were mapped on their clinical phenotypes. RESULTS: The prevalence of heterozygous rare sequence variants in GNRHR was significantly higher in probands vs. controls (P < 0.01). Among the G1-G3 groups (homozygous subjects with successively decreasing severity and number of mutations), the hypogonadotropic phenotype related to their genetic load. In contrast, subjects in G4, with only monoallelic mutations, demonstrated a greater diversity of clinical phenotypes. CONCLUSIONS: In patients with GnRH deficiency and biallelic mutations in GNRHR, genetic burden defined by severity and dose is associated with clinical phenotype. In contrast, for patients with monoallelic GNRHR mutations this correlation does not hold. Taken together, these data indicate that as-yet-unidentified genetic and/or environmental factors may combine with singly mutated GNRHR alleles to produce reproductive phenotypes

TAC3/TACR3 Mutations Reveal Preferential Activation of Gonadotropin-Releasing Hormone Release by Neurokinin B in Neonatal Life Followed by Reversal in Adulthood

Context: Mutations in TAC3 and TACR3 (encoding neurokinin B and its receptor) have been identified in Turkish patients with idiopathic hypogonadotropic hypogonadism (IHH), but broader populations have not yet been tested and genotype-phenotype correlations have not been established