Aihua Liu

Purpose While metformin is known to regulate thyroid stimulating hormone (TSH) levels, the effects of acarbose on thyroid function remain unreported. Our study was designed to evaluate the impact of acarbose and metformin on thyroid function and thyroid hormone sensitivity in type 2 diabetic patients. Methods In the MARCH study, 788 patients with type 2 diabetes were randomly assigned to treat with acarbose (300 mg) or metformin (1,500 mg) for 48 weeks. Thyroid function was assessed at baseline, 24 weeks, and 48 weeks, and the thyroid feedback quantile index (TFQI) and parameterized thyroid feedback quantile index (PTFQI) were calculated. Generalized estimating equations adjusted for confounders were used to analyze changes over time. Results Eighty-four patients with subclinical hypothyroidism (SCH) exhibited a decrease in TSH levels (p = 0.001) with no significant differences between the two treatment groups (p = 0.460). Both TFQI (p = 0.029) and PTFQI (p < 0.001) also decreased over time. Mediation analysis revealed that these change over time were not mediated by BMI (all p < 0.05). Among the 489 euthyroid subjects, no significant changes in TSH levels were observed (p > 0.05). Stratification by baseline TSH levels revealed significant increases in TSH, TFQI, and PTFQI (all p < 0.05) in the normal-low TSH group and significant decreases in PTFQI (all p < 0.05) in the normal-high TSH group after treatment with acarbose and metformin. Conclusions Acarbose and metformin have similar buffering effects on TSH levels, the TFQI and the PTFQI. In patients with lower TSH levels, acarbose and metformin do not further decrease TSH levels. Clinical Trial Registry number ChiCTR-TRC-08000231.

Objective: Gestational transient thyrotoxicosis (GTT) and Graves’ disease (GD) are the most common causes of hyperthyroidism during pregnancy. However, few studies have compared pregnancy outcomes of patients who had GTT to those who had GD in the first trimester of pregnancy. Methods: We conducted a prospective, multicenter cohort study in China. Participants received questionnaires, physical examinations, and underwent measurements of TSH, FT4, TPOAb, TRAb, and urinary iodine in the first trimester. The patients diagnosed with either GTT or GD and normal thyroid function (NTF) group were followed until delivery. The thyroid function and pregnancy outcomes were reported. Results: A total of 125 pregnant women with thyrotoxicosis and 246 age-matched pregnant women with NTF were included. (1) The thyroid function of GTT group returned to normal range in the third trimester, but was consistently abnormal in GD group. (2) The incidence of gestational diabetes mellitus (GDM) in GTT group (11.5%, 9/78) was significantly higher than that in NTF group (4.9%, 12/246) (P = 0.037). The incidence of premature delivery in GD untreated (30.8%, 8/26, P = 0.002) and treated group (28.6%, 6/21, P = 0.008) were both respectively higher than in the NTF group (7.7%, 19/246). Miscarriage (15.4%, 4/26 vs. 3.7%, 9/246, P = 0.026) and gestational hypertension were more prevalent in GD untreated group (19.2%, 5/26 vs. 3.3%, 8/246, P = 0.004) than in NTF group. (3) The presence of positive TRAb and positive TPOAb in the first trimester were independent risk factors for miscarriage (OR = 5.23, 95% CI = 1.11–24.78, P = 0.037) and low birth weight infants (OR = 7.76, 95% CI = 1.23–48.86, P = 0.029), respectively. Conclusion: In conclusion, pregnancy outcomes appear variable, according to the etiology of first trimester thyrotoxicosis. GTT appears to be associated with GDM. GD appears to be associated with an increased risk of premature delivery, gestational hypertension, and miscarriage. The diagnosis of GTT and GD patients in early pregnancy and appropriate treatment of GD patients may be associated with improved pregnancy outcomes.

Maternal subclinical hypothyroidism (SCH) during pregnancy can adversely affect the neurodevelopment of the offspring. The balance of nerve growth factor (NGF)-related tropomyosin receptor kinase A/p75 neurotrophin receptor (TrkA/p75^NTR) signaling in the hippocampus is important in brain development, and whether it affects cognitive function in maternal SCH’s offspring is not clear. In this study, we found that compared with the control (CON) group, expression of proliferation-related proteins [NGF, p-TrkA, phospho-extracellular signal-regulated kinase 1/2 (p-ERK1/2) and phospho-cAMP response element-binding protein (p-CREB)] decreased in the hippocampus of the offspring in the SCH group, overt hypothyroidism (OHT) group, and the group with levothyroxine (L-T₄) treatment for SCH from gestational day 17 (E17). In contrast, expression of apoptosis-related proteins [pro-NGF, p75^NTR, phospho-C-Jun N-terminal kinase (p-JNK), p53, Bax and cleaved caspase-3] was increased. The two groups with treatment with L-T₄for SCH from E10 and E13, respectively, showed no significant difference compared with the CON group. L-T₄treatment enhanced relative expression of NGF by increasing NGF/proNGF ratio in offspring from maternal SCH rats. In conclusion, L-T₄treatment for SCH from early pregnancy dramatically ameliorated cognitive impairment via TrkA/p75^NTRsignaling, which involved activation of the neuronal proliferation and inhibition of neuronal apoptosis in SCH rats’ offspring.

Numerous epidemiological studies have shown that subclinical hypothyroidism (SCH) can impair endothelial function and cause dyslipidemia. Studies have evaluated the effects of thyroid stimulating hormone (TSH) on endothelial cells, but the mechanism underlying the proatherosclerotic effect of increased TSH levels remains unclear. In the present study, SCH rat models were established in thyroidectomized Wistar rats that were given ʟ-T₄ daily. The results showed that in vivo, the expression of osteopontin (OPN) vascular cell adhesion molecule (VCAM-1), and levels of integrin α_vβ₃ in the aortic tissue in SCH and Hypothyroidism (CH) groups was higher than in the control group. However, the effect in the SCH group was higher than in the CH group. In vitro, results showed that different concentration and time gradients of TSH stimulation could increase the expression of OPN, VCAM-1, and integrin α_vβ₃, and this was accompanied by extracellular signal regulated kinase 1/2 (Erk1/2) and Akt activation in human umbilical vein endothelial cells (HUVECs). TSH induced elevation of these proatherosclerotic factors was partially suppressed by a specific Akt inhibitor but not by a specific Erk inhibitor. Findings suggested that the endothelial dysfunction caused by SCH was related to increased proatherosclerotic factors induced by TSH via Akt activation.