Pharmacological intervention for diabetes after pregnancy prevention in women with prior gestational diabetes: A scoping review.

Women with previous gestational diabetes mellitus (GDM) are at increased risk of developing diabetes after pregnancy (DAP), especially 5-10 years postpartum. Two well-known diabetes prevention trials demonstrated a significant reduction in DAP incidence using metformin and troglitazone; however, since their publication, several novel classes of anti-hyperglycemic agents have emerged. This review aimed to conduct a systematic literature search for new evidence in support of pharmacotherapy in DAP prevention and to analyze the results based on special considerations for women of reproductive potential. The only studies whose primary outcome was DAP incidence were those examining metformin, the thiazolidinediones troglitazone and pioglitazone, and the dipeptidyl peptidase-4 inhibitor vildagliptin. Metformin was effective in DAP reduction and was well tolerated, but participants were on average 12 years beyond their GDM pregnancy. Troglitazone was also shown to prevent DAP, but was withdrawn from the market due to hepatotoxicity. There was no comparator arm in the pioglitazone study, which limits its interpretability. The vildagliptin study was underpowered. There are ongoing trials with glucagon-like peptide 1 receptor agonists and sodium-glucose cotransporter 2 inhibitors, but none with diabetes incidence as a primary outcome. This review highlights the limited evidence base for pharmacological prevention of DAP.

Effects of Cannabis Use in Youth and Young Adults With Type 1 Diabetes: The Highs, the Lows, the Don't Knows.

Our objective was to address the request by our Diabetes Canada/Canadian Institutes of Health Research-funded Virtual Patient Network (VPN) of youth and young adults with type 1 diabetes for information on the impact of cannabis use on type 1 diabetes. To respond to this patient-initiated request, we conducted a literature search in PubMed, with search terms relevant to the following: cannabis use in youth with type 1 diabetes, effects of cannabis use on glycemic control and diabetic emergencies and immune-modulating properties of cannabis. These were synthesized in a narrative review. The number of studies is limited and is based largely on self-report and cross-sectional assessment. The existing literature indicates that 10% to 30% of youth and young adults with type 1 diabetes report ever using cannabis, similarly to the general population. Use appears to be associated with higher glycated hemoglobin and greater diabetic ketoacidosis incidence. There is some evidence of poorer self-management during episodes of use. Cannabis has been shown to be protective against type 1 diabetes in animal models, but such findings have yet to be replicated in humans. Existing cross-sectional studies suggest adverse effects of cannabis use on glycemic control and self-management. However, it is not clear if the associations identified are due to use itself or other patient or contextual factors. Nonetheless, given high use rates, health-care providers should query use, discuss its potential impact on diabetes management and outcomes, and codevelop an action plan.

A thyroid gland with over 30 foci of papillary thyroid carcinoma with activating BRAF V600E mutation.

Multifocal papillary thyroid carcinoma (PTC) is common and the number of tumor foci rarely exceeds ten. The mechanism of multifocal disease is debated, with the two main hypotheses consisting of either intrathyroidal metastatic spread from a single tumor or independent multicentric tumorigenesis from distinct progenitor cells. We report the case of a 46-year-old woman who underwent total thyroidectomy and left central neck lymph node dissection after fine-needle aspiration of bilateral thyroid nodules that yielded cytological findings consistent with PTC. Final pathology of the surgical specimen showed an isthmic dominant 1.5 cm classical PTC and over 30 foci of microcarcinoma, which displayed decreasing density with increasing distance from the central lesion. Furthermore, all malignant tumors and lymph nodes harbored the activating BRAF V600E mutation. The present case highlights various pathological features that support a mechanism of intraglandular spread, namely a strategic isthmic location of the primary tumor, radial pattern of distribution and extensive number of small malignant foci and BRAF mutational homogeneity. Learning points: Multifocal papillary thyroid carcinoma (PTC) is commonly seen in clinical practice, but the number of malignant foci is usually limited to ten or less. There is no clear consensus in the literature as to whether multifocal PTC arises from a single or multiple distinct tumor progenitor cells. Strategic location of the dominant tumor in the thyroid isthmus may favor intraglandular dissemination of malignant cells by means of the extensive lymphatic network. An important pathological finding that may be suggestive of intrathyroidal metastatic spread is a central pattern of distribution with a reduction in the density of satellite lesions with increasing distance from the dominant focus. PTCs originating from the isthmus with intraglandular metastatic dissemination behave more aggressively. As such, a more aggressive treatment course may be warranted, particularly with regard to the extent of surgery.

Low dietary folate and methylenetetrahydrofolate reductase deficiency may lead to pregnancy complications through modulation of ApoAI and IFN-γ in spleen and placenta, and through reduction of methylation potential.

SCOPE: Genetic or nutritional disturbances in folate metabolism lead to hyperhomocysteinemia and adverse reproductive outcomes. Folate-dependent homocysteine remethylation is required for methylation reactions and may influence choline/betaine metabolism. Hyperhomocysteinemia has been suggested to play a role in inflammation. The goal of this study was to determine whether folate-related pregnancy complications could be due to altered expression of some inflammatory mediators or due to disturbances in methylation intermediates. METHODS AND RESULTS: Pregnant mice with or without a deficiency of methylenetetrahydrofolate reductase (MTHFR) were fed control diets or folate-deficient (FD) diets; tissues were collected at embryonic day 14.5. FD decreased plasma phosphocholine and increased plasma glycerophosphocholine and lysophosphatidylcholine. Liver betaine, phosphocholine, and S-adenosylmethionine:S-adenosylhomocysteine ratios were reduced in FD. In liver, spleen, and placenta, the lowest levels of apolipoprotein AI (ApoAI) were observed in Mthfr(+/-) mice fed FD. Increased interferon-gamma (IFN-γ) was observed in spleen and placentae due to FD or Mthfr genotype. Plasma homocysteine correlated negatively with liver and spleen ApoAI, and positively with IFN-γ. CONCLUSION: Low dietary folate or Mthfr deficiency during pregnancy may result in adverse pregnancy outcomes by altering expression of the inflammatory mediators ApoAI and IFN-γ in spleen and placenta. Disturbances in choline metabolism or methylation reactions may also play a role.

Disturbed one-carbon metabolism causing adverse reproductive outcomes in mice is associated with altered expression of apolipoprotein AI and inflammatory mediators PPARα, interferon-γ, and interleukin-10.

Low dietary choline or deficiency of methylenetetrahydrofolate reductase (Mthfr) leads to hyperhomocysteinemia (Hhcy) and adverse reproductive outcomes. Homocysteine reduces synthesis of ApoAI, the major lipoprotein in HDL-cholesterol; ApoAI is regulated by PPARα and has antiinflammatory properties. Our aim was to determine whether pregnancy complications due to genetic or nutritional deficiencies in 1-carbon metabolism could relate to dysregulation of ApoAI and inflammatory mediators. We fed pregnant mice, with or without a deficiency of Mthfr, control or choline-deficient (ChDD) diets for 10-12 wk and examined levels of ApoAI, PPARα, IFNγ, and IL-10. ApoAI mRNA was reduced in livers of Mthfr(+/-) mice and ApoAI protein was reduced due to Mthfr deficiency or choline deficiency in liver and plasma. Placental ApoAI protein was also reduced due to Mthfr genotype or choline-deficient diet and in developmentally delayed embryos. Reduced liver PPARα expression (mRNA and protein) was observed in ChDD-fed mice and was associated with increased methylation of a CpG dinucleotide in its promoter. Hepatic IFNγ increased due to genotype, and placental IFNγ was higher in Mthfr(+/-) ChDD-fed dams compared to Mthfr(+/+) mice fed ChDD or Mthfr(+/-) mice fed CD. IL-10 was reduced in livers of ChDD-fed mice. We propose that a deficiency of dietary choline or Mthfr leads to Hhcy and reduced expression of maternal ApoAI, with reduced ApoAI transfer to embryo. Disturbances in 1-carbon metabolism also reduce maternal PPARα expression, possibly through promoter hypermethylation, and increase IFNγ and decrease IL-10 levels. This disturbance of the T helper (Th1) (IFNγ):Th2 (IL-10) ratio and the increase in inflammatory mediators may contribute to pregnancy complications.