Pregnancy and lactation-associated osteoporosis (PLO) is very rare, but it can cause severe vertebral compression fractures with disabling back pain. PLO patients have commonly been treated with antiresorptive agents against high bone turnover. There are, however, some concerns regarding the use of bisphosphonates: (1) PLO occurs during the first pregnancy with a high possibility of recurrence during the second pregnancy, (2) long-term outcomes of bisphosphonates in PLO are lacking, and (3) there is a possibility of bisphosphonates accumulated in the bones crossing the placenta. Therefore, alternative therapies must be considered. We analyzed the effect of teriparatide (TPTD), the human recombinant parathyroid hormone (1-34), for 18 months in three women with PLO. Multiple vertebral fractures with severe back pain appeared within 6 months after their first childbirth. Two of them had a family history of osteoporosis. Lactation was discontinued immediately after diagnosis of PLO. Calcium carbonate, cholecalciferol, and TPTD were prescribed. The back pain immediately resolved. Bone mineral density (BMD) increased by 14.5-25.0% (mean 19.5%) at the lumbar spine and by 9.5-16.7% (mean 13.1%) at the femoral neck, after 18 months of treatment. The final Z scores in these PLO patients were nearly normalized. Two women had a second baby without any complication. BMD significantly improved after 18 months of treatment with TPTD without further fractures. In conclusion, TPTD should be considered to avoid long-term morbidity in young patients with PLO and is highly encouraged for use in PLO patients with multiple vertebral fractures.

No abstract

(2015) Chronic HMGCR/HMG-CoA reductase inhibitor treatment contributes to dysglycemia by upregulating hepatic gluconeogenesis through autophagy induction, Autophagy, 11:11, 2089-2101, DOI: 10.1080/15548627.2015 Keywords: autophagy, diabetes, gluconeogenesis, HMG-CoA reductase inhibitor, statin Abbreviations: ACTB, actin beta; AKT1, v-akt murine thymoma viral oncogene homolog 1; ATG7, autophagy-related 7; Baf A1, bafilomycin A 1 ; BECN1, Beclin 1 autophagy related; CQ, chloroquine; FOXO1, forkhead box O1; G6PC, glucose-6-phosphatase catalytic subunit; GCK, glucokinase (hexokinase 4); GFP, green fluorescent protein; HMGCR/HMG-CoA reductase, 3-hydroxy-3-methylglutaryl-CoA reductase; MAP1LC3A/LC3A, microtubule-associated protein 1 light chain 3 alpha; MTOR, mechanistic target of rapamycin (serine/threonine kinase); O-GluNAc, O-linked b-N-acetyl glucosamine; PCK1, phosphoenolpyruvate carboxykinase 1 (soluble); PIK3C3, phosphatidylinositol 3-kinase catalytic subunit type 3; PKLR, pyruvate kinase liver and RBC; qRT-PCR, quantitative reverse transcription-polymerase chain reaction; RFP, red fluorescent protein; RPS6KB1, ribosomal protein S6 kinase; 70kDa, polypeptide 1; shRNA, short hairpin RNA; T2DM, type 2 diabetes mellitus; XBP1, X-box binding protein 1.Statins (HMGCR/HMG-CoA reductase [3-hydroxy-3-methylglutaryl-CoA reductase] inhibitors) are widely used to lower blood cholesterol levels but have been shown to increase the risk of type 2 diabetes mellitus. However, the molecular mechanism underlying diabetogenic effects remains to be elucidated. Here we show that statins significantly increase the expression of key gluconeogenic enzymes (such as G6PC [glucose-6-phosphatase] and PCK1 (phosphoenolpyruvate carboxykinase 1 [soluble]) in vitro and in vivo and promote hepatic glucose output. Statin treatment activates autophagic flux in HepG2 cells. Acute suppression of autophagy with lysosome inhibitors in statin treated HepG2 cells reduced gluconeogenic enzymes expression and glucose output. Importantly, the ability of statins to increase gluconeogenesis was impaired when ATG7 was deficient and BECN1 was absent, suggesting that autophagy plays a critical role in the diabetogenic effects of statins. Moreover autophagic vacuoles and gluconeogenic genes expression in the liver of diet-induced obese mice were increased by statins, ultimately leading to elevated hepatic glucose production, hyperglycemia, and insulin resistance. Together, these data demonstrate that chronic statin therapy results in insulin resistance through the activation of hepatic gluconeogenesis, which is tightly coupled to hepatic autophagy. These data further contribute to a better understanding of the diabetogenic effects of stains in the context of insulin resistance.

No abstract

Supplemental Digital Content is available in the text