A Wnt coreceptor low-density lipoprotein receptor-related protein 5 (LRP5) plays an essential role in bone accrual and eye development. Here, we show that LRP5 is also required for normal cholesterol and glucose metabolism. The production of mice lacking LRP5 revealed that LRP5 deficiency led to increased plasma cholesterol levels in mice fed a high-fat diet, because of the decreased hepatic clearance of chylomicron remnants. In addition, when fed a normal diet, LRP5-deficient mice showed a markedly impaired glucose tolerance. The LRP5-deficient islets had a marked reduction in the levels of intracellular ATP and Ca 2؉ in response to glucose, and thereby glucoseinduced insulin secretion was decreased. The intracellular inositol 1,4,5-trisphosphate (IP3) production in response to glucose was also reduced in LRP5؊͞؊ islets. Real-time PCR analysis revealed a marked reduction of various transcripts for genes involved in glucose sensing in LRP5؊͞؊ islets. Furthermore, exposure of LRP5؉͞؉ islets to Wnt-3a and Wnt-5a stimulates glucose-induced insulin secretion and this stimulation was blocked by the addition of a soluble form of Wnt receptor, secreted Frizzled-related protein-1. In contrast, LRP5-deficient islets lacked the Wnt-3a-stimulated insulin secretion. These data suggest that Wnt͞LRP5 signaling contributes to the glucose-induced insulin secretion in the islets.and LRP6 are coreceptors involved in the Wnt signaling pathway (1-6). The Wnt signaling pathway plays a pivotal role in embryonic development (7,8) and oncogenesis (9) through various signaling molecules including Frizzled receptors (10), recently characterized LRP5 and LRP6 (1-6), and Dickkopf proteins (4, 6). In addition, the Wnt signaling is also involved in adipogenesis by negatively regulating adipogenic transcription factors (Tcfs) (11). Although Wnt signaling has been characterized in both developmental and oncogenic processes, little is known about its function in the normal adult.Recent studies have revealed that loss of function mutations in the LRP5 gene cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (12). LRP5 is expressed in osteoblasts and transduces Wnt signaling via the canonical pathway, thereby modulating bone accrual development (12, 13). A point mutation in a ''propeller'' motif in LRP5 causes a dominant-positive high bone density by impairing the action of a normal antagonist of the Wnt pathway, Dickkopf, thereby increasing Wnt signaling (14,15). In addition, the human LRP5 gene is mapped within the region (IDDM4) linked to type 1 diabetes on chromosome 11q13 (16).In previous studies, we and others showed that LRP5 is highly expressed in many tissues, including hepatocytes and pancreatic beta cells (17,18). We also showed that LRP5 can bind apolipoprotein E (apoE) (18). This finding raises the possibility that LRP5 plays a role in the hepatic clearance of apoE-containing chylomicron remnants, a major plasma lipoprotein carrying diet-derived cholesterol.To evaluate the in vivo roles of LRP5, we generated LRP...

These results indicate that the clinical subtype with slowly progressive course (slowly progressive IDDM) has distinct findings including late-age onset, high prevalence of islet cell antibodies, preserved beta-cell function, and high family history of NIDDM. An additive effect of class I and class II major histocompatibility complex antigens is suggested as an explanation for the acute clinical manifestations and more severe beta-cell destruction in group A patients.

Aim The aim of this study was to investigate the therapeutic potential of sodium glucose cotransporter 2 inhibitor (SGLT2I) as an effective therapeutic option for non‐alcoholic fatty liver disease (NAFLD). Methods In this prospective study, nine patients with NAFLD complicated by type 2 diabetes mellitus (DM), were introduced to the regimen of canagliflozin 100 mg once daily for 24 weeks and were evaluated by liver histology at pretreatment and at 24 weeks after the start of treatment. The primary outcome was histological improvement, defined as a decrease in NAFLD activity score of one point or more without worsening in fibrosis stage. Glucose metabolism was evaluated based on the meal tolerance test. The usefulness of extracellular and exosome microRNA‐122 (miR‐122) as early predictors of histological improvement was investigated. Results All of the nine patients achieved histological improvement. Scores of steatosis, lobular inflammation, ballooning, and fibrosis stage decreased by 78%, 33%, 22%, and 33% at 24 weeks compared to the pretreatment, respectively. Six patients showed improvement in insulin resistance, and the other three patients showed partial improvement of insulin secretion function. Six patients, who showed a decrease in both extracellular and exosome miR‐122 ratios (the ratio of miR‐122 levels at 1 day after treatment to that at baseline), showed histological improvement. Furthermore, one patient, who showed a decrease in exosome miR‐122 ratios regardless of the increase in extracellular miR‐122 ratios, also showed decreases in NAFLD activity score and fibrosis stage. Conclusion A prospective study showed that SGLT2I for NAFLD complicated by DM improved histological features in connection with glucose metabolism. This trial was registered as clinical trial UMIN000018166.