Mesenteric Fat Lipolysis Mediates Obesity-Associated Hepatic Steatosis and Insulin Resistance

Hepatic steatosis and insulin resistance are among the most prevalent metabolic disorders and are tightly associated with obesity and type 2 diabetes. However, the underlying mechanisms linking obesity to hepatic lipid accumulation and insulin resistance are incompletely understood. Glycoprotein 130 (gp130) is the common signal transducer of all interleukin 6 (IL-6) cytokines. We provide evidence that gp130-mediated adipose tissue lipolysis promotes hepatic steatosis and insulin resistance. In obese mice, adipocyte-specific gp130 deletion reduced basal lipolysis and enhanced insulin’s ability to suppress lipolysis from mesenteric but not epididymal adipocytes. Consistently, free fatty acid levels were reduced in portal but not in systemic circulation of obese knockout mice. Of note, adipocyte-specific gp130 knockout mice were protected from high-fat diet–induced hepatic steatosis as well as from insulin resistance. In humans, omental but not subcutaneous IL-6 mRNA expression correlated positively with liver lipid accumulation (r = 0.31, P < 0.05) and negatively with hyperinsulinemic-euglycemic clamp glucose infusion rate (r = –0.28, P < 0.05). The results show that IL-6 cytokine-induced lipolysis may be restricted to mesenteric white adipose tissue and that it contributes to hepatic insulin resistance and steatosis. Therefore, blocking IL-6 cytokine signaling in (mesenteric) adipocytes may be a novel approach to blunting detrimental fat-liver crosstalk in obesity.

Source Diabetes Pathophysiology http://ift.tt/1IovPvY

High Glucose-Repressed CITED2 Expression Through miR-200b Triggers the Unfolded Protein Response and Endoplasmic Reticulum Stress

High glucose in vivo and in vitro induces neural tube defects (NTDs). CITED2 (CBP/p300-interacting transactivator with ED-rich tail 2) is essential for neural tube closure. We explored the regulatory mechanism underlying CITED2 expression and its relationship with miRNA and endoplasmic reticulum (ER) stress. miR-200b levels were increased by maternal diabetes or high glucose in vitro, and this increase was abrogated by transgenic overexpression of superoxide dismutase 1 (SOD1) or an SOD1 mimetic. CITED2 was the target of miR-200b and was downregulated by high glucose. Two miR-200b binding sites in the 3'-untranslated region of the CITED2 mRNA were required for inhibiting CITED2 expression. The miR-200b mimic and a CITED2 knockdown mimicked the stimulative effect of high glucose on unfolded protein response (UPR) and ER stress, whereas the miR-200b inhibitor and CITED2 overexpression abolished high glucose–induced UPR signaling, ER stress, and apoptosis. The ER stress inhibitor, 4-phenylbutyrate, blocked CITED2 knockdown–induced apoptosis. Furthermore, the miR-200b inhibitor reversed high glucose–induced CITED2 downregulation, ER stress, and NTDs in cultured embryos. Thus, we showed a novel function of miR-200b and CITED2 in high glucose–induced UPR and ER stress, suggesting that miR-200b and CITED2 are critical for ER homeostasis and NTD formation in the developing embryo.

Source Diabetes Pathophysiology http://ift.tt/1QWnNM3

Metals in Urine and Diabetes in U.S. Adults

Our objective was to evaluate the relationship of urine metals including barium, cadmium, cobalt, cesium, molybdenum, lead, antimony, thallium, tungsten, and uranium with diabetes prevalence. Data were from a cross-sectional study of 9,447 participants of the 1999–2010 National Health and Nutrition Examination Survey, a representative sample of the U.S. civilian noninstitutionalized population. Metals were measured in a spot urine sample, and diabetes status was determined based on a previous diagnosis or an A1C ≥6.5% (48 mmol/mol). After multivariable adjustment, the odds ratios of diabetes associated with the highest quartile of metal, compared with the lowest quartile, were 0.86 (95% CI 0.66–1.12) for barium (P_trend = 0.13), 0.74 (0.51–1.09) for cadmium (P_trend = 0.35), 1.21 (0.85–1.72) for cobalt (P_trend = 0.59), 1.31 (0.90–1.91) for cesium (P_trend = 0.29), 1.76 (1.24–2.50) for molybdenum (P_trend = 0.01), 0.79 (0.56–1.13) for lead (P_trend = 0.10), 1.72 (1.27–2.33) for antimony (P_trend < 0.01), 0.76 (0.51–1.13) for thallium (P_trend = 0.13), 2.18 (1.51–3.15) for tungsten (P_trend < 0.01), and 1.46 (1.09–1.96) for uranium (P_trend = 0.02). Higher quartiles of barium, molybdenum, and antimony were associated with greater HOMA of insulin resistance after adjustment. Molybdenum, antimony, tungsten, and uranium were positively associated with diabetes, even at the relatively low levels seen in the U.S. population. Prospective studies should further evaluate metals as risk factors for diabetes.

Source Diabetes Pathophysiology http://ift.tt/1Zo6syu

Why I Give: Isabella’s Story

During the holiday season, the American Diabetes Association® encourages people to share their story on why they give. Whether it’s through local events, planned giving, annual donations or in memory of a loved one, these gifts go a long way in helping us save lives and continue the search for a cure.

The following are stories from a few of our generous supporters and organizations that have donated or fundraised on our behalf in 2015.

---

 

Hello! My name is Isabella (Bella) and I live in Highlands Ranch, Colorado. I am on the Junior Olympic Archery team and on a drill swim team. Archery and swimming are my favorite hobbies because they’re so much fun AND they keep me active, which helps control my blood sugar levels.

Oh, did I mention I’ve been living with type 1 diabetes since I was 8 years old? I will be celebrating my 13^th birthday in January!

I enjoy attending the many different diabetes-related activities that the American Diabetes Association holds in my area through its program Family Link. That’s how I learned about Camp Colorado. All year long I look forward to attending this camp that has been created especially for kids like me. The staff and volunteers are great at teaching us the ways to manage our diabetes, like improving our ability to inject insulin and use our pumps and continuous glucose monitors, counting carbs and other important skills. My favorite part about Camp Colorado is being able to have so much fun with other kids who have diabetes and to feel “normal” for four days. I always feel more confident about managing my diabetes after I come home—I wish camp lasted longer than a week!

In addition to attending Camp Colorado, I also love participating in the Step Out: Walk to Stop Diabetes® event with the Association’s Denver office because I get to have fun and help fight diabetes at the same time! As a Red Strider, Step Out gives me a chance to walk with other kids who have diabetes. It’s great to know that we are in this fight together and that diabetes can’t stop us.  This year I raised $1,000! Next year I plan on creating a team and doubling that amount. When I get older I want to volunteer and participate in even more events like Step Out.

I live with this disease every single day of my life, 24/7! There’s no time off for good behavior and no vacation from testing. Even though I won’t let diabetes stop me from doing the things I love, it’s very hard to live with this disease. No one should have to live with it.

Fundraising is important to me because I want to see the end to this disease! I know the money I raise goes to fund research that has advanced the treatment of diabetes by leaps and bounds in the last decade. A lot more still needs to be done.

I will continue to step up my efforts until we Stop Diabetes®! The holidays are a great time to make a donation: What better gift to give someone you love who has diabetes than donating to help find a cure and make their life better in the meantime? I know I would rather have my friends and family give a gift to the Association than buy me another pair of jeans or CD!

---

We hope you’re inspired by Isabella’s story as much as we are. Please take a moment now to make generous year end gift to change the future of diabetes. Your donation no matter what size will help us fund cutting-edge research and also allow us to advocate for billions of dollars of federal government research and provide community-based programs to help people across the U.S. live healthier lives today.

Visit diabetes.org/donate to help make a difference.

Source Diabetes Stops Here http://ift.tt/1OIrsbJ