Background Constipation is highly prevalent in the United States. The association of dietary fat intake with constipation has not been well studied. We recently reported that mice fed a high-fat diet had higher incidence of constipation than regular diet fed mice. The aim of this study was to assess if increased intake of dietary saturated fat in humans is also associated with higher risk of constipation and reduced stool frequency. Methods Analyses were based on data from 6,207 adults (≥20 years) from the 2005–2006 and 2007–2008 cycles of the National Health and Nutrition Examination Surveys (NHANES) who had completed the bowel health questionnaire. Constipation was defined as a stool frequency of less than three times per week. Multivariable logistic regression analysis was used to calculate adjusted prevalence odds ratio estimates. Statistical analyses were performed using R and RStudio softwares. Key Results The prevalence of constipation in this sample was 3.1%. After multivariable adjustment high saturated fat remained associated with constipation. The odds ratio for high saturated fat intake associated with constipation was much higher in diabetics above 65 years, especially in non-Hispanic blacks, females, and those with poor glycemic control, compared to the control group. Conclusions & Inferences To our knowledge, this is the first report to investigate the association of high saturated fat diet, bowel frequency and diabetes. This study demonstrates that a high dietary saturated fat intake is associated with significant increase in the prevalence of constipation, especially in the uncontrolled diabetic, non-Hispanic black, female patients.
Type 1 diabetes mellitus (T1DM) is caused by immune destruction of insulin-producing pancreatic β-cells. Commonly used insulin injection therapy does not provide a dynamic blood glucose control to prevent long-term systemic T1DM-associated damages. Donor shortage and the limited long-term success of islet transplants have stimulated the development of novel therapies for T1DM. Gene therapy-based glucose-regulated hepatic insulin production is a promising strategy to treat T1DM. We have developed gene constructs which cause glucose-concentration–dependent human insulin production in liver cells. A novel set of human insulin expression constructs containing a combination of elements to improve gene transcription, mRNA processing, and translation efficiency were generated as minicircle DNA preparations that lack bacterial and viral DNA. Hepatocytes transduced with the new constructs, ex vivo, produced large amounts of glucose-inducible human insulin. In vivo, insulin minicircle DNA (TA1m) treated streptozotocin (STZ)-diabetic rats demonstrated euglycemia when fasted or fed, ad libitum. Weight loss due to uncontrolled hyperglycemia was reversed in insulin gene treated diabetic rats to normal rate of weight gain, lasting ∼1 month. Intraperitoneal glucose tolerance test (IPGT) demonstrated in vivo glucose-responsive changes in insulin levels to correct hyperglycemia within 45 minutes. A single TA1m treatment raised serum albumin levels in diabetic rats to normal and significantly reduced hypertriglyceridemia and hypercholesterolemia. Elevated serum levels of aspartate transaminase, alanine aminotransferase, and alkaline phosphatase were restored to normal or greatly reduced in treated rats, indicating normalization of liver function. Non-viral insulin minicircle DNA-based TA1m mediated glucose-dependent insulin production in liver may represent a safe and promising approach to treat T1DM.
Moderate macrovesicular steatosis (>30%), which is present in almost 50% of livers considered for transplantation increases the risk of primary graft dysfunction. Our previously published data showed that glial cell line-derived neurotrophic factor (GDNF) is protective against high-fat diet (HFD)-induced hepatic steatosis in mice. Hence, we hypothesized that perfusion of steatotic livers with GDNF may reduce liver fat content prior to transplantation. Livers from 8 weeks regular diet (RD) and HFD-fed mice were perfused ex-vivo for 4 hours with either vehicle, GDNF, or a previously described defatting cocktail. Liver’s residual fat was quantified colorimetrically using a triglyceride assay kit, and by Oil Red-O and Nile Red/Hoechst staining. Liver tissue injury was assessed using an LDH activity assay. In vitro induction of lipolysis in HepG2 cells was assessed by measuring glycerol and free fatty acid release. Oil Red-O staining showed significantly more steatosis in liver from HFD-fed mice compared with RD-fed mice (P<0.001). HFD Livers perfused with GDNF had significantly less steatosis than those not perfused (P=0.001) or perfused with vehicle (P<0.05). GDNF is equally effective in steatotic liver defatting compared to the defatting cocktail; however, GDNF induces less liver damage than the defatting cocktail. These observations were consistent with data obtained from assessment of liver triglyceride content. Assessment of liver injury revealed significant hepatocyte injury in livers perfused with the control defatting cocktail but no evidence of injury in livers perfused with either GDNF or vehicle. In vitro, GDNF reduced triglyceride accumulation in HepG2 cells and stimulated increased triglyceride lipolysis. Conclusion GDNF can decrease mice liver fat content to an acceptable range and could be a potential defatting agent prior to liver transplantation.
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