Steroid-mediated liver steatosis is CD1d-dependent, while steroid-induced liver necrosis, inflammation, and metabolic changes are CD1d-independent.

INTRODUCTION: Glucocorticoids contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Natural killer T cells play a role in the pathogenesis of NAFLD and response to steroids. The present study aimed to determine the role of CD1d in steroid-mediated metabolic derangement and the steroid-protective effect of glycosphingolipids. METHODS: Ten groups of mice were studied. Steroids were orally administered to C57BL/6 mice to assess the therapeutic effect of ß-glucosylceramide (GC) on the development of steroid-mediated liver damage and metabolic derangements. The role of CD1d in the pathogenesis of steroid-induced liver damage and in mediating the hepatoprotective effect of GC was studied in CD1d-/- mice. RESULTS: A model of oral administration of steroids was established, resulting in insulin resistance, hyperinsulinemia, hypertriglyceridemia, liver steatosis, and hepatocellular injury. Steroid administration to CD1d-/- mice was associated with hyperglycemia and hypertriglyceridemia. However, CD1d-/- mice did not manifest marked steroid-induced steatosis. GC treatment alleviated steroid-associated metabolic derangements and liver injury independent of CD1d expression. CONCLUSION: A steroid-mediated model of NAFLD and metabolic derangements was established in which steroid-mediated steatosis was CD1d-dependent while steroid-induced liver necrosis, inflammation, and metabolic changes were CD1d-independent, which may support a dichotomy between steatosis and steatohepatitis in NAFLD.

Surveillance Endoscopy in the Management of Hereditary Diffuse Gastric Cancer Syndrome.

Hereditary diffuse gastric cancer (HDGC) syndrome results from a germline CDH1 mutation, and microscopic foci of signet-ring carcinoma cells (SRCC) are present in nearly all gastrectomy specimens.1 The lifetime risk of invasive gastric cancer (GC) has been thought to be 70%,2 but recent data have suggested a lower risk of 37%.3 Prophylactic total gastrectomy is considered the standard of care, but many patients choose surveillance endoscopy instead. We sought to define the outcomes in CDH1-positive individuals who pursued endoscopic surveillance.

The assembly of glycosphingolipid determines their immunomodulatory effect: A novel method for structure-based design of immunotherapy.

Structure-activity relationships provide insight into the binding interactions of beta-glycosphingolipids (GSLs) with both the TCR and the CD1d molecules, as well as the subsequent immunologic response of regulatory NKT cells. AIM: To determine the effects of synthetic GSL structures on their immune modulatory functions. METHODS: GSLs of various structures were tested in vitro and in an animal model of Concanavalin A (ConA) immune-mediated hepatitis. RESULTS: In vitro, using SV40 binding to live monkey CV1 cells, the l-threo stereoisomer of C8-ß-LacCer inhibits caveolar internalization, reducing viral binding to the cell surface. In vivo, in the ConA model, LR172, which has a saturated C8 chain, and LR178, which has a trans double bond at C-2 in the C8 chain, suppressed the immune-mediated liver inflammation and reduced IFNγ levels in a dose dependent manner. The beneficial effects of LR172 and of LR178 are associated with suppression of liver apoptosis, increased phosphorylated STAT3 expression in the liver, and an increase in the NKT liver/spleen ratio. SUMMARY: The assembly of GSLs determines their immunomodulatory effect and can serve as a method for structure-based design of immunotherapy.

Universal screening of both endometrial and colon cancers increases the detection of Lynch syndrome.

BACKGROUND: Lynch syndrome (LS) is the most common hereditary cause of colorectal cancer (CRC) and endometrial cancer (EC). Screening of all CRCs for LS is currently recommended, but screening of ECs is inconsistent. The objective of this study was to determine the added value of screening both CRC and EC tumors in the same population. METHODS: A prospective, immunohistochemistry (IHC)-based screening program for all patients with newly diagnosed CRCs and ECs was initiated in 2011 and 2013, respectively, at 2 centers (primary and tertiary). Genetic testing was recommended for those who had tumors with absent mutS homolog 2 (MSH2), MSH6, or postmeiotoic segregation increased 2 (PMS2) expression and for those who had tumors with absent mutL homolog 1 (MLH1) expression and no v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutation or MLH1 promoter methylation. Amsterdam II criteria, revised Bethesda criteria, and scores from prediction models for gene mutations (the PREMM1,2,6 and PREMM5 prediction models) were ascertained in patients with LS. RESULTS: In total, 1290 patients with CRC and 484 with EC were screened for LS, and genetic testing was recommended for 137 patients (10.6%) and 32 patients (6.6%), respectively (P = .01). LS was identified in 16 patients (1.2%) with CRC and in 8 patients (1.7%) with EC. Among patients for whom genetic testing was recommended, the LS diagnosis rate was higher among those with EC (25.0% vs 11.7%, P = .052). The Amsterdam II criteria, revised Bethesda criteria, and both PREMM calculators would have missed 62.5%, 50.0%, and 12.5% of the identified patients with LS, respectively. CONCLUSIONS: Expanding a universal screening program for LS to include patients who had EC identified 50% more patients with LS, and many of these patients would have been missed by risk assessment tools (including PREMM5 ). Universal screening programs for LS should include both CRC and EC. Cancer 2018. © 2018 American Cancer Society.

Features of Patients With Hereditary Mixed Polyposis Syndrome Caused by Duplication of GREM1 and Implications for Screening and Surveillance.

Hereditary mixed polyposis syndrome is a rare colon cancer predisposition syndrome caused by a duplication of a noncoding sequence near the gremlin 1, DAN family BMP antagonist gene (GREM1) originally described in Ashkenazi Jews. Few families with GREM1 duplications have been described, so there are many questions about detection and management. We report 4 extended families with the duplication near GREM1 previously found in Ashkenazi Jews; 3 families were identified at cancer genetic clinics in Israel and 1 family was identified in a cohort of patients with familial colorectal cancer. Their clinical features include extracolonic tumors, onset of polyps in adolescence, and rapid progression of some polyps to advanced adenomas. One family met diagnostic criteria for Lynch syndrome. Expansion of the hereditary mixed polyposis syndrome phenotype can inform surveillance strategies for carriers of GREM1 duplications.

Liver involvement in Gaucher disease - Review and clinical approach.

Gaucher disease (GD), one of the most prevalent lysosomal storage diseases, is associated with glucocerebroside accumulation in cells of the monocyte-macrophage system in various organs, including the liver. Evaluating and managing liver disease in patients with Gaucher disease may be challenging. While hepatic involvement is common in Gaucher disease, its severity, and clinical significance span a wide spectrum, ranging from sub-clinical involvement to liver cirrhosis with its associated complications including portal hypertension. Apart from liver involvement in Gaucher disease, patients with may also suffer from other comorbidities involving the liver. That Gaucher disease itself can mimic hepatic lesions, affect laboratory tests used to characterize liver disease, and may be associated with non-cirrhotic portal hypertension, complicates the diagnostic approach even more. Better understanding of liver involvement in Gaucher disease can spare patients unnecessary invasive testing, and assist physicians in decision making when evaluating patients with Gaucher disease suspected for significant liver disease. This review describes the various clinical manifestations, laboratory and imaging abnormalities that may be encountered when following patients with Gaucher disease for liver involvement. The mechanism for liver disease are discussed, as well as the possible hepato-protective effect of glucocerebroside, and the a diagnostic and treatment approaches.

Sleep Disturbances Can Be Prospectively Observed in Patients with an Inactive Inflammatory Bowel Disease.

BACKGROUND: Poor sleep quality is associated with adverse health consequences. Sleep disturbances can impact the immune function and inflammatory processes. Little is known about sleep disturbances in patients with inflammatory bowel disease (IBD), while not in flare, i.e., inactive. AIMS: To prospectively explore the sleep quality of patients with an inactive IBD. METHODS: This pilot study included 36 consecutive patients with IBD and 27 healthy volunteers. All IBD patients had an inactive disease. Participants underwent an overnight ambulatory polysomnography. Data on disease duration, medications, complications, and treatment were collected from the medical records. RESULTS: The mean age of the IBD and the control groups was 39 ± 15 and 34.6 ± 9.6 years. A significantly less rapid eye movement (REM) sleep was noted in the IBD group vs. control (23.7 vs. 27.8%, p = 0.047); light sleep percentage and REM latency were also longer in the IBD group. Moreover, oxygen desaturation below 90% was more common in the IBD group. All other sleep parameters including respiratory disturbance index, apnea-hypopnea index, number of wakes, sleep latency, and snoring strength were similar in both groups. CONCLUSIONS: Inactive IBD is associated with sleep disturbances. A larger prospective study should be conducted to confirm these findings.

A tailored approach to BRAF and MLH1 methylation testing in a universal screening program for Lynch syndrome.

To determine the correlation between BRAF genotype and MLH1 promoter methylation in a screening program for Lynch syndrome (LS), a universal screening program for LS was established in two medical centers. Tumors with abnormal MLH1 staining were evaluated for both BRAF V600E genotype and MLH1 promoter methylation. Tumors positive for both were considered sporadic, and genetic testing was recommended for all others. A total 1011 colorectal cancer cases were screened for Lynch syndrome, and 148 (14.6%) exhibited absent MLH1 immunostaining. Both BRAF and MLH1 methylation testing were completed in 126 cases. Concordant results (both positive or both negative) were obtained in 86 (68.3%) and 16 (12.7%) cases, respectively, with 81% concordance overall. The positive and negative predictive values for a BRAF mutation in predicting MLH1 promoter methylation were 98.9% and 41%, respectively, and the negative predictive value fell to 15% in patients ≥70 years old. Using BRAF genotyping as a sole test to evaluate cases with absent MLH1 staining would have increased referral rates for genetic testing by 2.3-fold compared with MLH1 methylation testing alone (31% vs 13.5%, respectively, P<0.01). However, a hybrid approach that reserves MLH1 methylation testing for BRAF wild-type cases only would significantly decrease the number of methylation assays performed and reduce the referral rate for genetic testing to 12.7%. A BRAF mutation has an excellent positive predictive value but poor negative predictive value in predicting MLH1 promoter methylation. A hybrid use of these tests may reduce the number of low-risk patients referred to genetic counseling and facilitate wider implementation of Lynch syndrome screening programs.

A prospective study of fecal calprotectin and lactoferrin as predictors of small bowel Crohn's disease in patients undergoing capsule endoscopy.

BACKGROUND: Capsule endoscopy (CE) is often used to investigate small bowel Crohn's disease (CD). AIM: The aim of this study is to prospectively assess the value of fecal calprotectin and lactoferrin to predict CE findings. PATIENTS AND METHODS: Sixty-eight consecutive patients that were referred for CE were included. Stool samples for calprotectin and lactoferrin and blood samples were collected for relevant parameters. Correlation between fecal markers and CE findings was assessed and receiver operating characteristic (ROC) curves were built to determine the predictive values of fecal markers for the diagnosis of CD. RESULTS: Fecal calprotectin data was available for all the patients and lactoferrin data for 38. CE findings compatible with CD were found in 23 (33%) patients and 45 (67%) were negative for CD. The average age of the CD group was 34 compared to 46 in the non-CD group (p = .048). Median calprotectin and lactoferrin in the CD group and in the control group were 169 mg/kg vs. 40 (p = .004) and 6.6 mg/kg vs. 1 (p = .051), respectively. The area under the ROC curve was 0.767 for calprotectin and 0.70 for lactoferrin. A fecal calprotectin concentration of 95 mg/kg and fecal lactoferrin of 1.05 mg/kg had a sensitivity, specificity, positive predictive value and negative predictive value of 77 and 73%, 60 and 65%, 50 and 50%, and 84 and 84% in predicting CE findings compatible with CD. CONCLUSIONS: Fecal markers are simple and noninvasive surrogates for predicting CE findings compatible with CD. Fecal markers can help determine which patients should be referred for CE. ClinicalTrials.gov Identifier: NCT01266629.

The Importance of Intestinal Eotaxin-1 in Inflammatory Bowel Disease: New Insights and Possible Therapeutic Implications.

BACKGROUND: Involvement of eotaxin-1 in inflammatory bowel disease has been previously suggested and increased levels of eotaxin-1 have been described in both ulcerative colitis and in Crohn's disease. The association between serum levels of eotaxin-1 and that within the colonic mucosa has not been well defined, as is the potential therapeutic value of targeting eotaxin-1. AIMS: To characterize serum and intestinal wall eotaxin-1 levels in various inflammatory bowel disease patients and to explore the effect of targeting eotaxin-1 by specific antibodies in dextran sodium sulfate-induced colitis model. METHODS: Eotaxin-1 levels were measured in colonic biopsies and in the sera of 60 ulcerative colitis patients, Crohn's disease patients and healthy controls. We also followed in experimental colitis the effect of targeting eotaxin-1 by a monoclonal antibody. RESULTS: Colon eotaxin-1 levels were significantly increased in active but not in quiescent ulcerative colitis and Crohn's disease patients compared to healthy controls. Levels of eotaxin-1 in the colon were correlated with eosinophilia only in tissues from active Crohn's disease patients. Our results did not show any statistically significant change in serum eotaxin-1 levels among ulcerative colitis, Crohn's disease and healthy controls. Moreover, we demonstrate that in dextran sodium sulfate-induced colitis, targeting of eotaxin-1 with 2 injections of anti eotaxin-1 monoclonal antibody ameliorates disease activity along with decreasing colon weight and improving histologic inflammation. CONCLUSION: Eotaxin-1 is increasingly recognized as a major mediator of intestinal inflammation. Our preliminary human and animal results further emphasize the value of targeting eotaxin-1 in inflammatory bowel disease.

Ameliorating Active Ulcerative Colitis via an Orally Available Toll-Like Receptor-9 Modifier: A Prospective Open-Label, Multicenter Phase II Trial.

BACKGROUND: Treatment of active ulcerative colitis is associated with incomplete efficacy, adverse events, and loss of response. Toll-like receptor-9 mediates innate and adaptive immune response toward intestinal microorganisms. The oral synthetic oligonucleotide toll-like receptor-9 modulator has demonstrated anti-inflammatory properties in colitis murine models and a satisfactory safety profile in humans. AIM: To evaluate the efficacy and safety of BL-7040 (a Toll-like receptor-9 modulator) in patients with moderately active ulcerative colitis. METHODS: Moderately active ulcerative colitis patients were included in this multicenter, open-label phase IIa trial. Concomitant mesalamine and steroids at a stable dose were allowed. Clinical outcome was evaluated using the Mayo score, histology, and mucosal cytokine levels. Side effects were registered. RESULTS: Sixteen out of 22 patients completed a 5-week treatment course and 2-week follow-up. Six patients discontinued the study, three of them due to adverse events. Clinical remission was observed in two patients (12.5 %), and clinical response as well as mucosal healing were achieved in half (50 %) of the patients, while all others remained stable. Furthermore, mucosal neutrophil (p = 0.002) and mucosal interleukin-6 levels (p = 0.046) were significantly reduced in responders compared to non-responders. Toll-like receptor-9 was well tolerated with only one unrelated to study drug serious adverse event (hemoglobin decrease) and 29 mild-to-moderate adverse events. CONCLUSIONS: Oral administration of the Toll-like receptor-9 agonist BL-7040 appeared efficacious, safe and well tolerated in patients with moderately active ulcerative colitis.

Oral Administration of OKT3 MAb to Patients with NASH, Promotes Regulatory T-cell Induction, and Alleviates Insulin Resistance: Results of a Phase IIa Blinded Placebo-Controlled Trial.

UNLABELLED: Oral administration of anti-CD3 antibodies induced regulatory T cells (Tregs) alleviating the insulin resistance and liver damage in animal models. OBJECTIVE: To determine the safety and biological effects of oral OKT3 monoclonal antibody (Balashov et al. Neurology 55:192-8, 2000) in patients with NASH. DESIGN: In this Phase-IIa trial, four groups of patients with biopsy-proven NASH (n = 9/group) received placebo (group A) or oral OKT3 (group B: 0.2; C: 1.0; D: 5.0 mg/day) for 30 days. Patients were followed for safety, liver enzymes, glucose, lipid profile, oral glucose tolerance test (OGTT), serum cytokines and Tregs. RESULTS: Oral OKT3 was well tolerated without treatment-related adverse events. OKT3 induced Tregs: with significant increases of CD4(+)LAP(+) (Latency associated peptide) and CD4(+)CD25(+)LAP(+) cells in Group D, and a significant increase in TGF-ß in Groups C and D. AST decreased significantly in group D and a trend in Groups B and C. Fasting plasma glucose decreased significantly in all treatment groups compared with placebo. OGTT decreased significantly in Group D. Correlations were observed between the changes in several immune-modulatory effects and clinical biomarkers. While serum anti-CD3 levels where undetectable increases in human anti-mouse antibody levels were observed in Groups C and D. CONCLUSION: Oral administration of anti-CD3 MAb to patients with NASH was safe and well tolerated. Positive biological effects were noted in several hepatic, metabolic and immunologic parameters. These findings provide the basis for future trials to investigate the effect of oral anti-CD3 MAb immunotherapy in patients with NASH.

Pregnancy and the Immune System: General Overview and the Gastroenterological Perspective.

Pregnancy represents a unique immune tolerant condition that cannot be attributed merely to generalized immunosuppression. A variety of mechanisms have been described, ranging from the non-self recognition, immunomodulation of specific inflammatory cell populations and a Th2-directed shift of the immune response, which are mediated by both localized and systemic mediators. Furthermore, an inflammatory response directed toward the conceptus is no longer considered an obligatory deleterious response; instead, it is considered an important factor that is necessary for normal growth and development. These immunomodulatory changes during pregnancy may also affect concurrent conditions and alter the course of inflammatory diseases. Herein, we review the main immunomodulatory changes that occur during pregnancy and their effect on coexisting inflammatory conditions, with a specific focus on gastrointestinal disorders.

["Do two walk together unless they have agreed to do so?"--Combining conventional and complementary medicine in the treatment of gastroparesis].

Gastroparesis is a chronic disorder of abnormal gastric motility causing considerable suffering. We describe two cases of gastroparesis which were treated by methods which were not part of routine conventional therapy, but which, nevertheless, led to significant clinical improvement. In the first case, the patient suffered from gastroparesis following a vagal injury while undergoing a lung transplant. During his illness a mega-bezoar formed, a well-described complication of gastroparesis. After conservative measures failed, and in order to avoid a surgical intervention that carried considerable risk under the circumstances, a successful trial consisting of imbibing large amounts of "Coca Cola" and acupuncture was initiated. The bezoar dissolved completely and considerable improvement of the patient's gastric motility was achieved. In the second case, the patient was a young woman suffering from idiopathic gastroparesis, which responded well to treatment with tricyclic antidepressants. Due to her intention to become pregnant, this treatment was discontinued and she was admitted to receive homeopathic treatment. After two failed attempts in finding the right homeopathic remedy to replace the conventional treatment, the third remedy (Sepia) used brought dramatic improvement in her general condition and her dyspepsia. Today, over two years after her successful homeopathic treatment, she is in the middle of her second pregnancy, without any treatment and free of complaints. These two cases are examples of simple solutions for seemingly complicated and complex conditions alleviated by an integration of conventional and complementary/alternative medicine.

From airway inflammation to inflammatory bowel disease: eotaxin-1, a key regulator of intestinal inflammation.

Eotaxin-1 (CCL-11) is a potent eosinophil chemoattractant that is considered a major contributor to tissue eosinophilia. Elevated eotaxin-1 levels have been described in various pathologic conditions, ranging from airway inflammation, to Hodgkin lymphoma, obesity and coronary artery disease. The main receptor for eotaxin-1 is CCR3; however, recent evidence indicates that eotaxin-1 may also bind to other receptors expressed by various cell types, suggesting a more widespread regulatory role for eotaxin-1 beyond the recruitment of eosinophils. Eotaxin-1 is also strongly associated with various gastrointestinal (GI) disorders. Although the etiology of inflammatory bowel disease (IBD) is still unknown, eotaxin-1 may play a key role in the development of mucosal inflammation. In this review, we summarize the biological context and effects of eotaxin-1, as well as its potential role as a therapeutic target, with a special focus on gastrointestinal inflammation.

Radiofrequency ablation for the treatment of radiation proctitis.

BACKGROUND AND STUDY AIMS: The main endoscopic therapy for radiation proctitis is argon plasma coagulation (APC); however treatment is not always successful. Radiofrequency ablation (RFA) is a possible treatment for radiation proctitis but data are scarce. The aim of this study was to report on the safety and efficacy of RFA in the treatment of radiation proctitis. PATIENTS AND METHODS: This study was an open-label, retrospective, multicenter study of patients with chronic hemorrhagic radiation proctitis who were treated with RFA. Data included a three-item symptom score, the number of packed red blood cell transfusions, the lowest hemoglobin concentration, and complications, during the 6 months prior to and after RFA. Clinical success was defined as a decrease in the symptom score. Biological success was defined as an increase in the hemoglobin rate with equal or decreased number of transfusions required. RESULTS: A total of 17 patients underwent a median of 2 RFA sessions (range 1 - 4), without perioperative complications. Symptom scores decreased in 16 patients (clinical success 94 %), from a mean score of 3.6 (median 4) to 1.4 (median 1) (P < 0.01). Two patients developed rectal ulceration, with no local symptoms. During the 6 months after RFA, hemoglobin concentration increased in all 17 patients (from mean 8.3 ± 2.8 g/dL [median 7.5] to 11.3 ± 2.2 g/dL [median 11.0]; P < 0.01). Among 13 patients who were transfusion dependent prior to RFA (mean 7.2 ± 7.7 transfusions [median 4]), 9 patients (69 %) were weaned off transfusions after RFA. A significant increase in the hemoglobin level was observed in this subgroup of patients (from mean 7.2 ± 1.4 g/dL [median 7.3] to 10.7 ± 1.5 g/dL [median 10.5]; P < 0.001). Biological success was 100 %. CONCLUSIONS: RFA seems to significantly decrease clinical symptoms and increase the hemoglobin concentration, thus reducing the need for transfusions.

Radiofrequency ablation for the treatment of gastric antral vascular ectasia.

BACKGROUND AND STUDY AIMS: The traditional endoscopic treatment for gastric antral vascular ectasia (GAVE) is argon plasma coagulation, but results are not always positive. Radiofrequency ablation (RFA) is a new endoscopic therapy that may be an attractive option for the treatment of GAVE. The aim of this study was to assess the efficacy and safety of RFA for the treatment of GAVE. PATIENTS AND METHODS: This was an open-label, retrospective, case series study. The main outcome measures were number of red blood cell (RBC) packs transfused (transfusion requirement) and hemoglobin concentrations (g/dL) in the 6 months prior to and after RFA. Success was defined as a decrease in transfusion requirement in the 6 months after RFA compared with before treatment. RESULTS: A total of 24 patients underwent a mean of 1.8 ± 0.8 RFA sessions. No complications were reported. One patient was referred for additional argon plasma coagulation during follow-up. The mean number of RBC packs decreased in all 23 transfusion-dependent patients, from a mean of 10.6 ± 12.1 during the 6 months prior to RFA, to a mean of 2.5 ± 5.9 during the 6 months after RFA treatment (P < 0.001), and 15 patients (65.2 %) were weaned off transfusions completely. An increase in the hemoglobin concentration was reported in all patients after RFA (from 6.8 ± 1.4 g/dL to 9.8 ± 1.8 g/dL; P < 0.001). CONCLUSION: RFA for the treatment of GAVE seems feasible and safe, and significantly reduced the need for RBC transfusion and increased the hemoglobin level in this retrospective case series.

Increased hepatic Akt phosphorylation alleviated glucose intolerance and improved liver function in leptin-deficient mice.

Aim of the study: Akt is involved in upregulating the insulin-signaling pathways essential for maintaining glucose metabolism. Glycosphingolipids are involved in the pathogenesis of glucose intolerance and associated target organ injury. On the other hand, oral administration of b-glucosylceramide (GC) has been shown to alleviate insulin resistance. The present study aimed to determine the effects of oral administration of insulin and GC, separately and in combination, on Akt expression and the subsequent effect on metabolic syndrome characteristics in leptin-deficient mice. Material and methods: Four groups of leptin-deficient ob/ob mice were orally administered for four weeks: vehicle, GC, short-acting insulin, and GC combined with insulin. Mice were followed for hepatic Akt expression and changes in tumor necrosis factor a (TNF-a) level, hyperlipidemia, and liver damage. Results: In mice that received insulin or GC, particularly those that received both, the liver phosphorylation of Akt was significantly increased compared to those that received only vehicle. Serum TNF-a levels decreased in insulin-treated mice. These effects were associated with alleviating glucose intolerance and hyperlipidemia, as manifested by a significant glucose tolerance test improvement and reductions in serum triglyceride and cholesterol levels. Significant liver damage alleviation was noted by liver enzyme reductions in all treated groups, along with liver steatosis in the insulin-treated mice. Conclusions: These data established the potential use of oral insulin administration with glycosphingolipids to alleviate glucose intolerance and associated liver damage and hyperlipidemia via increased Akt expression in the liver. The data support targeting Akt as a potent therapeutic target for metabolic syndrome.