Endocannabinoid receptor blockade increases hepatocyte growth factor and reduces insulin levels in obese women with polycystic ovary syndrome

There is evidence from animal and in-vitro studies that activation of the endocannabinoid system (EC) through cannabinoid receptor 1 (CB-1) is associated with liver injury, inflammation and hepatocellular carcinoma.1 Data suggests endogenous cannabinoids (EC) are related to fatty liver metabolism with a role in non-alcoholic fatty liver disease (NAFLD) through modulating lipid metabolism that may be ameliorated by CB1 receptor antagonism with rimonabant.2 This is of particular importance as NAFLD is the most common cause of chronic liver disease with liver dysfunction leading liver cirrhosis. The diagnosis of NAFLD can only be confirmed by a liver biopsy, as liver enzymes such as alanine aminotransferase (ALT) used, as a serum marker may not be elevated

Association of Differing Qatari Genotypes with Vitamin D Metabolites

This work aimed to determine the possible association between Qatari genotypes and vitamin-D deficiency and diabetes complications. Through next-generation exome sequencing three major genetic Qatari genotypes were determined, Q1 - Bedouin, Q2 - Persian-South Asian and Q3 - African. The hypothesis was that Qatari genotypes would affect vitamin D and metabolite levels independent of cultural factors, perhaps exacerbated by diabetes.Materials and Methods. Affymetrix 500k SNP arrays determined 398 Qataris genotype (mean age 49.8 years, 56.8% male; type 2 diabetes (T2DM) 220; control 178). LC-MS/MS analysis measured 1,25-dihydroxyvitamin-D (1,25(OH)2D), 25-hydroxyvitamin-D2 (25(OH)D2), 25-hydroxyvitamin-D3 (25(OH)D3), 24,25-dihydroxyvitamin-D (24,25(OH)2D) and 25-hydroxy-3epi-Vitamin-D (3epi25(OH)D). The same study population was used to investigate the association of diabetes and its complications with various genotypes.Results. There was no difference in 25(OH)D levels between genotype groups; however, 1,25(OH)2D was higher for Q2 and 24,25(OH)2D was higher in Q1 compared to the ‘admixed’ group. Additionally, the genotype-based ancestry and type 2 diabetes (T2DM) prevalence: 164 (41.2%) with Q1, 60.4% with T2DM; 149 (37.4%) with Q2, 49.7% with T2DM; 31 (7.8%) with Q3, 61.3% with T2DM; and 54 (13.6%) with “admixed”, 51.9% with T2DM. In patients with diabetes, hypertension (p<0.035) and retinopathy (p<0.016) were greater in Q3.Conclusion. Overall, the study population was vitamin-D deficient, total 25(OH)D was higher in patients with concomitant T2DM, 1,25(OH)2D, 24,25(OH)2D and 3epi25(OH)D were lower in diabetes. Vitamin D levels were not associated with a specific genotype. Q3 was found to have a higher frequency of diabetic retinopathy and hypertension

Association of Differing Qatari Genotypes with Vitamin D Metabolites

Objective. Genetic studies have identified four Qatari genotypes: Q1 Arab, Bedouin; Q2 Asian/Persian; Q3 African; and a fourth admixed group not fitting into the previous 3 groups. This study was undertaken to determine if there was an increased risk of deficiency of vitamin D and its metabolites associated with differing genotypes, perhaps due to genetic differences in skin pigmentation. Methods. 398 Qatari subjects (220 type 2 diabetes and 178 controls) had their genotype determined by Affymetrix 500 k SNP arrays. Total values of 1,25-dihydroxyvitamin D (1,25(OH)2D), 25-hydroxyvitamin D (25(OH)D), 24,25-dihydroxyvitamin D (24,25(OH)2D), and 25-hydroxy-3epi-vitamin D (3epi-25(OH)D) concentrations were measured by the LC-MS/MS analysis. Results. The distribution was as follows: 164 (41.2%) genotyped Q1, 149 (37.4%) genotyped Q2, 31 (7.8%) genotyped Q3, and 54 (13.6%) genotyped “admixed.” Median levels of 25(OH)D and 3epi-25(OH)D did not differ across Q1, Q2, Q3, and “admixed” genotypes, respectively. 1,25(OH)2D levels were lower (p<0.04) between Q2 and the admixed groups, and 24,25(OH)2D levels were lower (p<0.05) between Q1 and the admixed groups. Vitamin D metabolite levels were lower in females for 25(OH)D, 1,25(OH)2D (p<0.001), and 24,25(OH)2D (p<0.006), but 3epi-25(OH)D did not differ (p<0.26). Diabetes prevalence was not different between genotypes. Total 1,25(OH)2D (p<0.001), total 24,25(OH)2D (p<0.001), and total 3epi-25(OH)D (p<0.005) were all significantly lower in diabetes patients compared to controls whilst the total 25(OH)D was higher in diabetes than controls (p<0.001). Conclusion. Whilst 25(OH)D levels did not differ between genotype groups, 1,25(OH)2D and 24,25(OH)2D were lower in the admixed group, suggesting that there are genetic differences in vitamin D metabolism that may be of importance in a population that may allow a more targeted approach to vitamin D replacement. This may be of specific importance in vitamin D replacement strategies with the Q2 genotype requiring less, and the other genotypes requiring more to increase 1,25(OH)2D. Whilst overall the group was vitamin D deficient, total 25(OH)D was higher in diabetes, but 1,25(OH)2D, 24,25(OH)2D, and 3epi-25(OH)D were lower in diabetes that did not affect the relationship to genotype

Qatari Genotype May Contribute to Complications in Type 2 Diabetes

Objective. There is increasing evidence of a strong genetic component in type 2 diabetes (T2DM) that may contribute to diabetes complications. Given the high prevalence of diabetes with its associated complications in the Middle East, we sought to determine if the genotype within a Middle East population may be contributory. Therefore, three genotype-based Qatari ancestral groups, Q1 Arab Bedouin, Q2 Asian/Persian, and Q3 sub-Saharan African, with a fourth admixed group were correlated with T2DM prevalence and its complications to determine if they differed between the 4 Qatari ancestries, particularly for the SLMAP allele-associated diabetic retinopathy. Methods. In this cross-sectional study, 398 Qatari subjects, 220 with and 178 without T2DM, were genotyped by Affymetrix 500k SNP arrays. Ancestry was correlated with diabetes complications. Results. 398 subjects were included, the mean age was 49.8 years, and 56.8% were male. The genotype-based ancestry and T2DM prevalence were as follows: 164 (41.2%) with ancestry Q1, 60.4% with T2DM; 149 (37.4%) with ancestry Q2, 49.7% with T2DM; 31 (7.8%) with ancestry Q3, 61.3% with T2DM; and 54 (13.6%) with “admixed” ancestry, 51.9% with T2DM. For patients with diabetes, hypertension (p<0.035) and retinopathy (p<0.016) were greater in the Q3 ancestry. Conclusion. These data suggest that the genotype may contribute to complication risk, as exemplified by the increase in hypertension and retinopathy in the Q3 ancestry, though the SLMAP allele was not implicated; however, diabetes prevalence did not differ between the four Qatari ancestries

Endocannabinoid receptor blockade reduces alanine aminotransferase in polycystic ovary syndrome independent of weight loss

Abstract Background Evidence suggests that endocannabinoid system activation through the cannabinoid receptor 1 (CB1) is associated with enhanced liver injury, and CB1 antagonism may be beneficial. The aim of this study was to determine the impact of rimonabant (CB1 antagonist) on alanine aminotransferase (ALT), a hepatocellular injury marker, and a hepatic inflammatory cytokine profile. Methods Post hoc review of 2 studies involving 50 obese women with PCOS and well matched for weight, randomised to weight reducing therapy; rimonabant (20 mg od) or orlistat (120 mg tds), or to insulin sensitising therapy metformin, (500 mg tds), or pioglitazone (45 mg od). No subject had non-alcoholic fatty liver disease (NAFLD). Results Treatment with rimonabant for 12 weeks reduced both ALT and weight (p < 0.01), and there was a negative correlation between Δ ALT and Δ HOMA-IR (p < 0.001), but not between Δ ALT and Δ weight. There was a significant reduction of weight with orlistat (p < 0.01); however, orlistat, metformin and pioglitazone had no effect on ALT. The free androgen index fell in all groups (p < 0.05). The inflammatory marker hs-CRP was reduced by pioglitazone (p < 0.001) alone and did not correlate with changes in ALT. The inflammatory cytokine profile for IL-1β, IL-6, IL-7, IL-10, IL12, TNF-α, MCP-1 and INF-γ did not differ between groups. None of the interventions had an effect on biological variability of ALT. Conclusion Rimonabant through CB1 receptor blockade decreased serum ALT that was independent of weight loss and hepatic inflammatory markers in obese women with PCOS without NAFLD. Trial registration ISRCTN58369615 (February 2007; retrospectively registered) ISRCTN75758249 (October 2007; retrospectively registered)

Qatari genotype may contribute to complications in type 2 diabetes

Objective: There is increasing evidence of a strong genetic component in type 2 diabetes (T2DM) that may contribute to diabetes complications. Given the high prevalence of diabetes with its associated complications in the Middle East, we sought to determine if the genotype within a Middle East population may be contributory. Therefore, three genotype-based Qatari ancestral groups, Q1 Arab Bedouin, Q2 Asian/Persian, and Q3 sub-Saharan African, with a fourth admixed group were correlated with T2DM prevalence and its complications to determine if they differed between the 4 Qatari ancestries, particularly for the SLMAP allele-associated diabetic retinopathy. Methods: In this cross-sectional study, 398 Qatari subjects, 220 with and 178 without T2DM, were genotyped by Affymetrix 500k SNP arrays. Ancestry was correlated with diabetes complications. Results: 398 subjects were included, the mean age was 49.8 years, and 56.8% were male. The genotype-based ancestry and T2DM prevalence were as follows: 164 (41.2%) with ancestry Q1, 60.4% with T2DM; 149 (37.4%) with ancestry Q2, 49.7% with T2DM; 31 (7.8%) with ancestry Q3, 61.3% with T2DM; and 54 (13.6%) with "admixed" ancestry, 51.9% with T2DM. For patients with diabetes, hypertension (p p Conclusion: These data suggest that the genotype may contribute to complication risk, as exemplified by the increase in hypertension and retinopathy in the Q3 ancestry, though the SLMAP allele was not implicated; however, diabetes prevalence did not differ between the four Qatari ancestries.</p

Progressive loss of corneal nerve fibers is associated with physical inactivity and glucose lowering medication associated with weight gain in type 2 diabetes

Aims/introductionLimited studies have identified risk factors linked to the progression of diabetic peripheral neuropathy (DPN) in type 2 diabetes. This study examined the association of risk factors with change in neuropathy measures over 2 years.Materials and methodsParticipants with type 2 diabetes (n = 78) and controls (n = 26) underwent assessment of clinical and metabolic parameters and neuropathy using corneal confocal microscopy (CCM), vibration perception threshold (VPT), and the DN4 questionnaire at baseline and 2 year follow-up.ResultsParticipants with type 2 diabetes had a lower corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) (P ≤ 0.0001) and a higher VPT (P ≤ 0.01) compared with controls. Over 2 years, despite a modest reduction in HbA1c (P ≤ 0.001), body weight (P ≤ 0.05), and LDL (P ≤ 0.05) the prevalence of DPN (P = 0.28) and painful DPN (P = 0.21) did not change, but there was a significant further reduction in CNBD (P ≤ 0.0001) and CNFL (P ≤ 0.05). CNFD, CNBD, and CNFL decreased significantly in physically inactive subjects (P ConclusionsIn participants with type 2 diabetes, despite a modest improvement in HbA1c, body weight, and LDL there was a progressive loss of corneal nerve fibers; except in those who were physically active or on glucose lowering medication associated with weight loss

Progressive loss of corneal nerve fibers is associated with physical inactivity and glucose lowering medication associated with weight gain in type 2 diabetes

Aims/introduction: Limited studies have identified risk factors linked to the progression of diabetic peripheral neuropathy (DPN) in type 2 diabetes. This study examined the association of risk factors with change in neuropathy measures over 2 years. Materials and methods: Participants with type 2 diabetes (n = 78) and controls (n = 26) underwent assessment of clinical and metabolic parameters and neuropathy using corneal confocal microscopy (CCM), vibration perception threshold (VPT), and the DN4 questionnaire at baseline and 2 year follow-up. Results: Participants with type 2 diabetes had a lower corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) (P ≤ 0.0001) and a higher VPT (P ≤ 0.01) compared with controls. Over 2 years, despite a modest reduction in HbA1c (P ≤ 0.001), body weight (P ≤ 0.05), and LDL (P ≤ 0.05) the prevalence of DPN (P = 0.28) and painful DPN (P = 0.21) did not change, but there was a significant further reduction in CNBD (P ≤ 0.0001) and CNFL (P ≤ 0.05). CNFD, CNBD, and CNFL decreased significantly in physically inactive subjects (P Conclusions: In participants with type 2 diabetes, despite a modest improvement in HbA1c, body weight, and LDL there was a progressive loss of corneal nerve fibers; except in those who were physically active or on glucose lowering medication associated with weight loss.</p