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 < 0.05-0.0001), whilst there was no change in CNFD (P = 0.07) or CNFL (P = 0.85) in physically active subjects. Furthermore, there was no change in CNFD (P = 0.82), CNBD (P = 0.08), or CNFL (P = 0.66) in patients treated with glucose lowering medication associated with weight loss, whilst CNBD (P = 0.001) decreased in patients on glucose lowering medication associated with weight gain. 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.

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.

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.

Prediabetes and diabetes in a cohort of Qatari women screened for polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is associated with an increased risk of type 2 diabetes mellitus (T2DM) but its association with prediabetes and T2DM is unknown in Qatar. A cross sectional analysis of 3,017 Qatari subjects from the Qatar Biobank, identified 749 women aged 18-40 years, 720 of whom were assessed by the National Institute for Health (NIH) Guidelines for PCOS. Prediabetes (HbA1c 5.7-6.4% and/or impaired fasting glucose (IFG): fasting plasma glucose (FPG) 100-125 mg/dL (5.6-6.9 mmol/L)), and T2DM (fasting plasma glucose > 125 mg/dL (≥7 mmol/L), and/or HbA1c ≥ 6.5%) were determined. The prevalence of prediabetes was 10.6% and the prevalence of undiagnosed diabetes was found to be 4.0% in the total population. Overall, 12.1% of 720 women had PCOS, of whom FPG and HbA1c were available in 62 women with PCOS: 19.4% had prediabetes and 9.7% had diabetes. An adverse cardiovascular risk profile for IFG women compared to normal women was found. Women with PCOS alone had a similar adverse cardiovascular profile as those with IFG alone and T2DM. Thus, the risk of prediabetes and diabetes is increased in Qatari women with PCOS, with an adverse cardiovascular risk profile similar to that seen in prediabetes and T2DM.

Androstenedione and testosterone levels correlate with in vitro fertilization rates in insulin-resistant women.

BACKGROUND: The free androgen index (FAI) calculated using total testosterone measured by immunoassay does not correlate with oocyte fertilization rates; however, there is considerable cross-reactivity for testosterone with other androgens by immunoassay that is not found using isotope dilution liquid chromatography-tandem mass spectrometry (LC/MS/MS). AIMS: This study was done to determine relationship between total testosterone and androstenedione measured by LC/MS/MS and fertilization rates. STUDY DESIGN: 49 infertile women without polycystic ovary syndrome were recruited preceding an in vitro fertilization (IVF) cycle. Serum testosterone and androstenedione were measured by LC/MS/MS and correlated with IVF parameters non-insulin resistant compared with insulin resistant (homeostatic model assessment >2.5) women. RESULTS: For non-insulin resistant women, total testosterone FAI and androstenedione did not correlate with oocyte fertilization rates. In insulin-resistant women, there was a negative correlation between both testosterone and FAI and fertilization rates (r=-0.62, p<0.03) and r=-0.73, p=0.02, respectively). There was a positive correlation between androstenedione and fertilization rates (r=0.87, p<0.01). CONCLUSION: For insulin-resistant women, increases in testosterone and FAI were associated with reduced fertilization rates and androstenedione was associated with increased fertilization rates when measured by LC/MS/MS that should be considered to be the measurement method of choice.

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

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-1ß, 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).