Common variants in SOCS7 gene predict obesity, disturbances in lipid metabolism and insulin resistance.

BACKGROUND AND AIMS: Specific Suppressor of Cytokine Signaling (SOCS) members, such as SOCS7, may play a role in the development of insulin resistance (IR) owing to their ability to inhibit insulin signaling pathways. The objective was to explore the association between common variants and related haplotypes in SOCS7 gene and metabolic traits related to obesity, lipid metabolism and IR. METHODS AND RESULTS: 780 unrelated men were included in a cross-sectional study. We selected three tagged SNPs that capture 100% of SNPs with minor allele frequency ≥ 0.10. Analyses were done separately for each SNP and followed up by haplotype analysis. rs8074124C was associated with both obesity (p = 0.005) and abdominal obesity (p = 0.002) and allele C carriers showed, in comparison with TT carriers, lower BMI (p = 0.001) and waist circumference (p = 0.001). rs8074124CC- carriers showed lower fasting insulin (p = 0.017) and HOMA-IR (p = 0.018) than allele T carriers. rs12051836C was associated with hypertriglyceridemia (p = 0.009) and hypertriglyceridemic waist (p = 0.006). rs12051836CC- carriers showed lower fasting insulin (p = 0.043) and HOMA-IR (p = 0.042). Haplotype-based association analysis (rs8074124 and rs12051836 in that order) showed associations with lipid and obesity -related phenotypes, consistent with single locus analysis. Haplotype analysis also revealed association between haplotype CT and both decreased HDL-C (p = 0.026) and HDL-C (p = 0.014) as a continuous variable. CONCLUSIONS: We found, for the first time, significant associations between SOCS7 common variants and related haplotypes and obesity, IR and lipid metabolism disorders.

[Genetics of diabetic complications: retinopathy]. / Génétique des complications du diabète: rétinopathie.

Multiple clinical and physiopathological studies as well as genetic analysis, suggest that diabetic retinopathy (DR) is a consequent of interactions between environmental factors, especially hyperglycaemia, and several genetic factors. The genes of aldose reductase (AR), inducible nitric oxide synthase (NOS2A), endothelial nitric oxide synthase (NOS3), vascular endothelial growth factor (VEGF), pigmented epithelium-derived factor (PEDF), protein kinase C-beta (PKC-beta) and receptor for advanced glycation end products (RAGE) implicated in the pathogenesis of DR. The only genetic marker associated with risk of DR in several studies is a microsatellite (A-C)n at 5'end of AR. The synergistic combination of conventional approaches (e.g. candidate gene association studies) with new emerging technologies (e.g. biochips) will be a key factor in the elucidation of the genetic aspects of DR.

eNOS4 polymorphism of the endothelial nitric oxide synthase predicts risk for severe diabetic retinopathy.

BACKGROUND: Genetic factors may be involved in the development, and particularly in the severity, of diabetic retinopathy (DR), in addition to chronic hyperglycaemia. Increased nitric oxide generation has been suggested to play a significant role in the pathogenesis of DR. AIMS AND METHODS: To examine whether the eNOS4 is involved in the risk of severe DR, 200 unrelated Caucasian Type 1 diabetic patients of long duration were randomly selected (M/F 103/97, age 44.4 +/- 12.4 years, diabetes duration 27.7 +/- 10.0 years, body mass index 24.3 +/- 3.4 kg/m2, HbA1c 8.6 +/- 1.3%). The eNOS4 polymorphism was analysed by polymerase chain reaction, and DR by retinal angiography and classified as presence (n = 101) or absence (n = 99) of severe (proliferative or pre-proliferative) DR. RESULTS: The genotype distribution of eNOS4b/b (wild-type), eNOS4b/a (heterozygous) and eNOS4a/a (homozygous) was 72%, 24.5% and 3.5%, respectively. Frequency of eNOS4a/a was significantly lower in patients with severe DR (n = 0) when compared with controls (n = 7, odds ratio (OR) = 0 (95% confidence interval (CI) = 0.5-0.74), P = 0.02). eNOS4b/b was more frequent in patients with severe DR (n = 80) when compared with controls (n = 64, OR = 2.1 (95% CI = 1.1-4.12), P = 0.032). Frequency of eNOS4b/a was not different between the study (n = 21) and control groups (n = 28, ns). The allelic frequencies between the study and control groups were different (4b: n = 181 vs. n = 156, respectively, OR = 2.3 (95% CI = 1.27-4.25), P = 0.005; 4a: n = 21 vs. n = 42, respectively, OR = 0.4 (95% CI = 0.24-0.79), P = 0.005). CONCLUSIONS: We demonstrate in Caucasians with Type 1 diabetes that (i) eNOS4a/a is associated with absent or non-severe DR, and (ii) eNOS4b/b is associated with severe DR.

Taq I polymorphism of the vitamin D receptor and risk of severe diabetic retinopathy.

AIMS/HYPOTHESIS: Vitamin D, a molecule with antiproliferative, antiangiogenic, antioxidant and immunosuppressive effects, could play a role in the pathogenesis of severe diabetic retinopathy. We examined whether Taq I polymorphism of the vitamin D receptor is involved in the development of severe diabetic retinopathy. METHODS: 200 unrelated C-peptide-negative French Type I diabetic patients were randomly selected (male:female, 103:97, age 44.4 +/- 12.4 years, diabetes duration: 27.7 +/- 10.0 years, BMI: 24.3 +/- 3.4 kg/m(2), HbA(1c): 8.6 +/- 1.3 %). The Taq I site was analysed by PCR followed by digestion with Taq I enzyme. Diabetic retinopathy was assessed by retinal angiography and classified as presence (n = 101) or absence (n = 99) of severe (preproliferative or proliferative) diabetic retinopathy. RESULTS: Frequency of wild-type genotype TT was lower in patients with severe diabetic retinopathy (n = 27) when compared with control subjects (n = 42, OR = 0.5, p = 0.028). Allele frequencies were not different between patients (T: n = 112 and t: n = 90) and control subjects (T: n = 128, and t: n = 70, p = 0.075). Global chi(2) (df = 2): p = 0.064. In subjects with diabetes duration of more than 25 years, TT was lower in severe diabetic retinopathy (n = 14) than control subjects (n = 18, OR = 0.3, p = 0.01). Allele frequencies were different between patients (T: n = 68 and t: n = 66) and control subjects (T: n = 52, OR = 0.5, and t: n = 26, OR = 1.9, p = 0.034). Global chi(2) (df = 2): p = 0.024. In subjects with HbA(1c) over 9 %, Tt was higher in patients (n = 28) than control subjects (n = 15, OR = 3.1, p = 0.019). Allele frequencies were not different between patients (T: n = 52 and t: n = 38) and control subjects (T: n = 57, and t: n = 29, p = 0.31). Global chi(2) (df = 2): p = 0.035. CONCLUSION/INTERPRETATION: In French Type I (insulin-dependent) diabetic patients, we demonstrate an association between TT form (VDR) and low risk for severe diabetic retinopathy, especially in patients with long duration, and between Tt variant and high risk for severe diabetic retinopathy in subjects with poor glycaemic control.

Beta-cell function evaluated by HOMA as a predictor of secondary sulphonylurea failure in Type 2 diabetes.

BACKGROUND AND AIMS: Secondary failure to oral hypoglycaemic agents, a common evolution of long-standing Type 2 diabetes, is usually assessed by non-standardized indices requiring fine clinical assessment, including hyperglycaemia resistant to maximum doses of sulphonylureas despite appropriate diet and follow-up. The goal of this study was to evaluate if HOMA, a modelized plasma insulin/glucose ratio allowing simple evaluation of residual insulin secretion and sensitivity, is a better predictor of the insulin requiring stage than clinical indices. MATERIALS AND METHODS: HOMA was measured in 84 Type 2 diabetic patients aged 58 +/- SD 6 years, with diabetes duration 11 +/- 4 years, hospitalized because of hyperglycaemia resistant to maximal doses of sulphonylureas (e.g. glibenclamide > or = 15 mg/day), with no apparent external reason for hyperglycaemia. Despite reinforced appropriate diet recommendations, 62 of these patients remained hyperglycaemic (insulin-requiring group). RESULTS: Age, duration of diabetes, body mass index (BMI) and HOMA value for insulin sensitivity (71 +/- 6% vs. 76 +/- 7%, normal values 59-161%) were comparable in the two groups. HbA(1c) was higher (10.0 +/- 0.2% vs. 8.3 +/- 0.3%, P < 0.001) and HOMA insulin secretion values lower (25 +/- 2% vs. 43 +/- 6%, normal values 70-150%, P < 0.01) in the insulin-requiring group. Of the following potential predictors: HbA(1c) > 8%, duration of diabetes > or = 10 years, HbA(1c) combined with diabetes duration, insulin sensitivity < or = 40%, insulin secretion < or = 20%, the latter showed the best positive predictivity (86% patients with low insulin secretion were insulin-requiring). CONCLUSIONS: (i) HOMA is a simple and good predictor of the insulin-requiring stage in Type 2 diabetes mellitus; (ii) this stage of diabetes is characterized by a further decline of insulin secretion rather than of insulin sensitivity. Diabet. Med. 18, 584-588 (2001)

Insufficient adaptation of hypoglycaemic threshold for cognitive impairment in tightly controlled type 1 diabetes.

UNLABELLED: It is well known that hypoglycaemic thresholds for hormones and symptoms occur at lower plasma glucose levels in patients with strict glycaemic control. However, whether the threshold for cognitive impairment also shifts is still an unresolved question. We studied 19 type 1 diabetic patients, including 8 with hypoglycaemia unawareness, aged 37.0 +/- 7.4 y.r., with diabetes duration 15.2 +/- 10.7 yr, and HbA1c 7.6 +/- 1.1%. Hypoglycaemic thresholds for hormones, symptoms, awareness and cognitive function using the 4-choice reaction time test (4RT), were measured every 30 min during a 150 min stepped 4.4 to 2.2 mM hypoglycaemic hyperinsulinemic clamp. We found that 4RT- accuracy deteriorated earlier than 4RT-time (3.2 and 2.7 mM, respectively, p<0.01), and that both correlated poorly with HbA1C before and after adjustment for age and diabetes duration (r=0.11, and 0.18, respectively). On the opposite, adrenaline, autonomic and neuroglycopenic symptoms, and awareness significantly correlated with HbA1c values (r=0.56, 0.70, 0.61, and 0.63, after adjustment, respectively). Furthermore, after allocating the patients into two subgroups according to HbA1c values (<8% n=12, and >=8% n=7), we found that, as opposed to other thresholds, accuracy and 4RT-time were minimally and not significantly influenced by glycaemic control, therefore exhibiting the smaller glucose thresholds shifts (- 0.2 and - 0.5 mM for accuracy and time, respectively, vs. 0.6 -0.8 for other thresholds). IN CONCLUSION: 1) the hypoglycaemic thresholds for cognitive dysfunction shift with strict glycaemic control, but not significantly and less than other thresholds, 2) as opposed to other reports, accuracy deteriorates earlier than speed during the 4RT test, and 3) these "maladapted" reactions may contribute to the higher risk for severe hypoglycaemia in subjects with tight glycaemic control.