EIF4A2 is a positional candidate gene at the 3q27 locus linked to type 2 diabetes in French families

One of the most replicated loci influencing type 2 diabetes-related quantitative traits (quantitative trait loci [QTL]) is on chromosome 3q27 and modulates both type 2 diabetes-and metabolic syndrome-associated phenotypes. A QTL for type 2 diabetes age of onset (logarithm of odds [LOD] score = 3.01 at D3S3686, P = 0.0001) was identified in a set of French families. To assess genetic variation underlying both age-of-onset QTL and our previous type 2 diabetes linkage in a 3.87-Mb interval, we explored 36 single nucleotide polymorphisms (SNPs) in two biologically relevant candidate genes for glucose homeostasis, kininogen (KNG1), and eukaryotic translation initiation factor 4alpha2 (EIF4A2). Analysis of 148 families showed significant association of a frequent SNP, rs266714, located 2.47 kb upstream of EIF4A2, with familial type 2 diabetes (family-based association test, P = 0.0008) and early age of onset (P = 0.0008). This SNP also contributes to both age-of-onset QTL (1.13 LOD score decrease P = 0.02) and type 2 diabetes linkage (genotype identical-by-descent sharing test, P = 0.02). However, no association was observed in three independent European diabetic cohorts. EIF4A2 controls specific mRNA translation and protein synthesis rate in pancreatic beta-cells, and our data indicates that EIF4A2 is downregulated by high glucose in rat beta-INS832/13 cells. The potential role of EIF4A2 in glucose homeostasis and its putative contribution to type 2 diabetes in the presence of metabolic stress will require further investigation.     

Glycemic thresholds for diabetes-specific retinopathy: implications for diagnostic criteria for diabetes

OBJECTIVE

To re-evaluate the relationship between glycemia and diabetic retinopathy.

RESEARCH DESIGN AND METHODS

We conducted a data-pooling analysis of nine studies from five countries with 44,623 participants aged 20–79 years with gradable retinal photographs. The relationship between diabetes-specific retinopathy (defined as moderate or more severe retinopathy) and three glycemic measures (fasting plasma glucose [FPG; n = 41,411], 2-h post oral glucose load plasma glucose [2-h PG; n = 21,334], and A1C [n = 28,010]) was examined.

RESULTS

When diabetes-specific retinopathy was plotted against continuous glycemic measures, a curvilinear relationship was observed for FPG and A1C. Diabetes-specific retinopathy prevalence was low for FPG <6.0 mmol/l and A1C <6.0% but increased above these levels. Based on vigintile (20 groups with equal numbers) distributions, glycemic thresholds for diabetes-specific retinopathy were observed over the range of 6.4–6.8 mmol/l for FPG, 9.8–10.6 mmol/l for 2-h PG, and 6.3–6.7% for A1C. Thresholds for diabetes-specific retinopathy from receiver-operating characteristic curve analyses were 6.6 mmol/l for FPG, 13.0 mmol/l for 2-h PG, and 6.4% for A1C.

CONCLUSIONS

This study broadens the evidence based on diabetes diagnostic criteria. A narrow threshold range for diabetes-specific retinopathy was identified for FPG and A1C but not for 2-h PG. The combined analyses suggest that the current diabetes diagnostic level for FPG could be lowered to 6.5 mmol/l and that an A1C of 6.5% is a suitable alternative diagnostic criterion.The current diagnostic cut points for diabetes (fasting plasma glucose [FPG] of 7.0 mmol/l and 2-h post oral glucose load plasma glucose [2-h PG] of 11.1 mmol/l) are largely based on glycemic levels associated with a substantially increased risk of diabetes-associated microvascular complications, particularly retinopathy, above these levels (1,2). These cut points were derived from cross-sectional epidemiological studies that examined retinopathy across a range of glycemic levels. The datasets used for this purpose were from Pima Indians, an Egyptian study, and unpublished data from the Third National Health and Nutrition Examination Survey (NHANES) (2).Other studies (3–5) also have examined this relationship, but the results have been inconsistent. All studies reported to date have had limited statistical power to examine this relationship in detail and have adopted a very broad definition of retinopathy that included many cases of mild retinopathy, now known to have causes other than hyperglycemia (6). A more clinically relevant end point is diabetes-specific retinopathy (moderate or more severe levels of retinopathy) that is invariably attributed to hyperglycemia. Also different statistical methods have been used in previous studies, which has an important effect on derived cut points (5,7).Several new datasets with retinopathy data have become available since the original studies used to derive current diabetes diagnostic cut points (1,2). The DETECT-2 collaboration has pooled these datasets to examine and re-evaluate the relationship between retinopathy and three glycemic measures: FPG, 2-h PG, and A1C. The size of the DETECT-2 dataset has allowed us to focus on the relationship between measures of glycemia and diabetes-specific retinopathy (i.e., moderate or more severe levels of retinopathy). These analyses were designed to inform current deliberations on possible revisions to the diagnostic criteria for diabetes.     

Waist circumference and the metabolic syndrome predict the development of elevated albuminuria in non-diabetic subjects: the DESIR Study

OBJECTIVE: Metabolic determinants of microalbuminuria remain poorly understood in non-diabetic individuals and particularly in women. We investigated in both sexes whether an elevated waist circumference (WC) or the presence of the metabolic syndrome (MetS) predict the development of elevated albuminuria at 6 years. DESIGN AND PATIENTS: We studied 2738 subjects from the DESIR cohort without microalbuminuria or diabetes at baseline and who were followed up for 6 years. RESULTS: At 6 years, 254 individuals [9.3%; 95% confidence interval (CI) 8.2-10.4%] had developed elevated albuminuria (> or = 20 mg/l), which was significantly and positively associated with WC and blood pressure, but not with fasting glucose, lipids or body mass index in either sex. In both sexes, subjects with a high WC or with MetS at baseline were more likely to develop elevated albuminuria at 6 years compared with those with a normal WC or absence of MetS. In multivariate logistic analysis, WC as a continuous variable or a WC of 94 cm or greater for men and a WC greater than 88 cm for women were predictive of the development of elevated albuminuria, after adjusting for age, hypertension, the use of angiotensin-converting enzyme inhibitors, fibrinogen and glycaemia. MetS was a risk factor for elevated albuminuria in men (odds ratio 1.87; 95% CI 1.25-2.81), with differences according to the MetS definition. CONCLUSION: Abdominal adiposity is related to the development of elevated albuminuria in both sexes, suggesting that the measurement of WC may improve the identification of non-diabetic individuals at risk of developing microalbuminuria and emphasizing the interest of screening for albuminuria among those with MetS.     

Correlation of the leptin:adiponectin ratio with measures of insulin resistance in non-diabetic individuals

Aims/hypothesis

Obesity is the dominant cause of insulin resistance. In adult humans it is characterised by a combination of adipocyte hypertrophy and, to a lesser extent, adipocyte hyperplasia. As hypertrophic adipocytes secrete more leptin and less adiponectin, the plasma leptin:adiponectin ratio (LAR) has been proposed as a potentially useful measure of insulin resistance and vascular risk. We sought to assess the usefulness of the LAR as a measure of insulin resistance in non-diabetic white adults.

Methods

Leptin and adiponectin levels were measured in 2,097 non-diabetic individuals from the Ely and European Group for the Study of Insulin Resistance (EGIR) Relationship between Insulin Sensitivity and Cardiovascular Risk (RISC) study cohorts. LAR was compared with fasting insulin and HOMA-derived insulin sensitivity (HOMA-S) in all individuals and with the insulin sensitivity index (M/I) from hyperinsulinaemic–euglycaemic clamp studies in 1,226 EGIR RISC participants.

Results

The LAR was highly correlated with HOMA-S in men (r?=??0.58, p?=?4.5?×?10^?33 and r?=??0.65, p?=?1.1?×?10^?66 within the Ely and EGIR RISC study cohorts, respectively) and in women (r?=??0.51, p?=?2.8?×?10^?36 and r?=??0.61, p?=?2.5?×?10^?73). The LAR was also strongly correlated with the clamp M/I value (r?=??0.52, p?=?4.5?×?10^?38 and r?=??0.47, p?=?6.6?×?10^?40 in men and women, respectively), similar to correlations between HOMA-S and the M/I value.

Conclusions/interpretation

The leptin:adiponectin ratio is a useful measure of insulin resistance in non-diabetic white adults. These data highlight the central role of adipocyte dysfunction in the pathogenesis of insulin resistance. Given that variations between fasting and postprandial leptin and adiponectin levels tend to be small, the leptin to adiponectin ratio might also have potential value in assessing insulin sensitivity in the non-fasted state.     

Physical activity, adiponectin, and cardiovascular structure and function

Physical activity (PA) may modify cardiovascular structure and function as well as insulin sensitivity and level of plasma adipokines in relation to its extent, duration, and intensity. To evaluate the associations of average daily PA and bouts of moderate-to-vigorous-intensity PA with cardiovascular and metabolic measures, 45 healthy volunteers (mean age = 42 ± 9 years) not involved in regular intensive exercise training and competitive sport activity underwent the following examinations: (1) accelerometer monitoring of ambulatory movements (average monitoring time = 6.1 ± 1.3 days); (2) complete carotid and cardiac ultrasound; (3) measurement of carotid-femoral pulse-wave velocity; (4) anthropometric measurements; (5) euglycemic hyperinsulinemic clamp; and (6) assessment of plasma levels of leptin, adiponectin, and high-sensitivity C-reactive protein (hsCRP). Average PA measured by accelerometer correlated with carotid beta-stiffness index (inversely) and with longitudinal systolic myocardial velocity (directly), independently of age, anthropometric, hemodynamic, and metabolic parameters. Subjects with periods of moderate-to-vigorous-intensity PA lasting at least 10 min (n = 28) had higher left ventricular (LV) mass index and lower plasma adiponectin, leptin, and hsCRP (P < 0.05 for all) compared with those who spent the monitoring time only in sedentary and light-intensity PA (n = 17). Minutes per day spent in moderate-to-vigorous PA correlated with LV mass index (directly) and with plasma adiponectin (inversely). Plasma adiponectin was an independent determinant of LV mass, together with body surface area, stroke volume, and systolic blood pressure (cumulative r ² = 0.80). We conclude that in healthy subjects, average daily PA is independently related to longitudinal systolic myocardial function and to local carotid stiffness. Bouts of moderate-to-vigorous PA seem to induce LV mass increase, which may be partially related to a decrease in plasma adiponectin level.     

Liver enzymes are associated with hepatic insulin resistance, insulin secretion, and glucagon concentration in healthy men and women

OBJECTIVE

The pathophysiological mechanisms to explain the association between risk of type 2 diabetes and elevated concentrations of γ-glutamyltransferase (GGT) and alanineaminotransferase (ALT) remain poorly characterized. We explored the association of liver enzymes with peripheral and hepatic insulin resistance, insulin secretion, insulin clearance, and glucagon concentration.

RESEARCH DESIGN AND METHODS

We studied 1,309 nondiabetic individuals from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study; all had a euglycemic-hyperinsulinemic clamp and an oral glucose tolerance test (OGTT) with assessment of insulin secretion and hepatic insulin extraction. The hepatic insulin resistance index was calculated in 393 individuals.

RESULTS

In both men and women, plasma concentrations of GGT and ALT were inversely related with insulin sensitivity (M/I) (all P < 0.01). Likewise, the hepatic insulin resistance index was positively correlated with both GGT (r = 0.37, P < 0.0001, men; r = 0.36, P < 0.0001, women) and ALT (r = 0.25, P = 0.0005, men; r = 0.18, P = 0.01, women). These associations persisted in multivariable models. Increased GGT and ALT were significantly associated with higher insulin secretion rates and with both reduced endogenous clearance of insulin and hepatic insulin extraction during the OGTT (P = 0.0005 in men; P = 0.003 in women). Plasma fasting glucagon levels increased over ALT quartiles (men, quartile 4 vs. quartile 1 11.2 ± 5.1 vs. 9.3 ± 3.8 pmol/L, respectively, P = 0.0002; women, 9.0 ± 4.3 vs. 7.6 ± 3.1, P = 0.001).

CONCLUSIONS

In healthy individuals, increased GGT and ALT were biomarkers of both systemic and hepatic insulin resistance with concomitant increased insulin secretion and decreased hepatic insulin clearance. The novel finding of a positive correlation between ALT and fasting glucagon level concentrations warrants confirmation in type 2 diabetes.Markers of liver function, specifically γ-glutamyltransferase (GGT) and alanine aminotransferase (ALT), predict incident type 2 diabetes in various populations (1–5). This has been confirmed by a recent meta-analysis that suggested that GGT may be a better diabetes predictor than ALT (6). We recently reported that a moderate elevation of GGT concentration within the normal range is a strong risk marker for incident type 2 diabetes in a large nonobese population, independently of the homeostasis model assessment index (7). However, the physiopathological mechanisms that underlie the association between GGT, ALT, and the risk of diabetes remain poorly understood. Studies have shown that elevated levels of ALT reflect peripheral insulin resistance (8,9), but specific assessment of hepatic insulin sensitivity with appropriate methods is lacking. Furthermore, the relationship between elevated liver markers, including GGT, and both insulin secretion and insulin clearance has not previously been addressed.The aim of the current study is to determine whether liver markers (GGT and ALT) are mainly associated with peripheral insulin resistance (assessed by the hyperinsulinemic-euglycemic clamp), hepatic insulin resistance (assessed through endogenous glucose production), or insulin secretion (assessed during the oral glucose tolerance test [OGTT]) in a large cohort of healthy men and women participating in the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study (10,11). We performed a sex-specific analysis because both GGT and ALT values are classically higher in men compared with women.