Diabetes as a risk factor for sudden death

Although a family history of sudden death was a risk factor for sudden death in the Paris Prospective Study I, diabetes was also a strong risk factor, with a similar risk after accounting for other cardiovascular risk factors. Diabetes, however, was not a risk factor for death by myocardial infarction.     

The prevalence of and factors associated with diabetic retinopathy in the Australian population

OBJECTIVE: To determine the prevalence and factors associated with diabetic retinopathy in the Australian population and to estimate the time difference between disease onset and clinical diagnosis of type 2 diabetes. RESEARCH DESIGN AND METHODS: The Australian Diabetes, Obesity and Lifestyle study (AusDiab) included 11,247 adults aged > or =25 years in 42 randomly selected areas of Australia. Retinopathy was assessed in participants identified as having diabetes (based on self-report and oral glucose tolerance test), impaired fasting glucose, and impaired glucose tolerance and in a random sample with normal glucose tolerance. Data were available for 2,177 participants. RESULTS: Overall, 15.3% of those with diabetes had retinopathy. The prevalence of retinopathy was 21.9% in those with known type 2 diabetes (KDM) and 6.2% in those newly diagnosed (NDM). The prevalence of proliferative diabetic retinopathy (PDR) was 2.1% in those with KDM. No cases of PDR were found in those with NDM. Untreated vision threatening retinopathy (presence of PDR or macular edema) was present in 1.2% (n = 4). Factors associated with retinopathy were duration of diabetes, HbA(1c), and systolic blood pressure. Using linear extrapolation of the prevalence of retinopathy with diabetes duration, the onset of diabetes in this population was approximately the time of diagnosis. CONCLUSIONS: This is one of the first national studies of diabetic retinopathy in a developed country. The prevalence of retinopathy was similar to that in other population-based studies. Vision threatening retinopathy was relatively rare; however, four untreated cases were identified. Regular screening for diabetic retinopathy and more aggressive management of modifiable risk factors could reduce the numbers of people who develop vision-threatening retinopathy.     

Standardized comparison of glucose intolerance in west African-origin populations of rural and urban Cameroon, Jamaica, and Caribbean migrants to Britain

OBJECTIVE: To compare the prevalence of glucose intolerance in genetically similar African-origin populations within Cameroon and from Jamaica and Britain. RESEARCH DESIGN AND METHODS: Subjects studied were from rural and urban Cameroon or from Jamaica, or were Caribbean migrants, mainly Jamaican, living in Manchester, England. Sampling bases included a local census of adults aged 25-74 years in Cameroon, districts statistically representative in Jamaica, and population registers in Manchester. African-Caribbean ethnicity required three grandparents of this ethnicity. Diabetes was defined by the World Health Organization (WHO) 1985 criteria using a 75-g oral glucose tolerance test (2-h > or = 11.1 mmol/l or hypoglycemic treatment) and by the new American Diabetes Association criteria (fasting glucose > or = 7.0 mmol/l or hypoglycemic treatment). RESULTS: For men, mean BMIs were greatest in urban Cameroon and Manchester (25-27 kg/m2); in women, these were similarly high in urban Cameroon and Jamaica and highest in Manchester (27-28 kg/m2). The age-standardized diabetes prevalence using WHO criteria was 0.8% in rural Cameroon, 2.0% in urban Cameroon, 8.5% in Jamaica, and 14.6% in Manchester, with no difference between sexes (men: 1.1%, 1.0%, 6.5%, 15.3%, women: 0.5%, 2.8%, 10.6%, 14.0%), all tests for trend P < 0.001. Impaired glucose tolerance was more frequent in Jamaica. CONCLUSIONS: The transition in glucose intolerance from Cameroon to Jamaica and Britain suggests that environment determines diabetes prevalence in these populations of similar genetic origin.     

Genetic Variant in HK1 Is Associated With a Proanemic State and A1C but Not Other Glycemic Control�CRelated Traits

OBJECTIVE

A1C is widely considered the gold standard for monitoring effective blood glucose levels. Recently, a genome-wide association study reported an association between A1C and rs7072268 within HK1 (encoding hexokinase 1), which catalyzes the first step of glycolysis. HK1 deficiency in erythrocytes (red blood cells [RBCs]) causes severe nonspherocytic hemolytic anemia in both humans and mice.

RESEARCH DESIGN AND METHODS

The contribution of rs7072268 to A1C and the RBC-related traits was assessed in 6,953 nondiabetic European participants. We additionally analyzed the association with hematologic traits in 5,229 nondiabetic European individuals (in whom A1C was not measured) and 1,924 diabetic patients. Glucose control–related markers other than A1C were analyzed in 18,694 nondiabetic European individuals. A type 2 diabetes case-control study included 7,447 French diabetic patients.

RESULTS

Our study confirms a strong association between the rs7072268–T allele and increased A1C (β = 0.029%; P = 2.22 × 10⁻⁷). Surprisingly, despite adequate study power, rs7072268 showed no association with any other markers of glucose control (fasting- and 2-h post-OGTT–related parameters, n = 18,694). In contrast, rs7072268–T allele decreases hemoglobin levels (n = 13,416; β = −0.054 g/dl; P = 3.74 × 10⁻⁶) and hematocrit (n = 11,492; β = −0.13%; P = 2.26 × 10⁻⁴), suggesting a proanemic effect. The T allele also increases risk for anemia (836 cases; odds ratio 1.13; P = 0.018).

CONCLUSIONS

HK1 variation, although strongly associated with A1C, does not seem to be involved in blood glucose control. Since HK1 rs7072268 is associated with reduced hemoglobin levels and favors anemia, we propose that HK1 may influence A1C levels through its anemic effect or its effect on glucose metabolism in RBCs. These findings may have implications for type 2 diabetes diagnosis and clinical management because anemia is a frequent complication of the diabetes state.Type 2 diabetes is a major source of early excess morbidity and mortality, which result from lack of adequate blood glucose control in most diabetic patients (1). In the absence of widely available continuous glucose monitoring, the A1C assay has become the most popular index to evaluate the efficiency of type 2 diabetes treatments on long-term blood glucose control (2,3). A1C, which is formed through the nonenzymatic attachment of glucose to the NH₂-terminal of the β-chain of hemoglobin, is indeed commonly considered a surrogate marker of mean blood glucose concentration over the previous 8–12 weeks (i.e., a 120-day life span of erythrocytes) (4). Furthermore, the A1C assay is often used for confirming type 2 diabetes diagnosis when fasting plasma glucose (FPG) is in the pre-diabetes range (6.1 ≤ FPG <7.0 mmol/l, defining normal glycemia and overt diabetes, respectively [2]), as postprandial or post–glucose load measurements of blood glucose are difficult to widely apply in clinical practice. However, the A1C measurement displays well-known caveats, such as genetically inherited hemoglobin defects or erythrocyte (red blood cell [RBC]) life span heterogeneity in hematologically normal people, that would oblige the use of more complex measurement of glycated serum proteins or fructosamine as a surrogate of blood glucose levels (5,6).Thus far, several genome-wide association (GWA) studies have identified 22 genes or loci, increasing the risk for type 2 diabetes or modulating FPG levels (7–19). Recently, Pare et al. (20) reported a single nucleotide polymorphism (SNP), rs7072268, at the hexokinase 1 (HK1) locus (chr10q22) that strongly associates with increased A1C in a nondiabetic population. The four isozymes of the hexokinase family (HK1, HK2, HK3, and glucokinase) contribute to commit glucose to the glycolytic pathway. The predominant HK1 isozyme is expressed in the vast majority of cells and tissues, including cells that are strictly dependent on glucose uptake for their metabolic needs (21). Importantly, while most tissues express more than one HK isozyme, RBC glucose metabolism only depends on HK1 activity (22). In humans, mutations including nonsynonymous substitutions in the active site of HK1 and intragenic deletions have been shown to cause HK1 enzymatic deficiency associated with autosomal recessive severe nonspherocytic hemolytic anemia (21,23–25). A similar phenotype has been described in the Downeast Anemia (dea) mice displaying HK1 deficiency (22).Based on these observations, we postulated that HK1 genetic variation may modulate the maintenance of the RBC pool and thus indirectly alter A1C measurements independently of the ambient blood glucose concentration. We evaluated this hypothesis by assessing the impact of HK1 rs7072268 on A1C, other glucose control-related traits, type 2 diabetes risk, and RBC-related parameters in several prospective and case-control European cohorts. Our data suggest that HK1 variation through its anemic effect impairs A1C assays, which may have important clinical implications for both type 2 diabetes diagnosis and management because anemia is commonly associated with diabetes.     

Minor contribution of SMAD7 and KLF10 variants to genetic susceptibility of type 2 diabetes

BACKGROUND: Transgenic mice over-expressing SMAD7 in pancreatic beta-cells develop type 2 diabetes (T2D). The expression of SMAD7 is affected by KLF11, which contains gene variants that have previously been shown to be involved in genetic susceptibility to T2D, and by the highly homologous KLF10. This study aims to assess the genetic contribution of SMAD7 and KLF10 gene variants to T2D susceptibility in the French population. METHODS: We screened both genes to identify rare and frequent variants by direct sequencing and then genotyped these variants. Six frequent variants of SMAD7 and six of KLF10 were analyzed in 349 T2D patients and 349 normoglycaemic adult subjects. Variants with statistically significant differences in allele and/or genotype distribution were further analyzed in a population sample of 1.712 T2D patients and 1.072 normoglycaemic subjects. RESULTS: Two variants showed a significant association under a recessive model: The intronic SMAD7 IVS2 -21 had an odds ratio of 0.62 (P=0.007, 95% CI=0.44-0.88; P=0.034 when adjusting for age, sex and BMI by logistic regression), and the KLF10 3'UTR +1002 variant had an Odds Ratio of 0.81 (P=0.009, 95% CI=0.69-0.95; P=0.042 when adjusting for age, sex and BMI). CONCLUSION: Although the observed association of SMAD7 and KLF10 gene variants with T2D is modest, they may weakly contribute to a particular genetic background that increases the susceptibility to development of T2D.     

Calcium consumption and insulin resistance syndrome parameters. Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR)

Background and aimA number of studies have investigated the role of dietary calcium in lipid metabolism and weight regulation, and the influence of dairy products on the incidence of insulin resistance syndrome. In this study we have examined the relationship between dietary calcium and the established parameters of the insulin resistance syndrome.Methods and resultsThe study population (n = 4372) was taken from the DESIR (Data from the Epidemiological Study on the Insulin Resistance Syndrome) cohort. Data for parameters relating to the syndrome were recorded, including glucose, serum insulin, triglycerides, HDL-cholesterol, waist circumference and blood pressure. Total energy, calcium and alcohol intake were estimated using a food-frequency questionnaire. Relationships between dietary calcium density and the above parameters were analyzed by multiple linear regression models, adjusted for age, smoking, alcohol consumption and physical activity. From one quartile of calcium density to the next, mean systolic and diastolic blood pressures and insulin concentrations decreased in women by 0.9 mmHg, 0.5 mmHg and 2.4%, respectively, and HDL-cholesterol increased by 0.007 mmol/l (all p < 0.05) after adjustment for age, smoking, alcohol intake and physical activity. In men, there was an increase of 0.2 kg/m² in the body mass index(BMI) and a decrease of 0.4 mmHg in diastolic blood pressure (both p < 0.05).ConclusionsThese results confirm a beneficial association between dietary calcium and arterial blood pressure, insulin and HDL-cholesterol levels in women, whereas in men there was only a beneficial association with diastolic blood pressure.     

Prevalence of melanocortin-4 receptor deficiency in Europeans and their age-dependent penetrance in multigenerational pedigrees

OBJECTIVE— Melanocortin-4 receptor (MC4R) deficiency is the most frequent genetic cause of obesity. However, there is uncertainty regarding the degree of penetrance of this condition, and the putative impact of the environment on the development of obesity in MC4R mutation carriers is unknown.RESEARCH DESIGN AND METHODS— We determined the MC4R sequence in 2,257 obese individuals and 2,677 nonobese control subjects of European origin and established the likely functional impact of all variants detected. We then included relatives of probands carriers and studied 25 pedigrees, including 97 carriers and 94 noncarriers from three generations.RESULTS— Of the MC4R nonsynonymous mutations found in obese subjects, 68% resulted in a loss of function in vitro. They were found in 1.72% of obese versus 0.15% of nonobesed subjects (P = 6.9 × 10⁻¹⁰). Among the families, abnormal eating behavior was more frequent in both MC4R-deficient children and adults than in noncarriers. Although BMI was inversely associated with educational status in noncarrier adults, no such relationship was seen in MC4R mutation carriers. We observed a generational effect, with a penetrance of 40% in MC4R-deficient adults aged >52 years, 60% in 18- to 52-year-old adults, and 79% in children. The longitudinal study of adult carriers showed an increasing age-dependent penetrance (37% at 20 years versus 60% at >40 years).CONCLUSIONS— We have established a robust estimate of age-related penetrance for MC4R deficiency and demonstrated a generational effect on penetrance, which may relate to the development of an “obesogenic” environment. It remains to be seen whether appropriate manipulation of environmental factors may contribute to preventing the development of obesity even in those strongly genetically predisposed to it.The leptin-melanocortin axis controls human energy homeostasis, and the melanocortin-4 receptor (MC4R) is a key player in its central regulation (1). Loss-of-function mutations in MC4R cause severe familial forms of obesity (2,3), and infrequent gain-of-function polymorphisms have been associated with protection against obesity (4,5). At least 72 nonsynonymous mutations have been discovered so far, but some have no obvious functional consequences (6,7), highlighting the importance of functional characterization of MC4R mutations in the determination of potential pathogenicity. MC4R is a membrane-bound G-protein–coupled receptor that activates adenylate cyclase. Loss-of-function mutations result in a partial or complete loss of function as measured by cAMP production. The majority of missense mutations in MC4R result in intracellular retention of the mutated protein, whereas some primarily affect ligand binding or ligand/receptor activation (8,9). In some cases, the alteration of the basal activity of the receptor (8,10) has been reported.The prevalence of loss-of-function MC4R mutations ranges from 0.5 to 5.8% in childhood-onset obesity (11–14). The contribution of MC4R mutations to late-onset obesity is still debated (13,15–18). Obesity due to MC4R mutations has been extensively studied, and although heterozygous loss-of-function mutations can clearly cause familial obesity, they can be found in individuals who are not obese (19). There is a need for reliable estimates of penetrance. Furthermore, no study has thoroughly assessed the effect of loss-of-function MC4R mutations in elderly subjects. Previous studies using part of our French cohort evidenced the first mutation in MC4R and demonstrated that most of them lead to an intracellular retention of the receptor (2,13,18).Although hyperphagia is a key feature of MC4R deficiency, with increased food intake at an ad libitum test meal reported in severely obese MC4R-deficient children (10), an apparent amelioration of obesity and food intake disturbances has been suggested in adulthood in some studies (6,11). Obesity is a complex trait, and MC4R mutations offer a unique opportunity to analyze the effects of both aging and shared environment on the evolution of body mass in this paradigm. In this extensive study of 2,257 unrelated obese subjects, 2,677 control subjects of European descent, and 25 multigenerational pedigrees with several MC4R mutations carriers, we provide a comprehensive picture of the prevalence of this condition and of factors that determine the expression of the obesity phenotype and support previous observations reported in a German familial study (20).