Combined influence of insulin resistance, overweight/obesity, and fatty liver as risk factors for type 2 diabetes

OBJECTIVE

There is dissociation between insulin resistance, overweight/obesity, and fatty liver as risk factors for type 2 diabetes, suggesting that different mechanisms are involved. Our aim was to 1) quantify risk of incident diabetes at follow-up with different combinations of these risk factors at baseline and 2) determine whether each is an independent risk factor for diabetes.

RESEARCH DESIGN AND METHODS

We examined 12,853 subjects without diabetes from a South Korean occupational cohort, and insulin resistance (IR) (homeostasis model assessment-IR ≥75th centile, ≥2.0), fatty liver (defined by standard ultrasound criteria), and overweight/obesity (BMI ≥25 kg/m²) identified at baseline. Odds ratios (ORs) and 95% confidence intervals (CIs) for incident diabetes at 5-year follow-up were estimated using logistic regression.

RESULTS

We identified 223 incident cases of diabetes from which 26 subjects had none of the three risk factors, 37 had one, 56 had two, and 104 had three. In the fully adjusted model, the OR and CI for diabetes were 3.92 (2.86–5.37) for IR, 1.62 (1.17–2.24) for overweight/obesity, and 2.42 (1.74–3.36) for fatty liver. The OR for the presence of all three factors in a fully adjusted model was 14.13 (8.99–22.21).

CONCLUSIONS

The clustering of IR, overweight/obesity, and fatty liver is common and markedly increases the odds of developing type 2 diabetes, but these factors also have effects independently of each other and of confounding factors. The data suggest that treatment for each factor is needed to decrease risk of type 2 diabetes.People who develop type 2 diabetes represent a heterogeneous group of individuals, some of whom have normal insulin sensitivity, normal weight, and β-cell failure; others have insulin resistance (IR) and inadequate compensatory hyperinsulinemia; and others have a combination of defects in both insulin sensitivity and β-cell function (1,2). The prevalence of diabetes is predicted to double between the years 2000 and 2030 (3) and, although an ageing population and increasing urbanization in developing countries will contribute to this marked increase in prevalence (3), the predicted prevalence is likely to be underestimated because of the increasing global burden of obesity. Several potential mechanisms may explain why obesity is a strong risk factor for diabetes (4). These mechanisms include increased production of nonesterfied fatty acids; adipokines/cytokines, including tumor necrosis factor-α, resistin, and retinol-binding protein 4; as well as reduced levels of adiponectin and mitochondrial dysfunction that compromise β-cell function (5). Although obesity has undoubtedly contributed to the burden of diabetes (4) and strategies to decrease body fat are effective in decreasing risk of diabetes, there are several unanswered questions regarding the mechanism(s) of the link between obesity and diabetes (5).IR is also a risk factor for type 2 diabetes (6,7) and has a close association with obesity. Both obesity and IR are also strongly associated with fatty liver (8,9), and it is now evident that fatty liver is a risk factor for type 2 diabetes (10–13). However, fatty liver may occur in both normal weight and overweight/obese individuals, and the precise mechanism by which fatty liver increases risk of type 2 diabetes is uncertain. Fatty liver may affect risk of diabetes via an effect on the secretion of hepatokines (14), increased gluconeogenesis, decreased glycogen synthesis, and inhibition of insulin signaling (15,16). Although fatty liver is associated with diabetes, not all individuals with fatty liver have IR (17–19). Thus, although IR, overweight/obesity, and fatty liver are strongly correlated, there is clear evidence of dissociation between these three risk factors. The dissociation between these risk factors suggests that different pathogenetic mechanisms may operate by which insulin resistance, overweight/obesity, and fatty liver contribute to type 2 diabetes. Affected individuals who develop type 2 diabetes may have any one, two, or three of these risk factors, but the impact of different combinations of risk factors is uncertain. Establishing the roles of the different combinations of these risk factors may be helpful to understand the pathogenesis of type 2 diabetes and to inform approaches to prevention and treatment. Using data from a cohort study with measurements of IR, overweight/obesity, and fatty liver at baseline, the aim of our study was to 1) estimate the strength of the association between different combinations of these three risk factors and incident diabetes and 2) determine whether the effects of each factor are independent of each other and potential confounding factors.     

Fatty Liver,Insulin Resistance,and Features of Metabolic Syndrome: Relationships with coronary artery calcium in 10,153 people

OBJECTIVE

Nonalcoholic fatty liver disease (NAFLD) coexists with insulin resistance (IR), but it is uncertain whether NAFLD and IR contribute independently to atherosclerosis. We tested whether fatty liver, IR, and metabolic syndrome (MetS) features (waist, glucose, triglyceride, HDL cholesterol [HDL-C], and blood pressure) were associated with a marker of atherosclerosis (coronary artery calcium [CAC] score >0), independently of cardiovascular risk factors and cardiovascular disease (CVD).

RESEARCH DESIGN AND METHODS

Data were analyzed from a South Korean occupational cohort of 10,153 people who all received ultrasound measurements of fatty liver and a cardiac computed tomography CAC score. IR was defined by homeostasis model assessment of IR (HOMA-IR) ≥75th percentile. Odds ratios (ORs) (95% CIs) for the presence of a CAC score >0 were estimated using logistic regression.

RESULTS

There were 915 people with a CAC score >0. MetS features were increased (glucose, blood pressure, triglyceride, and waist) or decreased (HDL-C) among people with a CAC score >0 (all comparisons against CAC score ≤0; P < 0.0001). Of subjects with a CAC score >0, 55% had fatty liver and 33.7% were insulin resistant. Fatty liver (OR 1.21 [95% CI 1.01–1.45]; P = 0.04) and HOMA-IR (1.10 [1.02–1.18]; P = 0.02) were associated with CAC score >0, independently of all MetS features, conventional cardiovascular risk factors, and prior evidence of CVD. The presence of IR and fatty liver combined was associated with CAC score >0 (1.53 [1.20–1.95]; P = 0.001).

CONCLUSIONS

Fatty liver and HOMA-IR are both associated with a CAC score >0 (independently of each other), features of MetS, conventional cardiovascular risk factors, and existing CVD.Nonalcoholic fatty liver disease (NAFLD) often coexists with type 2 diabetes and insulin resistance (IR) but each factor may occur in the absence of the other factors. Several prospective studies have reported an increased incidence of cardiovascular events in people with NAFLD (1–12), but it is still unclear whether NAFLD is simply a risk marker that coexists with other recognized cardiovascular disease (CVD) risk factors, such as type 2 diabetes and central obesity, that are associated with IR or whether it is an independent cardiovascular risk factor (13,14). IR has been shown to be associated with coronary artery calcium (CAC) (15) as a marker of early atherosclerosis, but in this study, IR was not associated with CAC, after adjustment for metabolic syndrome (MetS) features, and the presence of NAFLD was not described in this cohort.NAFLD is now recognized as a very common condition in people with type 2 diabetes and, if it were proven that NAFLD is an independent CVD risk factor, independently of type 2 diabetes and IR, a diagnosis of NAFLD could be used to identify subgroups of individuals who would receive particular benefit from intensive lifestyle modification and pharmacological treatment to decrease CVD risk (16,17). Moreover future treatments for NAFLD would need to test whether treating fatty liver specifically affects risk of CVD.CAC scoring with cardiac computed tomography (CT) is a sensitive method to demonstrate the presence of early atherosclerosis, and the use of CAC scores may improve CV risk prediction in asymptomatic individuals (18). Thus, estimation of the CAC score provides a useful, noninvasive tool to investigate relationships between NAFLD, IR, and development of early coronary artery atherosclerosis in order to better understand the relationship between NAFLD, IR, and atherosclerosis.Using data from a retrospective cohort study with measurements of fatty liver and CAC score, together with measurement of BMI, waist circumference, features of MetS, IR, conventional cardiovascular risk factors, and diabetes status in all subjects, we have investigated the relationship between fatty liver, IR, and a CAC score >0. We tested whether 1) fatty liver, IR, and conventional, easily measured features of MetS (waist, glucose, triglyceride, HDL cholesterol [HDL-C], and blood pressure) were associated with a CAC score >0 (as a marker of the presence of early atherosclerosis) and 2) any relationships were independent of conventional cardiovascular risk factors and existing vascular disease.     

Gene therapy for aromatic L-amino acid decarboxylase deficiency

Aromatic L-amino acid decarboxylase (AADC) is required for the synthesis of the neurotransmitters dopamine and serotonin. Children with defects in the AADC gene show compromised development, particularly in motor function. Drug therapy has only marginal effects on some of the symptoms and does not change early childhood mortality. Here, we performed adeno-associated viral vector-mediated gene transfer of the human AADC gene bilaterally into the putamen of four patients 4 to 6 years of age. All of the patients showed improvements in motor performance: One patient was able to stand 16 months after gene transfer, and the other three patients achieved supported sitting 6 to 15 months after gene transfer. Choreic dyskinesia was observed in all patients, but this resolved after several months. Positron emission tomography revealed increased uptake by the putamen of 6-[(18)F]fluorodopa, a tracer for AADC. Cerebrospinal fluid analysis showed increased dopamine and serotonin levels after gene transfer. Thus, gene therapy targeting primary AADC deficiency is well tolerated and leads to improved motor function.     

Sustained in vivo release from imprinted therapeutic contact lenses

In this paper, we demonstrate the successful in vivo extended release of a small molecular weight therapeutic, ketotifen fumarate (MW=425), from molecularly imprinted, therapeutic contact lenses. This is the first time that a steady, effective concentration of drug is maintained in the tear film from a contact lens for an extended period of time for the entire duration of lens wear. Poly(HEMA-co-AA-co-AM-co-NVP-co-PEG200DMA) soft contact lenses were prepared (100±5 μm thickness, diameter 11.8 mm, power zero), and a constant tear film concentration of 170±30 μg/mL was measured for up to 26 hrs in a New Zealand white rabbit model. The results showed a dramatic increase in ketotifen mean residence time (MRT) and bioavailability compared to topical drop therapy and drug soaked lenses. The MRT for imprinted lenses was 12.47±3.99 hrs, ~4 and 50 fold greater than non-imprinted lenses and 0.035% eye drops (Zaditor?), respectively. Furthermore, AUC(0-26 hrs) was 9 and 94 fold greater for imprinted lenses than non-imprinted lenses and eye drops, respectively. The results indicate that molecular imprinting provides an exciting rational engineering strategy for sustained release. It is clear that imprinted lenses are very promising combination devices and are much more effective and efficient delivery devices than eye drops.     

The 2009 National Environmental Public Health Conference: one model for planning green and healthy conferences

The Centers for Disease Control and Prevention's National Center for Environmental Health and the Agency for Toxic Substances and Disease Registry committed to making their 2009 National Environmental Public Health Conference a model for green and healthy conferences. The conference included increased opportunities for physical activity, both as part of conference events and for transportation to the conference. In addition, conference meals were healthy and sustainably sourced. The conference also implemented intuitive, accessible recycling; online scheduling and evaluation to minimize hard-copy materials; and the purchase of carbon offsets to reduce the unwanted environmental impact of the conference. Public health professionals have an opportunity and obligation to support healthy behaviors at their events and to serve as leaders in this area. Facilitating healthy and sustainable choices is in alignment with goals for both public health and broader social issues-such as environmental quality-that have a direct bearing on public health.     

"I'm satisfied … but": clients' and families' contingent responses about home care

Home care service organizations need a means of gaining useful feedback about satisfaction with care from clients and their families. Interviews were conducted with 82 older adult clients and 52 family members about their satisfaction with home care. A subgroup of participants (n = 39) provided "contingent" satisfaction responses. Contingent responses reflect the duality of perceptions that clients and families convey about services. Three themes emerged as critical to understanding these types of responses: adept versus inept staff, predictable versus precarious scheduling, and responsive versus restrictive care plans. Understanding the reasons for contingent responses could help home care agencies to target quality improvement initiatives for individual clients and families.     

Current status of hybrid coronary revascularization

Hybrid coronary revascularization combines coronary artery bypass surgery with percutaneous coronary intervention techniques to treat coronary artery disease. The potential benefits of such a technique are to offer the patients the best available treatments for coronary artery disease while minimizing the risks of the surgery. Hybrid coronary revascularization has resulted in the establishment of new 'hybrid operating suites', which incorporate and integrate the capabilities of a cardiac surgery operating room with that of an interventional cardiology laboratory. Hybrid coronary revascularization has greatly augmented teamwork and cooperation between both fields and has demonstrated encouraging as well as good initial outcomes.     

The extent and nature of need for mealtime support among adults with intellectual disabilities

Background For many adults with an intellectual disability (ID), mealtimes carry significant health risks. While research and allied clinical guidance has focused mainly on dysphagia, adults with a range of physical and behavioural difficulties require mealtime support to ensure safety and adequate nutrition. The extent of need for and nature of such support within the wider ID population has yet to be reported. Methods In this study, we have estimated the prevalence of need for mealtime support among people with ID in the UK, using a population of 2230 adults known to specialist ID services (in Cambridgeshire, UK, total population 586 900). In a sample (n = 69, aged 19 to 79 years, with mild to profound ID), we characterised the support provided, using a structured proforma to consult support workers and carers providing mealtime support, and health and social care records. Results Mealtime support was found to be required by a significant minority of people with ID for complex and varied reasons. Prevalence of need for such support was estimated at 15% of adults known to specialist ID services or 56 per 100 000 total population. Within a sample, support required was found to vary widely in nature (from texture modification or environmental adaptation to enteral feeding) and in overall level (from minimal to full support, dependent on functional skills). Needs had increased over time in almost half (n = 34, 49.3%). Reasons for support included difficulties getting food into the body (n = 56, 82.2%), risky eating and drinking behaviours (n = 31, 44.9%) and slow eating or food refusal (n = 30, 43.5%). These proportions translate into crude estimates of the prevalence of these difficulties within the known ID population of 11.9%, 6.6% and 6.4% respectively. Within the sample of those requiring mealtime support, need for support was reported to be contributed to by the presence of additional disability or illness (e.g. visual impairment, poor dentition and dementia; n = 45, 65.2%) and by psychological or behavioural issues (e.g. challenging behaviour, emotional disturbance; n = 36, 52.2%). Conclusions These findings not only highlight the need for a multidisciplinary approach to mealtime interventions (paying particular attention to psychological and environmental as well as physical issues), but also signal the daily difficulties faced by carers and paid support workers providing such support and illustrate their potentially crucial role in managing the serious health risks associated with eating and drinking difficulties in this population.