Smoking Is Associated With Reduced Risk of Autoimmune Diabetes in Adults Contrasting With Increased Risk in Overweight Men With Type 2 Diabetes: A 22-year follow-up of the HUNT study

OBJECTIVE

To investigate the association between smoking habits and risk of autoimmune diabetes in adults and of type 2 diabetes.

RESEARCH DESIGN AND METHODS

We used data from the three surveys of the Nord-Trøndelag Health Study, spanning 1984–2008 and including a cohort of 90,819 Norwegian men (48%) and women (52%) aged ≥20 years. Incident cases of diabetes were identified by questionnaire and classified as type 2 diabetes (n = 1,860) and autoimmune diabetes (n = 140) based on antibodies to glutamic decarboxylase (GADA) and age at onset of diabetes. Hazard ratios (HRs) adjusted for confounders were estimated by Cox proportional hazards regression models.

RESULTS

The risk of autoimmune diabetes was reduced by 48% (HR 0.52 [95% CI 0.30–0.89]) in current smokers and 58% in heavy smokers (0.42 [0.18–0.98]). The reduced risk was positively associated with number of pack-years. Heavy smoking was associated with lower levels of GADA (P = 0.001) and higher levels of C-peptide (964 vs. 886 pmol/L; P = 0.03). In contrast, smoking was associated with an increased risk of type 2 diabetes, restricted to overweight men (1.33 [1.10–1.61]). Attributable proportion due to an interaction between overweight and heavy smoking was estimated to 0.40 (95% CI 0.23–0.57).

CONCLUSIONS

In this epidemiological study, smoking is associated with a reduced risk of autoimmune diabetes, possibly linked to an inhibitory effect on the autoimmune process. An increased risk of type 2 diabetes was restricted to overweight men.Data on the influence of smoking on autoimmune diabetes are limited. A protective effect seems plausible because an anti-inflammatory effect of nicotine has been demonstrated both in vitro (1) and in vivo (2). Also, an inhibitory effect of nicotine on autoimmune diabetes has been documented in one animal study (3). In a previous study based on prospective data from the Norwegian Nord-Trøndelag Health Study (HUNT) 1984–1997, we found a reduced risk of latent autoimmune diabetes in adults (LADA) in smokers (4). Confirmatory and extended evidence for such an effect is, however, desirable.In contrast, smoking, in particular heavy smoking, is clearly associated with an increased risk of type 2 diabetes (5). The increased risk has been attributed to impaired insulin sensitivity (6), increased systematic inflammation (7), greater accumulation of abdominal adipose tissue (8), and/or adverse effects on pancreatic tissue and β-cell function (9). Overweight may modify the influence of smoking on type 2 diabetes; in one Japanese study, the association between smoking and type 2 diabetes was limited to overweight individuals (10), and findings from a Finnish study suggest that smoking is more detrimental in individuals with high BMI (11). Further studies on a possible interaction are, however, needed.The aim of this study was to extend our previous analyses of smoking in autoimmune diabetes in adults with regard to cases and follow-up time and also to include in-depth analysis of the established association of smoking with type 2 diabetes.     

Sex Differences in the Risk of Coronary Heart Disease Associated With Type 2 Diabetes: A Mendelian Randomization Analysis

OBJECTIVEObservational studies have demonstrated that type 2 diabetes is a stronger risk factor for coronary heart disease (CHD) in women compared with men. However, it is not clear whether this reflects a sex differential in the causal effect of diabetes on CHD risk or results from sex-specific residual confounding.RESEARCH DESIGN AND METHODSUsing 270 single nucleotide polymorphisms (SNPs) for type 2 diabetes identified in a type 2 diabetes genome-wide association study, we performed a sex-stratified Mendelian randomization (MR) study of type 2 diabetes and CHD using individual participant data in UK Biobank (251,420 women and 212,049 men). Weighted median, MR-Egger, MR-pleiotropy residual sum and outlier, and radial MR from summary-level analyses were used for pleiotropy assessment.RESULTSMR analyses showed that genetic risk of type 2 diabetes increased the odds of CHD for women (odds ratio 1.13 [95% CI 1.08–1.18] per 1-log unit increase in odds of type 2 diabetes) and men (1.21 [1.17–1.26] per 1-log unit increase in odds of type 2 diabetes). Sensitivity analyses showed some evidence of directional pleiotropy; however, results were similar after correction for outlier SNPs.CONCLUSIONSThis MR analysis supports a causal effect of genetic liability to type 2 diabetes on risk of CHD that is not stronger for women than men. Assuming a lack of bias, these findings suggest that the prevention and management of type 2 diabetes for CHD risk reduction is of equal priority in both sexes.     

n-3 Fatty Acids Attenuate the Risk of Diabetes Associated With Elevated Serum Nonesterified Fatty Acids: The Multi-Ethnic Study of Atherosclerosis

OBJECTIVE

Chronically high nonesterified fatty acids (NEFAs) are a marker of metabolic dysfunction and likely increase risk of type 2 diabetes. By comparison, n-3 fatty acids (FAs) have been shown to have various health benefits and may protect against disease development. In 5,697 participants of the Multi-Ethnic Study of Atherosclerosis (MESA), we examined whether serum levels of NEFAs relate to risk of incident type 2 diabetes and further tested whether plasma n-3 FA levels may interact with this relation.

RESEARCH DESIGN AND METHODS

NEFAs were measured in fasting serum using an enzymatic colorimetric assay and phospholipid n-3 FAs eicosapentaenoic and docosahexaenoic acids were determined in plasma through gas chromatography-flame ionization detection in 5,697 MESA participants. Cox proportional hazards regression evaluated the association between NEFA levels and incident type 2 diabetes and whether plasma n-3 FAs modified this association adjusting for age, sex, race, education, field center, smoking, and alcohol use.

RESULTS

Over a mean 11.4 years of the study period, higher diabetes incidence was found across successive NEFA quartiles (Q) (hazard ratio [95% CI]): Q1, 1.0; Q2, 1.35 (1.07, 1.71); Q3, 1.58 (1.24, 2.00); and Q4, 1.86 (1.45, 2.38) (P_trend < 0.001). A significant interaction of n-3 FAs on the relation between NEFAs and type 2 diabetes was also observed (P_interaction = 0.03). For individuals with lower n-3 levels (<75th percentile), a higher risk of type 2 diabetes was observed across quartiles of NEFAs: Q1, 1.0; Q2, 1.41 (1.07, 1.84); Q3, 1.77 (1.35, 2.31); and Q4, 2.18 (1.65, 2.88) (P_trend < 0.001). No significant associations were observed in those with n-3 FAs ≥75th percentile (P_trend = 0.54).

CONCLUSIONS

NEFAs are a marker of type 2 diabetes and may have clinical utility for detecting risk of its development. The modifying influence of n-3 FAs suggests a protective effect against disease and/or metabolic dysfunction related to NEFAs and requires further study.     

Regression From Prediabetes to Normal Glucose Regulation Is Associated With Reduction in Cardiovascular Risk: Results From the Diabetes Prevention Program Outcomes Study

OBJECTIVE

Restoration of normal glucose regulation (NGR) in people with prediabetes significantly decreases the risk of future diabetes. We sought to examine whether regression to NGR is also associated with a long-term decrease in cardiovascular disease (CVD) risk.

RESEARCH DESIGN AND METHODS

The Framingham (2008) score (as an estimate of the global 10-year CVD risk) and individual CVD risk factors were calculated annually for the Diabetes Prevention Program Outcomes Study years 1–10 among those patients who returned to NGR at least once during the Diabetes Prevention Program (DPP) compared with those who remained with prediabetes or those in whom diabetes developed during DPP (N = 2,775).

RESULTS

The Framingham scores by glycemic exposure did not differ among the treatment groups; therefore, pooled estimates were stratified by glycemic status and were adjusted for differences in risk factors at DPP baseline and in the treatment arm. During 10 years of follow-up, the mean Framingham 10-year CVD risk scores were highest in the prediabetes group (16.2%), intermediate in the NGR group (15.5%), and 14.4% in people with diabetes (all pairwise comparisons P < 0.05), but scores decreased over time for those people with prediabetes (18.6% in year 1 vs. 15.9% in year 10, P < 0.01). The lower score in the diabetes group versus other groups, a declining score in the prediabetes group, and favorable changes in each individual risk factor in all groups were explained, in part, by higher or increasing medication use for lipids and blood pressure.

CONCLUSIONS

Prediabetes represents a high-risk state for CVD. Restoration of NGR and/or medical treatment of CVD risk factors can significantly reduce the estimated CVD risk in people with prediabetes.     

Changes in A1C Levels Are Significantly Associated With Changes in Levels of the Cardiovascular Risk Biomarker hs-CRP: Results from the SteP study

OBJECTIVE

The effect of therapeutic strategies on cardiovascular (CV) disease can be evaluated by monitoring changes in CV risk biomarkers. This study investigated the effect of a structured self-monitoring of blood glucose (SMBG) protocol and the resulting improvements in glycemic control on changes in high-sensitivity C-reactive protein (hs-CRP) in insulin-naïve patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

The Structured Testing Program (STeP) study was a prospective, cluster-randomized, multicenter trial in which 483 poorly controlled, insulin-naïve patients with type 2 diabetes were randomized to active control (ACG) or structured testing (STG) that included quarterly structured SMBG. Changes in A1C, hs-CRP, and glycemic variability (STG subjects only) were measured at baseline and quarterly.

RESULTS

Reductions in geometric mean hs-CRP values were significantly greater in the STG group at months 3 (P = 0.005), 6 (P = 0.0003), and 12 (P = 0.04) than in the ACG group. STG patients at high CV risk (>3 mg/L) showed significantly greater reductions in hs-CRP levels than ACG patients at high CV risk: −3.64 mg/dL (95% CI −4.21 to −3.06) versus −2.18 mg/dL (−2.93 to −1.43), respectively (P = 0.002). There was a strong correlation between reductions in hs-CRP and A1C in both groups: standardized coefficient (β) was 0.25 for the entire cohort (P < 0.0001), 0.31 for STG (P < 0.0001), and 0.16 for ACG (P = 0.02).

CONCLUSIONS

Reductions in hs-CRP level are associated with reductions in A1C but not reductions in lipids or glycemic variability. Comprehensive structured SMBG-based interventions that lower A1C may translate into improvements in CV risk, as evidenced by levels of the biomarker hs-CRP.It is widely acknowledged that early and intensive glycemic intervention reduces the risk of diabetes-associated complications, in particular, microvascular complications (1–4). However, there is still a need for further reductions in comorbidities, in particular, the risk of cardiovascular (CV) disease (CVD), which is the most common cause of death in patients with diabetes (5). Although the ultimate measure of CVD management is a reduction in morbidity and mortality, it may be possible to monitor the effectiveness of therapeutic strategies to reduce CVD using surrogate markers of CV risk such as high-sensitivity C-reactive protein (hs-CRP).Several studies have linked high levels of hs-CRP to an increased risk of thrombotic events, including myocardial infarction (6–8), and have identified hs-CRP as a predictive biomarker of CV risk and CV mortality in various patient populations, including diabetic patients (9). In diabetic patients with an acute myocardial infarction and elevated hs-CRP levels, hospital outcome is poorer than in nondiabetic patients with an acute myocardial infarction (10).The link between hs-CRP and poor glycemic control in diabetes still remains to be fully elucidated. An early study by King et al. (11) using cross-sectional data, found that a higher A1C is significantly associated with a greater likelihood of higher hs-CRP among adults with diabetes; however, there is a growing body of evidence to suggest that in patients with type 2 diabetes (T2DM), short-term glycemic excursions, such as postprandial hyperglycemia, are even more damaging than long-term high blood glucose levels, that their negative effect on diabetes-related complications is independent of A1C levels (12–14), and that medications targeting postprandial excursions are associated with reductions in hs-CRP levels (15). Further, although abnormal lipid levels have long been considered to be a significant risk factor and possible mechanism for CVD (16), prospective analyses of 12 recognized markers of inflammation (including inflammation, lipids, and lipoproteins), among healthy women, found hs-CRP was the strongest predictor of CV events (17).To further explore the relationship between glycemic control and levels of hs-CRP, we examined data from the Structured Testing Program (STeP) study, a 12-month, cluster-randomized, multicenter clinical trial in primary care that evaluated whether 483 poorly controlled insulin-naïve T2DM patients would benefit from a comprehensive, integrated physician/patient intervention using a structured data collection form before each quarterly clinic visit (18). At 12 months, the intent-to-treat analysis showed significantly greater reductions in mean A1C in the structured testing group (STG) patients than in the active control group (ACG) patients (P = 0.04). Per protocol analysis showed even greater A1C reductions in STG patients (P < 0.003). STG patients also experienced significantly lower average preprandial and postprandial glucose levels at all meals and at bedtime (P < 0.001), with significant reductions in preprandial-to-postprandial glucose excursions at all meals (P < 0.005). There were also significant reductions in glycemic variability among STG patients as measured by mean amplitude of glucose excursions (MAGE) at month 12 (P = 0.0003). No significant changes were noted in lipid levels.This report addresses three research questions. First, to explore further the relationship between glycemic control and hs-CRP, was there a relationship between change in glycemic control and change in hs-CRP over time in patients of the STG or the ACG group? Second, what additional effect, if any, did reduced glycemic variability have on the relationship between A1C and hs-CRP? Third, did lipids mediate the relationship between A1C and hs-CRP?     

Low HDL Cholesterol Is Associated With the Risk of Stroke in Elderly Diabetic Individuals: Changes in the risk for atherosclerotic diseases at various ages

OBJECTIVE

To clarify the relationship between lipid levels and ischemic heart disease (IHD) and cerebrovascular disease (CVD) in diabetic individuals.

RESEARCH DESIGN AND METHODS

The Japan Cholesterol and Diabetes Mellitus Study is a prospective cohort study of 4,014 type 2 diabetic patients (1,936 women; mean ± SD age 67.4 ± 9.5 years). Lipid and glucose levels and other factors were investigated in relation to occurrence of IHD or CVD.

RESULTS

IHD and CVD occurred in 1.59 and 1.43% of participants, respectively, over a 2-year period. The relation of lower HDL or higher LDL cholesterol to occurrence of IHD in subjects <65 years old was significant. Lower HDL cholesterol was also significantly related to CVD in subjects ≥65 years old and especially in those >75 years old (n = 1,016; odds ratio 0.511 [95% CI 0.239–0.918]; P < 0.05). Stepwise multiple regression analysis with onset of CVD as a dependent variable showed the same result.

CONCLUSIONS

Lower HDL cholesterol is an important risk factor for not only IHD but also CVD, especially in diabetic elderly individuals.Type 2 diabetes, dyslipidemia, and aging are independent risk factors for cardiovascular diseases. Japanese individuals have lower rates of ischemic heart disease (IHD) and higher rates of cerebrovascular disease (CVD); however, diabetic individuals have an increased risk of IHD (1,2). Risk factors for IHD or CVD in elderly diabetic individuals are not fully known (3), and the Japan Cholesterol and Diabetes Mellitus Study was formulated to evaluate them (Umin Clinical Trials Registry, clinical trial reg. no. UMIN00000516; http://www.umin.ac.jp/ctr/index.htm).     

Lower Quadriceps Rate of Force Development Is Associated With Worsening Physical Function in Adults With or at Risk for Knee Osteoarthritis: 36-Month Follow-Up Data From the Osteoarthritis Initiative

Objective

To determine the association between quadriceps rate of force development (RFD) and decline in self-reported physical function and objective measures of physical performance.

Corticomotor Depression is Associated With Higher Pain Severity in the Transition to Sustained Pain: A Longitudinal Exploratory Study of Individual Differences

Aberrant motor cortex plasticity is hypothesized to contribute to chronic musculoskeletal pain, but evidence is limited. Critically, studies have not considered individual differences in motor plasticity or how this relates to pain susceptibility. Here we examined the relationship between corticomotor excitability and an individual's susceptibility to pain as pain developed, was sustained and resolved over 21 days. Nerve growth factor was injected into the right extensor carpi radialis brevis muscle of 20 healthy individuals on day 0, 2, and 4. Corticomotor excitability, pressure pain thresholds and performance on a cognitive conflict task were examined longitudinally (day 0, 2, 4, 6, and 14). Pain and disability were assessed on each alternate day (1,3…21). Two patterns of motor plasticity were observed in response to pain––corticomotor depression or corticomotor facilitation (P = .009). Individuals who displayed corticomotor depression experienced greater pain (P = .027), and had worse cognitive task performance (P = .038), than those who displayed facilitation. Pressure pain thresholds were reduced to a similar magnitude in both groups. Corticomotor depression in the early stage of pain could indicate a higher susceptibility to pain. Further work is required to determine whether corticomotor depression is a marker of pain susceptibility in musculoskeletal conditions.PerspectiveThis article explores individual differences in motor plasticity in the transition to sustained pain. Individuals who developed corticomotor depression experienced higher pain and worse cognitive task performance than those who developed corticomotor facilitation. Corticomotor depression in the early stage of pain could indicate a higher susceptibility to pain.     

Type 1 Diabetes Is Associated With an Increased Risk of Fracture Across the Life Span: A Population-Based Cohort Study Using The Health Improvement Network (THIN)

OBJECTIVE

This study was conducted to determine if type 1 diabetes is associated with an increased risk of fracture across the life span.

RESEARCH DESIGN AND METHODS

This population-based cohort study used data from The Health Improvement Network (THIN) in the U.K. (data from 1994 to 2012), in which 30,394 participants aged 0–89 years with type 1 diabetes were compared with 303,872 randomly selected age-, sex-, and practice-matched participants without diabetes. Cox regression analysis was used to determine hazard ratios (HRs) for incident fracture in participants with type 1 diabetes.

RESULTS

A total of 334,266 participants, median age 34 years, were monitored for 1.9 million person-years. HR were lowest in males and females age <20 years, with HR 1.14 (95% CI 1.01–1.29) and 1.35 (95% CI 1.12–1.63), respectively. Risk was highest in men 60–69 years (HR 2.18 [95% CI 1.79–2.65]), and in women 40–49 years (HR 2.03 [95% CI 1.73–2.39]). Lower extremity fractures comprised a higher proportion of incident fractures in participants with versus those without type 1 diabetes (31.1% vs. 25.1% in males, 39.3% vs. 32% in females; P < 0.001). Secondary analyses for incident hip fractures identified the highest HR of 5.64 (95% CI 3.55–8.97) in men 60–69 years and the highest HR of 5.63 (95% CI 2.25–14.11) in women 30–39 years.

CONCLUSIONS

Type 1 diabetes was associated with increased risk of incident fracture that began in childhood and extended across the life span. Participants with type 1 diabetes sustained a disproportionately greater number of lower extremity fractures. These findings have important public health implications, given the increasing prevalence of type 1 diabetes and the morbidity and mortality associated with hip fractures.