HDL Cholesterol and Cancer Risk Among Patients With Type 2 Diabetes

OBJECTIVETo investigate the relationship between HDL cholesterol (HDL-C) and cancer risk among type 2 diabetic patients.RESULTSDuring a mean follow-up period of 6.4 years, 3,711 type 2 diabetic patients had a cancer diagnosis. A significant inverse association between HDL-C and the risk of cancer was found among men and women. The multivariable-adjusted hazard ratios (HRs) of cancer at various levels of HDL-C at baseline (<30, 30–39.9, 40–49.9, 50–59.9, 60–69.9, 70–79.9, and ≥80 mg/dL) were 1.00, 0.87, 0.95, 1.01, 0.61, 0.45, and 0.37, respectively, in men (P_trend = 0.027) and 1.00, 0.98, 0.88, 0.85, 0.84, 0.86, and 0.84, respectively, in women (P_trend = 0.025). When stratified by race, BMI, smoking status, or medication use, the inverse association was still present. With an updated mean of HDL-C used in the analysis, the inverse association of HDL-C with cancer risk did not change. The inverse association substantially attenuated after excluding patients who died of or were diagnosed with cancer during the first 2 years of follow-up.CONCLUSIONSThe study suggests an inverse association of HDL-C with cancer risk among men and women with type 2 diabetes, whereas the effect of HDL-C was partially mediated by reverse causation.     

Chronotype Is Independently Associated With Glycemic Control in Type 2 Diabetes

OBJECTIVE

To examine whether chronotype and daily caloric distribution are associated with glycemic control in patients with type 2 diabetes independently of sleep disturbances.

RESEARCH DESIGN AND METHODS

Patients with type 2 diabetes had a structured interview and completed questionnaires to collect information on diabetes history and habitual sleep duration, quality, and timing. Shift workers were excluded. A recently validated construct derived from mid-sleep time on weekends was used as an indicator of chronotype. One-day food recall was used to compute the temporal distribution of caloric intake. Hierarchical linear regression analyses controlling for demographic and sleep variables were computed to determine whether chronotype was associated with HbA_1c values and whether this association was mediated by a higher proportion of caloric intake at dinner.

RESULTS

We analyzed 194 completed questionnaires. Multiple regression analyses adjusting for age, sex, race, BMI, insulin use, depressed mood, diabetes complications, and perceived sleep debt found that chronotype was significantly associated with glycemic control (P = 0.001). This association was partially mediated by a greater percentage of total daily calories consumed at dinner.

CONCLUSIONS

Later chronotype and larger dinner were associated with poorer glycemic control in patients with type 2 diabetes independently of sleep disturbances. These results suggest that chronotype may be predictive of disease outcomes and lend further support to the role of the circadian system in metabolic regulation.The circadian system, controlled by the master circadian clock located in the suprachiasmatic nuclei of the hypothalamus, plays a major role in regulating daily rhythms of sleep/wake and various metabolic outputs, such as feeding behavior, peripheral tissue metabolism, and hormone secretions (1–3). Despite having this genetically regulated master circadian clock, humans living in modern industrialized societies with 24-h access to light often engage in behaviors that are inappropriately timed relative to their endogenous circadian rhythms. This mismatch in timing is termed “circadian misalignment” and has been associated with a number of negative health outcomes. Night shift work is an example of severe circadian misalignment, as workers are awake, active, and eating during their circadian night and trying to sleep and fast during their circadian day. Epidemiologic studies reveal that shift work is associated with health problems including peptic ulcer disease, coronary heart disease, and metabolic syndrome, as well as certain types of cancers (4). In controlled laboratory studies, experimentally induced circadian misalignment in healthy human volunteers resulted in impaired glucose tolerance (5,6). In animal experiments, mice fed a high-fat diet during their inactive period gained significantly more weight than mice fed during their active phase, despite consuming the equivalent amount of calories (7). Taken together, these data suggest that severe circadian misalignment involving eating and sleeping at an abnormal circadian time leads to impaired energy metabolism.Many individuals in modern society experience a form of mild circadian misalignment, especially during the work or school week as they follow social rhythms imposed by professional obligation, school schedules, family, and other commitments (8). The degree of misalignment is dependent on the individual’s “chronotype” (8). Chronotype is a construct that captures an individual’s preference for being a “morning” or “evening” person. Late chronotype is typically associated with a greater degree of misalignment between social rhythms and the circadian clock (8). This misalignment phenomenon has been termed “social jetlag,” as it resembles the condition experienced after traveling across time zones (8) and can be observed by comparing the difference in sleep timing between work/school days and free days. In a large population study, larger amounts of social jetlag were recently reported to be associated with higher BMI in overweight individuals (9). In addition, a recent study found that patients with type 2 diabetes had significantly later bedtimes and wake times than participants without diabetes, suggesting that chronotype may play a role in glucose metabolism (10).In addition to chronic circadian misalignment, late chronotypes or “evening types” tend to minimize or skip breakfast (11,12). Therefore, the daily distribution of food intake may be mismatched with circadian-controlled metabolic rhythms. It is well recognized that glucose tolerance is worse in the evening (13), suggesting that eating late may result in adverse metabolic consequences. Indeed, a study of healthy volunteers reported that the amount of calories consumed after 8:00 p.m. predicted a higher BMI after controlling for sleep timing and duration (14), suggesting that the timing of food intake across the waking day is of metabolic relevance.To date, little is known about chronotypic variations in patients with type 2 diabetes and the potential associations with glycemic control. There is abundant evidence that sleep disturbances such as short sleep duration and poor sleep quality are linked to the risk of diabetes and obesity, as well as glycemic control in subjects with type 2 diabetes (15,16), but little is known about the association between chronotype and metabolism independently of these sleep characteristics. The aim of this study was to examine whether chronotype was independently associated with glycemic control in patients with type 2 diabetes. We hypothesized that late chronotype would be associated with worse glycemic control independently of sleep disturbances. Because the distribution of food intake across the day is associated with chronotype, we also examined whether daily caloric distribution contributed to glycemic control. We hypothesized that a greater percentage of daily calories consumed at dinner would be associated with worse glycemic control.     

Poor Glycemic Control Is Related to Increased Nitric Oxide Activity Within the Renal Circulation of Patients With Type 2 Diabetes

OBJECTIVE

Experimental studies have shown that glucose releases endothelial nitric oxide (NO) and that NO contributes to renal hyperperfusion in models of diabetes. To examine whether this translates into the human condition, we studied the relationship between glycemic control and renal NO activity in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

A total of 113 patients with type 2 diabetes and a wide range of HbA_1c concentrations were included. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were determined by constant infusion input clearance. Functional NO activity in the renal circulation was determined as change of RPF to infusion of the NO synthase (NOS) inhibitor N(G)-monomethyl-l-arginine (l-NMMA) (4.25 mg/kg). As additional markers, we measured urinary excretion of NO (UNOx) and l-arginine–to–asymmetrical dimethylarginine (ADMA) ratio in plasma.

RESULTS

Subjects within the highest tertile of HbA_1c concentration had increased RPF (low, medium, and high tertiles 576 ± 17 vs. 585 ± 22 vs. 627 ± 33 mL/min/m², P = 0.05 by one-way ANOVA), while GFR was similar across tertiles. The response of RPF to NOS blockade was augmented in subjects with higher HbA_1c levels (−55 ± 7 vs. −64 ± 8 vs. −86 ± 8 mL/min, P = 0.04 by one-way ANOVA). Further, l-arginine–to–ADMA ratio and UNOx were increased in subjects with higher HbA_1c levels.

CONCLUSIONS

In line with experimental evidence, we could demonstrate in humans that poor glycemic control is related to higher NO activity and hyperperfusion of the kidney. The renal NO system may thus be a novel therapeutic target for improving renal hemodynamics in patients with diabetes.The incidence of end-stage renal disease owing to diabetic nephropathy is increasing in developed countries (1). In order to reduce the burden of end-stage diabetic kidney disease, targeting glomerular hyperfiltration and hyperperfusion, early hemodynamic abnormalities that have been linked with greater risk of developing albuminuria and loss of renal function over time (2,3), may be an attractive therapeutic option.Others and we have shown that nitric oxide (NO) is an important regulator of renal hemodynamics in humans (4–6). Experimental studies have demonstrated that increased production of NO in the kidney contributes to the renal hemodynamic alterations in models of type 1 and type 2 diabetes (7–12). As a pathogenetic factor, hyperglycemia has been shown to stimulate acute release of NO from cultured endothelial cells (13,14), including endothelial cells derived from the glomerulum (15).In human subjects with diabetes, data on the role of NO for renal hemodynamics are very limited. A few studies are available that have assessed NO production with a biochemical approach. Hiragushi et al. showed that in subjects with type 2 diabetes, urinary NO (UNOx) excretion rates were higher in those with increased glomerular filtration rate (GFR) versus those with normal GFR (16). Additional studies suggested that it is the hyperglycemia that drives increased NO production associated with glomerular hyperfiltration (17,18).Using a much more direct way of assessing the functional contribution of NO to renal hemodynamics, Cherney et al. (19) studied the renal response to pharmacological NO synthase (NOS) inhibition in subjects with type 1 diabetes without complications. NOS inhibition led to a significantly greater decline of GFR and renal plasma flow (RPF) in hyperfiltering versus the normofiltering subjects with type 1 diabetes.The role of NO in renal hemodynamics of subjects with type 2 diabetes, a more heterogenous group of subjects with regard to concomitant diseases and vascular risk factors, and the influence of glycemic control have not been studied. To this end, we examined renal hemodynamic responses to pharmacological NOS inhibition across a wide range of HbA_1c levels in a large cohort of subjects with type 2 diabetes.     

Inpatient Diabetes Education Is Associated With Less Frequent Hospital Readmission Among Patients With Poor Glycemic Control

OBJECTIVE

To explore the relationship between inpatient diabetes education (IDE) and hospital readmissions in patients with poorly controlled diabetes.

RESEARCH DESIGN AND METHODS

Patients with a discharge diagnosis of diabetes (ICD-9 code 250.x) and HbA_1c >9% who were hospitalized between 2008 and 2010 were retrospectively identified. All-cause first readmissions were determined within 30 days and 180 days after discharge. IDE was conducted by a certified diabetes educator or trainee. Relationships between IDE and hospital readmission were analyzed with stepwise backward logistic regression models.

RESULTS

In all, 2,265 patients were included in the 30-day analysis and 2,069 patients were included in the 180-day analysis. Patients who received IDE had a lower frequency of readmission within 30 days than did those who did not (11 vs. 16%; P = 0.0001). This relationship persisted after adjustment for sociodemographic and illness-related factors (odds ratio 0.66 [95% CI 0.51–0.85]; P = 0.001). Medicaid insurance and longer stay were also independent predictors in this model. IDE was also associated with reduced readmissions within 180 days, although the relationship was attenuated. In the final 180-day model, no IDE, African American race, Medicaid or Medicare insurance, longer stay, and lower HbA_1c were independently associated with increased hospital readmission. Further analysis determined that higher HbA_1c was associated with lower frequency of readmission only among patients who received a diabetes education consult.

CONCLUSIONS

Formal IDE was independently associated with a lower frequency of all-cause hospital readmission within 30 days; this relationship was attenuated by 180 days. Prospective studies are needed to confirm this association.Hospital readmission is an important contributor to total medical expenditures and is an emerging indicator of quality of care. The Affordable Care Act is placing increasing focus on medical homes and accountable care organizations, and transition programs for hospitalized patients have garnered increasing attention (1). In addition, the Medicare Payment Advisory Commission has reduced reimbursement rates for patients who have early rehospitalizations for certain conditions such as congestive heart failure (CHF) (2). Diabetes, similar to other chronic medical conditions, is associated with increased risk of hospital readmission (3). Robbins et al. (4) showed that rehospitalizations within 30 days of discharge occurred in 20% of patients with diabetes, which is more than the 5–14% estimated for all hospital discharges. Among patients with diabetes who had been hospitalized, Jiang et al. (5) showed that 30% of these patients were hospitalized more than once within 1 year, and these patients accounted for a majority of the inpatient costs for patients with diabetes. These findings are particularly relevant because hospital stays for patients with diabetes numbered >7.7 million in 2008, accounting for 20% of hospitalizations and $83 billion (23% of total hospital costs) in the U.S. (6).Rehospitalizations occur disproportionately among socioeconomically disadvantaged groups, including Hispanics and African Americans (AAs), those living in lower income zip codes, and those without private insurance (5,7). Other risk factors include previous hospitalization, extremes of age, and socioeconomic barriers. Failure to acknowledge diabetes at discharge is associated with increased 30-day readmissions, suggesting that suboptimal diabetes management may be an important factor for successful transitions in care (4).The involvement of a diabetes specialist team may reduce readmissions according to limited data from some (8,9) but not all (10) studies. Results may depend on the individual components of the program and attention to discharge needs. Inpatient diabetes management teams generally incorporate some component of diabetes education (11). In the outpatient setting, nursing education has resulted in improved HbA_1c and adherence to medication and glucose monitoring, so the potential benefits are not limited to readmission (12–14). In the case of heart failure, self-management education has been associated with improved readmission rates (15), so such a relationship in patients with diabetes would not be unprecedented.The objective of the study was to determine whether diabetes education, conducted by a dedicated trained diabetes educator during hospitalization, improves the frequency of readmission in patients with poorly controlled diabetes (HbA_1c >9%).     

Assessing Glycemic Control in Maintenance Hemodialysis Patients With Type 2 Diabetes

OBJECTIVE

Optimizing glycemic control in diabetic patients undergoing maintenance hemodialysis requires accurate assessment. We hypothesize that 1) 48-h continuous glucose monitoring (CGM) provides additional, clinically relevant, information to that provided by the A1C measurement and 2) glycemic profiles differ significantly between day on and day off dialysis.

RESEARCH DESIGN AND METHODS

With the use of GlucoDay S, 48-h CGM was performed in 19 type 2 diabetic subjects undergoing hemodialysis to capture consecutive 24-h periods on and off dialysis. Energy intake was calculated using food diaries. A1C was assayed by a high-performance liquid chromatography method.

RESULTS

CGM data were available for 17 subjects (13 male) with a mean (range) age of 61.5 years (42–79 years) and diabetes duration of 18.8 years (4–30 years). The 24-h CGM area under the glucose curve and 24-h mean glucose values were significantly higher during the day off dialysis than on dialysis (5,932.1 ± 2,673.6 vs. 4,694 ± 1,988.0 mmol · 3 min⁻¹ · l⁻¹, P = 0.022, and 12.6 ± 5.6 vs. 9.8 ± 3.8 mmol/l, P = 0.013, respectively), independent of energy intake. Asymptomatic hypoglycemia occurred in 4 subjects, 3 within 24 h of dialysis, and the glucose nadir in 14 subjects occurred within 24 h of dialysis.

CONCLUSIONS

Glucose values are significantly lower on dialysis days than on nondialysis days despite similar energy intake. The risk of asymptomatic hypoglycemia was highest within 24 h of dialysis. Physicians caring for patients undergoing hemodialysis need to be aware of this phenomenon and consider enhanced glycemic monitoring after a hemodialysis session. CGM provides glycemic information in addition to A1C, which is potentially relevant to clinical management.Diabetic nephropathy is the leading cause of end-stage renal failure (ESRF) (1), representing 30–45% of the U.K. and U.S. (2) populations undergoing long-term maintenance hemodialysis. The patients typically are elderly type 2 diabetic patients with established micro- and macrovascular disease (3). Hypoglycemia is common because of impaired renal gluconeogenesis, malnutrition, and the increased half-life of insulin and hypoglycemic agents (4). The annual mortality among diabetic patients undergoing hemodialysis is high and is predominately due to cardiovascular disease (CVD) (2).Intensive glycemic management delays progression of microvascular disease (5–8) and improves malnutrition (9); however, large randomized controlled trials show no mortality benefit in high-risk groups with CVD (7),(10). Hypoglycemic events increase with intensive treatment and in the presence of CVD can cause fatal dysrhythmia (11). U.K. diabetes guidelines advise against intensive treatment aimed to lower A1C levels <6.5% (12), whereas American guidelines caution against values <7% (13). No evidence-based guidelines for the glycemic targets for diabetic patients with ESRF undergoing long-term maintenance hemodialysis are available.In patients without ESRF, the A1C value is routinely used to assess long-term glycemic control, and assays are standardized to those used in the Diabetes Control and Complications Trial (14). There is a strong correlation between A1C values and the weighted mean glucose values of the preceding 2–3 months (14).The validity of the A1C measurement in patients with ESRF undergoing hemodialysis depends on the methodology (15). A number of factors may influence the assay including altered red blood cell (RBC) life span and metabolic and mechanical factors (16). Potential metabolic factors are interference from carbamylated hemoglobin formed in uremia and acetylated hemoglobin formed from long-term aspirin use (17).A limitation of the A1C value in patients undergoing hemodialysis is that it is not informative regarding glycemic control on the days on and off dialysis. In the U.K., maintenance hemodialysis is typically given in a hospital setting three times a week, with sessions lasting 4–5½ h. The CGM devices that measure glucose every 3 min using a biosensor and a subcutaneous microbore cannula are, in contrast, ideally suited to examine the effect of dialysis on glucose profiles over a 48-h period. Thus, in the present study we test the hypotheses 1) that 48-h CGM provides additional, clinically relevant, information to that provided by the A1C measurement in patients undergoing hemodialysis and 2) that 24-h glucose profiles are different on the day that includes a dialysis session compared with those on a day that does not.     

Glycemic Control Influences Serum Angiogenin Concentrations in Patients With Type 2 Diabetes

OBJECTIVEBecause diabetes is the most frequent factor responsible for microvascular and macrovascular disease, we investigated angiogenin serum levels within the diabetic patient group.RESULTSSerum angiogenin levels of poorly controlled patients with type 2 diabetes were significantly lower than those of group with well-controlled diabetes (361.23 ± 126.03 ng/ml vs. 446.37 ± 134.10 ng/ml; P = 0.001). Moreover, they were characterized by a significantly longer duration of the disease (P = 0.006), higher BMI (P = 0.0003), and higher systolic blood pressure (P = 0.01). Levels of total cholesterol, triglycerides, LDL, and HDL were not significantly different in both groups.CONCLUSIONSPatients with poorly controlled type 2 diabetes (A1C >7%) have lower angiogenin levels than patients with well-controlled diabetes.Diabetes is associated with angiopathy, which increases the risk of a variety of complications. To minimize the degree of ischemic damage, collateral vessels of the large arteries are developed. This process is, unfortunately, insufficient in diabetic patients, leading to a three- to fourfold increase in mortality risk. Both coronary vessel formation and capillary density are poorer in patients with diabetes than in a healthy control group (1,2).Angiogenesis is a complex process regulated by stimulatory and inhibitory factors. It is well established in research that the expression of different angiogenic growth factors are reduced in diabetes. On the other hand, diabetic patients with coronary artery disease exhibit higher levels of angiostatin and endostatin (3). In the meantime, the molecular angiogenic signaling pathways influencing coronary collateral formation remain poorly understood.We have previously demonstrated that the serum level of one of the angiogenic growth factors, namely angiogenin, is reduced in diabetes (4). The present investigation was designed to test the hypothesis that the serum level of angiogenin depends on glucose concentration control.     

Ethnic Differences in Glycemic Markers in Patients With Type 2 Diabetes

OBJECTIVE

Recent studies have reported hemoglobin A_1c (HbA_1c) differences across ethnic groups that could limit its use in clinical practice. The authors of the A1C-Derived Average Glucose study have advocated to report HbA_1c in estimated average glucose (AG) equivalents. The aim of this study was to assess the relationships between HbA_1c and the mean of three 7-point self-monitored blood glucose (BG) profiles, and to assess whether estimated AG is an accurate measure of glycemia in different ethnic groups.

RESEARCH DESIGN AND METHODS

We evaluated 1,879 participants with type 2 diabetes in the DURABLE trial who were 30 to 80 years of age, from 11 countries, and, according to self-reported ethnic origin, were Caucasian, of African descent (black), Asian, or Hispanic. We performed logistic regression of the relationship between the mean self-monitored BG and HbA_1c, and estimated AG, according to ethnic background.

RESULTS

Baseline mean (SD) HbA_1c was 9.0% (1.3) (75 [SD, 14] mmol/mol), and mean self-monitored BG was 12.1 mmol/L (3.1) (217 [SD, 55] mg/dL). In the clinically relevant HbA_1c range of 7.0–9.0% (53–75 mmol/mol), non-Caucasian ethnic groups had 0.2–0.5% (2–6 mmol/mol) higher HbA_1c compared with Caucasians for a given BG level. At the mean self-monitored BG levels ≤11.6 mmol/L, estimated AG overestimated the actual average BG; at levels >11.6 mmol/L, estimated AG underestimated the actual BG levels.

CONCLUSIONS

For a given degree of glycemia, HbA_1c levels vary among different ethnic groups. Ethnicity needs to be taken into account when using HbA_1c to assess glycemic control or to set glycemic targets. Estimated AG is not a reliable marker for mean glycemia and therefore is of limited clinical value.The results of hemoglobin A_1c (HbA_1c) measurements are used to evaluate quality of glycemic control in individuals with diabetes mellitus (1). However, several studies have reported that HbA_1c levels may be significantly higher in non-Caucasian patients with diabetes for a given blood glucose (BG) range (2–4). It has become clear that HbA_1c levels not only depend on the long-term BG concentration (5–7) but also may be influenced by genetic factors (8–10) as well as environmental factors such as smoking and obesity (11).The authors of the A1C-Derived Average Glucose study proposed to translate HbA_1c into estimated average glucose (AG) equivalents for monitoring glycemic control (12). They asserted that this could facilitate the patient’s comprehension of the value of a given HbA_1c measurement and could be used instead of HbA_1c. However, the potential racial and ethnic differences in hemoglobin glycation (3) and the impact of hemoglobin variants and erythrocyte survival on the HbA_1c assay (13) suggest that estimated AG may be a biased estimate of mean self-monitored BG (SMBG), depending on the specific ethnic group.The aims of the current study were to analyze in the participants of the DURABLE trial the relationships between HbA_1c and mean SMBG across different ethnic groups with type 2 diabetes and to compare HbA_1c-derived estimated AG with mean SMBG to determine whether estimated AG is an accurate measure of glycemia.     

Organizational Justice in Primary-Care Health Centers and Glycemic Control in Patients With Type 2 Diabetes

BACKGROUND:: Organizational justice has been put forward as a measure of leadership quality that is associated with better health among employees. OBJECTIVES:: We extended that idea to test whether perceived organizational justice among health care providers might be positively associated with glycemic control among their diabetic patients. SETTING:: Eighteen primary-care health centers (HCs) in Finland. PARTICIPANTS:: Type 2 diabetes patients (n=8954) and HC staff (n=422). MEASUREMENTS:: Mean of 1 year's measurements of glycated hemoglobin [≥7.0 (the least optimal); 6.5-6.9; 6.0-6.4; and 4.5-5.9 (the most optimal)], health-center psychosocial work characteristics (staff-reported procedural justice and relational justice, effort-reward imbalance, and work-unit team climate), and individual-level and work-unit-level covariates. RESULTS:: Perceptions of higher levels of procedural justice among staff were associated with more optimal glycated hemoglobin levels among patients (cumulative odds ratio per 1-U increase in justice=1.54, 95% confidence interval, 1.08-2.18) after adjustment for patient-level and unit-level covariates. Relational justice, effort-reward imbalance, and work-unit team climate were not associated with glycemic control. CONCLUSION:: The quality of leadership at HCs, as indicated by staff perceptions of procedural justice, may play a role in achieving good glycemic control among type 2 diabetes patients.     

Four-Year Screening Interval and Vision-Threatening Retinopathy in Type 2 Diabetes Patients With Good Glycemic Control

ObjectiveTo assess whether vision-threatening retinopathy developed after 4 years in patients with type 2 diabetes with good glycemic control during follow-up.Patients and MethodsUsing data from the Action to Control Cardiovascular Risk in Diabetes and Action to Control Cardiovascular Risk in Diabetes Follow-on studies (conducted from January 1, 2001, to October 14, 2014), we investigated the incidence of vision-threatening retinopathy after 4 years in patients with type 2 diabetes with good or poor glycemic control. Patients with proliferative diabetic retinopathy at baseline were excluded. Vision-threatening retinopathy was defined as severe nonproliferative diabetic retinopathy, proliferative diabetic retinopathy, laser photocoagulation, or vitrectomy. Good and poor glycemic control was defined as mean glycated hemoglobin level less than 7% and 7% or greater during follow-up, respectively.ResultsThis study included 2285 patients. Among patients with no retinopathy at baseline, the 4-year incidence of vision-threatening retinopathy was 0% (0 of 386) and 0.8% (6 of 721) in those with good and poor glycemic control, respectively (P=.54). Similarly, severe retinopathy was not observed at 8 years in patients who did not have retinopathy at 4 years. Among patients with mild to moderate nonproliferative diabetic retinopathy at baseline, the 4-year incidence of vision-threatening retinopathy was significantly higher in those with poor glycemic control than in those with good glycemic control (9.7% [77 of 790] vs 4.4% [13 of 297]; P=.004). Additionally, the remission rate of diabetic retinopathy was low in patients with a long duration of diabetes. Four-year incidences of vision-threatening retinopathy were higher in patients with retinopathy at baseline who had poorer glycemic control and longer durations of diabetes.ConclusionIt may be safe to extend screening intervals for diabetic retinopathy to 4 years or longer in patients with type 2 diabetes with no retinopathy.     

Dialysis Treatment Is an Independent Risk Factor for Foot Ulceration in Patients With Diabetes and Stage 4 or 5 Chronic Kidney Disease

OBJECTIVE

To determine whether dialysis treatment is an independent risk factor for foot ulceration in patients with diabetes and renal impairment.

RESEARCH DESIGN AND METHODS

We performed a cross-sectional study of consecutive patients with diabetes and stage 4 or 5 chronic kidney disease (CKD) attending clinics in Manchester (U.K.). Patients were classified as either receiving dialysis therapy (dialysis) or not (no dialysis). Foot assessment included diabetic peripheral neuropathy (DPN), peripheral arterial disease (PAD), prior foot ulceration and amputation, and foot self-care. Risk factors for prevalent foot ulceration were assessed by logistic regression.

RESULTS

We studied 326 patients with diabetes and CKD (mean age 64 years; 61% male; 78% type 2 diabetes; 11% prevalent foot ulceration). Compared with no dialysis patients, dialysis patients had a higher prevalence of DPN (79 vs. 65%), PAD (64 vs. 43%), prior amputations (15 vs. 6.4%), prior foot ulceration (32 vs. 20%), and prevalent foot ulceration (21 vs. 5%, all P < 0.05). In univariate analyses, foot ulceration was related to wearing bespoke footwear (odds ratio 5.6 [95% CI 2.5–13]) dialysis treatment (5.1 [2.3–11]), prior foot ulceration (4.8 [2.3–9.8], PAD (2.8 [1.3–6.0], and years of diabetes (1.0 [1.0–1.1], all P < 0.01). In multivariate logistic regression, only dialysis treatment (4.2 [1.7–10], P = 0.002) and prior foot ulceration (3.1 [1.3–7.1], P = 0.008) were associated with prevalent foot ulceration.

CONCLUSIONS

Dialysis treatment was independently associated with foot ulceration. Guidelines should highlight dialysis as an important risk factor for foot ulceration requiring intensive foot care.The lifetime risk of an individual with diabetes developing foot ulceration has been estimated to be 25% (1). Foot ulceration is a serious problem for people with diabetes, which also results in huge economic costs (2).Causal pathways to foot ulceration are multifactorial and involve combinations of physiological and mechanical factors, self-care, and treatment factors. Diabetic nephropathy has been identified to be an important risk factor for foot ulceration and amputation (3,4). Retrospective studies in patients with diabetes have shown that incident foot ulceration increases with progressive renal impairment (5), and one study reported a close temporal relation among the onset of dialysis, foot ulceration, and amputations (6).Studies reporting an association between renal failure and foot ulceration have failed to separate dialysis-treated patients from those not receiving dialysis (5,7). We therefore aimed to determine whether dialysis treatment is an independent risk factor for foot ulceration among diabetic patients with stage 4 or 5 chronic kidney disease (CKD). We hypothesized that dialysis treatment would be associated with a higher prevalence of foot ulceration after adjustment for potential confounders.     

Mortality in Adult-Onset Autoimmune Diabetes Is Associated With Poor Glycemic Control: Results from the HUNT Study

OBJECTIVE

Knowledge on mortality in autoimmune diabetes with adult onset is limited. We compared mortality in adult-onset autoimmune diabetes and type 2 diabetes, taking into account metabolic risk factors, HbA_1c, lifestyle, and socioeconomic factors.

RESEARCH DESIGN AND METHODS

Participants of the population-based HUNT2 Study (second survey of the Norwegian HelseUndersøkelsen i Nord-Trøndelag Study; n = 64,264) were followed up prospectively for mortality in the Cause of Death Registry (1995–2009). Diabetes with onset ≥35 years was classified as autoimmune diabetes in adults if anti-GAD was positive (n = 208) and as type 2 diabetes if anti-GAD was negative (n = 2,425). Hazard ratios (HRs) of mortality from all-causes, cardiovascular disease (CVD), and ischemic heart disease (IHD) were calculated using the Cox proportional hazards model.

RESULTS

Prevalence of the metabolic syndrome was lower in autoimmune diabetes than in type 2 diabetes (55 vs. 77%, P < 0.001). Still, autoimmune diabetes was associated with an increased risks of mortality from all-causes (HR 1.55 [95% CI 1.25–1.92]), CVD (1.87 [1.40–2.48]), and IHD (2.39 [1.57–3.64]), equally high as in type 2 diabetes in analyses where individuals without diabetes were used as the reference group. The increased risk was not explained by overweight, lifestyle, socioeconomic position, or presence of the metabolic syndrome. Excess mortality was primarily observed in individuals with elevated HbA_1c.

CONCLUSIONS

Mortality in autoimmune diabetes was as high as in type 2 diabetes, despite a more favorable baseline metabolic risk profile. Excess risk was associated with poor glycemic control. The results from this study, the largest so far on mortality in autoimmune diabetes in adults, underscore the importance of optimal treatment modalities to improve survival in adult-onset autoimmune diabetes.All forms of diabetes are associated with increased mortality, primarily from cardiovascular disease (CVD) and, in particular, ischemic heart disease (IHD) (1–3). A meta-analysis of 102 prospective studies reported that diabetes confers about a twofold excess risk of CVD, independent of other risk factors (4). Prolonged exposure to hyperglycemia is a well-recognized etiological factor. Hyperglycemia initiates a complex chain of events that damage blood vessels and potentially accelerate the atherosclerotic process (5). However, other factors are also bound to be important and may modify the total risk differently in different forms of diabetes. Hence, excess mortality in type 2 diabetes has also been attributed to traditional risk factors, such as obesity and other components of the metabolic syndrome (6,7), and to socioeconomic factors (8).The effect of juvenile-onset type 1 diabetes on CVD and mortality is well recognized (1). Less so is the effect of autoimmune diabetes with adult onset. Still, autoimmune diabetes constitutes a significant part of diabetes, especially in the phenotype termed latent autoimmune diabetes in adults (LADA), which is estimated to account for ∼10% of all diabetes (9–11). Autoimmune diabetes is characterized by antibodies against the insulin-producing β-cells (9,12). Compared with “classic” type 1 diabetes, LADA progresses more slowly and is typically not treated with insulin at the time of diagnosis.On one hand, fewer features of the metabolic syndrome have been reported in individuals with adult-onset autoimmune diabetes than in individuals with type 2 diabetes (13–17), and this may indicate a lower risk of complications. On the other hand, worse glycemic control has been suggested in LADA patients than in patients with type 2 diabetes (15,18–20), something that could put these individuals at increased risk of complications and mortality. Only two previous studies, based on Australian and Finnish populations, have addressed mortality in autoimmune diabetes in adults/LADA (18,21). In addition, a recent U.S. article (22) reported markedly worse prognosis among normal-weight compared with overweight diabetic patients. They speculated about the role of LADA, but did not have information on indicators of autoimmunity to separate patients with LADA from those with type 2 diabetes.From the large population-based and prospective Norwegian HUNT Study (an acronym for the Norwegian name: HelseUndersøkelsen i Nord-Trøndelag), in conjunction with the Cause of Death Registry, it is possible to identify different forms of diabetes and to analyze mortality and cause of death. The size of the study would provide data for the largest study to date on mortality in autoimmune diabetes in adults.Here, we aimed to investigate the risk of all-cause, CVD, and IHD mortality in autoimmune diabetes in adults and type 2 diabetes, taking into account the influence of metabolic risk factors, glycemic control, lifestyle, and socioeconomic factors.     

Costs and Consequences Associated With Newer Medications for Glycemic Control in Type 2 Diabetes

OBJECTIVE

Newer medications offer more options for glycemic control in type 2 diabetes. However, they come at considerable costs. We undertook a health economic analysis to better understand the value of adding two newer medications (exenatide and sitagliptin) as second-line therapy to glycemic control strategies for patients with new-onset diabetes.

RESEARCH DESIGN AND METHODS

We performed a cost-effectiveness analysis for the U.S. population aged 25–64. A lifetime analytic horizon and health care system perspective were used. Costs and quality-adjusted life years (QALYs) were discounted at 3% annually, and costs are presented in 2008 U.S. dollars. We compared three glycemic control strategies: 1) glyburide as a second-line agent, 2) exenatide as a second-line agent, and 3) sitagliptin as a second-line agent. Outcome measures included QALYs gained, incremental costs, and the incremental cost-effectiveness ratio associated with each strategy.

RESULTS

Exenatide and sitagliptin conferred 0.09 and 0.12 additional QALYs, respectively, relative to glyburide as second-line therapy. In base case analysis, exenatide was dominated (cost more and provided fewer QALYs than the next most expensive option), and sitagliptin was associated with an incremental cost-effectiveness ratio of $169,572 per QALY saved. Results were sensitive to assumptions regarding medication costs, side effect duration, and side effect–associated disutilities.

CONCLUSIONS

Exenatide and sitagliptin may confer substantial costs to health care systems. Demonstrated gains in quality and/or quantity of life are necessary for these agents to provide economic value to patients and health care systems.Diabetes is increasingly endemic in the U.S. In 2007, 23.5 million Americans aged >20 years had diabetes compared with 18.0 million in 2002 (1). Diabetes was the seventh leading cause of death in 2006 (1). It remains the leading cause of blindness, end-stage renal disease, and nontraumatic amputations. A total of $116 billion in direct health care costs are attributable to diabetes annually (2).Large clinical trials from the U.S. and Europe have demonstrated that tighter glycemic control can prevent diabetes complications in individuals with recent-onset disease (3,4); in older individuals with longer disease duration, recent studies have found no cardiovascular benefit of tight control (5) and possible harm (6). In the past several years, the U.S. Food and Drug Administration (FDA) approved nine new products for glycemic control (7). Some are new forms or combinations of existing classes, whereas others belong to new therapeutic classes such as amylin analogs, glucagon-like peptide-1 receptor agonists, incretins, and dipeptidyl peptidase-IV inhibitors.Although these agents increase the management options available, they come at increased costs (8). Previous analyses of the health economics of glycemic control were published before the FDA approval of many new agents (9–11). Recent studies have examined the cost-effectiveness of exenatide or sitagliptin in European populations, reflecting costs and management appropriate for the modeled populations but not necessarily reflective of the U.S. (12–14).In this analysis, we estimate the costs associated with two of the most prescribed examples of these new medications: exenatide and sitagliptin. We project the gains in health outcomes necessary to have these newer medications pose good economic value for patients with new-onset diabetes, using the incremental cost-effectiveness ratio as our metric.     

Effect of Ranolazine Monotherapy on Glycemic Control in Subjects With Type 2 Diabetes

OBJECTIVE

Ranolazine is an antianginal drug that mediates its effects by inhibition of cardiac late sodium current. Although ranolazine is not approved for the treatment of type 2 diabetes, in post hoc analyses of pivotal angina trials, ranolazine was associated with reductions in percent glycosylated hemoglobin (HbA_1c) in subjects with type 2 diabetes. The study prospectively assessed the safety and efficacy of ranolazine in subjects with type 2 diabetes with inadequate glycemic control managed by lifestyle alone.

RESEARCH DESIGN AND METHODS

The study was conducted worldwide in 465 subjects, with baseline HbA_1c of 7–10% (53–86 mmol/mol) and fasting serum glucose of 130–240 mg/dL, randomized to placebo versus ranolazine.

RESULTS

Compared with placebo, there was a greater decline in HbA_1c at week 24 from baseline (primary end point) in subjects taking ranolazine (mean difference −0.56% [−6.1 mmol/mol]; P < 0.0001). Moreover, the proportion of subjects achieving an HbA_1c <7.0% was greater with ranolazine (25.6% vs. 41.2%; P = 0.0004). Ranolazine was associated with reductions in fasting (mean difference −8 mg/dL; P = 0.0266) and 2-h postprandial glucose (mean difference −19 mg/dL; P = 0.0008 vs. placebo). Subjects taking ranolazine trended toward a greater decrease from baseline in fasting insulin (P = 0.0507), a greater decrease in fasting glucagon (P = 0.0003), and a lower postprandial 3-h glucagon area under the curve (P = 0.0031 vs. placebo). Ranolazine was safe and well tolerated.

CONCLUSIONS

Compared with placebo, use of ranolazine monotherapy over 24 weeks, in subjects with type 2 diabetes and inadequate glycemic control on diet and exercise alone, significantly reduced HbA_1c and other measures of glycemic control.     

Low Serum Level of the Endogenous Secretory Receptor for Advanced Glycation End Products (esRAGE) Is a Risk Factor for Prevalent Vertebral Fractures Independent of Bone Mineral Density in Patients With Type 2 Diabetes

OBJECTIVE

Patients with type 2 diabetes are known to have an increased risk for fracture compared with non–type 2 diabetic control subjects, despite having higher bone mineral density (BMD). We previously showed that serum pentosidine, one of the advanced glycation end products (AGEs), was associated with prevalent vertebral fractures (VFs) in those with type 2 diabetes. The involvement of the endogenous secretory receptor for AGEs (esRAGE) in VFs in those with type 2 diabetes, however, is still unknown.

RESEARCH DESIGN AND METHODS

We compared parameters including esRAGE, pentosidine, and BMD in Japanese type 2 diabetic patients (137 men >50 years old and 140 postmenopausal women) with and without VFs.

RESULTS

The esRAGE-to-pentosidine ratio in type 2 diabetic patients with VFs was significantly lower than in those without VFs (men: 7.1 ± 2.8 vs. 9.4 ± 6.2, P = 0.013, respectively; women: 4.7 ± 2.7 vs. 8.2 ± 5.4, P < 0.001, respectively). Multivariate logistic regression analysis adjusted for age, BMI, A1C, serum creatinine, duration of diabetes, therapeutic agents, diabetes complications, osteoporotic risk factors, and lumbar BMD identified the serum esRAGE level and esRAGE-to-pentosidine ratio as factors associated with the presence of VFs, independent of BMD in men (odds ratio [OR] 0.46 [95% CI 0.25–0.84], P = 0.012; and OR 0.34 [0.15–0.76], P = 0.009, respectively) and in women (OR 0.32 [0.16–0.67], P = 0.002; and OR 0.14 [0.04–0.43], P = 0.001, respectively).

CONCLUSIONS

These results show that serum esRAGE level and esRAGE-to-pentosidine ratio are more useful than BMD for assessing the risk of VFs in type 2 diabetic patients.The association between diabetes and osteoporosis has been investigated in many studies because these two disorders affect a large proportion of the elderly population. Recent meta-analyses of accumulating studies have shown that patients with type 2 diabetes have an increased risk for hip fracture compared with non–type 2 diabetic control subjects, despite their higher bone mineral density (BMD) (1,2). We have also shown that patients with type 2 diabetes have an increased risk for vertebral fractures (VFs) and that BMD at any site fails to assess the risk of VF (3). Because bone strength reflects integration of bone density and bone quality (4), these findings suggest that bone quality may be more important than bone density in defining bone strength in type 2 diabetic patients.Bone quality is known to be determined by bone architecture, turnover, accumulation of microdamage, mineralization, and properties of bone matrix proteins such as collagen (4). In diabetic patients, advanced glycation end products (AGEs) are generated by sequential nonenzymatic glycosylation of protein amino groups (5). Pentosidine is one of the well-known AGEs, and its bone content in spontaneous diabetic rats has been shown to increase concurrently with the onset of diabetes, resulting in impaired mechanical properties of the bone despite normal BMD (6). We have shown clinically that the serum pentosidine level is associated with the presence of VFs in postmenopausal diabetic women independent of BMD (7). These findings suggest that AGEs, including pentosidine, may act as causative factors for poor bone quality in type 2 diabetic patients.The receptor for AGEs (RAGE) belongs to the immunoglobulin superfamily of cell surface receptors and is capable of interacting with multiple ligands, including AGEs (8). When transgenic mice overexpressing human RAGE in vascular cells were crossbred with a transgenic line that develops insulin-dependent diabetes shortly after birth, a more progressive histological change of diabetic nephropathy was observed compared with controls (9), confirming that RAGE is associated with the development of diabetes complications. Endogenous secretory RAGE (esRAGE), a splice variant of one of the naturally occurring secretory forms, is known to carry all the extracellular domains but lacks the transmembrane and cytoplasmic domains (10). Secreted esRAGE in the extracellular space is thought to act as a decoy receptor that binds AGEs and results in reducing the activity of intercellular signal pathways via RAGE (10). Indeed, administration of a genetically engineered murine-soluble RAGE suppressed the development of diabetic atherosclerosis in a dose-dependent manner in streptozotocin-induced apoE-null diabetic mice (11). Recently, RAGE-knockout mice have been shown to increase BMD and biomechanical bone strength by decreasing osteoclast formation as well as serum levels of interleukin-6 and pyridinoline (12). We have also shown that the combination of high glucose with AGEs inhibits osteoblastic mineralization through glucose-induced increases in the expression of RAGE in vitro (13). These experimental findings suggest that enhanced RAGE activity may also be clinically linked to reduced bone strength in diabetic patients. Given the neutralizing nature of esRAGE, it is possible that the ratio of serum esRAGE-to-AGE levels could be linked to clinical bone problems, such as fractures, more prominently than either parameter alone.To examine this issue, we compared serum levels of esRAGE and pentosidine as well as the esRAGE-to-pentosidine ratio between type 2 diabetic patients with and without VFs and evaluated the usefulness of these markers for assessing the risk of VFs in the population.     

Skin Autofluorescence Reflects Integration of Past Long-Term Glycemic Control in Patients With Type 1 Diabetes

OBJECTIVE

The aim was to investigate the relationships between skin autofluorescence (AF) and the impact of past glycemic control and microvascular complications in Japanese patients with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Two hundred forty-one patients and 110 controls were enrolled. Advanced glycation end product accumulation was measured with AF reader. Three monthly HbA_1c levels during the past 20 years were determined from medical records, and the HbA_1c area under the curve (AUC) was calculated. We performed multivariate regression analyses to examine the associations between the severity of diabetes complications and various variables.

RESULTS

Skin AF values increased with increasing the severity of retinopathy (P < 10⁻¹¹, linear regression analysis) and nephropathy (P < 10⁻⁵ for chronic kidney disease stage; P < 10⁻⁵ for albuminuria-based stage). HbA_1c AUC values over the past 15 years were significantly correlated with skin AF values (past 5 years: R = 0.35, P < 0.0001; past 10 years: R = 0.36, P < 0.0001; past 15 years: R = 0.55, P < 0.0001; past 20 years: R = 0.22, P = 0.13). HbA_1c AUC values over the past 3, 5, 10, and 15 years were significantly associated with the severity of both nephropathy and retinopathy. Multivariate analyses in which HbA_1c AUC value was removed from the independent variables indicated that only skin AF was independently associated with nephropathy, whereas age at registration, age at onset of diabetes, and skin AF were independently associated with retinopathy.

CONCLUSIONS

Skin AF reflects past long-term glycemic control and may serve as a surrogate marker for the development of microvascular complications in place of HbA_1c AUC value.Advanced glycation end products (AGEs) are generated via nonenzymatic reactions of ketone or aldehyde groups of sugars with free amino groups of proteins, lipids, or nucleic acids, and these reactions are referred to as Maillard reactions (1). The accumulation of AGEs on tissue proteins has been implicated in the aging of proteins and progression of chronic age-related diseases (2). The measurement of AGE accumulation in skin biopsy specimens, as determined via AGE assays, was found to correlate with serum AGEs (3). Monnier et al. (4) reported that the average age-adjusted fluorescence values in skin biopsy specimens were two-fold greater in patients with type 1 diabetes compared with nondiabetic control subjects, and these values increased with the severity of diabetic retinopathy and nephropathy. To measure the collagen glycation in skin, invasive skin biopsy method is not applicable in routine clinical diabetes care in outpatient clinic. The measurement of plantar fascia thickness via ultrasound is a noninvasive method of measuring tissue glycation and is a significant predictor of the subsequent development of microvascular complications in type 1 diabetes (5). Recently, a noninvasive method using an autofluorescence (AF) reader for the measurement of skin AGE accumulation was developed. An AF reader calculates AF by dividing the average light intensity emitted per nanometer over the 420- to 600-nm range by the average light intensity emitted per nanometer over the 300- to 420-nm range. Meerwaldt et al. (3) reported that skin AF offers a simple alternative to invasive measurements of AGE accumulation after pepsin digestion of skin biopsy samples via collagen-linked fluorescence (CLF) (excitation at 370 nm and emission at 440 nm) and pentosidine measurements with high-performance liquid chromatography (excitation at 328 nm and emission at 378 nm), N^ε-carboxymethyllysine (CML), and N^ε-carboxyethyllysine (CEL) (6). They reported that skin AF correlated with pentosidine, CML, CEL, and CLF measurements obtained from skin biopsy samples (5).However, the majority of previous studies of the measurement of AGE accumulation include Caucasian patients and, thus, the issue of racial differences is not addressed. Furthermore, previous studies using skin AF in Japanese subjects studied patients with end-stage renal disease (7), rheumatoid arthritis, osteoarthritis (8), and cerebral infarction (9). It was found that skin AF was significantly higher in patients with end-stage renal disease, rheumatoid arthritis, and cerebral infarction than that of healthy controls.Thus, the aim of the current study was to investigate the relationships between skin AF, glucose metabolism, and diabetic vascular complications using an AF reader in Japanese patients with type 1 diabetes.     

Predicting the Glycemic Response to Gastric Bypass Surgery in Patients With Type 2 Diabetes

OBJECTIVE

To find clinically meaningful preoperative predictors of diabetes remission and conversely inadequate glycemic control after gastric bypass surgery. Predicting the improvement in glycemic control in those with type 2 diabetes after bariatric surgery may help in patient selection.

RESEARCH DESIGN AND METHODS

Preoperative details of 154 ethnic Chinese subjects with type 2 diabetes were examined for their influence on glycemic outcomes at 1 year after gastric bypass. Remission was defined as HbA_1c ≤6%. Analysis involved binary logistic regression to identify predictors and provide regression equations and receiver operating characteristic curves to determine clinically useful cutoff values.

RESULTS

Remission was achieved in 107 subjects (69.5%) at 12 months. Diabetes duration <4 years, body mass >35 kg/m², and fasting C-peptide concentration >2.9 ng/mL provided three independent preoperative predictors and three clinically useful cutoffs. The regression equation classification plot derived from continuous data correctly assigned 84% of participants. A combination of two or three of these predictors allows a sensitivity of 82% and specificity of 87% for remission. Duration of diabetes (with different cutoff points) and C-peptide also predicted those cases in which HbA_1c ≤7% was not attained. Percentage weight loss after surgery was also predictive of remission and of less satisfactory outcomes.

CONCLUSIONS

The glycemic response to gastric bypass is related to BMI, duration of diabetes, fasting C-peptide (influenced by insulin resistance and residual β-cell function), and weight loss. These data support and refine previous findings in non-Asian populations. Specific ethnic and procedural regression equations and cutoff points may vary.Surgery is the most effective treatment for clinically severe obesity. Although most patients display a dramatic improvement in type 2 diabetes, not every patient has remission of diabetes after surgery, with some not seeing substantial improvement and many having recurrence at a later date, sometimes in association with weight regain (1–5). Bariatric surgery, now often referred to as “metabolic surgery,” has been recommended as an effective treatment option for type 2 diabetes for those obese patients who do not have satisfactory control with lifestyle change (1). Optimal outcomes of surgical treatment of diabetes will be obtained if the patients best suited to the surgery are selected, but a clinically relevant grading system to categorize and predict outcomes of metabolic surgery is lacking (1). To develop such a grading system, the responses of patients to metabolic surgery need to be carefully observed, and the characteristics of responders that may have predicted their successful outcomes must be identified. Perhaps even more important is the identification of a group that does not respond well to metabolic surgery, so that such patients are not exposed to the unnecessary risk of surgery without expectation of clear benefit.Many preoperative patient factors have been associated with outcomes, including age, diabetes duration, glycemic control (HbA_1c), fasting C-peptide concentration, BMI, ethnicity, and medications used to manage blood glucose, including oral hypoglycemic agents and insulin (6–10). There are a number of weaknesses in many of these studies, and these include insufficient numbers to identify all independent clinically relevant factors, dealing in a univariate manner with a number of factors that are clearly related to one another, use of varying criteria for remission, and failure to record potentially important clinical predictors.The primary aim of this study was to seek, in a clinically meaningful way, the preoperative predictors of diabetes remission (HbA_1c ≤6.0%) at 12 months after gastric bypass surgery in a cohort of ethnic Chinese patients with type 2 diabetes who reside in Taiwan. Secondary aims included the identification of preoperative predictors of HbA_1c ≤7.0% at 12 months, a comparison of the effectiveness of mini gastric bypass (MGB) and Roux-en-Y gastric bypass (RYGB) for weight loss and glycemic control, and examination of the relevance of weight loss after gastric bypass as a predictor of diabetes remission.     

Visit-to-Visit Blood Pressure Variability Is a Novel Risk Factor for the Development and Progression of Diabetic Nephropathy in Patients With Type 2 Diabetes

OBJECTIVE

Recent study has suggested that not only the presence of hypertension but also the variability in systolic blood pressure (SBP) are risk factors for vascular disease and organ damage. The aim of this study was to investigate the relationship between visit-to-visit variability in SBP and change in urinary albumin excretion (UAE) or development of albuminuria in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS

We measured SBP in 354 consecutive patients at every visit during 1 year and calculated the coefficient of variation (CV) of SBP. We performed a follow-up study to assess change in UAE or development of albuminuria, the mean interval of which was 3.76 ± 0.71 years. Then, we evaluated relationships of variability of SBP to diabetic nephropathy using multiple regression analysis and multiple Cox regression model.

RESULTS

Multiple regression analysis demonstrated that CV of SBP was independently associated with change in UAE (β = 0.1758; P = 0.0108). Adjusted Cox regression analyses demonstrated that CV of SBP was associated with an increased hazard of development of albuminuria; hazard ratio was 1.143 (95% CI 1.008–1.302).

CONCLUSIONS

Visit-to-visit variability in SBP could be a novel risk factor for the development and progression of diabetic nephropathy in patients with type 2 diabetes.Cardiovascular disease (CVD) is the primary cause of mortality and morbidity in patients with type 2 diabetes, and several risk factors including smoking, hypertension, and dyslipidemia have been shown to accelerate the progression of CVD (1,2). Elevated albumin excretion rate, which is a useful marker for diabetic nephropathy, has been reported to be associated with increased risk of cardiovascular mortality and the progression of CVD (3,4). The presence of hypertension and the variability in blood pressure are strong predictors of all mortality (5), CVD (6–8), and organ damage such as chronic kidney disease (9). However, there is a recent study that does not favor a prognostic role of variability in blood pressure. Mancia et al. (10) reported that in patients with mild-to-moderate hypertension, carotid intima-media thickness and cardiovascular outcomes were not related to on-treatment visit-to-visit clinic or 24-h blood pressure variability. A recent study suggested that visit-to-visit variability in blood pressure was associated with the development of diabetic nephropathy in patients with type 1 diabetes (9). Also, we recently reported that visit-to-visit variability in systolic blood pressure (SBP) is correlated with albuminuria in a cross-sectional study (11). However, a relationship between visit-to-visit variability in blood pressure and the progression or development of diabetic nephropathy in patients with type 2 diabetes has not been investigated. Therefore, we evaluated the relationship between visit-to-visit variability in SBP and change in the urinary albumin excretion (UAE) or the development of albuminuria in patients with type 2 diabetes.     

Short Sleep Duration Measured by Wrist Actimetry Is Associated With Deteriorated Glycemic Control in Type 1 Diabetes

OBJECTIVE

Sleep restriction has been associated with deteriorated insulin sensitivity. The effects of short sleep duration have been explored little in patients with type 1 diabetes. This study addresses the question of whether sleep curtailment affects HbA_1c levels in patients with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Seventy-nine adult patients with type 1 diabetes (median age 40 years [IQR 23–49]; 47% men) were recruited to wear a wrist actimetry sensor during 3 consecutive days to assess mean sleep duration during normal daily life. A subsample of 37 patients also performed 24-h ambulatory blood pressure monitoring (ABPM). Medical history, sleep questionnaires, and diabetes-related quality of life (DQOL) were assessed.

RESULTS

Patients having shorter sleep duration—less than 6.5 h (n = 21)—had higher levels of HbA_1c (P = 0.01) than patients with longer sleep duration, above 6.5 h (n = 58). In a multivariable regression model including shorter versus longer sleep duration, diabetes duration, DQOL score, and daily activity, sleep duration was the only variable independently associated with HbA_1c (R² = 10%). In patients who performed 24-h ABPM, patients with a nondipping pattern of blood pressure exhibited shorter sleep duration than patients with a dipping pattern of blood pressure.

CONCLUSIONS

Shorter sleep duration is associated with higher HbA_1c levels in patients with type 1 diabetes, as well as with a nondipping pattern of blood pressure, anticipating a long-term deleterious impact on the risk of microvascular complications. Further studies should test whether extending the duration of sleep may improve both HbA_1c and blood pressure in type 1 diabetes.Voluntary sleep curtailment is spreading among our societies, particularly in children and adolescents (1). Such chronic sleep deprivation is also frequent among patients suffering from type 1 diabetes as well as their families (2). Several prospective cohorts in the general population demonstrate a link between short sleep duration and incident obesity (3), type 2 diabetes (4–6), and hypertension (7,8). The main weakness of these studies, which were conducted with large samples, is that sleep duration was not objectively assessed but only estimated subjectively by sleep questionnaires. Mechanisms underlying such associations seem to involve down-regulation of the satiety hormone leptin and up-regulation of the appetite-stimulating hormone ghrelin, increasing hunger and food intake (9). Sleep restriction has been associated with deterioration of insulin sensitivity (10).The effects of short sleep duration have been poorly explored in patients with type 1 diabetes. Short sleep duration has been associated with a nondipping pattern of blood pressure in patients with type 1 diabetes (11), which means that nocturnal blood pressure did not demonstrate the normal 10% decrease compared with daytime values. No study has yet addressed the question of the potential deleterious effect of sleep curtailment on HbA_1c in type 1 diabetes. Priou et al. (12) recently have shown that sleep apnea syndrome (obstructive sleep apnea [OSA]) was associated with increased levels of HbA_1c in subjects with OSA but without any diabetes, suggesting that sleep respiratory disorders could alter plasma glucose levels; however, this work did not evaluate the potential association of total sleep time with HbA_1c.Strict control of HbA_1c and blood pressure levels, including the normal dip of nocturnal blood pressure, have been clearly associated with lower incidence of microvascular complications in type 1 diabetes (13–15). Thus, this study looked for the effects of sleep duration on glycemic control and nocturnal blood pressure patterns in patients with type 1 diabetes.