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OBJECTIVE Severity of obstructive sleep apnea (OSA) has been associated with poorer glycemic control in type 2 diabetes. It is not known whether obstructive events during rapid eye movement (REM) sleep have a different metabolic impact compared with those during non-REM (NREM) sleep. Treatment of OSA is often limited to the first half of the night, when NREM rather than REM sleep predominates. We aimed to quantify the impact of OSA in REM versus NREM sleep on hemoglobin A1c (HbA1c) in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS All participants underwent polysomnography, and glycemic control was assessed by HbA1c. RESULTS Our analytic cohort included 115 subjects (65 women; age 55.2 ± 9.8 years; BMI 34.5 ± 7.5 kg/m2). In a multivariate linear regression model, REM apnea–hypopnea index (AHI) was independently associated with increasing levels of HbA1c (P = 0.008). In contrast, NREM AHI was not associated with HbA1c (P = 0.762). The mean adjusted HbA1c increased from 6.3% in subjects in the lowest quartile of REM AHI to 7.3% in subjects in the highest quartile of REM AHI (P = 0.044 for linear trend). Our model predicts that 4 h of continuous positive airway pressure (CPAP) use would leave 60% of REM sleep untreated and would be associated with a decrease in HbA1c by approximately 0.25%. In contrast, 7 h of CPAP use would cover more than 85% of REM sleep and would be associated with a decrease in HbA1c by as much as 1%. CONCLUSIONS In type 2 diabetes, OSA during REM sleep may influence long-term glycemic control. The metabolic benefits of CPAP therapy may not be achieved with the typical adherence of 4 h per night.

OBJECTIVE Sexual dysfunction is a prevalent problem in obese women with type 2 diabetes. This study examined the effects of intensive lifestyle intervention (ILI) in these women. RESEARCH DESIGN AND METHODS Look AHEAD is a 16-center, randomized, controlled trial evaluating the health effects of ILI compared with a control group (diabetes support and education [DSE]). The Look AHEAD Sexual Function Ancillary study included 375 female participants at five Look AHEAD sites. Participants completed the Female Sexual Function Inventory (FSFI) and Beck Depression Inventory (BDI), and assessments of weight and cardiovascular risk factors at baseline and 1 year were made. RESULTS At baseline, 50% of the 229 participants who reported being sexually active met criteria for female sexual dysfunction (FSD); only BDI score was related to FSD. One-year weight losses were greater in the ILI group than in the DSE group (7.6 vs. 0.45 kg; P < 0.001). Among women with FSD at baseline, those in the ILI group (N = 60) compared with those in the DSE group (N = 53) were significantly more likely to remain sexually active (83 vs. 64%; P < 0.008), reported greater improvement in total FSFI scores and in most FSFI domains (P < 0.05), and were more likely to experience remission of FSD (28 vs. 11%; P < 0.04) at 1 year. No significant differences between ILI and DSE were seen in women who did not have FSD at baseline. CONCLUSIONS Participation in ILI appeared to have beneficial effects on sexual functioning among obese women with diabetes, particularly in those who had FSD at baseline.

OBJECTIVE To assess the success and baseline predictors of maintaining glycemic control for up to 5 years of therapy using basal insulin glargine or standard glycemic care in people with dysglycemia treated with zero or one oral glucose-lowering agents. RESEARCH DESIGN AND METHODS Data from 12,537 participants in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial were examined by baseline glycemic status (with or without type 2 diabetes) and by therapeutic approach (titrated insulin glargine or standard therapy) using an intention-to-treat analysis. Median values for fasting plasma glucose (FPG) and A1C and percentages with A1C RESULTS Median A1C in the whole population was 6.4% at baseline; at 5 years, it was 6.2% with glargine treatment and 6.5% with standard care. Of those with diabetes at baseline, 60% using glargine and 45% using standard care had A1C CONCLUSIONS Systematic intervention with basal insulin glargine or standard care early in the natural history of dysglycemia can maintain glycemic control near baseline levels for at least 5 years, whether diabetes is present at baseline or not. Keeping mean A1C

OBJECTIVE The current study aimed to determine in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications cohort whether or not abnormal levels of markers of inflammation and endothelial dysfunction measured in samples collected at DCCT baseline were able to predict the development of macroalbuminuria. RESEARCH DESIGN AND METHODS Levels of inflammation and endothelial cell dysfunction biomarkers were measured in 1,237 of 1,441 patients enrolled in the DCCT study who were both free of albuminuria and cardiovascular disease at baseline. To test the association of log-transformed biomarkers with albuminuria, generalized logistic regression models were used to quantify the association of increased levels of biomarkers and development of abnormal albuminuria. Normal, micro-, and macroalbuminuria were the outcomes of interest. RESULTS In the logistic regression models adjusted by DCCT treatment assignment, baseline albumin excretion rate, and use of ACE/angiotensin receptor blocker drugs, one unit increase in the standardized levels of soluble E-selectin (sE-selectin) was associated with an 87% increase in the odds to develop macroalbuminuria and one unit increase in the levels of interleukin-6 (IL-6), plasminogen activator inhibitor 1 (PAI-1; total and active), and soluble tumor necrosis factor receptors (TNFR)-1 and -2 lead to a 30–50% increase in the odds to develop macroalbuminuria. Following adjustment for DCCT baseline retinopathy status, age, sex, HbA1c, and duration of diabetes, significant associations remained for sE-selectin and TNFR-1 and -2 but not for IL-6 or PAI-1. CONCLUSIONS Our study indicates that high levels of inflammatory markers, mainly E-selectin and sTNRF-1 and -2, are important predictors of macroalbuminuria in patients with type 1 diabetes.

OBJECTIVE The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) trial demonstrated that combination therapy with metformin plus rosiglitazone provided superior durability of glycemic control compared with metformin alone, with significantly lower treatment failure rates (38.6 vs. 51.7%), and metformin plus lifestyle was intermediate. Herein we describe the temporal changes in measures of β-cell function and insulin sensitivity over a 4-year period among the three treatments. RESEARCH DESIGN AND METHODS TODAY participants (699) were tested periodically with an oral glucose tolerance test to determine insulin sensitivity (1/fasting insulin [1/IF]), insulinogenic index (△I30/△G30) or C-peptide index (△C30/△G30), and β-cell function relative to insulin sensitivity (oral disposition index [oDI]). RESULTS During the first 6 months, metformin plus rosiglitazone exhibited a significantly greater improvement in insulin sensitivity and oDI versus metformin alone and versus metformin plus lifestyle; these improvements were sustained over 48 months of TODAY. Irrespective of treatment, those who failed to maintain glycemic control had significantly lower β-cell function (∼50%), higher fasting glucose concentration, and higher HbA1c at randomization compared with those who did not fail. CONCLUSIONS The beneficial change in insulin sensitivity and the resultant lower burden on β-cell function achieved in the first 6 months with metformin plus rosiglitazone appear to be responsible for its superior glycemic durability over metformin alone and metformin plus lifestyle. However, initial β-cell reserve and HbA1c at randomization are independent predictors of glycemic durability. Therefore, efforts to preserve β-cell function before significant loss occurs and to reduce HbA1c may be beneficial in the treatment of youth with type 2 diabetes.

In June 2012, 13 thought leaders convened in a Diabetes Care Editors’ Expert Forum to discuss the concept of personalized medicine in the wake of a recently published American Diabetes Association/European Association for the Study of Diabetes position statement calling for a patient-centered approach to hyperglycemia management in type 2 diabetes. This article, an outgrowth of that forum, offers a clinical translation of the underlying issues that need to be considered for effectively personalizing diabetes care. The medical management of type 2 diabetes has become increasingly complex, and its complications remain a great burden to individual patients and the larger society. The burgeoning armamentarium of pharmacological agents for hyperglycemia management should aid clinicians in providing early treatment to delay or prevent these complications. However, trial evidence is limited for the optimal use of these agents, especially in dual or triple combinations. In the distant future, genotyping and testing for metabolomic markers may help us to better phenotype patients and predict their responses to antihyperglycemic drugs. For now, a personalized (“n of 1”) approach in which drugs are tested in a trial-and-error manner in each patient may be the most practical strategy for achieving therapeutic targets. Patient-centered care and standardized algorithmic management are conflicting approaches, but they can be made more compatible by recognizing instances in which personalized A1C targets are warranted and clinical circumstances that may call for comanagement by primary care and specialty clinicians.

Because the negative consequences of new-onset diabetes mellitus after transplantation (NODAT) diminish the significant gains of kidney transplantation, it is imperative to develop clinical interventions to reduce the incidence of NODAT. In this review, we discuss whether intensive lifestyle interventions that delay or prevent type 2 diabetes mellitus may decrease the incidence of NODAT. We examine the literature pertaining to incidence and timing of onset of NODAT, as well as the risk factors and pathophysiology that NODAT shares with type 2 diabetes mellitus, namely pathways related to increased insulin resistance and decreased insulin secretion. Our central hypothesis is that NODAT results from the same metabolic risk factors that underlie type 2 diabetes mellitus. These risk factors are altered and enhanced by transplantation, “tipping” some transplant recipients with seemingly normal glucose homeostasis before transplant toward the development of NODAT. We describe the diabetogenic properties of transplant immunosuppressive drugs. We describe novel methods of prevention that are being explored, including resting the pancreatic β-cells by administration of basal insulin during the period immediately after transplant. On the basis of the current evidence, we propose that intensive lifestyle modification, adapted for individuals with chronic kidney disease or end-stage renal disease, as well as resting pancreatic β-cells during the immediate postoperative period, may lower the incidence of NODAT.

OBJECTIVE Depression is associated with the onset of type 2 diabetes. A systematic review and meta-analysis of observational studies, controlled trials, and unpublished data was conducted to examine the association between depression and insulin resistance (IR). RESEARCH DESIGN AND METHODS Medline, EMBASE, and PsycINFO were searched for studies published up to September 2011. Two independent reviewers assessed the eligibility of each report based on predefined inclusion criteria (study design and measure of depression and IR, excluding prevalent cases of diabetes). Individual effect sizes were standardized, and a meta-analysis was performed to calculate a pooled effect size using random effects. Subgroup analyses and meta-regression were conducted to explore any potential source of heterogeneity between studies. RESULTS Of 967 abstracts reviewed, 21 studies met the inclusion criteria of which 18 studies had appropriate data for the meta-analysis (n = 25,847). The pooled effect size (95% CI) was 0.19 (0.11–0.27) with marked heterogeneity (I2 = 82.2%) using the random-effects model. Heterogeneity between studies was not explained by age or sex, but could be partly explained by the methods of depression and IR assessments. CONCLUSIONS A small but significant cross-sectional association was observed between depression and IR, despite heterogeneity between studies. The pathophysiology mechanisms and direction of this association need further study using a purposively designed prospective or intervention study in samples at high risk for diabetes.

OBJECTIVE Adverse effects of hypercaloric, high-fructose diets on insulin sensitivity and lipids in human subjects have been shown repeatedly. The implications of fructose in amounts close to usual daily consumption, however, have not been well studied. This study assessed the effect of moderate amounts of fructose and sucrose compared with glucose on glucose and lipid metabolism. RESEARCH DESIGN AND METHODS Nine healthy, normal-weight male volunteers (aged 21–25 years) were studied in this double-blind, randomized, cross-over trial. All subjects consumed four different sweetened beverages (600 mL/day) for 3 weeks each: medium fructose (MF) at 40 g/day, and high fructose (HF), high glucose (HG), and high sucrose (HS) each at 80 g/day. Euglycemic-hyperinsulinemic clamps with [6,6]-2H2 glucose labeling were used to measure endogenous glucose production. Lipid profile, glucose, and insulin were measured in fasting samples. RESULTS Hepatic suppression of glucose production during the clamp was significantly lower after HF (59.4 ± 11.0%) than HG (70.3 ± 10.5%, P < 0.05), whereas fasting glucose, insulin, and C-peptide did not differ between the interventions. Compared with HG, LDL cholesterol and total cholesterol were significantly higher after MF, HF, and HS, and free fatty acids were significantly increased after MF, but not after the two other interventions (P < 0.05). Subjects’ energy intake during the interventions did not differ significantly from baseline intake. CONCLUSIONS This study clearly shows that moderate amounts of fructose and sucrose significantly alter hepatic insulin sensitivity and lipid metabolism compared with similar amounts of glucose.

OBJECTIVE To assess the association between serum adiponectin level and all-cause mortality in people with type 2 diabetes. Because of the insulin-sensitizing, anti-inflammatory, and antiatherogenic effects of adiponectin, we hypothesized that higher adiponectin level would be associated with lower all-cause mortality. RESEARCH DESIGN AND METHODS A total of 609 men and women aged 72 ± 6.3 years with type 2 diabetes and information on total and high molecular weight adiponectin were followed for a median of 5 years. The longitudinal association between adiponectin and all-cause mortality was analyzed with Cox proportional hazards models with time from adiponectin measurement to death as the time-to-event variable. Analyses were adjusted for demographic variables and significant diabetes parameters, significant cardiovascular parameters, and significant diabetes medications. RESULTS Total and high molecular weight adiponectin were highly correlated. The highest adiponectin quartile was strongly associated with higher all-cause mortality compared with the lowest quartile (hazard ratio = 4.0 [95% CI: 1.7–9.2]) in the fully adjusted model. These results did not change in analyses stratified by sex and thiazolidinedione use, after exclusion of people who died within one year of adiponectin measurement, or when change in weight before adiponectin measurement was considered. CONCLUSIONS Contrary to our hypothesis, higher adiponectin level was related to higher all-cause mortality. This association was not explained by confounding by other characteristics, including medications or preceding weight loss.

OBJECTIVE Chronic infections could be contributing to the socioeconomic gradient in chronic diseases. Although chronic infections have been associated with increased levels of inflammatory cytokines and cardiovascular disease, there is limited evidence on how infections affect risk of diabetes. RESEARCH DESIGN AND METHODS We examined the association between serological evidence of chronic viral and bacterial infections and incident diabetes in a prospective cohort of Latino elderly. We analyzed data on 782 individuals aged >60 years and diabetes-free in 1998–1999, whose blood was tested for antibodies to herpes simplex virus 1, varicella virus, cytomegalovirus, Helicobacter pylori, and Toxoplasma gondii and who were followed until June 2008. We used Cox proportional hazards regression to estimate the relative incidence rate of diabetes by serostatus, with adjustment for age, sex, education, cardiovascular disease, smoking, and cholesterol levels. RESULTS Individuals seropositive for herpes simplex virus 1, varicella virus, cytomegalovirus, and T. gondii did not show an increased rate of diabetes, whereas those who were seropositive for H. pylori at enrollment were 2.7 times more likely at any given time to develop diabetes than seronegative individuals (hazard ratio 2.69 [95% CI 1.10–6.60]). Controlling for insulin resistance, C-reactive protein and interleukin-6 did not attenuate the effect of H. pylori infection. CONCLUSIONS We demonstrated for the first time that H. pylori infection leads to an increased rate of incident diabetes in a prospective cohort study. Our findings implicate a potential role for antibiotic and gastrointestinal treatment in preventing diabetes.

OBJECTIVE To evaluate the changes in circulating endotoxin after a high–saturated fat meal to determine whether these effects depend on metabolic disease state. RESEARCH DESIGN AND METHODS Subjects (n = 54) were given a high-fat meal (75 g fat, 5 g carbohydrate, 6 g protein) after an overnight fast (nonobese control [NOC]: age 39.9 ± 11.8 years [mean ± SD], BMI 24.9 ± 3.2 kg/m2, n = 9; obese: age 43.8 ± 9.5 years, BMI 33.3 ± 2.5 kg/m2, n = 15; impaired glucose tolerance [IGT]: age 41.7 ± 11.3 years, BMI 32.0 ± 4.5 kg/m2, n = 12; type 2 diabetic: age 45.4 ± 10.1 years, BMI 30.3 ± 4.5 kg/m2, n = 18). Blood was collected before (0 h) and after the meal (1–4 h) for analysis. RESULTS Baseline endotoxin was significantly higher in the type 2 diabetic and IGT subjects than in NOC subjects, with baseline circulating endotoxin levels 60.6% higher in type 2 diabetic subjects than in NOC subjects (P < 0.05). Ingestion of a high-fat meal led to a significant rise in endotoxin levels in type 2 diabetic, IGT, and obese subjects over the 4-h time period (P < 0.05). These findings also showed that, at 4 h after a meal, type 2 diabetic subjects had higher circulating endotoxin levels (125.4%↑) than NOC subjects (P < 0.05). CONCLUSIONS These studies have highlighted that exposure to a high-fat meal elevates circulating endotoxin irrespective of metabolic state, as early as 1 h after a meal. However, this increase is substantial in IGT and type 2 diabetic subjects, suggesting that metabolic endotoxinemia is exacerbated after high fat intake. In conclusion, our data suggest that, in a compromised metabolic state such as type 2 diabetes, a continual snacking routine will cumulatively promote their condition more rapidly than in other individuals because of the greater exposure to endotoxin.

OBJECTIVE Individuals at high risk for chronic cardiometabolic disease (cardiovascular disease [CVD], type 2 diabetes, and chronic kidney disease [CKD]) share many risk factors and would benefit from early intervention. We developed a nonlaboratory-based risk-assessment tool for identification of people at high cardiometabolic disease risk. RESEARCH DESIGN AND METHODS Data of three population-based cohorts from different regions of the Netherlands were merged. Participants were 2,840 men and 3,940 women, white, aged 28–85 years, free from CVD, type 2 diabetes, and CKD diagnosis at baseline. The outcome was developing cardiometabolic disease during 7 years follow-up. RESULTS Age, BMI, waist circumference, antihypertensive treatment, smoking, family history of myocardial infarction or stroke, and family history of diabetes were significant predictors, whereas former smoking, history of gestational diabetes, and use of lipid-lowering medication were not. The models showed acceptable calibration (Hosmer and Lemeshow statistics, P > 0.05) and discrimination (area under the receiver operating characteristic [ROC] curve 0.82 [95% CI 0.81–0.83] for women and 0.80 [0.78–0.82] for men). Discrimination of individual outcomes was lowest for diabetes (area under the ROC curve 0.70 for men and 0.73 for women) and highest for CVD mortality (0.83 for men and 0.85 for women). CONCLUSIONS We demonstrate that a single risk stratification tool can identify people at high risk for future CVD, type 2 diabetes, and/or CKD. The present risk-assessment tool can be used for referring the highest risk individuals to health care for further (multivariable) risk assessment and may as such serve as an important part of prevention programs targeting chronic cardiometabolic disease.

OBJECTIVE In women with gestational diabetes mellitus, who were randomized to metformin or insulin treatment, pregnancy outcomes were similar (Metformin in Gestational diabetes [MiG] trial). Metformin crosses the placenta, so it is important to assess potential effects on growth of the children. RESEARCH DESIGN AND METHODS In Auckland, New Zealand, and Adelaide, Australia, women who had participated in the MiG trial were reviewed when their children were 2 years old. Body composition was measured in 154 and 164 children whose mothers had been randomized to metformin and insulin, respectively. Children were assessed with anthropometry, bioimpedance, and dual energy X-ray absorptiometry (DEXA), using standard methods. RESULTS The children were similar for baseline maternal characteristics and pregnancy outcomes. In the metformin group, compared with the insulin group, children had larger mid-upper arm circumferences (17.2 ± 1.5 vs. 16.7 ± 1.5 cm; P = 0.002) and subscapular (6.3 ± 1.9 vs. 6.0 ± 1.7 mm; P = 0.02) and biceps skinfolds (6.03 ± 1.9 vs. 5.6 ± 1.7 mm; P = 0.04). Total fat mass and percentage body fat assessed by bioimpedance (n = 221) and DEXA (n = 114) were not different. CONCLUSIONS Children exposed to metformin had larger measures of subcutaneous fat, but overall body fat was the same as in children whose mothers were treated with insulin alone. Further follow-up is required to examine whether these findings persist into later life and whether children exposed to metformin will develop less visceral fat and be more insulin sensitive. If so, this would have significant implications for the current pandemic of diabetes.

OBJECTIVE To determine, in a small but carefully physiologically characterized cohort of subjects with uncomplicated type 1 diabetes, the changes in renal hemodynamic function and arterial stiffness that occur over time as the participants transitioned from adolescence into early adulthood. The classical paradigm for type 1 diabetes suggests that glomerular filtration rate (GFR) declines in patients with renal hyperfiltration, but the natural history of peripheral vascular function abnormalities in uncomplicated type 1 diabetes is less well understood, particularly as patients transition from adolescence to early adulthood. RESEARCH DESIGN AND METHODS Renal hemodynamic function (inulin and p-aminohippuric acid clearance), blood pressure, arterial stiffness (radial augmentation index), albumin excretion, and circulating renin-angiotensin system measures were obtained during clamped euglycemia at baseline and at follow-up 6.8 ± 2.5 years later in 10 patients with hyperfiltration (GFR ≥135 mL/min/1.73 m2) and in 8 with normofiltration. RESULTS Compared with baseline values, GFR (171 ± 20 to 120 ± 15 mL/min/1.73 m2) and filtration fraction (FF, 0.24 ± 0.06 to 0.18 ± 0.03) declined in hyperfilterers (ANOVA P ≤ 0.033), and renal vascular resistance increased (0.0678 ± 0.0135 to 0.0783 ± 0.0121 mmHg/L/min, P = 0.017). GFR and FF did not change in normofiltering subjects. In contrast, the radial augmentation index decreased in hyperfiltering (1.2 ± 11.7 to −11.0 ± 7.8%) and normofiltering (14.3 ± 14.0 to 2.5 ± 14.6%) subjects (within-group changes, ANOVA P ≤ 0.030). The decline in circulating aldosterone levels was similar in both groups. CONCLUSIONS During the transition from adolescence to early adulthood, hyperfiltration is not sustained in subjects with type 1 diabetes, whereas GFR remains stable in normofiltering subjects. Our findings suggest early normofiltration may predict stable renal function. In contrast, arterial stiffness decreased in all patients regardless of filtration status, suggesting that age-related increases in arterial stiffness occur at older ages.

OBJECTIVE Some preclinical in vivo studies and limited human data suggest a possible increased risk of bladder cancer with pioglitazone therapy. This is an interim report of an ongoing cohort study examining the association between pioglitazone therapy and the risk of bladder cancer in patients with diabetes. RESEARCH DESIGN AND METHODS This study includes 193,099 patients in the Kaiser Permanente Northern California diabetes registry who were ≥40 years of age between 1997 and 2002. Those with prior bladder cancer were excluded. Ever use of each diabetes medication (defined as two or more prescriptions within 6 months) was treated as a time-dependent variable. Cox regression–generated hazard ratios (HRs) compared pioglitazone use with nonpioglitazone use adjusted for age, sex, race/ethnicity, diabetes medications, A1C, heart failure, household income, renal function, other bladder conditions, and smoking. RESULTS The group treated with pioglitazone comprised 30,173 patients. There were 90 cases of bladder cancer among pioglitazone users and 791 cases of bladder cancer among nonpioglitazone users. Overall, ever use of pioglitazone was not associated with risk of bladder cancer (HR 1.2 [95% CI 0.9–1.5]), with similar results in men and women (test for interaction P = 0.8). However, in the a priori category of >24 months of therapy, there was an increased risk (1.4 [1.03–2.0]). Ninety-five percent of cancers diagnosed among pioglitazone users were detected at early stage. CONCLUSIONS In this cohort of patients with diabetes, short-term use of pioglitazone was not associated with an increased incidence of bladder cancer, but use for more than 2 years was weakly associated with increased risk.

OBJECTIVE Many guidelines recommend that patients with type 2 diabetes should aim to reduce their intake of salt. However, the precise relationship between dietary salt intake and mortality in patients with type 2 diabetes has not been previously explored. RESEARCH DESIGN AND METHODS Six hundred and thirty-eight patients attending a single diabetes clinic were followed in a prospective cohort study. Baseline sodium excretion was estimated from 24-h urinary collections (24hUNa). The predictors of all-cause and cardiovascular mortality were determined by Cox regression and competing risk modeling, respectively. RESULTS The mean baseline 24hUNa was 184 ± 73 mmol/24 h, which remained consistent throughout the follow-up (intraindividual coefficient of variation [CV] 23 ± 11%). Over a median of 9.9 years, there were 175 deaths, 75 (43%) of which were secondary to cardiovascular events. All-cause mortality was inversely associated with 24hUNa, after adjusting for other baseline risk factors (P < 0.001). For every 100 mmol rise in 24hUNa, all-cause mortality was 28% lower (95% CI 6–45%, P = 0.02). After adjusting for the competing risk of noncardiovascular death and other predictors, 24hUNa was also significantly associated with cardiovascular mortality (sub-hazard ratio 0.65 [95% CI 0.44–0.95]; P = 0.03). CONCLUSIONS In patients with type 2 diabetes, lower 24-h urinary sodium excretion was paradoxically associated with increased all-cause and cardiovascular mortality. Interventional studies are necessary to determine if dietary salt has a causative role in determining adverse outcomes in patients with type 2 diabetes and the appropriateness of guidelines advocating salt restriction in this setting.

OBJECTIVE To assess the effect of three premeal timings of rapid-acting insulin on postprandial glucose excursions in type 1 diabetes. RESEARCH DESIGN AND METHODS Ten subjects participated in a three-way randomized crossover trial. Mean ± SD age was 45.5 ± 12.1 years, A1C was 8.55 ± 1.50%, duration of diabetes was 23.8 ± 7.8 years, and duration of continuous subcutaneous insulin infusion therapy was 8.5 ± 6.1 years. Insulin aspart was administered at 30, 15, or 0 min before mealtime. RESULTS Area under the curve was lower in the −15 stratum (0.41 ± 0.51 mmol/l/min) than that in the −30 stratum (1.89 ± 0.72 mmol/l/min, P = 0.029) and 0 stratum (2.11 ± 0.66 mmol/l/min, P = 0.030). Maximum glucose excursion was lower in the −15 stratum (4.77 ± 0.52 mmol/l) than that in the −30 (6.48 ± 0.76 mmol/l, P = 0.025) and 0 stratum (6.93 ± 0.76 mmol/l, P = 0.022). Peak glucose level was lower in the −15 stratum (9.26 ± 0.72 mmol/l) than that in the −30 stratum (11.74 ± 0.80 mmol/l, P = 0.007) and the 0 stratum (12.29 ± 0.93, P = 0.009). Time spent in the 3.5–10 mmol/l range was higher in the −15 stratum (224.5 ± 25.0 min) than that in the 0 stratum (90.5 ± 23.2 min, P = 0.001). There was no significant difference in occurrence of glucose levels CONCLUSIONS Administration of rapid-acting insulin analogs 15 min before mealtime results in lower postprandial glucose excursions and more time spent in the 3.5–10.0 mmol/l range, without increased risk of hypoglycemia.

The use of A1C for the identification of persons with undiagnosed diabetes has been investigated for a number of years (1–3). A1C better reflects long-term glycemic exposure than current diagnostic tests based on point-in-time measures of fasting and postload blood glucose (4,5) and has improved test-retest reliability (6). In addition, A1C includes no requirement for fasting or for the oral glucose tolerance test's 2-h wait. These advantages should lead to increased identification and more timely treatment of persons with diabetes. Recently, an American Diabetes Association (ADA)-organized international expert committee recommended the adoption of the A1C assay for the diagnosis of diabetes at a cut point of 6.5% (7). This cut point was primarily derived from a review of studies that examined the association of A1C values with incident retinopathy, and some of the most influential data were obtained from recently published prospective studies. Retinopathy was chosen as the ultimate criterion because it is among the main complications of diabetes. Identification of the point on the A1C distribution most closely related to future retinopathy will identify persons in the greatest need of interventions for the prevention of diabetes complications. In addition to utility and convenience, A1C could help identify persons at increased risk of developing diabetes. This is an important public health priority since a structured lifestyle program or the drug metformin can reduce the incidence of diabetes by at least 50 and 30%, respectively (8). Ideally, selection of diagnostic cut points for pre-diabetes would be based on evidence that intervention, when applied to the high-risk group of interest, results not only in the prevention of diabetes but also later complications. However, currently there are no trials that can provide data to determine the ideal method for defining cut points. In the absence of such data, expert committees had to rely on information about the shape of risk curves for complications such as retinopathy. Previous expert committees assembled to address this issue have noted that there is no clear difference in retinopathy risk between different levels of impaired glucose tolerance (7). We are unaware of published prospective studies of adequate sample size or duration that have followed people in various pre-diabetic categories across the full span of time until complications developed. In the absence of informative trials (as well as prospective studies), the studies that measure A1C at baseline and incident diabetes may provide the definitions of high-risk states. To better define A1C ranges that might identify persons who would benefit from interventions to prevent or delay type 2 diabetes, we carried out a systematic review of published prospective studies that have examined the relationship of A1C to future diabetes incidence.

OBJECTIVE This study aims to describe body composition in term infants of mothers with gestational diabetes mellitus (GDM) compared with infants of mothers with normal glucose tolerance (NGT). RESEARCH DESIGN AND METHODS This cross-sectional study included 599 term babies born at Royal Prince Alfred Hospital, Sydney, Australia. Neonatal body fat percentage (BF%) was measured within 48 h of birth using air-displacement plethysmography. Glycemic control data were based on third-trimester HbA1c levels and self-monitoring blood glucose levels. Associations between GDM status and BF% were investigated using linear regression adjusted for relevant maternal and neonatal variables. RESULTS Of 599 babies, 67 (11%) were born to mothers with GDM. Mean ± SD neonatal BF% was 7.9 ± 4.5% in infants with GDM and 9.3 ± 4.3% in infants with NGT, and this difference was not statistically significant after adjustment. Good glycemic control was achieved in 90% of mothers with GDM. CONCLUSIONS In this study, neonatal BF% did not differ by maternal GDM status, and this may be attributed to good maternal glycemic control.

OBJECTIVE This study investigated the association between arterial stiffness and plasma adiponectin in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS Participants were normotensive patients with type 1 diabetes who were up to age 40 years. Subjects on statins with macrovascular disease or overt nephropathy were excluded. Large artery stiffness was assessed by measurement of carotid-femoral pulse wave velocity (PWV), whereas plasma adiponectin was measured by radioimmunoassay. RESULTS Data from 80 patients (age 27.1 ± 6.1 years, BMI 24.2 ± 3.1 kg/m2, HbA1c 7.5 ± 1.6%, 39 men, adiponectin 13.9 ± 6.7 μg/mL, and PWV 5.6 ± 0.9 m/s) were analyzed. Log adiponectin inversely correlated with age-adjusted PWV (r = −0.291, P = 0.009) and waist circumference (r = −0.427, P < 0.001). In a fully adjusted model, age, expiration/inspiration index, and log adiponectin were independently associated with PWV, explaining 39.6% of its variance. CONCLUSIONS Arterial stiffness is inversely related to adiponectin concentration in young patients with type 1 diabetes without major complications.

With great interest, we read the excellent study by Laker et al. (1) in this issue of Diabetes . The authors showed that exercise in mice on a high-fat diet, corresponding to “an unhealthy maternal lifestyle” scenario, can counteract the negative effects of diet-induced obesity through a metabolic pathway in the offspring in mice. Specifically, Laker et al. provided evidence that voluntary wheel exercise spanning 6 weeks prior to and throughout pregnancy reduces DNA methylation of Pgc-1α in muscle but not …

We sought to establish β-cell mass, β-cell apoptosis, and β-cell replication in humans in response to obesity and advanced age.We examined human autopsy pancreas from 167 nondiabetic individuals 20-102 years of age. The effect of obesity on β-cell mass was examined in 53 lean and 61 obese subjects, and the effect of aging was examined in 106 lean subjects.β-Cell mass is increased by ~50% with obesity (from 0.8 to 1.2 g). With advanced aging, the exocrine pancreas undergoes atrophy but β-cell mass is remarkably preserved. There is minimal β-cell replication or apoptosis in lean humans throughout life with no detectable changes with obesity or advanced age.β-Cell mass in human obesity increases by ~50% by an increase in β-cell number, the source of which is unknown. β-Cell mass is well preserved in humans with advanced aging.

The comment letter by McElduff (1) acknowledges that our study (2) is an excellent example of the research needed to determine optimal glycemic targets for mothers with gestational diabetes mellitus (GDM). The primary objective of our study was to describe the body composition at birth of infants born to mothers with GDM compared with infants born to mothers with normal glucose tolerance using air-displacement plethysomography (2). Body composition at birth, measured accurately by air-displacement plethysomography, is a more sensitive marker of the intrauterine environment than weight alone, and includes estimates of fat mass and fat-free mass. To our knowledge, this is the first study to show that infant body composition …

The article by Zhu et al. published inDiabetes Care concludes that a fasting plasma glucose (FPG) at 24–28 weeks’ gestation can be used in low-resource regions as a screening test to identify gestational diabetes mellitus (GDM) in Chinese patients. However, in their experience, a screening protocol using FPG cutoff points of $4.4 and #5.0 mmol/L would fail to identify about 12% of the GDM cases and require a formal oral glucose tolerance test (OGTT) to be performed in about half of the pregnant population. These observations contrast with our findings in a circum-Mediterranean population., peer-reviewed

We thank Trento et al. (1) for their interest in our recent article on the benefit of diabetes behavioral interventions for improving A1C in long-duration, poorly controlled older diabetic patients. Our article describes a secondary analysis of data from a three-arm, parallel-designed randomized controlled trial that tested the efficacy of a highly structured behavioral diabetes intervention via comparisons with standard group education and individual education (2). Thus, the original aim of the study was not to assess age differences in group versus individual education. Also, the study did not recruit adults aged 76 years and above, so the findings may not be representative for adults aged 76 years and …

Bardenheier et al. (1) presented data on prevalence of gestational diabetes mellitus (GDM) associated with delivery as a function of state and race. They identified a number of important risk factors including race, maternal age, state, insurance, and obesity. Overlooked in the article was any discussion of the role of vitamin D. Vitamin D deficiency is an important risk factor for GDM. A review found that “serum 25-hydroxyvitamin D (25OHD)

We thank Dr. Grant (1) for his interest in our study (2). Dr. Grant pointed out that our analysis overlooked any discussion of the role of vitamin D in the variability of gestational diabetes mellitus (GDM) prevalence across states. Although we might have speculated about a possible role for vitamin D in the regional variability of GDM prevalence, we chose not to for several reasons. First, state-level data available from the Healthcare Cost and Utilization Project (HCUP) are insufficient to fully assess potential sunlight exposure before or during pregnancy …

To evaluate whether LY2605541 results in lower fasting blood glucose (FBG) versus insulin glargine (GL).This 12-week, randomized, open-label, Phase 2 study enrolled patients with type 2 diabetes (hemoglobin A(1c) [A1C] ≤ 10.5%), taking metformin and/or sulfonylurea with GL or NPH insulin once daily. Patients converted to morning insulin administration during lead-in were randomized 2:1 from GL (n = 248) or NPH insulin (n = 39) to LY2605541 (n = 195) or GL (n = 95) once daily in the morning.At 12 weeks, FBG (mean ± SE) was similar with LY2605541 and GL (118.2 ± 2.0 mg/dL [6.6 ± 0.1 mmol/L] vs. 116.9 ± 2.7 mg/dL [6.5 ± 0.2 mmol/L], P = 0.433) as was A1C (7.0 ± 0.1 vs. 7.2 ± 0.1%, P = 0.279). Intraday blood glucose variability was reduced with LY2605541 (34.4 vs. 39.1 mg/dL [1.9 vs. 2.2 mmol/L], P = 0.031). LY2605541 patients had weight loss (-0.6 ± 0.2 kg, P = 0.007), whereas GL patients gained weight (0.3 ± 0.2 kg, P = 0.662; treatment difference: -0.8 kg, P = 0.001). The incidence and rate of both total hypoglycemia and nocturnal hypoglycemia were comparable between LY2605541 and GL, although, LY2605541 had a 48% reduction in nocturnal hypoglycemia after adjusting for baseline hypoglycemia (P = 0.021). Adverse events were similar across treatments. Alanine aminotransferase and aspartate aminotransferase remained within normal range but were significantly higher with LY2605541 (P ≤ 0.001).In patients with type 2 diabetes, LY2605541 and GL had comparable glucose control and total hypoglycemia rates, but LY2605541 showed reduced intraday variability, lower nocturnal hypoglycemia, and weight loss relative to GL.

OBJECTIVE Peripheral nerve imaging by portable ultrasound (US) may serve as a noninvasive and lower-cost alternative to nerve conduction studies (NCS) for diagnosis and staging of diabetic sensorimotor polyneuropathy (DSP). We aimed to examine the association between the size of the posterior tibial nerve (PTN) and the presence and severity of DSP. RESEARCH DESIGN AND METHODS We performed a cross-sectional study of 98 consecutive diabetic patients classified by NCS as subjects with DSP or control subjects. Severity was determined using the Toronto Clinical Neuropathy Score. A masked expert sonographer measured the cross-sectional area (CSA) of the PTN at 1, 3, and 5 cm proximal to the medial malleolus. RESULTS Fifty-five patients had DSP. The mean CSA of the PTN in DSP compared with control subjects at distances of 1 (23.03 vs. 17.72 mm2; P = 0.004), 3 (22.59 vs. 17.69 mm2; P < 0.0001), and 5 cm (22.05 vs. 17.25 mm2; P = 0.0005) proximal to the medial malleolus was significantly larger. Although the area under the curve (AUC) for CSA measurements at all three anatomical levels was similar, the CSA measured at 3 cm above the medial malleolus had an optimal threshold value for identification of DSP (19.01 mm2) with a sensitivity of 0.69 and a specificity of 0.77 by AUC analysis. CONCLUSIONS This large study of diabetic patients confirms that the CSA of the PTN is larger in patients with DSP than in control subjects, and US is a promising point-of-care screening tool for DSP.

OBJECTIVE Evaluate the effects of two dipeptidyl peptidase-IV (DPP-4) inhibitors, sitagliptin and vildagliptin, known to have different efficacy on mean amplitude of glycemic excursions (MAGE), on oxidative stress, and on systemic inflammatory markers in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A prospective, randomized, open-label PROBE design (parallel group with a blinded end point) study was performed in 90 patients with type 2 diabetes inadequately controlled by metformin. The study assigned 45 patients to receive sitagliptin (100 mg once daily; sitagliptin group) and 45 patients to receive vildagliptin (50 mg twice daily; vildagliptin group) for 12 weeks. MAGE, evaluated during 48 h of continuous subcutaneous glucose monitoring, allowed an assessment of daily glucose fluctuations at baseline and after 12 weeks in all patients. Assessment of oxidative stress (nitrotyrosine) and systemic levels of inflammatory markers interleukin (IL)-6 and IL-18 was performed at baseline and after 12 weeks in all patients. RESULTS HbA1c, fasting and postprandial glucose, MAGE, and inflammatory and oxidative stress markers were similar between the groups at baseline. After 12 weeks, MAGE (P < 0.01) was lower in the vildagliptin group than in the sitagliptin group. After treatment, HbA1c and postprandial glucose evidenced similar changes between the groups (P = NS). Vildagliptin treatment was associated with a stronger decrease in nitrotyrosine (P < 0.01), IL-6 (P < 0.05), and IL-18 (P < 0.05) than sitagliptin treatment. Nitrotyrosine and IL-6 changes significantly correlated with changes in MAGE but not in fasting glucose and HbA1c. CONCLUSIONS MAGE reduction is associated with reduction of oxidative stress and markers of systemic inflammation in type 2 diabetic patients. These effects were greater in the vildagliptin group than in the sitagliptin group.

We read with great interest the recent article by van Dijk et al. (1) supporting the importance of exercise in the treatment of diabetes. The authors deserve credit for conducting a difficult study on a topic that is of interest to researchers and clinicians alike. We wish to comment on the study design as well as important findings of the study that were overlooked in the manuscript. Authors compared the glucose control between daily exercise (DE) (30 min) to exercise done every other day (EEOD) (60 min). We compliment the authors for controlling …

Epidemiological studies have repeatedly investigated the association between depression and metabolic syndrome (MetS). However, the results have been inconsistent. This meta-analysis aimed to summarize the current evidence from cross-sectional and prospective cohort studies that evaluated this association.MEDLINE, EMBASE, and PsycINFO databases were searched for articles published up to January 2012. Cross-sectional and cohort studies that reported an association between the two conditions in adults were included. Data on prevalence, incidence, unadjusted or adjusted odds ratio (OR), and 95% CI were extracted or provided by the authors. The pooled OR was calculated separately for cross-sectional and cohort studies using random-effects models. The I(2) statistic was used to assess heterogeneity.The search yielded 29 cross-sectional studies (n = 155,333): 27 studies reported unadjusted OR with a pooled estimate of 1.42 (95% CI 1.28-1.57; I(2) = 55.1%); 11 studies reported adjusted OR with depression as the outcome (1.27 [1.07-1.57]; I(2) = 60.9%), and 12 studies reported adjusted OR with MetS as the outcome (1.34 [1.18-1.51]; I(2) = 0%). Eleven cohort studies were found (2 studies reported both directions): 9 studies (n = 26,936 with 2,316 new-onset depression case subjects) reported adjusted OR with depression as the outcome (1.49 [1.19-1.87]; I(2) = 56.8%), 4 studies (n = 3,834 with 350 MetS case subjects) reported adjusted OR with MetS as the outcome (1.52 [1.20-1.91]; I(2) = 0%).Our results indicate a bidirectional association between depression and MetS. These results support early detection and management of depression among patients with MetS and vice versa.

OBJECTIVE In this secondary analysis, we examined whether older adults with diabetes (aged 60–75 years) could benefit from self-management interventions compared with younger adults. Seventy-one community-dwelling older adults and 151 younger adults were randomized to attend a structured behavioral group, an attention control group, or one-to-one education. RESEARCH DESIGN AND METHODS We measured A1C, self-care (3-day pedometer readings, blood glucose checks, and frequency of self-care), and psychosocial factors (quality of life, diabetes distress, frustration with self-care, depression, self-efficacy, and coping styles) at baseline and 3, 6, and 12 months postintervention. RESULTS Both older (age 67 ± 5 years, A1C 8.7 ± 0.8%, duration 20 ± 12 years, 30% type 1 diabetes, 83% white, 41% female) and younger (age 47 ± 9 years, A1C 9.2 ± 1.2%, 18 ± 12 years with diabetes, 59% type 1 diabetes, 82% white, 55% female) adults had improved A1C equally over time. Importantly, older and younger adults in the group conditions improved more and maintained improvements at 12 months (older structured behavioral group change in A1C −0.72 ± 1.4%, older control group −0.65 ± 0.9%, younger behavioral group −0.55 ± 1.2%, younger control group −0.43 ± 1.7%). Furthermore, frequency of self-care, glucose checks, depressive symptoms, quality of life, distress, frustration with self-care, self-efficacy, and emotional coping improved in older and younger participants at follow-up. CONCLUSIONS The findings suggest that, compared with younger adults, older adults receive equal glycemic benefit from participating in self-management interventions. Moreover, older adults showed the greatest glycemic improvement in the two group conditions. Clinicians can safely recommend group diabetes interventions to community-dwelling older adults with poor glycemic control.

OBJECTIVE Increased adiponectin levels may play a protective role in the development of metabolic abnormalities, but prospective studies of the predictive value of serum adiponectin to identify individuals at high risk of new-onset metabolic syndrome are lacking. We investigated whether serum adiponectin predicts incident cases of the metabolic syndrome in a population-based longitudinal study. RESEARCH DESIGN AND METHODS A prospective cohort study was conducted of 2,044 adults (831 men and 1,213 women) aged 40–70 years without metabolic syndrome examined in 2005–2008 (baseline) and 2008–2011 (follow-up). Baseline serum adiponectin concentrations were measured by radioimmunoassay. RESULTS During an average of 2.6 years of follow-up, 153 men (18.4%) and 199 women (16.4%) developed metabolic syndrome. In multivariable-adjusted models, the odds ratio for incident metabolic syndrome comparing the highest with the lowest quartiles of adiponectin levels was 0.25 (95% CI 0.14–0.47) in men and 0.45 (0.28–0.74) in women. While serum adiponectin did not improve the area under the ROC curve for predicting new-onset metabolic syndrome based on information from metabolic syndrome components, the net reclassification improvement and the integrated discrimination improvement of prediction models including adiponectin were significantly higher compared with those of models not including adiponectin among men, with a significant difference between men and women (P = 0.001). CONCLUSIONS Increased adiponectin is an independent protective factor for incident metabolic syndrome in men and women, and it may have a clinical role in predicting new-onset metabolic syndrome among men.

Rizzo et al. (1) report some remarkable differences in mean absolute glucose excursions (MAGE), markers of oxidative stress, and markers of inflammation in a randomized, open-label trial of sitagliptin 100 mg once daily versus vildagliptin 50 mg twice daily. MAGE is a measure of large glycemic swings, taking into account only …

OBJECTIVE Current guidelines for intensive treatment of type 1 diabetes base the mealtime insulin bolus calculation exclusively on carbohydrate counting. There is strong evidence that free fatty acids impair insulin sensitivity. We hypothesized that patients with type 1 diabetes would require more insulin coverage for higher-fat meals than lower-fat meals with identical carbohydrate content. RESEARCH DESIGN AND METHODS We used a crossover design comparing two 18-h periods of closed-loop glucose control after high-fat (HF) dinner compared with low-fat (LF) dinner. Each dinner had identical carbohydrate and protein content, but different fat content (60 vs. 10 g). RESULTS Seven patients with type 1 diabetes (age, 55 ± 12 years; A1C 7.2 ± 0.8%) successfully completed the protocol. HF dinner required more insulin than LF dinner (12.6 ± 1.9 units vs. 9.0 ± 1.3 units; P = 0.01) and, despite the additional insulin, caused more hyperglycemia (area under the curve >120 mg/dL = 16,967 ± 2,778 vs. 8,350 ± 1,907 mg/dL⋅min; P < 0001). Carbohydrate-to-insulin ratio for HF dinner was significantly lower (9 ± 2 vs. 13 ± 3 g/unit; P = 0.01). There were marked interindividual differences in the effect of dietary fat on insulin requirements (percent increase significantly correlated with daily insulin requirement; R2 = 0.64; P = 0.03). CONCLUSIONS This evidence that dietary fat increases glucose levels and insulin requirements highlights the limitations of the current carbohydrate-based approach to bolus dose calculation. These findings point to the need for alternative insulin dosing algorithms for higher-fat meals and suggest that dietary fat intake is an important nutritional consideration for glycemic control in individuals with type 1 diabetes.

OBJECTIVE Time-related biases in observational studies of drug effects have been described extensively in different therapeutic areas but less so in diabetes. Immortal time bias, time-window bias, and time-lag bias all tend to greatly exaggerate the benefits observed with a drug. RESEARCH DESIGN AND METHODS These time-related biases are described and shown to be prominent in observational studies that have associated metformin with impressive reductions in the incidence of and mortality from cancer. As a consequence, metformin received much attention as a potential anticancer agent; these observational studies sparked the conduction of randomized, controlled trials of metformin as cancer treatment. However, the spectacular effects reported in these studies are compatible with time-related biases. RESULTS We found that 13 observational studies suffered from immortal time bias; 9 studies had not considered time-window bias, whereas other studies did not consider inherent time-lagging issues when comparing the first-line treatment metformin with second- or third-line treatments. These studies, subject to time-related biases that are avoidable with proper study design and data analysis, led to illusory extraordinarily significant effects, with reductions in cancer risk with metformin ranging from 20 to 94%. Three studies that avoided these biases reported no effect of metformin use on cancer incidence. CONCLUSIONS Although observational studies are important to better understand the effects of drugs, their proper design and analysis is essential to avoid major time-related biases. With respect to metformin, the scientific evidence of its potential beneficial effects on cancer would need to be reassessed critically before embarking on further long and expensive trials.

OBJECTIVE Ad36, a human adenovirus, increases adiposity but improves glycemic control in animal models. Similarly, natural Ad36 infection is cross-sectionally associated with greater adiposity and better glycemic control in humans. This study compared longitudinal observations in indices of adiposity (BMI and body fat percentage) and glycemic control (fasting glucose and insulin) in Ad36-infected versus uninfected adults. RESEARCH DESIGN AND METHODS Baseline sera from Hispanic men and women (n = 1,400) were screened post hoc for the presence of Ad36-specific antibodies. Indices of adiposity and glycemic control at baseline and at ∼10 years past the baseline were compared between seropositive and seronegative subjects, with adjustment for age and sex. In addition to age and sex, indices of glycemic control were adjusted for baseline BMI and were analyzed only for nondiabetic subjects. RESULTS Seropositive subjects (14.5%) had greater adiposity at baseline, compared with seronegative subjects. Longitudinally, seropositive subjects showed greater adiposity indices but lower fasting insulin levels. Subgroup analyses revealed that Ad36-seropositivity was associated with better baseline glycemic control and lower fasting insulin levels over time in the normal-weight group (BMI ≤25 kg/m2) and longitudinally, with greater adiposity in the overweight (BMI 25–30 kg/m2) and obese (BMI >30 kg/m2) men. Statistically, the differences between seropositive and seronegative individuals were modest in light of the multiple tests performed. CONCLUSIONS This study strengthens the plausibility that in humans, Ad36 increases adiposity and attenuates deterioration of glycemic control. Panoptically, the study raises the possibility that certain infections may modulate obesity or diabetes risk. A comprehensive understanding of these under-recognized factors is needed to effectively combat such metabolic disorders.

We aimed to compare the discriminative power of prognostic models for early prediction of women at risk for the development of gestational diabetes mellitus (GDM) using four currently recommended diagnostic criteria based on the 75-g oral glucose tolerance test (OGTT). We also described the potential effect of application of the models into clinical practice.A prospective cross-sectional study of 2,772 pregnant women was conducted at a referral maternity center in Vietnam. GDM was determined by the American Diabetes Association (ADA), International Association of the Diabetes and Pregnancy Study Groups (IADPSG), Australasian Diabetes in Pregnancy Society (ADIPS), and World Health Organization (WHO) criteria. Prognostic models were developed using the Bayesian model averaging approach, and discriminative power was assessed by area under the curve. Different thresholds of predicted risk of developing GDM were applied to describe the clinical impact of the diagnostic criteria.The magnitude of GDM varied substantially by the diagnostic criteria: 5.9% (ADA), 20.4% (IADPSG), 20.8% (ADIPS), and 24.3% (WHO). The ADA prognostic model, consisting of age and BMI at booking, had the best discriminative power (area under the curve of 0.71) and the most favorable cost-effective ratio if implemented in clinical practice. Selective screening of women for GDM using the ADA model with a risk threshold of 3% gave 93% sensitivity for identification of women with GDM with a 27% reduction in the number of OGTTs required.A simple prognostic model using age and BMI at booking could be used for selective screening of GDM in Vietnam and in other low- and middle-income settings.

OBJECTIVE Low vitamin D levels predict the development of diabetes. This double-blind, randomized, control study in subjects with prediabetes and hypovitaminosis D evaluated whether high doses of vitamin D for 1 year affected insulin secretion, insulin sensitivity, and the development of diabetes. RESEARCH DESIGN AND METHODS A total of 1,551 subjects ≥40 years of age not known to have diabetes were screened with A1C levels. Subjects with A1C levels of 5.8–6.9% underwent an oral glucose tolerance test (OGTT). Subjects with prediabetes and 25-OH vitamin D (25-OHD) levels RESULTS 25-OHD levels rapidly rose from 22 to nearly 70 ng/mL after vitamin D supplementation with a mean weekly dose of 88,865 IU. There were no differences between the placebo and vitamin D groups regarding fasting plasma glucose, 2-h glucose, or insulin secretion and sensitivity or in the percent developing diabetes or returning to normal glucose tolerance. No subjects experienced increased serum or urinary calcium levels. At 12 months, A1C levels were significantly slightly less (0.2%) in the vitamin D group. CONCLUSIONS In individuals with prediabetes and hypovitaminosis D, doses of vitamin D supplementation designed to raise serum 25-OHD levels into the upper-normal range for 1 year had no effect on insulin secretion, insulin sensitivity, or the development of diabetes compared with placebo administration.

Insulin resistance plays a part in diabetic nephropathy (DN). The association between the peroxisome proliferator-activated receptor γ Pro to Ala alteration at codon 12 (Pro12Ala) polymorphism and the risk of insulin resistance has been confirmed. The association between the polymorphism and DN risk has also been widely studied recently, but no consensus was available up to now.A systematic search of electronic databases (MEDLINE, Embase, and China National Knowledge Infrastructure) and reference lists of relevant articles was carried out, and then 18 case-control studies involving 3,361 DN cases and 5,825 control subjects were identified.In the overall analysis, the Ala12 variant was observed to be significantly associated with decreased DN risk (odds ratio 0.76 [95% CI 0.61-0.93]). Some evidence of heterogeneity among the included studies was detected, which could be explained by the difference of ethnicity and stage of DN. Subgroup analyses stratified by ethnicity and stage of DN were performed, and results indicated the Pro12Ala polymorphism was associated with the risk of DN in Caucasians but no similar association was observed in Asians. Additionally, we observed that Ala12 was associated with decreased risk of albuminuria. With only a few of subjects were available, we failed to detect statistically significant association between the polymorphism and end-stage renal disease (ESRD).Our results indicated that the Ala12 variant is a significantly protective factor for DN. Future research should focus on the effect of Pro12Ala polymorphism on ESRD and gathering data of Africans.

OBJECTIVE Hyperandrogenemia is associated with cardiovascular risk factors in women but evidence about the relationship of testosterone levels with mortality is sparse. We aimed to evaluate whether total testosterone (TT), free testosterone (FT), and sex hormone–binding globulin (SHBG) are associated with all-cause and cardiovascular mortality in a cohort of postmenopausal women. RESEARCH DESIGN AND METHODS We measured TT and SHBG levels in 875 postmenopausal women who were referred for coronary angiography (during 1997–2000). FT was calculated according to the Vermeulen method. The main outcome measures were Cox proportional hazard ratios (HRs) for mortality from all causes and from cardiovascular causes. RESULTS After a median follow-up time of 7.7 years, 179 women (20.5%) had died. There were 101 deaths due to cardiovascular disease (56.4% of all deaths). We found no association of FT, TT, and SHBG levels with mortality in all postmenopausal women. In postmenopausal diabetic women, multivariable-adjusted HRs (with 95% CIs) in the fourth compared with the first FT quartile for all-cause and cardiovascular mortality were 0.38 (0.08–0.90), P = 0.025, and 0.28 (0.08–0.90), P = 0.032, respectively. We found no association of TT and SHBG with mortality in diabetic postmenopausal women. CONCLUSIONS In postmenopausal diabetic women referred for coronary angiography, low FT levels are independently associated with increased all-cause and cardiovascular mortality.

We thank Blanco et al. (1) for their letter on our article, which confirmed the utility of high-sensitivity C-reactive protein (hs-CRP) as a clinical biomarker to discriminate patients with HNF1A-MODY from patients with type 2 diabetes (2). We agree with the authors that the discrimination between HNF1A-MODY and type 2 diabetes is likely to be enhanced by elevated levels of hs-CRP in …

OBJECTIVE To determine the relative contributions of basal hyperglycemia (BHG) versus postprandial hyperglycemia (PPHG) before and after treatment intensification in patients with glycated hemoglobin A1c (A1C) >7.0% while on prior oral therapy. RESEARCH DESIGN AND METHODS Self-measured, plasma-referenced glucose profiles and A1C values were evaluated from participants in six studies comparing systematically titrated insulin glargine with an alternative regimen (adding basal, premixed, or prandial insulin, or increasing oral agents). Hyperglycemic exposure (>100 mg/dL [5.6 mmol/L]) as a result of BHG versus PPHG was calculated. RESULTS On prior oral therapy, 1,699 participants (mean age 59 years, diabetes duration 9 years) had mean fasting plasma glucose (FPG) of 194 mg/dL (10.8 mmol/L), and mean A1C was 8.7%. BHG contributed an average of 76–80% to hyperglycemia over the observed range of baseline A1C levels. Adding basal insulin for 24 or 28 weeks lowered mean FPG to 117 mg/dL (6.5 mmol/L), A1C to 7.0%, and BHG contribution to 32–41%. Alternative regimens reduced FPG to 146 mg/dL (8.1 mmol/L), A1C to 7.1%, and the contribution of BHG to 64–71%. BHG contributions for patients with A1C averaging 7.6–7.7% were 76% at baseline and 34 and 68% after adding basal insulin or other therapies, respectively. CONCLUSIONS When A1C is >7.0% despite oral therapy, BHG routinely dominates exposure. Intensified therapy reduces A1C and changes this relationship, but BHG amenable to further intervention still accounts for one-third of total hyperglycemia after basal insulin treatment and two-thirds after alternative methods.

OBJECTIVE New-onset diabetes after kidney transplantation (NODAT) has adverse clinical and economic implications. A risk score for NODAT could help identify research subjects for intervention studies. RESEARCH DESIGN AND METHODS We conducted a single-center retrospective cohort study using pretransplant clinical and laboratory measurements to construct a risk score for NODAT. NODAT was defined by hemoglobin A1c (HbA1c) ≥6.5%, fasting serum glucose ≥126 mg/dL, or prescribed therapy for diabetes within 1 year posttransplant. Three multivariate logistic regression models were constructed: 1) standard model, with both continuous and discrete variables; 2) dichotomous model, with continuous variables dichotomized at clinically relevant cut points; and 3) summary score defined as the sum of the points accrued using the terms from the dichotomous model. RESULTS A total of 316 subjects had seven pretransplant variables with P < 0.10 in univariate logistic regression analyses (age, planned corticosteroid therapy posttransplant, prescription for gout medicine, BMI, fasting glucose and triglycerides, and family history of type 2 diabetes) that were selected for multivariate models. Areas under receiver operating curves for all three models were similar (0.72, 0.71, and 0.70). A simple risk score calculated as the sum of points from the seven variables performed as well as the other two models in identifying risk of NODAT. CONCLUSIONS A risk score computed from seven simple pretransplant variables can identify risk of NODAT.

Despite the well-known influence of maternal glucose on infant birth weight (BW), the prevalence of large for gestational age (LGA) infants (≥90th percentile for age) has been increasing steadily over decades, particularly in pregnancies complicated by pregestational or gestational diabetes mellitus (1). Although the overall prevalence of macrosomia (BW ≥4,000 g) is 17–29% in women with untreated gestational diabetes, the majority of macrosomic infants are born to women with obesity but no gestational diabetes (2,3). Moreover, epidemiologic data show that a higher BW is associated with higher BMI and glucose intolerance later in life (4,5), suggesting life-long metabolic implications for offspring. Recent data from the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study suggested that concentrations of maternal glucose below the previously accepted diagnostic thresholds for gestational diabetes are predictive of LGA and fetal hyperinsulinemia (6). On the basis of this landmark study, the International Association of Diabetes in Pregnancy Study Group and the American Diabetes Association (ADA) recommended new lower diagnostic criteria for gestational diabetes (7,8). However, a significant number of women with gestational diabetes whose glucose values are within the current targeted therapeutic ranges deliver macrosomic infants (9). Although glucose plays a major role in fetal growth, this paradox underscores the likely role of other nutrients in fetal growth, but also the need to critically reexamine our definition of “normal” maternal patterns of glycemia and the effects on fetal growth. The new diagnostic criteria recommended by the International Association of Diabetes in Pregnancy Study Group and ADA are expected to increase the prevalence of gestational diabetes to 18%. Thus, treatment targets may need to be reevaluated. Historically, the treatment goal in pregnancies complicated by diabetes has been to mimic patterns of glycemia in normal pregnancy (1). Although the HAPO study better defined abnormal …

OBJECTIVE Diabetic foot infection is the predominant predisposing factor to nontraumatic lower-extremity amputation (LEA), but few studies have investigated which specific risk factors are most associated with LEA. We sought to develop and validate a risk score to aid in the early identification of patients hospitalized for diabetic foot infection who are at highest risk of LEA. RESEARCH DESIGN AND METHODS Using a large, clinical research database (CareFusion), we identified patients hospitalized at 97 hospitals in the U.S. between 2003 and 2007 for culture-documented diabetic foot infection. Candidate risk factors for LEA included demographic data, clinical presentation, chronic diseases, and recent previous hospitalization. We fit a logistic regression model using 75% of the population and converted the model coefficients to a numeric risk score. We then validated the score using the remaining 25% of patients. RESULTS Among 3,018 eligible patients, 21.4% underwent an LEA. The risk factors most highly associated with LEA (P < 0.0001) were surgical site infection, vasculopathy, previous LEA, and a white blood cell count >11,000 per mm3. The model showed good discrimination (c-statistic 0.76) and excellent calibration (Hosmer-Lemeshow, P = 0.63). The risk score stratified patients into five groups, demonstrating a graded relation to LEA risk (P < 0.0001). The LEA rates (derivation and validation cohorts) were 0% for patients with a score of 0 and ~50% for those with a score of ≥21. CONCLUSIONS Using a large, hospitalized population, we developed and validated a risk score that seems to accurately stratify the risk of LEA among patients hospitalized for a diabetic foot infection. This score may help to identify high-risk patients upon admission.

To assess complication prevalence and identify protective factors in patients with diabetes duration of ≥50 years. Characterization of a complication-free subgroup in this cohort would suggest that some individuals are protected from diabetes complications and allow identification of endogenous protective factors.Cross-sectional, observational study of 351 U.S. residents who have survived with type 1 diabetes for ≥50 years (Medalists). Retinopathy, nephropathy, neuropathy, and cardiovascular disease were assessed in relation to HbA(1c), lipids, and advanced glycation end products (AGEs). Retrospective chart review provided longitudinal ophthalmic data for a subgroup.A high proportion of Medalists remain free from proliferative diabetic retinopathy (PDR) (42.6%), nephropathy (86.9%), neuropathy (39.4%), or cardiovascular disease (51.5%). Current and longitudinal (the past 15 years) glycemic control were unrelated to complications. Subjects with high plasma carboxyethyl-lysine and pentosidine were 7.2-fold more likely to have any complication. Of Medalists without PDR, 96% with no retinopathy progression over the first 17 years of follow-up did not experience retinopathy worsening thereafter.The Medalist population is likely enriched for protective factors against complications. These factors might prove useful to the general population with diabetes if they can be used to induce protection against long-term complications. Specific AGE combinations were strongly associated with complications, indicating a link between AGE formation or processing with development of diabetic vasculopathy.

Hermida et al. (1) have recently shown an impressive reduction of asleep blood pressure and associated reduction of cardiovascular disease (CVD) events in type 2 diabetic patients treated with at least one antihypertensive drug at bedtime compared with patients who ingested all drugs in the morning. This is a subgroup analysis of the diabetic patients (20%) enrolled in the MAPEC (Monitorizacion Ambulatoria para Prediccion de Eventos Cardiovasculares [Ambulatory Blood Pressure Monitoring for …