R. Paul Wadwa

Prevalence and Correlates of Depression in Individuals With and Without Type 1 Diabetes

OBJECTIVE Depression is associated with poor glycemic control and complications in people with type 1 diabetes. We assessed the prevalence of depression and antidepressant medication use among adults with and without type 1 diabetes and the association between depression and diabetes complications. RESEARCH DESIGN AND METHODS In 2006–2008, the Coronary Artery Calcification in Type 1 Diabetes Study applied the Beck Depression Inventory II (BDI-II) to 458 participants with type 1 diabetes (47% male, aged 44 ± 9 years, type 1 diabetes duration 29 ± 9 years) and 546 participants without diabetes (nondiabetic group) (51% male, aged 47 ± 9 years). Use of antidepressant medication was self-reported. Depression was defined as a BDI-II score >14 and/or use of antidepressant medication. Occurrence of diabetes complications (retinopathy, blindness, neuropathy, diabetes-related amputation, and kidney or pancreas transplantation) was self-reported. RESULTS Mean BDI-II score, adjusted for age and sex, was significantly higher in participants with type 1 diabetes than in nondiabetic participants (least-squares mean ± SE: 7.4 ± 0.3 vs. 5.0 ± 0.3; P < 0.0001). Type 1 diabetic participants reported using more antidepressant medications (20.7 vs. 12.1%, P = 0.0003). More type 1 diabetic than nondiabetic participants were classified as depressed by BDI-II cut score (17.5 vs. 5.7%, P < 0.0001) or by either BDI-II cut score or antidepressant use (32.1 vs. 16.0%, P < 0.0001). Participants reporting diabetes complications (n = 209) had higher mean BDI-II scores than those without complications (10.7 ± 9.3 vs. 6.4 ± 6.3, P < 0.0001). CONCLUSIONS Compared with nondiabetic participants, adults with type 1 diabetes report more symptoms of depression and more antidepressant medication usage. Depression is highly prevalent in type 1 diabetes and requires further study on assessment and treatment.

A Randomized Trial of a Home System to Reduce Nocturnal Hypoglycemia in Type 1 Diabetes

OBJECTIVE Overnight hypoglycemia occurs frequently in individuals with type 1 diabetes and can result in loss of consciousness, seizure, or even death. We conducted an in-home randomized trial to determine whether nocturnal hypoglycemia could be safely reduced by temporarily suspending pump insulin delivery when hypoglycemia was predicted by an algorithm based on continuous glucose monitoring (CGM) glucose levels. RESEARCH DESIGN AND METHODS Following an initial run-in phase, a 42-night trial was conducted in 45 individuals aged 15–45 years with type 1 diabetes in which each night was assigned randomly to either having the predictive low-glucose suspend system active (intervention night) or inactive (control night). The primary outcome was the proportion of nights in which ≥1 CGM glucose values ≤60 mg/dL occurred. RESULTS Overnight hypoglycemia with at least one CGM value ≤60 mg/dL occurred on 196 of 942 (21%) intervention nights versus 322 of 970 (33%) control nights (odds ratio 0.52 [95% CI 0.43–0.64]; P < 0.001). Median hypoglycemia area under the curve was reduced by 81%, and hypoglycemia lasting >2 h was reduced by 74%. Overnight sensor glucose was >180 mg/dL during 57% of control nights and 59% of intervention nights (P = 0.17), while morning blood glucose was >180 mg/dL following 21% and 27% of nights, respectively (P < 0.001), and >250 mg/dL following 6% and 6%, respectively. Morning ketosis was present <1% of the time in each arm. CONCLUSIONS Use of a nocturnal low-glucose suspend system can substantially reduce overnight hypoglycemia without an increase in morning ketosis.

Lipid and Lipoprotein Profiles in Youth with and Without Type 1 Diabetes: The SEARCH Case-Control Study

OBJECTIVE—The purpose of this study was to compare the lipid profile and the prevalence of lipid abnormalities in youth with and without type 1 diabetes and explore the role of glycemic control on the hypothesized altered lipid profile in youth with type 1 diabetes. RESEARCH DESIGN AND METHODS—We conducted a cross-sectional analysis of 512 youth with type 1 diabetes (mean duration 4.22 years) and 188 healthy control subjects aged 10–22 years in Colorado and South Carolina. SEARCH for Diabetes in Youth (SEARCH) participants with type 1 diabetes and healthy control subjects recruited from primary care offices in the same geographic regions were invited to attend a research visit. Fasting lipid profiles were compared between youth with type 1 diabetes (stratified according to categories of optimal [A1C <7.5%] and suboptimal [A1C ≥7.5%] glycemic control) and healthy nondiabetic youth, using multiple linear and logistic regression. RESULTS—Youth with type 1 diabetes and optimal A1C had lipid concentrations that were similar (total cholesterol, LDL cholesterol, and LDL particle size) or even less atherogenic (HDL cholesterol, non-HDL cholesterol, triglyceride, and triglyceride–to–HDL cholesterol ratio) than those observed in nondiabetic youth, whereas youth with suboptimal glycemic control had elevated standard lipid levels (total cholesterol, LDL cholesterol, and non-HDL cholesterol). Youth with type 1 diabetes also had significantly elevated apolipoprotein B levels and more small, dense LDL particles than nondiabetic youth, regardless of glycemic control. CONCLUSIONS—Youth with type 1 diabetes have abnormal lipid levels and atherogenic changes in lipoprotein composition, even after a relatively short disease duration. As in adults, glycemic control is an important mediator of these abnormalities.

Measures of Arterial Stiffness in Youth With Type 1 and Type 2 Diabetes: The SEARCH for Diabetes in Youth study

OBJECTIVE Arterial stiffness occurs early in the atherosclerotic process; however, few data are available concerning risk factors for arterial stiffness in youth with diabetes. We identified factors associated with arterial stiffness in youth with diabetes and assessed the effects of these factors on the relationship between arterial stiffness and diabetes type (type 1 vs. type 2). RESEARCH DESIGN AND METHODS A subset of patients from the SEARCH for Diabetes in Youth study with type 1 (n = 535) and type 2 diabetes (n = 60), aged 10–23 years (52% male; 82% non-Hispanic white; diabetes duration 65 ± 49 months) had arterial stiffness, anthropometrics, blood pressure, fasting lipids, and A1C measured. Arterial stiffness was measured by brachial distensibility (brachD), pulse wave velocity (PWV), and augmentation index adjusted to heart rate of 75 beats/min (AI75). RESULTS Youth with type 2 diabetes had worse brachD (5.2 ± 0.9 vs. 6.1 ± 1.2%/mmHg), PWV (6.4 ± 1.3 vs. 5.3 ± 0.8 m/s), and AI75 (6.4 ± 9.9 vs. 2.2 ± 10.2%) than those with type 1 diabetes (P < 0.01 for each). These differences were largely mediated through increased central adiposity and higher blood pressure in youth with type 2 diabetes. We also found a pattern of association of arterial stiffness measures with waist circumference and blood pressure, independent of diabetes type. CONCLUSIONS Youth with type 2 diabetes have worse arterial stiffness than similar youth with type 1 diabetes. Increased central adiposity and blood pressure are associated with measures of arterial stiffness, independent of diabetes type. Whether these findings indicate that youth with type 2 diabetes will be at higher risk for future complications requires longitudinal studies.

Predictive Low-Glucose Insulin Suspension Reduces Duration of Nocturnal Hypoglycemia in Children Without Increasing Ketosis

OBJECTIVE Nocturnal hypoglycemia can cause seizures and is a major impediment to tight glycemic control, especially in young children with type 1 diabetes. We conducted an in-home randomized trial to assess the efficacy and safety of a continuous glucose monitor–based overnight predictive low-glucose suspend (PLGS) system. RESEARCH DESIGN AND METHODS In two age-groups of children with type 1 diabetes (11–14 and 4–10 years of age), a 42-night trial for each child was conducted wherein each night was assigned randomly to either having the PLGS system active (intervention night) or inactive (control night). The primary outcome was percent time <70 mg/dL overnight. RESULTS Median time at <70 mg/dL was reduced by 54% from 10.1% on control nights to 4.6% on intervention nights (P < 0.001) in 11–14-year-olds (n = 45) and by 50% from 6.2% to 3.1% (P < 0.001) in 4–10-year-olds (n = 36). Mean overnight glucose was lower on control versus intervention nights in both age-groups (144 ± 18 vs. 152 ± 19 mg/dL [P < 0.001] and 153 ± 14 vs. 160 ± 16 mg/dL [P = 0.004], respectively). Mean morning blood glucose was 159 ± 29 vs. 176 ± 28 mg/dL (P < 0.001) in the 11–14-year-olds and 154 ± 25 vs. 158 ± 22 mg/dL (P = 0.11) in the 4–10-year-olds, respectively. No differences were found between intervention and control in either age-group in morning blood ketosis. CONCLUSIONS In 4–14-year-olds, use of a nocturnal PLGS system can substantially reduce overnight hypoglycemia without an increase in morning ketosis, although overnight mean glucose is slightly higher.

Hypoglycemia, Diabetes, and Cardiovascular Disease

Cardiovascular disease (CVD) remains the leading cause of death in people with diabetes, and the risk of CVD for adults with diabetes is at least two to four times the risk in adults without diabetes. Complications of diabetes, including not only CVD but also microvascular diseases such as retinopathy and nephropathy, are a major health and financial burden. Diabetes is a disease of glucose intolerance, and so much of the research on complications has focused on the role of hyperglycemia. Clinical trials have clearly demonstrated the role of hyperglycemia in microvascular complications of diabetes, but there appears to be less evidence for as strong of a relationship between hyperglycemia and CVD in people with diabetes. Hypoglycemia has become a more pressing health concern as intensive glycemic control has become the standard of care in diabetes. Clinical trials of intensive glucose lowering in both type 1 and type 2 diabetes populations has resulted in significantly increased hypoglycemia, with no decrease in CVD during the trial period, although several studies have shown a reduction in CVD with extended follow-up. There is evidence that hypoglycemia may adversely affect cardiovascular risk in patients with diabetes, and this is one potential explanation for the lack of CVD prevention in trials of intensive glycemic control. Hypoglycemia causes a cascade of physiologic effects and may induce oxidative stress and cardiac arrhythmias, contribute to sudden cardiac death, and cause ischemic cerebral damage, presenting several potential mechanisms through which acute and chronic episodes of hypoglycemia may increase CVD risk. In this review, we examine the risk factors and prevalence of hypoglycemia in diabetes, review the evidence for an association of both acute and chronic hypoglycemia with CVD in adults with diabetes, and discuss potential mechanisms through which hypoglycemia may adversely affect cardiovascular risk.

Estimated Insulin Sensitivity and Cardiovascular Disease Risk Factors in Adolescents with and without Type 1 Diabetes

OBJECTIVEnTo test the hypothesis that cardiovascular disease (CVD) risk factors are similar in nondiabetic (non-DM) adolescents compared with those with type 1 diabetes (T1D) in the most insulin-sensitive (IS) tertile, and that CVD risk factors are more atherogenic with decreasing IS in adolescents with T1D.nnnSTUDY DESIGNnIS for adolescents with T1D (n = 292; age = 15.4 ± 2.1 years; duration = 8.8 ± 3.0 years, hemoglobin A1c = 8.9% ± 1.6%) and non-DM controls (n = 89; age = 15.4 ± 2.1 years) was estimated using the model: log(e)IS = .64725 - 0.02032 (waist [cm]) - 0.09779 (hemoglobin A1c [%]) - 0.00235 (triglycerides [mg/dL]). CVD risk factors (blood pressure, fasting total and low- and high-density lipoprotein-cholesterol (HDL-c), high sensitivity C-reactive protein, and body mass index z score) were compared between all non-DM adolescents and those with T1D in the most IS tertile, and then examined for a linear trend by IS tertile in adolescents with T1D, adjusted for sex, race/ethnicity, and Tanner stage.nnnRESULTSnEstimated IS was significantly lower in adolescents with T1D compared with those without (T1D = 7.8 ± 2.4, non-DM = 11.5 ± 2.9; P < .0001). CVD risk factors were similar for non-DM compared with the adolescents with T1D with the most IS, except for higher (HDL-c) and diastolic blood pressure in adolescents with T1D (P < .05). Among adolescents with T1D, all CVD risk factors except for (HDL-c), were more atherogenic across decreasing IS tertiles in linear regression analysis (P < .05).nnnCONCLUSIONnAdolescents with T1D who are the most IS have similar CVD risk factors compared with non-DM adolescents. CVD risk factors are inversely associated with IS in adolescents with T1D. IS may be an important therapeutic target for reducing CVD risk factors in adolescents with T1D.

Polymorphisms of the Renin-Angiotensin System Genes Predict Progression of Subclinical Coronary Atherosclerosis

Premature coronary artery disease (CAD) in subjects with type 1 diabetes dramatically affects quality of life and morbidity and leads to premature death, but there is still little known about the mechanisms and predictors of this complication. In the present study, we explored the role of genetic variants of angiotensinogen (AGT, M235T), ACE (I/D), and angiotensin type 1 receptor (ATR1, A1166C) as predictors of rapid progression of subclinical coronary atherosclerosis. Five-hundred eighty-five type 1 diabetic patients and 592 similar age and sex control subjects were evaluated for progression of coronary artery calcification (CAC), a marker of subclinical CAD, before and after a 2.5-year follow-up. In logistic regression analysis, CAC progression was dramatically more likely in type 1 diabetic subjects not treated with ACE inhibitor/angiotensin receptor blocker who had the TT-ID-AA/AC genotype combination than in those with other genotypes (odds ratio 11.6 [95%CI 4.5–29.6], P < 0.0001) and was even stronger when adjusted for cardiovascular disease risk factors and the mean A1C (37.5 [3.6–388], P = 0.002). In conclusion, a combination of genotype variants of the renin-angiotensin system genes is a powerful determinant of subclinical progression of coronary artery atherosclerosis in type 1 diabetic patients and may partially explain accelerated CAD in type 1 diabetes.

Dyslipidemia in Youth with Diabetes: To Treat or Not to Treat?

There are an estimated 1.5 million people with type 1 diabetes (T1D) and 20 million with type 2 diabetes (T2D) in the U.S. today including at least 150 000 younger than 20 years(1). Of concern, both T1D and T2D are increasing in youth and presenting at younger ages(2-4), implying a longer burden of disease and earlier onset of vascular complications(5). n nCardiovascular disease (CVD) is the leading cause of death in people with both T1D(6) and T2D(7) and the antecedents of adult CVD are present in children(8-10). Several studies demonstrate tracking of childhood CVD risk factors into adulthood(9-15). Furthermore, CVD risk factors in childhood correlate with abnormalities in surrogate markers of atherosclerosis (such as carotid intima thickness and arterial elasticity)(14;15) and atherosclerotic lesions in pathology evaluations(9;13). Although data indicate that progress has been made reducing microvascular complications in T1D(16;17) and that intensive management with lower HbA1c can reduce CVD events(18), evidence from the Pittsburgh Epidemiology of Diabetes Complications Study suggests a lack of similar progress in reduction of macrovascular as compared with microvascular complications(16). Furthermore, people with both T1D and T2D suffer macrovascular complications and death at earlier ages than non-diabetics(7;19). Importantly, dyslipidemia is a significant CVD risk factor in persons with diabetes(7;20-22) and target low-density lipoprotein cholesterol (LDL) levels continue to be lowered in adults with diabetes (DM)(7). n nObservational data have emerged recently on prevalence of dyslipidemia in youth with DM(23-26). Yet, despite recent American Diabetes Association (ADA) and American Heart Association (AHA) clinical recommendations on treatment of dyslipidemia in youth with DM(27-30), no treatment data exist in dyslipidemic youth with DM on which to base clinical care. Instead current pediatric recommendations are generated by consensus expert opinion or are extrapolated either from adult data or treatment data on youth with familial hypercholesterolemia(27-31). n nGiven that dyslipidemia is an important and potentially modifiable CVD risk factor, data to inform clinical decision making regarding screening criteria and treatment of dyslipidemia in this high-risk population are of significant public health importance(32). Data from clinical trials in youth with DM are needed to determine the appropriate management strategy. n nIn this article, recent data and current recommendations on dyslipidemia in youth with DM will be reviewed. Evidence supporting the treatment of dyslipidemia in youth with DM will be discussed as well as current treatment options and recommended monitoring. Finally, the question of whether lipid abnormalities in youth with DM should be treated will be addressed.

Frequency of morning ketosis after overnight insulin suspension using an automated nocturnal predictive low glucose suspend system.

OBJECTIVE To assess the effect of overnight insulin pump suspension in an automated predictive low glucose suspend system on morning blood glucose and ketone levels in an attempt to determine whether routine measurement of ketone levels is useful when a closed-loop system that suspends insulin delivery overnight is being used. RESEARCH DESIGN AND METHODS Data from an in-home randomized trial of 45 individuals with type 1 diabetes (age range 15–45 years) were analyzed, evaluating an automated predictive low glucose pump suspension system in which blood glucose, blood ketone, and urine ketone levels were measured on 1,954 mornings. RESULTS One or more pump suspensions occurred during 744 of the 977 intervention nights (76%). The morning blood ketone level was ≥0.6 mmol/L after 11 of the 744 nights (1.5%) during which a pump suspension occurred and 2 of the 233 nights (0.9%) during which there was no suspension compared with 11 of 977 control nights (1.1%). The morning blood ketone level was ≥0.6 mmol/L after only 2 of 159 nights (1.3%) with a pump suspension exceeding 2 h. Morning fasting blood glucose level was not a good predictor of the presence of blood ketones. CONCLUSIONS Routine measurement of blood or urine ketones during use of an automated pump suspension system using continuous glucose monitoring, whether threshold based or predictive, is not necessary. Recommendations for checking ketone levels should be no different when a patient is using a system with automated insulin suspension than it is for conventional diabetes self-management.