Distribution of HbA(1c) levels for children and young adults in the U.S.: Third National Health and Nutrition Examination Survey

OBJECTIVE: To describe the distribution of HbA(1c) levels among children and young adults in the U.S. and to evaluate the effects of age, sex, race/ethnicity, socioeconomic status, parental history of diabetes, overweight, and serum glucose on HbA(1c) levels. RESEARCH DESIGN AND METHODS: We analyzed HbA(1c) data from the Third National Health and Nutrition Examination Survey, 1988-1994, for 7,968 participants aged 5-24 years who had not been treated for diabetes. After adjusting for the complex sample design, we compared the distributions of HbA(1c) in subgroups and developed multiple linear regression models to examine factors associated with HbA(1c). RESULTS: Mean HbA(1c) level was 4.99% (SD 0.50%) and varied from 4.93% (95% CI +/-0.04) in non-Hispanic whites to 5.05% (+/-0.02) in Mexican-Americans to 5.17% (+/-0.02) in non-Hispanic blacks. There were very small differences among subgroups. Within each age- group, among men and women, among overweight and nonoverweight subjects, and at any level of education, mean HbA(1c) levels were higher in non-Hispanic blacks than in non-Hispanic whites. After adjusting for confounders, HbA(1c) levels for non-Hispanic blacks (5.15%, 95% CI +/-0.04) and Mexican-Americans (5.01%, +/-0.04) were higher than those for non-Hispanic whites (4.93%, +/-0.04). CONCLUSIONS: These data provide national reference levels for HbA(1c) distributions among Americans aged 5-24 years and show statistically significant racial/ethnic differences in HbA(1c) levels that are not completely explained by demographic and health-related variables.     

Racial and ethnic differences in glycemic control of adults with type 2 diabetes

OBJECTIVE: To evaluate glycemic control in a representative sample of U.S. adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: The Third National Health and Nutrition Examination Survey included national samples of non-Hispanic whites, non-Hispanic blacks, and Mexican Americans aged > or = 20 years. Information on medical history and treatment of diabetes was obtained to determine those who had been diagnosed with type 2 diabetes by a physician before the survey (n = 1,480). Fasting plasma glucose and HbA1c were measured, and the frequencies of sociodemographic and clinical variables related to glycemic control were determined. RESULTS: A higher proportion of non-Hispanic blacks were treated with insulin and a higher proportion of Mexican Americans were treated with oral agents compared with non-Hispanic whites, but the majority of adults in each racial or ethnic group (71-83%) used pharmacologic treatment for diabetes. Use of multiple daily insulin injections was more common in whites. Blood glucose self-monitoring was less common in Mexican Americans, but most patients had never self-monitored. HbA1c values in the nondiabetic range were found in 26% of non-Hispanic whites, 17% of non-Hispanic blacks, and 20% of Mexican Americans. Poor glycemic control (HbA1c > 8%) was more common in non-Hispanic black women (50%) and Mexican-American men (45%) compared with the other groups (35-38%), but HbA1c for both sexes and for all racial and ethnic groups was substantially higher than normal levels. Those with HbA1c > 8% included 52% of insulin-treated patients and 42% of those taking oral agents. There was no relationship of glycemic control to socioeconomic status or access to medical care in any racial or ethnic group. CONCLUSIONS: These data indicate that many patients with type 2 diabetes in the U.S. have poor glycemic control, placing them at high risk of diabetic complications. Non-Hispanic black women, Mexican-American men, and patients treated with insulin and oral agents were disproportionately represented among those in poor glycemic control. Clinical, public health, and research efforts should focus on more effective methods to control blood glucose in patients with diabetes.     

African-American women have higher initial HbA1c levels in diabetic pregnancy

OBJECTIVE: African-American women with diabetes are at greater risk for poor glycemic control outside of pregnancy. We evaluated the effect of race on glycemic control in a racially mixed population of women with diabetes entering prenatal care. RESEARCH DESIGN AND METHODS: HbA1c levels along with demographic data were collected at the first prenatal visit from a group of 234 women with preexisting diabetes. We applied logistic multivariate analysis to identify factors associated with HbA1c levels above the median for the group. RESULTS: The median HbA1c level for the group was 8%. HbA1c levels were 8.7 +/- 2.0% in African-Americans and 7.7 +/- 1.5% in Caucasians (P < 0.001). African-American racial designation was significantly and independently associated with high HbA1c when controlled for maternal age, parity, White classification, diabetes type, education, marital status, obesity, insurance type, and first trimester entry into care. The effect of race was confined to the nonobese patients, for whom the adjusted odds ratio for African-American race as a predictor of high HbA1c was 8.15 with a 95% CI of 2.41-27.58 (P = 0.001). CONCLUSIONS: We found a clear racial disparity in glycemic control among women entering prenatal care with preexisting diabetes. This study demonstrates that there generally is need for better glycemic control among reproductive-age women with diabetes, but especially among those who are African-American.     

Intensified blood glucose monitoring improves glycemic control in stable,insulin-treated veterans with type 2 diabetes: the Diabetes Outcomes in Veterans Study (DOVES)

OBJECTIVE: To examine the effect of intensified self-monitored blood glucose (SMBG) testing on glycemic control. RESEARCH DESIGN AND METHODS: Subjects with stable, insulin-treated type 2 diabetes performed SMBG using an electronic blood glucose meter before all meals and at bedtime for 8 weeks. Baseline data were collected on demographics, clinical characteristics, diet, and exercise. HbA(1c) was measured at baseline, at 4 weeks, and at 8 weeks. After the intensified monitoring period, subjects resumed their usual monitoring. HbA(1c) was then measured at 24, 37, and 52 weeks. Multivariate linear regression was used to determine the effect of monitoring on glycemic control. RESULTS: A total of 201 subjects completed the monitoring period. The baseline HbA(1c) (8.10 +/- 1.67%) decreased during the monitoring period by 0.30 +/- 0.68% (P < 0.001) at 4 weeks and by 0.36 +/- 0.88% (P < 0.001) at 8 weeks. Although entry HbA(1c) and compliance independently predicted the week 8 HbA(1c) (r = 0.862, P < 0.001), standardized regression analysis found that compliance with the SMBG protocol influenced the week 8 HbA(1c) more than age, sex, BMI, exercise level, carbohydrate consumption, or treatment intensity at baseline. However, SMBG benefited only subjects whose testing compliance exceeded 75% or with an entry HbA(1c) >8.0%. Decreases in HbA(1c) (-0.31 +/- 1.17%, P = 0.001) persisted in the 159 subjects followed for 52 weeks. CONCLUSIONS: Intensified blood glucose monitoring improved glycemic control in a large cohort of stable, insulin-treated veterans with type 2 diabetes. SMBG provided a strong stimulus for improved self-care resulting in clinically important and sustained reductions in HbA(1c).     

Effects of postmenopausal hormone replacement therapy on HbA(1c) levels

OBJECTIVE: Estrogen seems to contribute to glucose homeostasis in women. The objective of this study was to examine the effects of hormone replacement therapy (HRT) on HbA(1c) levels in Japanese postmenopausal women and to determine whether the effects varied with age. RESEARCH DESIGN AND METHODS: We studied 99 postmenopausal women taking HRT (mean +/- SD age 56.5 +/- 6.9 years, BMI 21.5 +/- 2.3 kg/m(2)) and 101 postmenopausal women not on HRT (51.4 +/- 6.1 years, 21.3 +/- 2.4 kg/m(2)). HRT consisted of continuous conjugated equine estrogen (CEE; 0.625 mg/day) and medroxyprogesterone acetate (MPA; 2.5 mg/day) for >2 years. RESULTS: HbA(1c) levels are positively associated with age and BMI in women who use HRT as well as in those who do not use HRT. After adjusting for age and BMI, HRT showed no effects on HbA(1c) levels. However, HbA(1c) levels were significantly lower in postmenopausal women aged 40-49 years who were taking HRT than in women of similar age who were not taking HRT (mean +/- SE 4.776 +/- 0.092 vs. 5.096 +/- 0.078%, P < 0.05). No differences in HbA(1c) levels between women who did and did not use HRT were observed in those older than 50 years. CONCLUSIONS: Oral HRT involving CEE combined with MPA may decrease HbA(1c) levels in women aged 40-49 years and is likely to have no adverse effects on HbA(1c) levels in women older than 50 years.     

Reduced prevalence of limited joint mobility in type 1 diabetes in a U.K. clinic population over a 20-year period

OBJECTIVE: Limited joint mobility (LJM), one of the earliest clinically apparent long-term complications of type 1 diabetes, is a risk marker for subsequent microvascular complications. We hypothesize that the prevalence of LJM may have decreased during the past two decades due to improved standards of glycemic control. RESEARCH DESIGN AND METHODS: A single observer performed a survey in 204 consecutive patients with type 1 diabetes (106 men and 98 women, age 27 +/- 1 years, HbA(1c) 8.3 +/- 0.1%, duration of diabetes 14.5 +/- 0.8 years, insulin dose 63 +/- 2 units/day). We used the same examination method and criteria for assessment of LJM as used by us in an earlier study in 1981-1982. RESULTS: The prevalence of LJM has fallen from 43 to 23% between the 1980s and 2002 (P < 0.0001). The relative risk for LJM in 2002 compared with the 1981-1982 cohort was 0.53 (0.40 < RR < 0.72, P < 0.0001). The prevalence of LJM was increased with longer duration of diabetes (<10 years, 13%; 10-20 years, 19%; 20-29 years, 30%; >30 years, 65%; P < 0.001). The relative risk for those with a mean HbA(1c) <7% in 2002 was 0.3 (0.1 < RR < 1.2, P = 0.05) when compared with those with mean HbA(1c) >7%. CONCLUSIONS: The present study confirms the hypothesis that the prevalence of LJM is lower than 20 years ago and that improved standards of glycemic control and diabetes care may have contributed to this occurrence. Joint limitation in type 1 diabetes is strongly associated with duration of diabetes. The presence of LJM remains a common and important clinical marker for subsequent microvascular disease and can be a useful clinical tool for identification of patients at increased risk.     

Effects of postmenopausal hormone replacement therapy on central abdominal fat, glycemic control, lipid metabolism, and vascular factors in type 2 diabetes: a prospective study.

OBJECTIVE: To examine the effects of hormone replacement therapy (HRT) on lipid metabolism, glycemic control, total body and central abdominal fat, blood pressure (BP), and arterial pulse wave velocity (APWV) in overweight postmenopausal females with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a 12-month prospective study of 14 subjects (mean +/- SD age 57.5+/-5.6 years, BMI 29.5+/-4.8 kg/m2) randomized to 6 months of observation or HRT before crossover. HRT consisted of 2 months of conjugated equine estrogen (CEE) 0.625 mg daily, followed by 4 months CEE and medroxyprogesterone 5 mg daily. Measures included anthropometry, fasting glucose, insulin, HbA1c, total and HDL cholesterol, triglycerides, apolipoprotein B, LDL particle size, nonesterified fatty acids (NEFA), sex hormone-binding globulin, resting energy expenditure (REE), total and central abdominal fat (by dual-energy X-ray absorptiometry), resting BP, APWV (by applanation tonometry), physical activity, well-being, and sexual function. RESULTS: Six months of HRT resulted in significant reductions in waist-to-hip ratio (-0.03+/-0.01 vs. 0.01+/-0.009, P = 0.007), HbA1c (-0.34+/-0.24 vs. 0.6+/-0.4%, P = 0.04), total cholesterol (-0.6+/-0.1 vs. 0.2+/-0.2 mmol/l, P = 0.001), central abdominal fat (-175+/-51 vs. -24+/-56 g, P = 0.05), and improved physical functioning (P = 0.05), compared with observation. There was a minor increase in REE with HRT (33+/-23 vs. -38+/-23 kJ/day, P = 0.04). Total fat mass, fasting glucose, insulin, triglyceride, apolipoprotein B, NEFA, resting BP, APWV, and physical activity were unchanged. CONCLUSIONS: Postmenopausal HRT in these overweight women with type 2 diabetes was associated with a reduction in central adiposity and improvement in lipid metabolism and glycemic control without deterioration in weight status or cardiovascular parameters measured. Whether HRT-induced improvements in these cardiovascular risk factors result in lower long-term cardiovascular morbidity and mortality, as observed in nondiabetic women, awaits further study.     

Risk indicators predictive for severe hypoglycemia during the first trimester of type 1 diabetic pregnancy

OBJECTIVES: To investigate the frequency of severe hypoglycemia (SH) and hypoglycemic coma during the first trimester of type 1 diabetic pregnancy and in the 4 months before gestation and to identify risk indicators predicting first trimester SH in a nonselected nationwide cohort of pregnant women with type 1 diabetes. RESEARCH DESIGN AND METHODS: We conducted a longitudinal cohort survey in 278 pregnant type 1 diabetic women using questionnaires at inclusion and at 17 weeks of gestation, addressing the frequencies of SH (i.e., external help required) and hypoglycemic coma, general characteristics, hypoglycemia awareness, blood glucose symptom threshold, and the Hypoglycemia Fear Survey. RESULTS: The occurrence of SH (including hypoglycemic coma) rose from 0.9 +/- 2.4 episodes per 4 months before gestation to 2.6 +/- 6.3 episodes during the first trimester (P < 0.001), including an increase in episodes of coma from 0.3 +/- 1.3 to 0.7 +/- 3.7 (P=0.03). The proportion of women affected by SH rose from 25 to 41% (P < 0.001). First-trimester SH was independently related to a history of SH before gestation (odds ratio [95%CI]: 9.2 [3.9-21.7]), a 10 years' longer diabetes duration (1.6 [1.0-2.4]), an HbA1c level < or = 6.5% (2.5 [1.3-5.0]), and a 0.1 unit/kg higher daily insulin dose (5.4 [1.5-18.9]), adjusted for a decreased symptom threshold. CONCLUSIONS: In type 1 diabetic pregnancy, the risk of SH is increased already before pregnancy and rises further during the first trimester. A history of SH before gestation, longer duration of diabetes, an HbA1c level < or = 6.5%, and a higher total daily insulin dose were risk indicators predictive for SH during the first trimester. Further research should aim to elucidate how the benefits of strict glycemic control balance with the markedly increased risk of SH early in pregnancy.     

Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes

OBJECTIVE: To assess the 12- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 versus placebo in patients with type 2 diabetes continuing metformin treatment. RESEARCH DESIGN AND METHODS: We conducted a 12-week, randomized, double-blind, placebo-controlled trial in 107 patients with type 2 diabetes with a 40-week extension in those completing the core study and agreeing, together with the investigator, to extend treatment to 1 year. Placebo (n=51) or LAF237 (50 mg once daily, n=56) was added to ongoing metformin treatment (1,500-3,000 mg/day). HbA1c and fasting plasma glucose (FPG) were measured periodically, and standardized meal tests were performed at baseline, week 12, and week 52. RESULTS: In patients randomized to LAF237, baseline HbA1c averaged 7.7 +/- 0.1% and decreased at week 12 (Delta=-0.6 +/- 0.1%), whereas HbA1c did not change from a baseline of 7.9 +/- 0.1% in patients given placebo (between-group difference in DeltaHbA1c=-0.7 +/- 0.1%, P <0.0001). Mean prandial glucose and FPG were significantly reduced in patients receiving LAF237 versus placebo by 2.2 +/- 0.4 mmol/l (P <0.0001) and 1.2 +/- 0.4 mmol/l (P=0.0057), respectively, but plasma insulin levels were not affected. At end point of the extension, the between-group differences in change in mean prandial glucose, insulin, and FPG were -2.4 +/- 0.6 mmol/l (P=0.0001), 40 +/- 16 pmol/l (P=0.0153), and -1.1 +/- 0.5 mmol/l (P=0.0312), respectively. HbA1c did not change from week 12 to week 52 in LAF237-treated patients (n=42) but increased in participants given placebo (n=29). The between-group difference in DeltaHbA1c after 1 year was -1.1 +/- 0.2% (P <0.0001). CONCLUSIONS: Data from this study demonstrate that LAF237 effectively prevents deterioration of glycemic control when added to metformin monotherapy in type 2 diabetes.     

Leisure time physical activity is associated with poor glycemic control in type 1 diabetic women: the FinnDiane study

OBJECTIVE: We studied the association between leisure time physical activity (LTPA) and glycemic control, insulin dose, and estimated glucose disposal rate (eGDR) in type 1 diabetes. RESEARCH DESIGN AND METHODS: This is a cross-sectional study of 1,030 type 1 diabetic patients participating in the Finnish Diabetic Nephropathy Study, a nationwide multicenter study. LTPA was assessed by a validated 12-month questionnaire and expressed in metabolic equivalent (MET) units. Patients were grouped as sedentary (LTPA <10 MET h/week, n = 247), moderately active (LTPA 10-40 MET h/week, n = 568), and active (LTPA >40 MET h/week, n = 215). Outcome measures were HbA(1c), insulin dose, and eGDR (estimate of insulin sensitivity based on waist-to-hip ratio, hypertension, and HbA(1c)). RESULTS: LTPA correlated with HbA(1c) in women (r = -0.12, P = 0.007) but not in men (r = -0.03, P = 0.592). Sedentary women had higher HbA(1c) than moderately active and active women: 8.8 +/- 1.4% vs. 8.3 +/- 1.4% vs. 8.3 +/- 1.4% (P = 0.004), whereas HbA(1c) in men was 8.4 +/- 1.3% vs. 8.2 +/- 1.4% vs. 8.2 +/- 1.3% (P = 0.774), respectively. In men, insulin doses were 0.74 +/- 0.21 vs. 0.71 +/- 0.20 vs. 0.68 +/- 0.23 IU . kg(-1) . 24 h(-1) (P = 0.003). In both sexes, sedentary patients had lower eGDRs than active patients [median (interquartile range) 5.5 (4.0-8.2) vs. 6.8 (4.7-8.8) vs. 6.7 (4.6-8.6) mg . kg(-1) . min(-1); P < 0.01 for sedentary vs. others]. Age, obesity, smoking, insulin dose, social class, diabetic nephropathy, or cardiovascular disease did not explain the results. CONCLUSIONS: Low levels of LTPA were associated with poor glycemic control in type 1 diabetic women. Men seem to use less insulin when physically active. Increased LTPA levels were associated with increased estimated insulin sensitivity. Longitudinal studies are needed to further clarify the effects of LTPA on type 1 diabetes.     

Prevalence and risk factors of microalbuminuria in a cohort of African-American women with gestational diabetes

OBJECTIVE: To study the prevalence of microalbuminuria (MA) in African-American women with a history of gestational diabetes (GDM) who are at high risk for insulin resistance and renal dysfunction and to study MA's relation to insulin resistance, type 2 diabetes, and hypertension. RESEARCH DESIGN AND METHODS: MA was assessed using 24-h, timed, and/or random urine samples in a cross-sectional sample (n = 289) from a cohort of African-American women with a history of GDM and followed for a median of 11 years (range 3.0-18.4) since their diabetic pregnancy. Subjects with a urine albumin excretion rate of 30-300 g/24 h or 30-300 microg/mg creatinine in a random sample were classified as having MA if two of three samples over a 3- to 6-month period were positive. These women were evaluated for family history of diabetes, smoking and alcohol use, BMI, diabetes, hypertension, and lipid abnormalities. Insulin sensitivity was determined using the homeostasis model assessment (HOMA) estimates, which used fasting insulin and glucose measurements obtained at the same time as the MA urine sample. RESULTS: At MA assessment, the women ranged in age from 22 to 57 years, with a median of 39 years. The overall prevalence of MA was 20%; 36% in those with diabetes. Those women with MA had higher rates of diabetes (63.8 vs. 28.6%, odds ratio [OR] = 4.4, P < 0.05), hypertension (82.8 vs. 42.9%, OR = 6.4, P < 0.05), and family history of diabetes (85.7 vs. 61.7%, OR = 3.7, P < 0.05). The proportion of subjects with MA with a family history of hypertension was nonsignificantly increased (92.9 vs. 82.4%). Subjects with MA were more obese (BMI 37.2 +/- 8.9 vs. 34.4 +/- 8.6 kg/m(2)) and had higher levels of HbA(1c) (8.8 +/- 3.3 vs. 6.6 +/- 1.8%, P < 0.001) and systolic (144.3 +/- 25.9 vs. 122.8 +/- 17.2 mmHg, P < 0.0001) and diastolic (95.1 +/- 15.4 vs. 82.5 +/- 11.9 mmHg, P < 0.0001) blood pressures. Lipid fractions were similar in those with and without MA. Although fasting glucose was much higher in subjects with MA (10.3 +/- 5.8 vs. 7.1 +/- 4.2 mmol/l, P = 0.0002), insulin levels were not significantly higher in subjects with MA (17.4 +/- 21.2 vs. 15.2 +/- 12.4 pmol/l). Insulin sensitivity, as measured using log HOMA, was similar (1.5 +/- 0.6 vs. 1.6 +/- 0.6) in women with and without MA, respectively. Multivariable logistic regression analyses indicated that HbA(1c), OR = 1.16 (1.07, 1.27), and systolic blood pressure, OR = 1.27 (1.14, 1.41), were independent risk factors for MA. In those with diabetes, the subjects with MA had higher rates of hypertension-83.8 vs. 56.1%, OR = 4.1 (1.5, 11.10)-which was reflected by their higher systolic and diastolic blood pressures, 146.1 mmHg (P = 0.001) and 94.8 mmHg (P = 0.002), respectively, and lower levels of VLDL (0.45 +/- 0.22 vs. 0.61 +/- 0.33 mmol/l, P = 0.021). In the multivariable analyses of those with diabetes, the two independent risk factors for MA were similar: HbA(1c), OR = 1.13 (1.01, 1.28), and systolic blood pressure, OR = 1.21 (1.04, 1.41). CONCLUSIONS: African-American women with a history of GDM have one of the highest rates for MA. Presence of MA was not associated with insulin resistance but was significantly independently associated with HbA(1c) levels and hypertension. These results, taken in context of the literature, suggest that hypertension and glucose intolerance, in part, influence MA through different mechanisms. Because of the high prevalence of MA in this population and MA's relation to all-cause and cardiovascular mortality, screening for MA should be considered.     

Circulating 1,5-anhydroglucitol levels in adult patients with diabetes reflect longitudinal changes of glycemia: a U.S. trial of the GlycoMark assay

OBJECTIVE: 1,5-Anhydroglucitol (1,5AG) is a major circulating polyol arising primarily from ingestion and excreted competitively with glucose. Japanese studies have demonstrated reduced concentrations of 1,5AG in serum in hyperglycemic patients in comparison with euglycemic subjects and a gradual normalization of 1,5AG values for patients responding to antihyperglycemic therapies. In this first U.S. study, we assessed the ability of 1,5AG measurements to monitor glycemic control in a cohort of 77 patients with diabetes (22 with type 1 diabetes, 55 with type 2 diabetes) who presented with suboptimal glycemic control at baseline (defined as HbA(1c) >or=7%). RESEARCH DESIGN AND METHODS: Each patient received therapies consisting of combinations of diabetes education, nutritional counseling, and addition or dose adjustment of various insulins or oral antihyperglycemic medications. Therapy was targeted to reduce mean HbA(1c) by >or=1.0% over the monitoring period. 1,5AG, HbA(1c), fructosamine, and random glucose measurements were performed at baseline and at 2, 4, and 8 weeks after the initiation of therapy. RESULTS: 1,5AG, fructosamine, and glucose values progressed significantly toward euglycemia by week 2 of monitoring (Wilcoxon's signed-rank test, P < 0.05), with median changes of 93, -7, and -13% for 1,5AG, fructosamine, and glucose, respectively. In contrast, HbA(1c) values did not respond significantly to therapy until week 4. On an individual patient basis, 89.6% of patients displayed longitudinal changes of 1,5AG from baseline to week 8 in concordance with HbA(1c). 1,5AG was also highly correlated with HbA(1c) and fructosamine (Spearman rho = -0.6459 and -0.6751, respectively; both P < 0.0001). CONCLUSIONS: We conclude that 1,5AG responds sensitively and rapidly to changes in glycemia and monitors glycemic control in accordance with established markers.     

Predictors of abnormal cardiovascular autonomic function measured by frequence domain analysis of heart rate variability and conventional tests in patients with type 1 diabetes

OBJECTIVE: Frequency domain analysis of heart rate variability (HRV) is used to assess cardiovascular autonomic function. There are no prospective data on the sensitivity of its various components to glycemia or other diabetes-related risk factors compared with conventional tests and with other complications of diabetes. RESEARCH DESIGN AND METHODS: In 1985, possible risk factors of future complications were determined in 115 children with type 1 diabetes. In 1996, the presence of complications (HRV analysis, conventional tests of autonomic function, urinary albumin excretion rate [UAER], and retinopathy) were assessed in 83 of these patients (age 32 +/- 1 years, duration of diabetes 22 +/- 1 years). RESULTS: Poor glycemic control (measured as lifetime glycemic exposure or HbA1c in 1985) was the most important independent predictor of decreases in all measures of absolute power of HRV (total power [TP] and very low frequency, low frequency [LF], and high frequency [HF] power) and square root of the mean square of R-R interval differences but not of changes of normalized measures or ratios (normalized HF and LF LF/HF). Other significant independent predictors of autonomic dysfunction were late age of onset of diabetes, female sex, and high BMI. To examine the sensitivity of the various tests to glycemia, the patients were divided into tertiles based on lifetime glycemic exposure (A1c months). Glycemic exposure in the tertiles averaged 194 +/- 25 A1c months (20 years of HbA1c 0.8% above normal), 556 +/- 19 A1c months(20 years of HbA1c 2.3% above normal), and 963 +/- 30 A1c months (20 years of HbA1c 4% above normal). Tests of complications that were significantly abnormal in patients already in the lowest tertile and were correlated with glycemia were TP and severity of retinopathy. Of conventional tests, only the ratio of length of R-R intervals during expiration to inspiration (E/I ratio) was significantly related to glycemic exposure, but it required high glycemic exposure (20 years of HbA1c 4% above normal) to be abnormal. UAER was significantly increased only in the highest tertile of glycemic exposure. CONCLUSIONS: TP and retinopathy score were much more sensitive to antecedent glycemia than conventional tests of autonomic function or UAER and were significantly abnormal in patients exposed to approximately 20 years' duration of an HbA1c 0.8% above normal.     

Evaluating once- and twice-daily self-monitored blood glucose testing strategies for stable insulin-treated patients with type 2 diabetes : the diabetes outcomes in veterans study

OBJECTIVE: To evaluate once- and twice-daily self-monitored blood glucose testing strategies in assessing glycemic control and detecting hypoglycemia or hyperglycemia in patients with stable insulin-treated type 2 diabetes. RESEARCH DESIGN AND METHODS: Subjects with stable insulin-treated type 2 diabetes monitored blood glucose four times daily (prebreakfast, prelunch, predinner, and bedtime) for 8 weeks. We correlated mean blood glucose values with HbA(1c) measured after 8 weeks and determined the number of hypoglycemic (< or =3.33 mmol/l) and hyperglycemic (> or =22.20 mmol/l) readings captured at the various testing times. RESULTS: A total of 150 subjects completed the monitoring period; their average age was 67 years, 90% were men, and the mean HbA(1c) at baseline was 8.0 +/- 1.8%. The overall correlation of glucose testing and HbA(1c) was 0.79 (P < 0.0001). Mean blood glucose values for each of the four once-daily testing strategies were significantly correlated with HbA(1c) (r = 0.65-0.70, P < 0.0001), as were mean blood glucose values for each of the six twice-daily testing strategies (r = 0.73-0.75, P < 0.0001). The prebreakfast/prelunch measurements captured the largest proportion (63.6%) of the hypoglycemic readings, the predinner/bedtime measurements captured the largest proportion (66.2%) of hyperglycemic readings, and the prelunch/predinner measurements captured the largest proportion (57.7%) of all out-of-range readings. CONCLUSIONS: Twice-daily testing strategies, particularly prelunch/predinner, effectively assess glycemic control and capture a substantial proportion of out-of-range readings. However, personal testing strategies will vary depending on an individual's risk for hypoglycemia and hyperglycemia.     

Addition of nateglinide to rosiglitazone monotherapy suppresses mealtime hyperglycemia and improves overall glycemic control

OBJECTIVE: To determine the effects of nateglinide added to rosiglitazone monotherapy on glycemic control and on postprandial glucose and insulin levels in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This 24-week, multicenter, double-blind, randomized study compared the efficacy of nateglinide (120 mg a.c.) and placebo added to rosiglitazone monotherapy (8 mg q.d.) in 402 patients with type 2 diabetes with HbA(1c) between 7 and 11% (inclusive). Efficacy parameters tested included HbA(1c) and plasma glucose and insulin levels in the fasting state and after a standardized meal challenge. Safety data were also collected. RESULTS: In placebo-treated patients, HbA(1c) did not change (Delta = 0.0 +/- 0.1%). In patients randomized to nateglinide, HbA(1c) decreased from 8.3 to 7.5% (Delta = -0.8 +/- 0.1%, P < 0.0001 vs. placebo). Target HbA(1c) (<7.0%) was achieved by 38% of patients treated with combination therapy and by 9% of patients remaining on rosiglitazone monotherapy. In nateglinide-treated patients, fasting plasma glucose levels decreased by 0.7 mmol/l, 2-h postprandial glucose levels decreased by 2.7 mmol/l, and 30-min insulin levels increased by 165 pmol/l compared with no changes from baseline of these parameters with placebo added to rosiglitazone (P < 0.001). CONCLUSIONS: By selectively augmenting early insulin release and decreasing prandial glucose excursions, nateglinide produced a clinically meaningful improvement in overall glycemic exposure in patients with type 2 diabetes inadequately controlled with rosiglitazone. Therefore, nateglinide substantially improves the likelihood of achieving a therapeutic target of HbA(1c) <7.0%.     

Impact of overweight on chronic microvascular complications in type 1 diabetic patients

OBJECTIVE: To investigate a possible association of BMI with retinopathy and neuropathy in type 1 diabetes. Retinopathy and neuropathy may not only be related to glycemic control and diabetes duration but also to blood pressure and BMI. RESEARCH DESIGN AND METHODS: A total of 592 type 1 diabetic patients without nephropathy were studied (M/F: 324/268; age: 41 +/- 12 years; duration: 19 +/- 11 years; HbA(1c) [A1C]: 7.9 +/- 1.1%). Patients were subdivided according to BMI: 168 men and 146 women with BMI <25 kg/m(2), and 156 men and 122 women with BMI > or =25 kg/m(2). Retinopathy was examined by fundoscopy and neuropathy by electromyography. RESULTS: Hypertension (>130/85 mmHg) was present in 40%, retinopathy in 53%, and neuropathy in 43% of patients. Overweight subjects had more retinopathy (63 vs. 45%, P < 0.0001, odds ratio [OR] = 2.1) and neuropathy (49 vs. 38%, P = 0.008, OR = 1.6) than normal-weight patients. Patients with retinopathy were older (45 +/- 12 vs. 37 +/- 11 years, P < 0.0001) and had a longer diabetes duration (25 +/- 10 vs. 12 +/- 8 years, P < 0.0001), a higher A1C (8.0 +/- 1.1 vs. 7.7 +/- 1.1%, P = 0.001), and a higher BMI (25.8 +/- 4.1 vs. 24.7 +/- 4.2 kg/m(2), P = 0.001) than individuals without retinopathy. The same results are found in neuropathy. Logistic regression analysis showed that diabetes duration (beta = 0.15, P < 0.0001), blood pressure (beta = 0.22, P = 0.0047), and A1C (beta = 0.24, P = 0.01), but not BMI, lipid levels, sex, or age, were independent risk factors for retinopathy. Likewise, duration (beta = 0.05, P < 0.0001), age (beta = 0.04, P = 0.0001), A1C (beta = 0.35, P < 0.0001), and sex (beta = 0.74, P = 0.0001) but not BMI, lipid levels, or hypertension were independently associated with neuropathy. Men had more neuropathy than women (50 vs. 34%, P < 0.0001, OR = 1.9). Leptin and adiponectin levels did not differ between individuals with or without microvascular complications. CONCLUSIONS: Retinopathy and neuropathy are more prevalent in overweight (BMI > or =25 kg/m(2)) type 1 diabetic subjects. However, logistic regression analysis showed that diabetes duration and A1C remain the main determinants for retinopathy and neuropathy.     

Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes

OBJECTIVE: This study evaluates the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing to achieve glycemic control with maximally effective metformin doses. RESEARCH DESIGN AND METHODS: A triple-blind, placebo-controlled, 30-week study at 82 U.S. sites was performed with 336 randomized patients. In all, 272 patients completed the study. The intent-to-treat population baseline was 53 +/- 10 years with BMI of 34.2 +/- 5.9 kg/m(2) and HbA(1c) of 8.2 +/- 1.1%. After 4 weeks of placebo, subjects self-administered 5 microg exenatide or placebo subcutaneously twice daily for 4 weeks followed by 5 or 10 microg exenatide, or placebo subcutaneously twice daily for 26 weeks. All subjects continued metformin therapy. RESULTS: At week 30, HbA(1c) changes from baseline +/- SE for each group were -0.78 +/- 0.10% (10 microg), -0.40 +/- 0.11% (5 microg), and +0.08 +/- 0.10% (placebo; intent to treat; adjusted P < 0.002). Of evaluable subjects, 46% (10 microg), 32% (5 microg), and 13% (placebo) achieved HbA(1c) < or =7% (P < 0.01 vs. placebo). Exenatide-treated subjects displayed progressive dose-dependent weight loss (-2.8 +/- 0.5 kg [10 microg], -1.6 +/- 0.4 kg [5 microg]; P < 0.001 vs. placebo). The most frequent adverse events were gastrointestinal in nature and generally mild to moderate. Incidence of mild to moderate hypoglycemia was low and similar across treatment arms, with no severe hypoglycemia. CONCLUSIONS: Exenatide was generally well tolerated and reduced HbA(1c) with no weight gain and no increased incidence of hypoglycemia in patients with type 2 diabetes failing to achieve glycemic control with metformin.     

Poor prognosis of young adults with type 1 diabetes: a longitudinal study

OBJECTIVE: To determine the role of early behavioral and psychological factors on later outcomes in young adults with childhood- or adolescent-onset type 1 diabetes. RESEARCH DESIGN AND METHODS: We conducted a longitudinal cohort study of patients recruited from the register of the young adult outpatient diabetes clinic, Oxford, U.K. A total of 113 individuals (51 male subjects) aged 17-25 years completed assessments, and 87 (77%) were reinterviewed as older adults (aged 28-37 years). Longitudinal assessments were made of glycemic control (HbA(1c)) and complications. Psychological state at baseline was assessed using the Present State Examination and self-report Symptom Checklist, with corresponding interview schedules administered at follow-up. RESULTS: There was no significant improvement between baseline and follow-up in mean HbA(1c) levels (8.5 vs. 8.6% in men, 9.3 vs. 8.7% in women). The proportion of individuals with serious complications (preproliferative or laser-treated retinopathy, proteinuria or more severe renal disease, peripheral neuropathy, and autonomic neuropathy) increased from 3-37% during the 11-year period. Women were more likely than men to have multiple complications (23 vs. 6%, difference 17%, 95% CI 4-29%, P = 0.02). Psychiatric disorders increased from 16 to 28% (20% in men, 36% in women at follow-up, difference NS), and 8% had psychiatric disorders at both assessments. Baseline psychiatric symptom scores predicted follow-up scores (beta = 0.32, SE [beta] 0.12, P = 0.008, 95% CI 0.09-0.56) and recurrent admissions with diabetic ketoacidosis (odds ratio 9.1, 95% CI 2.9-28.6, P < 0.0001). CONCLUSIONS: The clinical and psychiatric outcome in this cohort was poor. Psychiatric symptoms in later adolescence and young adulthood appeared to predict later psychiatric problems.     

Clinical and psychological course of diabetes from adolescence to young adulthood: a longitudinal cohort study

OBJECTIVE: To determine the clinical and psychological course of diabetes through adolescence and the relationship with glycemic control in young adulthood. RESEARCH DESIGN AND METHODS: A longitudinal cohort study of adolescents recruited from the register of the outpatient pediatric diabetes clinic. A total of 76 individuals (43 male patients, 33 female patients) aged 11-18 years completed baseline assessments, and 65 individuals (86%) were reinterviewed as young adults (20-28 years of age). Longitudinal assessments were made of glycemic control (HbA(1c)), weight gain (BMI), and development of complications. Adolescents completed self-report questionnaires to assess emotional and behavioral problems as well as self-esteem. As young adults, psychological state was assessed by the Revised Clinical Interview Schedule and the self-report Brief Symptom Inventory. RESULTS: Mean HbA(1c) levels peaked in late adolescence and were worse in female participants (average 11.1% at 18-19 years of age). The proportion of individuals who were overweight (BMI >25.0 kg/m(2)) increased during the 8-year period from 21 to 54% in female patients and from 2 to 28% in male patients. Serious diabetes-related events included death in one patient and cognitive impairment in two patients. Individuals in whom diabetic complications developed (25% of male patients and 38% of female patients) had significantly higher mean HbA(1c) levels than those without complications (difference 1.9%, 95% CI 1.1-2.7, P < 0.0001). Behavioral problems at baseline were related to higher mean HbA(1c) during the subsequent 8 years (beta = 0.15, SEM (beta) 0.04, P < 0.001, 95% CI 0.07-0.24). CONCLUSIONS: The outcome for this cohort was generally poor. Behavioral problems in adolescence seem to be important in influencing later glycemic control.