Effect of diabetes on caregiver burden in an observational study of individuals with Alzheimer's disease.

BACKGROUND: The burden on caregivers of patients with Alzheimer's disease (AD) is associated with the patient's functional status and may also be influenced by chronic comorbid medical conditions, such as diabetes. This post-hoc exploratory analysis assessed whether comorbid diabetes in patients with AD affects caregiver burden, and whether caregivers with diabetes experience greater burden than caregivers without diabetes. Caregiver and patient healthcare resource use (HCRU) were also assessed. METHODS: Baseline data from the GERAS observational study of patients with AD and their caregivers (both n = 1495) in France, Germany and the UK were analyzed. Caregiver burden was assessed using the Zarit Burden Interview (ZBI). Caregiver time on activities of daily living (ADL: basic ADL; instrumental ADL, iADL) and supervision (hours/month), and caregiver and patient HCRU (outpatient visits, emergency room visits, nights hospitalized) were assessed using the Resource Utilization in Dementia instrument for the month before the baseline visit. Regression analyses were adjusted for relevant covariates. Time on supervision and basic ADL was analyzed using zero-inflated negative binomial regression. RESULTS: Caregivers of patients with diabetes (n = 188) were younger and more likely to be female (both p < 0.05), compared with caregivers of patients without diabetes (n = 1307). Analyses showed caregivers of patients with diabetes spent significantly more time on iADL (+16 %; p = 0.03; increases were also observed for basic ADL and total caregiver time but did not reach statistical significance) and had a trend towards increased ZBI score. Patients with diabetes had a 63 % increase in the odds of requiring supervision versus those without diabetes (p = 0.01). Caregiver and patient HCRU did not differ according to patient diabetes. Caregivers with diabetes (n = 127) did not differ from those without diabetes (n = 1367) regarding burden/time, but caregivers with diabetes had a 91 % increase in the odds of having outpatient visits (p = 0.01). CONCLUSIONS: This cross-sectional analysis found caregiver time on iADL and supervision was higher for caregivers of patients with AD and diabetes versus without diabetes, while HCRU was unaffected by patient diabetes. Longitudinal analyses assessing change in caregiver burden over time by patient diabetes status may help clarify the cumulative impact of diabetes and AD dementia on caregiver burden.

An individualized inpatient diabetes education and hospital transition program for poorly controlled hospitalized patients with diabetes.

OBJECTIVE: To evaluate predictors of outcomes associated with an inpatient diabetes education and discharge support program for hospitalized patients with poorly controlled diabetes (glycated hemoglobin [HbA1c]>9%). METHODS: Patients participated in individualized diabetes education conducted by a certified diabetes educator (CDE) that included an exploration of barriers and goal setting during hospitalization with telephone follow-up and communication with primary providers at discharge. Predictors of HbA1c reduction, successful follow-up, and readmission were analyzed. RESULTS: There were 82 subjects, and 48% were insulin naïve. Patients with type 2 diabetes (T2D, n = 58) had a significant decrease in HbA1c at follow-up (-2.8%, P<.0001), while those with type 1 diabetes (T1D, n = 19) did not (+0.02%, P = .96). However, after adjustment for other factors, only increasing age, higher baseline HbA1c, earlier education, and initiation of basal insulin were significant predictors of reduction in HbA1c. Higher area level income and empowerment and earlier education were significant predictors of outpatient follow-up within 30 days. While 28% were admitted for severe hyperglycemia, only 1 patient was readmitted with severe hyperglycemia. Successful phone contact was 77% and 57% with and without the support of non-CDE assistants respectively, but all outcomes were similar. CONCLUSION: The study suggests that an individualized inpatient diabetes education and transition program is associated with a significant reduction in HbA1c that is dependent on baseline HbA1c, older age, initiation of insulin, and earlier enrollment. Additional interventions are needed to ensure better continuity of care.

Long-term safety and efficacy of a universal nursing-run intravenous insulin guideline.

BACKGROUND: Despite the plethora of data in the critical care setting, there are few studies to guide clinicians in the hospitalwide care of patients with hyperglycemia. METHODS: Patients 18 years of age and older who had a discharge diagnosis code for diabetes were admitted between January 1, 2005, and December 31, 2010, and received an insulin infusion for any reason were included in the analysis. Patients were receiving noncritical care or cardiac care (with interchangeable critical and noncritical care capacity). The effect of an insulin infusion guideline introduced in 2006 with a target glucose of 5.6-8.3 mmol/L was measured. Hyperglycemic (> 11.1 mmol/L) and hypoglycemic (< 3.9 or < 2.8 mmol/L) events were analyzed using multivariable models. RESULTS: After adjusting for age, gender, race, and nutrition, there was a significant decrease in time to first glucose < 8.3 mmol/L in hours (T8.3; p = .01) and hyperglycemia (p < .0001) in the year following implementation of the guideline in cardiac but not noncritical beds, which persisted through 2010. There was a significant decrease in hypoglycemic events by Year 3 in cardiac beds and by Year 5 in noncritical beds. Compared with patients who received nothing by mouth, patients eating discrete meals had significantly longer T8.3, greater variability, and more hyperglycemic and hypoglycemic events in cardiac and noncritical beds. CONCLUSIONS: Following the hospitalwide implementation of a nursing-run insulin infusion guideline, rapid, stable reduction in hyperglycemia was achieved in cardiac beds (having interchangeable ICU and non-ICU status), and the frequency of hypoglycemia steadily decreased over time in both cardiac and noncardiac beds. Oral intake and enteral feeding were associated with worse glycemic control.

Characterization of metabolically unhealthy overweight/obese African American women: significance of insulin-sensitive and insulin-resistant phenotypes.

BACKGROUND: Obesity is often associated with high cardiovascular disease risk factors. Obesity is common in African American women. We investigated the characteristics of metabolically healthy and metabolically unhealthy overweight/obese African American women based on the presence of insulin resistance. MATERIALS/METHODS: We studied 196 apparently healthy overweight/obese African American women with family history of type 2 diabetes. Waist circumference, fasting glucose, insulin, c-peptide, lipids and lipoproteins, and systolic and diastolic blood pressure were obtained in each subject. In addition, insulin sensitivity was calculated using Bergman's Minimal Model Method. We defined insulin-sensitive metabolically healthy African American women as individuals with insulin sensitivity greater than 2.7 x 10(-4) x min(-1) (uU/ mL)(-1) and insulin resistant, metabolically unhealthy as insulin sensitivity less than 2.7 x 10(-4) x min(-1) (uU/mL)(-1). RESULTS: Thirty-three percent of our subjects were metabolically healthy African American women, while 67% were metabolically unhealthy African American women. The metabolically healthy subjects were significantly younger and less obese than the metabolically unhealthy subgroup. Mean fasting serum glucose, insulin, and c-peptide were significantly lower (P = .001) in the metabolically healthy than in metabolically unhealthy subjects. However, the mean blood pressures were within normal in both subgroups. Mean serum cholesterol (p < .05) and triglyceride (p < .001) levels were significantly lower, whereas high-density lipoprotein cholesterol (p < .03) was significantly higher in the metabolically healthy than in the metabolically unhealthy subjects. We found 25.5% of our subjects had metabolic syndrome (30.3% metabolically unhealthy and 15.6% metabolically healthy). CONCLUSION: We concluded that: (1) despite obesity, metabolically healthy African American women appear to be less prone to type 2 diabetes and cardiovascular disease and (2) in view of the higher prevalence of metabolic syndrome, metabolically unhealthy African American women should be targeted for primary prevention of type 2 diabetes and cardiovascular disease.

The effect of glycaemic control and glycaemic variability on mortality in patients hospitalized with congestive heart failure.

BACKGROUND: diabetes and CHF are common comorbidities in hospitalized patients but the relationship between glycaemic control, glycaemic variability, and mortality in patients with both conditions is unclear. METHODS: we used administrative data to retrospectively identify patients with a diagnosis of CHF who underwent frequent glucose assessments. TWMG was compared with other measures of glycaemic control and a time-weighted measure of glycaemic variability, the glycaemic lability index. The outcome was hospital mortality. RESULTS: a total of 748 patients were included in the final analysis. Time-weighted mean glucose was higher than unadjusted mean glucose (137 + /- 44.7 mg/dL versus 167 + /- 54.9, p < 0.001), due in part to shorter sampling intervals at higher glucose levels. Hypoglycaemia, defined as a glucose level < 70 mg/dL, occurred during 6.3% of patient-days in survivors and 8.4% of patient-days among nonsurvivors (p = 0.05). Time-weighted mean glucose was similar (128 + /- 33.1 mg/dL versus 138 + /- 45.1 mg/dL) in nonsurvivors versus survivors, p = 0.19). However, relatively few patients had were significantly elevated readings. Median GLI was higher in nonsurvivors compared with that in survivors (18.1 versus 6.82, p = 0.0003). Increasing glycaemic lability index (odds ratio 1.32, 95% confidence interval 1.05-1.65), and hypoglycaemia (odds ratio 2.21, 95% confidence interval 1.07-4.65), were independently associated with higher mortality in logistic regression analysis. Respiratory failure was associated with mortality, but not standard deviation of glucose. CONCLUSIONS: future studies analysing glycaemic control should control for variable sampling intervals. In this analysis, glycaemic lability index was independently associated with increased mortality, independent of hypoglycaemia. Prospective studies are needed to evaluate these findings.

Metabolic syndrome in Black people of the African diaspora: the paradox of current classification, definition and criteria.

According to the third National Health and Nutrition Examination Survey, African Americans have a lower prevalence of metabolic syndrome than do Whites. Recent reports in Blacks in other regions have confirmed these observations, but the rates vary. This lower rate of metabolic syndrome in Blacks can be partly ascribed to the lower prevalent rates of some major components of metabolic syndrome, namely serum triglyceride and high-density lipoprotein cholesterol levels in Blacks. This is in contrast with the higher prevalence of obesity (waist circumference) and blood pressure that meet National Cholesterol Education Program criteria in Blacks. Despite these seemingly favorable lipids and lipoprotein profiles, Blacks continue to have higher cardiovascular disease (CVD) mortality and morbidity, even in the absence of diabetes, than do Whites. Insulin resistance is more prevalent in Blacks than in Whites. However, the relationships among insulin resistance and CVD risk factors such as hypertension, high-density lipoprotein cholesterol, and triglycerides are weak in contrast with Whites. The paradox of more favorable lipid profile and conversely the higher rates of unfavorable blood pressure in Blacks calls into question the validity of the current criteria for metabolic syndrome in Blacks. Thus, it can be argued that each of the components of the metabolic syndrome carry different CVD risk factors in Blacks. The greater CVD mortality and morbidity in Blacks appear to be multifactorial. With the emerging epidemic of noncommunicable diseases, chronic kidney diseases due to both diabetes and hypertension have emerged as major CVD risks that are associated with increasing mortality and morbidity in Blacks. We need to emphasize specific components of metabolic syndrome, specifically blood pressure and chronic kidney disease, that carry higher CVD risk with associated greater morbidity and mortality for primary prevention of CVD and type 2 diabetes in Blacks. To this end, we believe the higher prevalence of hypertension and chronic kidney diseases in Blacks suggests that the current classification, definition, and criteria for metabolic syndrome in Blacks should be reconsidered.

Short-term aerobic exercise training in obese humans with type 2 diabetes mellitus improves whole-body insulin sensitivity through gains in peripheral, not hepatic insulin sensitivity.

CONTEXT: Short-term aerobic exercise training can improve whole-body insulin sensitivity in humans with type 2 diabetes mellitus; however, the contributions of peripheral and hepatic tissues to these improvements are not known. OBJECTIVE: Our objective was to determine the effect of 7-d aerobic exercise training on peripheral and hepatic insulin sensitivity during isoglycemic/hyperinsulinemic clamp conditions. DESIGN: Subjects were randomly assigned to one of two groups. The energy balance group consumed an isocaloric diet consisting of 50% carbohydrate, 30% fat, and 20% protein for 15 d. The energy balance plus exercise group consumed a similar diet over the 15 d and performed 50-min of treadmill walking at 70% of maximum oxygen consumption maximum during the second 7 d of the 15-d study period. Each subject underwent an initial isoglycemic/hyperinsulinemic clamp after 1-wk dietary control and a second clamp after completing the study. SETTING: The study was performed at Ohio State University's General Clinical Research Center. PARTICIPANTS: There were 18 obese, mildly diabetic humans included in the study. INTERVENTION: Aerobic exercise training was performed for 7 d. MAIN OUTCOME MEASURES: Whole-body, peripheral, and hepatic insulin sensitivity were measured. RESULTS: Exercise training did not have an impact on peripheral glucose uptake or endogenous glucose production during the basal state or low-dose insulin. Likewise, it did not alter endogenous glucose production during high-dose insulin. However, 1-wk of exercise training increased both whole-body (P<0.05) and peripheral insulin sensitivity (P<0.0001) during high-dose insulin. CONCLUSION: Improvements to whole body insulin sensitivity after short-term aerobic exercise training are due to gains in peripheral, not heptic insulin sensitivity.

Resistance training differentially affects weight loss and glucose metabolism of White and African American patients with type 2 diabetes mellitus.

OBJECTIVE: We aimed to identify whether racial differences in body composition and glucose metabolism occur in response to exercise and determine whether aerobic and resistance exercise modalities bring about differential changes in these parameters in African Americans and White persons with type 2 diabetes. RESEARCH DESIGN AND METHODS: Participants included 36 African American and 23 White men and women with type 2 diabetes who were randomly assigned to eight weeks of either resistance or aerobic exercise. Before and after this intervention, each participant underwent a series of measurements that assessed anthropometrics and glucose metabolism. RESULTS: African Americans responded more favorably to resistance training than did Whites. This difference was manifested by a significant improvement in BMI (-2.57%+/-.90% vs 2.57%+/-1.09%, P<.01) and insulin resistance (-19.15%+/-9.00% vs 13.12%+/-11.86%, P<.05) in African Americans compared to Whites. When comparing exercise modalities within the races, African Americans demonstrated a preferential response to resistance training. CONCLUSIONS: Eight weeks of resistance training by African Americans may have a more positive effect on weight loss and glucose metabolism than aerobic exercise training. Furthermore, the changes observed appear to be unique to African Americans, as no changes were observed in Whites after an equal amount of resistance training. When an exercise program is designed for a person with type 2 diabetes, race should be taken into consideration, and resistance exercise for African Americans may lead to increased weight loss and improved insulin sensitivity than does aerobic exercise.

Association between glycosylated hemoglobin, left ventricular mass and aortic function in nondiabetic individuals with insulin resistance.

OBJECTIVE: An association between glycosylated hemoglobin (GHb) and cardiovascular mortality in nondiabetic individuals has recently been reported. Prompt detection of nondiabetic individuals with high-normal GHb and early cardiovascular involvement may be of value for preventive strategies. In this investigation, a possible relationship between GHb, aortic function and left ventricular (LV) mass in nondiabetic individuals has been studied. METHODS: A total of 263 nondiabetic African-Americans, aged 22-63 (mean 42 +/- 8) years were studied. All individuals were first degree relatives of diabetic patients, had normal oral glucose tolerance test (2-h OGTT) and decreased peripheral action of insulin. LV diameters and mass (echocardiography); ascending and abdominal aortic distensibility (echocardiography, arterial pressure); pulse wave velocity (PWV; electrocardiography, Doppler); fasting glucose; GHb; insulin sensitivity index (S(I)) and 2-h OGTT were measured. Multiple linear and logistic regression analyses were used to identify significant independent associations of fasting glucose; GHb; S(I) and 2-h OGTT with aortic function and LV mass. RESULTS: In fully adjusted multivariate logistic regression analysis, GHb predicted lower values of aortic distensibility (odds ratio (OR) 1.67 95% CI (1.04-2.75), P=0.04); higher PWV (OR 1.79 95% CI (1.09-2.93), P=0.022); and higher values of LV mass (OR 1.56 95% CI (1.08-2.88), P=0.029). Fasting glucose, S(I), and 2 h OGTT were not associated with aortic function and LV mass. CONCLUSION: Higher GHb concentrations, even within 'normal' range, are independently associated with stiffer aorta and increased LV mass and thus may detect nondiabetic individuals at increased cardiovascular risk.

Thiazolidinediones increase hepatic insulin extraction in African Americans with impaired glucose tolerance and type 2 diabetes mellitus. A pilot study of rosiglitazone.

Peripheral insulin levels are determined by beta-cell secretion, insulin sensitivity, and hepatic insulin extraction (HIE). We have previously shown that whereas sulfonylureas reduce insulin extraction, metformin enhances HIE. However, the effects of thiazolidinediones (TZDs) on HIE remain uncertain. Thus, we investigated the potential contribution of hepatic insulin clearance to peripheral insulin levels during rosiglitazone therapy in African Americans with impaired glucose tolerance (IGT) and type 2 diabetes mellitus (DM). The study was composed of 12 first-degree relatives with IGT and 17 patients with newly diagnosed type 2 DM. Nineteen healthy relatives with normal glucose tolerance served as controls. Serum glucose, insulin, and C-peptide, and HIE (C-peptide-insulin molar ratios) were measured at t = 0 and 120 minutes during oral glucose tolerance test (OGTT) in all the subjects. The OGTT was performed before and after 3 months of rosiglitazone therapy (4 mg/d x 4 weeks and >8 mg/d x 8 weeks) in patients with IGT and type 2 DM. Insulin resistance index and beta-cell function were calculated in each subject using homeostasis model assessment (HOMA). Rosiglitazone therapy improved but did not normalize the overall glycemic control in the IGT and type 2 DM groups. After rosiglitazone therapy, the mean serum insulin and C-peptide levels at fasting remained unchanged. However, the 2-hour serum glucose and insulin were lower, whereas serum C-peptide was unchanged during 3 months of rosiglitazone treatment. Mean insulin resistance index of HOMA was reduced by 30% (4.12 +/- 1.95 vs 6.33 +/- 3.54, P < .05) in the type 2 DM group and by 21% (3.78 +/- 2.45 vs 4.81 +/- 3.49, P = NS) in the IGT group. Mean HIE values were significantly lower (70%) in the type 2 DM and IGT groups when compared with the normal glucose tolerance group. At 3 months, basal HIE was not significantly changed by rosiglitazone therapy in IGT and type 2 DM groups when compared with the baseline (0 month). However, rosiglitazone therapy was associated with increased HIE at 2 hours during OGTT by 40% and 30% in the IGT and type 2 DM groups, respectively, from the baseline (0 month) values. Furthermore, HIE inversely correlated with the insulin resistance index of HOMA (r = -.46, P < .05). We conclude that rosiglitazone therapy improved overall glucose tolerance and enhanced insulin sensitivity in patients with IGT and type 2 DM. Although basal HIE remained unchanged, rosiglitazone therapy increased postglucose challenge HIE in African Americans with IGT and type 2 DM. We speculate that TZDs increase insulin clearance or HIE after oral glucose challenge. This study suggests that in addition to insulin sensitization, rosiglitazone may be involved in insulin metabolism. The significance of the increased insulin clearance by TZD therapy remains uncertain and deserves further investigation in patients with insulin resistance and glucose intolerance.

Metabolic syndrome in nondiabetic, obese, first-degree relatives of African American patients with type 2 diabetes: African American triglycerides-HDL-C and insulin resistance paradox.

OBJECTIVE: Metabolic syndrome (MetS) defines cardiovascular disease (CVD) risks. Despite higher rates of obesity, type 2 diabetes, and hypertension, African Americans have lower rates of MetS when compared to Caucasians, which is paradoxical, since African Americans are more insulin resistant and have higher rates of cardiovascular morbidity and mortality when compared to White Americans. We hypothesized that genetic inheritance predisposes African Americans to the greater cardiovascular risk and the associated morbidity and mortality. Therefore, we investigated the prevalence of components of MetS in obese, glucose-tolerant, first degree relatives of African American patients with type 2 diabetes. METHODS: We examined the clinical and metabolic characteristics of 201 first-degree relatives (159 females and 42 males, mean age 41 +/- 8 years, and mean body mass index (BMI) of 32 +/- 8 (kg/m2). The subjects were categorized with MetS according to the Adult Treatment Panel (ATP) III criteria. Insulin sensitivity (Bergman minimal model method) and insulin resistance (homeostasis model assessment [HOMA]) were determined. We compared the clinical and metabolic characteristics in the relatives with and without MetS. Where appropriate, we compared the prevalence of the components of MetS in our African American sample with those of African American data in the National Health and Nutrition Evaluation Survey (NHANES) III. RESULTS: Comparing the MetS group (n=65) vs control subjects (n=136), the mean age, BMI, and percent body fat were greater in the MetS group. Mean fasting serum glucose, insulin and C-peptide levels were also greater in the MetS group. Insulin resistance index (HOMA-IR) was higher in the MetS group (HOMA-IR: 3.7 +/- 2.7 vs 2.2 +/- 1.7, P=.0002). Mean insulin sensitivity tended to be lower in the MetS group (2.16 +/- 2.64 vs 2.82 +/- 2.31, P=.08). In addition, despite the moderately severe insulin resistance, the MetS group had very low serum triglyceride levels and was the parameter least likely to meet the ATP criteria. The metabolic cutoff points for ATP III criteria were much lower in African American first-degree relatives with MetS. Of the five components of the ATP III criteria, waist circumference was the single most common parameter to likely meet the MetS criteria. We found that the prevalence of MetS was 29% in women and 40% in men when compared with 20.9% in African American women and 13.9% for African American men in the NHANES III. CONCLUSION: We found that: 1) the prevalence of MetS is higher in a subgroup of African Americans who were first-degree relatives of patients with type 2 diabetes than that of African Americans in the NHANES III; and 2) waist circumference rather than metabolic parameters was the single most important parameter and was more likely to meet the MetS criteria in African American relatives.

Teriparatide in patients with osteoporosis and type 2 diabetes.

Despite evidence for higher fracture risk, clinical effects of osteoporosis treatments in type 2 diabetes (T2D) are largely unknown. Post hoc analyses of the DANCE observational study compared T2D patients and patients without diabetes to assess the effect of teriparatide, an osteoanabolic therapy on skeletal outcomes and safety. Patients included ambulatory men and women with osteoporosis receiving teriparatide 20µg/day SQ up to 24months followed by observation up to 24months. Main outcome measures included nonvertebral fracture incidence comparing 0-6months with 6+ months of teriparatide, change from baseline in BMD and back pain severity, and serious adverse events. Analyses included 4042 patients; 291 with T2D, 3751 without diabetes. Treatment exposure did not differ by group. For T2D patients, fracture incidence was 3.5 per 100 patient-years during 0-6months treatment, and 1.6 during 6months to treatment end (47% of baseline, 95% CI 12-187%); during similar periods, for patients without diabetes, fracture incidence was 3.2 and 1.8 (57% of baseline, 95% CI 39-83%). As determinants of fracture outcome during teriparatide treatment, diabetes was not a significant factor (P=0.858), treatment duration was significant (P=0.003), and the effect of duration was not significantly different between the groups (interaction P=0.792). Increases in spine and total hip BMD did not differ between groups; increase in femoral neck BMD was greater in T2D patients than in patients without diabetes (+0.34 and +0.004g/cm(2), respectively; P=0.014). Back pain severity decreased in both groups. Teriparatide was well tolerated without new safety findings. In conclusion, during teriparatide treatment, reduction in nonvertebral fracture incidence, increase in BMD, and decrease in back pain were similar in T2D and non-diabetic patients.

Discrepancies in the regulation of plasma adiponectin and TNF-alpha levels and adipose tissue gene expression in obese African Americans with glucose intolerance: a pilot study using rosiglitazone.

OBJECTIVES: We examined the effects of rosiglitazone: 1) on glucose homeostasis, insulin action, beta-cell function, and plasma adiponectin and TNF-alpha (TNF-alpha) levels; and 2) the expression of adipose tissue TNF-alpha and adiponectin mRNA in African Americans with parental history of type 2 diabetes and with varying degrees of glucose intolerance. SUBJECTS AND METHODS: The study groups comprised 11 African Americans with normal glucose tolerance and six with diabetes and impaired glucose tolerance. The glucose-intolerant subjects received rosiglitazone (4-8 mg/day) every morning for 12 weeks. They underwent oral glucose tolerance test (OGTT) and subcutaneous adipose tissue biopsy (under local anesthesia) before and after 12 weeks of rosiglitazone therapy. Beta cell function and insulin resistance were calculated by using homeostasis model assessment (HOMA). Adipose tissue gene expression (mRNA) was measured by real-time polymerase chain reaction in both groups. RESULTS: Rosiglitazone monotherapy improved both fasting and two-hour serum glucose levels during OGTT in the glucose-intolerant group. However, mean serum insulin and C-peptide levels did not change when compared with baseline. Rosiglitazone monotherapy improved insulin resistance but not overall beta-cell secretion. Mean adiponectin levels at fasting and two hours after oral glucose ingestion were significantly (50%) lower in the glucose-intolerant group than in the control group. Rosiglitazone monotherapy significantly increased plasma adiponectin levels at fasting and two hours after oral challenge by two-fold in the glucose-intolerant group. Mean plasma TNF-alpha levels were not significantly different at fasting and after two hours during OGTT. Rosiglitazone had no significant effect on plasma TNF-alpha levels during OGTT. No significant differences were seen in the expression of adipose tissue TNF-alpha and adiponectin mRNA in the groups at baseline. Rosiglitazone did not significantly change the adipose tissue adiponectin and TNF-alpha mRNA. Rosiglitazone was well tolerated, without experiencing weight gain, edema, and liver function test abnormality in the glucose intolerant subjects. SUMMARY: Rosiglitazone improved glucose homeostasis and insulin resistance in high-risk African Americans. We found that adiponectin was lower in the glucose-intolerant group, while TNF-alpha was similar. While rosiglitazone increased plasma adiponectin, it had no effect on adipose tissue adiponectin mRNA. In addition, rosiglitazone had no effect on plasma TNF-alpha and adipose tissue TNF-alpha mRNA. We conclude that the metabolic effects of rosiglitazone could be mediated by adiponectin but not TNF-alpha in African Americans with glucose intolerance. Our study demonstrates that: 1) the role of adipocytokines in the etiology of type 2 diabetes in African Americans is complex; and 2) that adiponectin, but not TNF-alpha, could mediate the metabolic benefits of thiazolidinediones in African Americans with glucose intolerance.

Cardiovascular effects of type 1 diabetes mellitus in children.

Previous studies have shown that type 1 diabetes mellitus (DM) is associated with cardiovascular abnormalities. Early detection and treatment of these abnormalities may help to prevent the natural progression of the disease. The present study was undertaken to define early cardiovascular abnormalities in children with type 1 DM. Simultaneous evaluation of multiple cardiovascular parameters was performed in 14 children with type 1 DM and 14 age-and gender-matched normal subjects. Measurements of carotid artery intima-media thickness (cIMT, echocardiography), carotid and aortic (ascending and abdominal) distensibility (echocardiography, brachial artery blood pressure), aortic pulse wave velocity (carotid to femoral artery, Doppler), and left ventricular dimensions, mass, and function (echocardiography) were performed. Diabetic children demonstrated a greater cIMT (0.36 +/- 0.04 mm vs 0.31 +/- 0.03 mm, p = 0.002) and decreased carotid artery distensibility (4.4 +/- 1.6 cm(2) . dynes(-1) . 10(-6) vs 6.0 +/- 1.9 cm(2) . dynes(-1) .10(-6), p < 0.01) compared to control. Aortic pulse wave velocity was increased in DM (6.70 +/- 0.39 vs 6.30 +/- 0.31, p = 0.02) compared to control. Left ventricular diameters, mass, and systolic and diastolic function did not differ between the 2 groups. Simultaneous assessment of multiple cardiovascular parameters in children with type 1 DM revealed impaired carotid artery structure and function, and decreased elastic properties of the aorta, before demonstrable changes in left ventricular structure and function could be detected.

Impaired insulin sensitivity, insulin secretion, and glucose effectiveness predict future development of impaired glucose tolerance and type 2 diabetes in pre-diabetic African Americans: implications for primary diabetes prevention.

OBJECTIVE: We examined the determinants of impaired glucose tolerance (IGT) and type 2 diabetes in first-degree relatives of African-American type 2 diabetic patients over 5-8 years (median 6). RESEARCH DESIGN AND METHODS: A total of 81 healthy subjects (age 41.5 +/- 4.8 years; BMI 31.3 +/- 3.6 kg/m(2)) participated in the study. Each subject underwent an oral glucose tolerance test (OGTT) and a frequently sampled intravenous glucose tolerance test at baseline. Insulin sensitivity index (S(i)) and glucose effectiveness index (S(g)) were determined by the minimal model method. Homeostasis model assessment (HOMA) was used to estimate insulin resistance (HOMA-IR) and beta-cell function (HOMA-%B). A total of 18 subjects progressed to either IGT or type 2 diabetes (progressors), whereas 19 subjects maintained normal glucose tolerance (nonprogressors). RESULTS: Comparing the progressors and nonprogressors, mean fasting serum glucose levels (95 +/- 8 vs. 80 +/- 14 mg/dl, P < 0.01) and 2-h serum glucose levels (149 +/- 27 vs. 100 +/- 60 mg/dl, P < 0.01) as well as 2-h serum insulin levels (117 +/- 81 vs. 72 +/- 87 microU/ml, P < 0.01) during OGTT were higher at baseline. Mean acute first-phase insulin secretion (205 +/- 217 vs. 305 +/- 230 microU/ml), HOMA-%B (148 +/- 60 vs. 346 +/- 372, P < 01), S(i) (1.61 +/- 1.13 vs. 2.48 +/- 1.25 x 10(-4). min(-1) [microU/ml](-1)), and S(g) (1.48 +/- 0.61 vs. 2.30 +/- 0.97 x 10(-2). min(-1)) were lower in the progressors than in the nonprogressors at baseline. Mean HOMA-IR (3.31 +/- 1.64 vs. 2.36 +/- 1.64) was significantly greater in the progressors than the nonprogressors. At the time of diagnosis of glucose intolerance (IGT + diabetes), HOMA-%B (101 +/- 48 vs. 148 +/- 60, P < 0.001) and HOMA-IR (5.44 +/- 2.55 vs. 3.31 +/- 1.64, P < 0.003) deteriorated in the progressors versus baseline. CONCLUSIONS: We conclude that nondiabetic, first-degree relatives of African-American type 2 diabetic patients who progressed to IGT and type 2 diabetes manifest triple defects (decreased insulin secretion, insulin action, and glucose effectiveness) that antecede the disease.

Factors associated with increased healthcare costs in Medicare Advantage patients with type 2 diabetes enrolled in a large representative health insurance plan in the US.

AIM: The objective of this study was to apply quantile regression (QR) methodology to a population from a large representative health insurance plan with known skewed healthcare utilization attributes, co-morbidities, and costs in order to identify predictors of increased healthcare costs. Further, this study provides comparison of the results to those obtained using ordinary least squares (OLS) regression methodology. METHODS: Members diagnosed with Type 2 Diabetes and with 24 months of continuous enrollment were included. Baseline patient demographic, clinical, consumer/behavioural, and cost characteristics were quantified. Quantile regression was used to model the relationship between the baseline characteristics and total healthcare costs during the follow-up 12 month period. RESULTS: The sample included 83,705 patients (mean age = 70.6 years, 48% male) residing primarily in the southern US (78.1%); 81.2% of subjects were on oral-only anti-diabetic therapy. Co-morbid conditions included nephropathy (43.5%), peripheral artery disease (26.4%), and retinopathy (18.0%). Variables with the strongest relationship with costs during the follow-up period included outpatient visits, ER visits, inpatient visits, and Diabetes Complications Severity Index score during the baseline period. In the top cost quantiles, each additional glycohemoglobin (HbA1c) test was associated with cost savings ($1400 in the 98th percentile). Stage 4 and Stage 5 chronic kidney disease were associated with an incremental cost increase of $33,131 and $106,975 relative to Stage 1 or no CKD in the 98th percentile ($US). CONCLUSIONS: These results demonstrate that QR provides additional insight compared to traditional OLS regression modeling, and may be more useful for informing resource allocation to patients most likely to benefit from interventions. This study highlights that the impact of clinical and demographic characteristics on the economic burden of the disease vary across the continuum of healthcare costs. Understanding factors that drive costs on an individual patient level provide important insights that will help in ameliorating the clinical, humanistic, and economic burden of diabetes.

Early Glycemic Response Predicts Achievement of Subsequent Treatment Targets in the Treatment of Type 2 Diabetes: A Post hoc Analysis.

INTRODUCTION: American Diabetes Association consensus guidelines emphasize individualized treatment in the management of type 2 diabetes mellitus (T2DM). Early glycemic response is a clinical marker that may predict longer term efficacy for individual patients and provide a clinical tool to enhance personalized treatment. This analysis evaluated whether glycemic response measured at week 12 ("early") could serve as a reliable predictor of glycemic control at weeks 24 and 52 of therapy in patients with T2DM. METHODS: We used data from 3 randomized, controlled clinical trials that evaluated patients with T2DM treated with 3 commonly prescribed glucose-lowering medications: metformin (n = 597), sulfonylurea (n = 626), and insulin glargine (n = 1046). The gradient boosting method was used to identify predictors of subsequent response; predictive accuracy was represented by sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Treatment success at weeks 24 and 52 was assessed for each patient and defined as achieving a glycated hemoglobin (HbA1c) level of <7.0% or a reduction from baseline of ≥1.0%. RESULTS: The predictive parameters (sensitivity, specificity, PPV, and NPV) for improvements in HbA1c at week 24 for metformin were 0.83, 0.81, 0.44, and 0.96; for sulfonylurea, 0.79, 0.94, 0.71, and 0.96; and for insulin glargine, 0.67, 0.89, 0.65, and 0.90. The predictive parameters for improvements in HbA1c at week 52 for metformin were 0.73, 0.84, 0.56, and 0.92 and for sulfonylurea, 0.45, 0.94, 0.74, and 0.82. CONCLUSION: High predictive values identified in this analysis support "early" response as an appropriate tool for predicting treatment success at weeks 24 and 52. The high NPV (lack of early glycemic response) appears to be an effective indicator of the likely need for change in (or intensification of) therapy. These data support the current guideline recommendations that clinicians evaluate therapeutic responses to pharmacologic interventions with metformin, sulfonylureas, or insulin glargine as early as week 12.

Associations Between Glycemic Control, Depressed Mood, Clinical Depression, and Diabetes Distress Before and After Insulin Initiation: An Exploratory, Post Hoc Analysis.

INTRODUCTION: Although depression is often associated with poor glycemic control in patients with type 2 diabetes mellitus (T2DM), this observation has been inconsistent. This exploratory, post hoc analysis investigated associations between depression parameters and glycemic control using data from a 24-month, prospective, observational, non-interventional study evaluating glycemic response following insulin initiation for T2DM. METHODS: We analyzed data from a 24-month, prospective, observational study that evaluated glycemic response in patients with T2DM who initiated insulin therapy (N = 985) in 5 European countries. Secondary measures included patient-reported diagnosis of depression at baseline, severity of depressed/anxious mood (EuroQol (EQ)-5D item) and diabetes-related distress (Psychological Distress domain of the Diabetes Health Profile, DHP-18). The latter two measures were assessed at baseline and 5 time points throughout the study. Glycemic control was measured by glycated hemoglobin (HbA1c) at these same time points. Analyses employed t tests to assess the unadjusted baseline difference in HbA1c between patients with and without the respective depression parameter. The potential effect of demographic and clinical confounding variables was controlled through a linear model structure. Patient HbA1c levels were analyzed by presence/absence of a history of diagnosed depression, depressed mood, and diabetes-related distress. RESULTS: Patients with higher depression parameters or distress at baseline had significantly higher rates of microvascular complications at baseline. Patients with a history of diagnosed depression or high diabetes-related distress had higher HbA1c than patients without. HbA1c of patients with or without depressed mood was not significantly different at baseline. The proportion of patients with depressed mood declined after insulin initiation, whereas the proportion of patients with high diabetes-related distress did not significantly change. HbA1c improved following insulin initiation, regardless of presence/absence of studied depression/distress parameters at baseline. CONCLUSION: History of diagnosed depression, diabetes-related distress, and depressed mood were associated with a higher rate of microvascular complications. Diagnosed depression and diabetes-related distress also showed higher HbA1c at baseline when insulin was initiated. Insulin therapy improved glycemic control, while preexisting depressed mood declined and diabetes-related distress remained unchanged.

Cognitive and Functional Decline in Patients With Mild Alzheimer Dementia With or Without Comorbid Diabetes.

PURPOSE: Although diabetes is recognized as a risk factor for the development of cognitive impairment and for accelerated progression to Alzheimer disease (AD), it is unclear whether patients with diabetes who have already progressed to AD have a different rate of cognitive and functional decline compared with that in those without diabetes. This post hoc exploratory analysis compared cognitive and functional decline over an 18-month period in patients with mild AD dementia with and without comorbid diabetes. Decline in quality of life was assessed as a secondary objective. METHODS: In a post hoc exploratory analysis, we analyzed data from the placebo groups of three 18-month, randomized, placebo-controlled trials of solanezumab and semagacestat in patients with AD. Data from patients with mild AD dementia (Mini-Mental State Examination [MMSE] score, 20-26) and comorbid diabetes at baseline were compared with data from patients with mild AD dementia without diabetes at baseline. Cognition was assessed using the 14-item AD Assessment Scale-Cognitive Subscale (ADAS-Cog14) and the MMSE. Functioning was assessed with the AD Cooperative Study-Activities of Daily Living Inventory (instrumental subset) (ADCS-iADL). Quality of life was assessed using the European Quality of Life-5 Dimensions scale, proxy version (proxy utility score and visual analog scale score), and the Quality of Life in AD scale, self-report and proxy (caregiver) versions. Group comparisons of changes from baseline to 18 months in cognitive, functional, and quality-of-life measures employed a repeated-measures model adjusted for propensity score, study, baseline cognition score (functional or quality of life), age, sex, level of education, genotype of the apolipoprotein E gene, and concurrent use of an acetylcholinesterase inhibitor or memantine. FINDINGS: At baseline, patients with mild AD dementia with and without diabetes did not significantly differ on the cognitive measures, but those without diabetes were functioning at a significantly higher level. At 18 months, compared with patients without diabetes, those with diabetes showed a numerically but statistically nonsignificantly lesser cognitive decline (least squares mean between-group differences: ADAS-Cog14 score, 1.61 [P = 0.21]; MMSE score, -0.40 [P = 0.49]) and a statistically significantly lesser functional decline (least squares mean between-group difference in ADCS-iADL score, -3.07; P = 0.01). The 2 groups did not differ on declines in the quality-of-life measures. IMPLICATIONS: The present findings suggest that diabetes may influence the rate of functional decline among patients with mild AD dementia. These results require replication in studies that address the limitations of the present post hoc exploratory analysis and that explore the potential causes of the observed differences.

Is glycosylated hemoglobin A1c a surrogate for metabolic syndrome in nondiabetic, first-degree relatives of African-American patients with type 2 diabetes?

Glycosylated hemoglobin (Hb)A1c provides a practical assessment of long-term glycemic control in patients with diabetes. However, whether HbA1c has any clinical significance in metabolic syndrome (MS) in nondiabetic subjects remains debatable. Therefore, we examined the impact of different levels of HbA1c on insulin sensitivity (Si), non-insulin-dependent glucose disposal, and blood pressure (BP), as well as lipids and lipoproteins in nondiabetic, first-degree relatives of African-American patients with type 2 diabetes. The study consisted of 219 nondiabetic, first-degree relatives (offspring and siblings) of African-American patients with type 2 diabetes. To examine the metabolic impact of HbA1c in our population, HbA1c was divided into tertiles (normal range, 3.3-6.4%). The mean HbA1c was 4.7% (range, 3.3-4.8%, n = 74) for tertile 1, 5.4% (range, 4.9-5.6%, n = 73) for tertile 2, and 5.8% (range, 5.7-6.4%, n = 72) for tertile 3. Si and glucose effectiveness (Sg) were determined by the Bergman's minimal model method. Homeostasis model assessment (HOMA)-insulin resistance and HOMA-beta-cell function were also estimated. BP, body compositional variables, and body fat distribution, as well as fasting serum lipid and lipoprotein concentrations, were determined in each subject. The mean age, body weight, body mass index, waist and hip circumference, and systolic and diastolic BPs were significantly (P < 0.02-0.001) greater in the subjects in tertile 3 than those in tertiles 1 and 2. The mean fasting serum glucose was significantly (P < 0.01) higher in tertile 3 (95.5 +/- 3.2 mg/dl) than in tertile 2 (83.0 +/- 2.7 mg/dl) and tertile 1 (78.8 +/- 1.5 mg/dl). Mean fasting serum insulin and c-peptide levels tended to be higher in tertile 3 subjects than in those in tertiles 1 and 2, but the mean differences did not reach statistical significance. The mean Si was significantly (P < 0.001) lower in the subjects in tertile 3 [1.66 +/- 0.2019 x 10(-4).min(-1)( micro U/ml)(-1)], when compared with those in tertile 1 [2.27 +/- 0.20 19 x 10(-4).min(-1)( micro U/ml)(-1)] and tertile 2 [2.61 +/- 0.19 x 10(-4).min(-1)( micro U/ml)(-1)]. The mean Sg was significantly (P < 0.02) lower in tertile 3 (1.95 +/- 0.12 x 10(-2).min(-1)), when compared with those of tertile 1 (2.27 +/- 0.10 x 10(-2).min(-1)) and tertile 2 (2.29 +/- 0.11 x 10(-2).min(-1)). In addition, the (HOMA)-insulin resistance was significantly (P < 0.01) higher in tertile 3 (3.62 +/- 0.26) than in tertile 1 (2.6 +/- 0.21) and tertile 2 (2.55 +/- 0.31) HbA1c. In contrast, HOMA-beta-cell function, was not different among tertiles 1, 2, and 3. Mean fasting serum triglycerides, cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol levels also were not significantly different in subjects in tertile 3, when compared with those in tertiles 1 and 2. In summary, the present study demonstrates that the upper tertile HbA1c level (tertile 3) reflects some components of MS in the nondiabetic, obese, first-degree relatives of African-Americans who are genetically predisposed to type 2 diabetes. The metabolic abnormalities in the upper tertile 3 subjects included a reduced insulin action (Si) and reduced Sg, as well as elevated systolic and diastolic BPs, but not beta-cell secretion and lipids and lipoproteins. We conclude that the upper tertile of HbA1c should be considered as a major surrogate of MS in high-risk African-Americans who are genetically predisposed to type 2 diabetes.