Edward W. Lipkin

Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-label substudy

Background Persons with type 2 diabetes (T2D) are at risk for cognitive impairment and brain atrophy. The ACCORD Memory in Diabetes (MIND) Study investigated whether persons randomized to an intensive glycaemic therapeutic strategy targeting HbA1c to <6% had better cognitive function and a larger brain volume at 40 months than persons randomized to a standard strategy targeting HbA1c to 7%–7.9%.BACKGROUND People with type 2 diabetes are at risk of cognitive impairment and brain atrophy. We aimed to compare the effects on cognitive function and brain volume of intensive versus standard glycaemic control. METHODS The Memory in Diabetes (MIND) study was done in 52 clinical sites in North America as part of Action to Control Cardiovascular Risk in Diabetes (ACCORD), a double two-by-two factorial parallel group randomised trial. Participants (aged 55-80 years) with type 2 diabetes, high glycated haemoglobin A(1c) (HbA(1c)) concentrations (>7·5%; >58 mmol/mol), and a high risk of cardiovascular events were randomly assigned to receive intensive glycaemic control targeting HbA(1c) to less than 6·0% (42 mmol/mol) or a standard strategy targeting HbA(1c) to 7·0-7·9% (53-63 mmol/mol). Randomisation was via a centralised web-based system and treatment allocation was not masked from clinic staff or participants. We assessed our cognitive primary outcome, the Digit Symbol Substitution Test (DSST) score, at baseline and at 20 and 40 months. We assessed total brain volume (TBV), our primary brain structure outcome, with MRI at baseline and 40 months in a subset of participants. We included all participants with follow-up data in our primary analyses. In February, 2008, raised mortality risk led to the end of the intensive treatment and transition of those participants to standard treatment. We tested our cognitive function hypotheses with a mixed-effects model that incorporated information from both the 20 and 40 month outcome measures. We tested our MRI hypotheses with an ANCOVA model that included intracranial volume and factors used to stratify randomisation. This study is registered with ClinicalTrials.gov, number NCT00182910. FINDINGS We consecutively enrolled 2977 patients (mean age 62·5 years; SD 5·8) who had been randomly assigned to treatment groups in the ACCORD study. Our primary cognitive analysis was of patients with a 20-month or 40-month DSST score: 1378 assigned to receive intensive treatment and 1416 assigned to receive standard treatment. Of the 614 patients with a baseline MRI, we included 230 assigned to receive intensive treatment and 273 assigned to receive standard treatment in our primary MRI analysis at 40 months. There was no significant treatment difference in mean 40-month DSST score (difference in mean 0·32, 95% CI -0·28 to 0·91; p=0·2997). The intensive-treatment group had a greater mean TBV than the standard-treatment group (4·62, 2·0 to 7·3; p=0·0007). INTERPRETATION Although significant differences in TBV favoured the intensive treatment, cognitive outcomes were not different. Combined with the non-significant effects on other ACCORD outcomes, and increased mortality in participants in the intensive treatment group, our findings do not support the use of intensive therapy to reduce the adverse effects of diabetes on the brain in patients with similar characteristics to those of our participants. FUNDING US National Institute on Aging and US National Heart, Lung, and Blood Institute.

Outcomes of Combined Cardiovascular Risk Factor Management Strategies in Type 2 Diabetes: The ACCORD Randomized Trial

OBJECTIVE To compare effects of combinations of standard and intensive treatment of glycemia and either blood pressure (BP) or lipids in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. RESEARCH DESIGN AND METHODS ACCORD enrolled 10,251 type 2 diabetes patients aged 40–79 years at high risk for cardiovascular disease (CVD) events. Participants were randomly assigned to hemoglobin A1c goals of <6.0% (<42 mmol/mol; intensive glycemia) or 7.0–7.9% (53–63 mmol/mol; standard glycemia) and then randomized a second time to either 1) systolic BP goals of <120 mmHg (intensive BP) or <140 mmHg (standard BP) or 2) simvastatin plus fenofibrate (intensive lipid) or simvastatin plus placebo (standard lipid). Proportional hazards models were used to assess combinations of treatment assignments on the composite primary (deaths due to CVD, nonfatal myocardial infarction [MI], and nonfatal stroke) and secondary outcomes. RESULTS In the BP trial, risk of the primary outcome was lower in the groups intensively treated for glycemia (hazard ratio [HR] 0.67; 95% CI 0.50–0.91), BP (HR 0.74; 95% CI 0.55–1.00), or both (HR 0.71; 95% CI 0.52–0.96) compared with combined standard BP and glycemia treatment. For secondary outcomes, MI was significantly reduced by intensive glycemia treatment and stroke by intensive BP treatment; most other HRs were neutral or favored intensive treatment groups. In the lipid trial, the general pattern of results showed no evidence of benefit of intensive regimens (whether single or combined) compared with combined standard lipid and glycemia treatment. The mortality HR was 1.33 (95% CI 1.02–1.74) in the standard lipid/intensive glycemia group compared with the standard lipid/standard glycemia group. CONCLUSIONS In the ACCORD BP trial, compared with combined standard treatment, intensive BP or intensive glycemia treatment alone improved major CVD outcomes, without additional benefit from combining the two. In the ACCORD lipid trial, neither intensive lipid nor glycemia treatment produced an overall benefit, but intensive glycemia treatment increased mortality.

Higher dietary fructose is associated with impaired hepatic adenosine triphosphate homeostasis in obese individuals with type 2 diabetes

Fructose consumption predicts increased hepatic fibrosis in those with nonalcoholic fatty liver disease (NAFLD). Because of its ability to lower hepatic adenosine triphosphate (ATP) levels, habitual fructose consumption could result in more hepatic ATP depletion and impaired ATP recovery. The degree of ATP depletion after an intravenous (IV) fructose challenge test in low‐ versus high‐fructose consumers was assessed. We evaluated diabetic adults enrolled in the Action for Health in Diabetes Fatty Liver Ancillary Study (n = 244) for whom dietary fructose consumption estimated by a 130‐item food frequency questionnaire and hepatic ATP measured by phosphorus magnetic resonance spectroscopy and uric acid (UA) levels were performed (n = 105). In a subset of participants (n = 25), an IV fructose challenge was utilized to assess change in hepatic ATP content. The relationships between dietary fructose, UA, and hepatic ATP depletion at baseline and after IV fructose challenge were evaluated in low‐ (<15 g/day) versus high‐fructose (≥15 g/day) consumers. High dietary fructose consumers had slightly lower baseline hepatic ATP levels and a greater absolute change in hepatic α‐ATP/ inorganic phosphate (Pi) ratio (0.08 versus 0.03; P = 0.05) and γ‐ATP /Pi ratio after an IV fructose challenge (0.03 versus 0.06; P = 0.06). Patients with high UA (≥5.5 mg/dL) showed a lower minimum liver ATP/Pi ratio postfructose challenge (4.5 versus 7.0; P = 0.04). Conclusions: High‐fructose consumption depletes hepatic ATP and impairs recovery from ATP depletion after an IV fructose challenge. Subjects with high UA show a greater nadir in hepatic ATP in response to fructose. Both high dietary fructose intake and elevated UA level may predict more severe hepatic ATP depletion in response to fructose and hence may be risk factors for the development and progression of NAFLD. (HEPATOLOGY 2012;56:952–960)

Obesity and albuminuria among adults with type 2 diabetes: the Look AHEAD (Action for Health in Diabetes) Study.

OBJECTIVE To determine the association between obesity measures and albuminuria in adults with type 2 diabetes. RESEARCH DESIGN AND METHODS In the Look AHEAD (Action for Health in Diabetes) Study, BMI and waist circumference were measured among 4,985 participants while total percent body fat was measured by whole-body DEXA scans among 1,351 participants. Odds of albuminuria by quartiles of BMI, waist circumference, and percent total body fat were calculated using logistic regression analysis while adjusting for covariates. RESULTS The highest quartile of BMI (odds ratio [OR] 1.72 [95% CI 1.40–2.11]) and waist circumference (OR 1.75 [95% CI 1.42–2.15]) was significantly associated with albuminuria compared with the lowest quartile after adjustment for covariates. No associations were noted between quartiles of percent total body fat and albuminuria in any model. CONCLUSIONS Increased BMI and abdominal obesity are associated with albuminuria in overweight and obese adults with type 2 diabetes.

Metabolic bone disease in adults receiving long-term parenteral nutrition: longitudinal study with regional densitometry and bone biopsy.

A syndrome of bone pain and fractures has been described in patients receiving long-term support from parenteral nutrition containing large quantities of aluminium or vitamin D2. Whether this same syndrome occurs in patients supported by current therapeutic regimens is controversial. In this study, bone health was longitudinally evaluated over 7 to 61 months in 14 subjects maintained on long-term parenteral nutrition. The parameters of bone health evaluated included bone mass as measured by single and dual photon absorptiometry and quantitative histomorphometry of bone biopsies. There was a striking heterogeneity in baseline measures of bone health. Mean bone density of parenteral nutrition patients was significantly below expected values on entry into the study at both the distal radius (z score = -0.76 +/- 0.27) and the lumbar spine (z score = -1.17 +/- 0.27). Mean areal density at the forearm was less severely depressed (z score = -0.62 +/- 0.34). The longitudinal changes in bone density and morphology were heterogeneous, with some subjects showing deterioration, others improvement, and still others no change. We conclude that patients already established on parenteral nutrition frequently have osteopenia. The group as a whole did not demonstrate normalization of the osteopenia, but our results also suggest that current parenteral nutrition formulations low in aluminum and vitamin D2 do not necessarily cause worsening of bone health. The etiology of this clinical syndrome merits additional study.

Bone physiology during pregnancy and lactation in young macaques

We used a nonhuman primate model (Macaca nemestrina) of adolescent human pregnancy to characterize bone remodeling at midpregnancy and at weaning and the associated changes in bone mass. In this longitudinal study, 125 nulliparous females were followed through pregnancy, 6 months of lactation, and 3 months postweaning; 13 nonpregnant females served as controls. Between early pregnancy and midpregnancy, the whole body bone mineral increased. There was no significant change between midpregnancy and parturition. Between parturition and 3 months lactation, the animals lost 3.0% of their bone mineral (p < 0.01), which was regained by 3 months after weaning. The vertebral bone mineral apparent density decreased during pregnancy and 6 months of lactation, followed by an increase during the 3 months after weaning. Calcium, phosphate, 25‐hydroxyvitamin D, and osteocalcin increased significantly from midpregnancy to weaning whereas 1,25‐dihydroxyvitamin D values showed significant decreases. Histomorphometric measurements from bone biopsies showed significant increases in most parameters of bone formation between pregnancy and weaning. These results are consistent with the hypothesis that at midpregnancy bone formation is decreased and cancellous bone resorption may have increased. During lactation, losses occur in both cortical and cancellous bone, partially depleting the maternal reservoir of calcium, but a subsequent increase in bone formation enables restoration of bone mineral after weaning to values similar to those in the control group.

Effect of parenteral nutrition and enteral feeding on D-lactic acidosis in a patient with short bowel

D-Lactic acid can accumulate in blood in some patients with intestinal failure, leading to a clinical syndrome of severe acidosis and encephalopathy. The possible impact of parenteral nutrition on its clinical course has not been established. One patient with a severe short-bowel syndrome supported by long-term parenteral nutrition who suffered repeated episodes of ataxia and disorientation associated with elevated serum levels of D-lactate was studied. Results demonstrated no impact of glucose- vs lipid-based parenteral nutrition formulations on total acid production or serum D-lactic acid levels, increased serum D-lactate levels during administration of neomycin, but prompt resolution of both acidosis and clinical symptoms with discontinuation of oral intake. This study confirms the findings of other investigators that D-lactic acidosis may be a significant, heretofore unappreciated complication in patients with severe short-bowel syndrome, and that prompt resolution may be effected with abrupt discontinuation of oral intake. Furthermore, the present study suggests neither a detrimental nor a beneficial effect of parenteral nutrition on this syndrome.

FTO predicts weight regain in the Look AHEAD clinical trial

Background:Genome-wide association studies have provided new insights into the genetic factors that contribute to the development of obesity. We hypothesized that these genetic markers would also predict magnitude of weight loss and weight regain after initial weight loss.Methods:Established obesity risk alleles available on the Illumina CARe iSelect (IBC) chip were characterized in 3899 overweight or obese participants with type 2 diabetes from the Look AHEAD (Action for Health in Diabetes), a randomized trial to determine the effects of intensive lifestyle intervention (ILI) and diabetes support and education (DSE) on cardiovascular morbidity and mortality. Primary analyses examined the interaction between 13 obesity risk polymorphisms in eight genes and randomized treatment arm in predicting weight change at year 1, and weight regain at year 4 among individuals who lost 3% or more of their baseline weight by year 1.Results:No single-nucleotide polymorphisms (SNPs) were significantly associated with magnitude of weight loss or interacted with treatment arm at year 1. However, fat mass and obesity associated gene (FTO) rs3751812 predicted weight regain within DSE (1.56 kg per risk allele, P=0.005), but not ILI (P=0.761), resulting in SNP × treatment arm interaction (P=0.009). In a partial replication of prior research, the obesity risk (G) allele at BDNF rs6265 was associated with greater weight regain across treatment arms (0.773 kg per risk allele), although results were of borderline statistical significance (P=0.051).Conclusions:Variations in the FTO and BDNF loci may contribute risk of weight regain after weight loss.

Appraisal of recommended respiratory infection control practices in primary care and emergency department settings

Background The severe acute respiratory syndrome (SARS) epidemic and concern about pandemic influenza prompted the Centers for Disease Control and Prevention (CDC) to develop guidelines to prevent the transmission of all respiratory infections in health care settings during first contact with a potentially infected person. The extent to which health care workers and institutions use these CDC recommended practices is uncertain. Methods The study examined health care worker adherence to CDC recommended respiratory infection control practices in primary care clinics and emergency departments of 5 medical centers in King County, Washington, using a self-administered questionnaire. All clinical, allied, and administrative health care workers in study settings were invited to participate: 653 (53%) responded, and 630 were included. Results The survey revealed important shortcomings in overall personal and institutional use of CDC recommended practices, including deficiencies in posted alerts, patient masking and separation, hand hygiene, personal protective equipment, staff training, and written procedures. Use of recommended measures was generally higher among nursing staff than medical practitioners. Conclusion This study found significant gaps in adherence to CDC recommendations for the control of respiratory infections in ambulatory care clinical settings. Practical strategies are needed to identify and reduce barriers to implementation of recommended practices for control of respiratory infections.

Serum markers of bone formation in parenteral nutrition patients.

SummaryBone gamma-carboxyglutamic acid containing protein (BGP) has been utilized effectively as a serum marker of bone turnover in healthy normals and in individuals with a variety of metabolic bone disorders including postmenopausal osteoporosis and Pagets disease. The utility of this serum marker in other bone disorders, including that associated with the maintenance of patients on long-term parenteral nutrition, still requires definition. Because of our interest in this clinical syndrome and the availability of serum and of bone formation rates (BFR) measured directly from double tetracycline labeling in 11 long-term parenteral nutrition patients, we measured BGP levels in these patients and attempted to correlate this measure with BFR. Serum vitamin D metabolites, immunoreactive parathyroid hormone (PTH), and alkaline phosphatase (alk phos) were also measured. Serum BGP was only weakly and not significantly correlated (r=0.24, p=NS) with bone formation rate for the group as a whole. However, in a subgroup of 10 patients without hyperparathyroidism, there was strong and significant correlation (r=0.81,P<0.01) between BGP and BFR. There was also a strong correlation between bone formation rate and serum 1,25 dihydroxyvitamin D [1,25(OH)2D] levels (r=0.89,P<0.01, n=11). The mechanism of this association could not be established. A correlation of borderline significance was observed between bone formation rate and serum alk phos (r=0.60,P=0.05, n=11). The current data suggest that additional studies may help to more fully define the utility of serum measurements in quantifying bone dynamics in parenteral nutrition patients, and that measures of vitamin D metabolites, BGP, and alk phos may prove useful.