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1.  Determinants of Successful Glycemic Control among Participants in the BARI 2D Trial: A Post-hoc Analysis 
The BARI 2D trial compared insulin provision (IP) versus insulin sensitization (IS) for the primary outcome of total mortality in participants with T2DM and cardiovascular disease (CVD). In this analysis we examine baseline characteristics that are associated with successful long-term glycemic control.
Research Design and Methods
In a 2×2 factorial design, 2,368 participants were randomized to either IP or IS therapy, and to either prompt revascularization with medical therapy or medical therapy alone. Successful long-term glycemic control (success) was defined by simultaneously meeting 1) a mean HbA1c level of <7.0% after each participant's third year of follow-up period, and 2) adherence with medications only from the assigned glycemic treatment arm during >80% of the BARI 2D follow-up. The association between baseline variables and success was determined using unadjusted and adjusted logistic regression models.
1,917 participants (962 IP and 955 IS participants) had sufficiently long follow-up and data for this analysis. Among these IP and IS participants, 235 and 335 participants met both criteria of success, respectively (p <0.001). Those not on insulin at entry had higher odds of success (OR 2.25; CI 1.79-2.82) when treated with IS versus IP medications, irrespective of baseline HbA1c levels. Younger age, shorter duration of T2DM, and lower HbA1c at baseline were also each independently associated with higher success when treated with IS versus IP medications.
Patients similar to those in the BARI 2D trial may have a higher chance of achieving success with IS versus IP medications if they are younger, have shorter duration of T2DM, have lower HbA1c levels, have moderate or strenuous physically activity, and are not on insulin. In contrast, increasing age, longer duration of T2DM, higher HbA1c, and insulin therapy are associated with increased chance of success if treated with IP medications.
PMCID: PMC4156479  PMID: 23478173
Cardiovascular Disease; Plasma Insulin levels; Predictors of Glycemic Control
2.  +Effect of thiazolidinediones and insulin on cognitive outcomes in ACCORD-MIND 
To examine the relationship of cognitive performance to exposure to insulin (INS) and thiazolidinediones (TZD) in the ACCORD-MIND cohort.
Participants (55-80 yrs) with type 2 diabetes (T2D), hemoglobin A1c (HbA1c) >7.5% (>58 mmol/mol), and a high risk of cardiovascular events were randomly assigned to receive intensive control targeting HbA1c to < 6.0% (42 mmol/mol) or a standard strategy targeting HbA1c to 7.0-7.9% (53-63 mmol/mol). The Digit Symbol Substitution Test (DSST) was assessed at baseline and at 20 and 40 mo. Exposure to INS was calculated as average daily dose/kg of body weight; exposure to rosiglitazone (ROS) was calculated as days of ROS prescription in the intervals preceding the 20 and 40-mo DSSTs.
At baseline, INS use was associated with reduced DSST performance, but not after controlling for co-morbidities and lab values. There was no relationship between use of a TZD and DSST performance on at baseline. ROS but not INS exposure was associated with greater decline in DSST performance over 40 mo in subjects randomized to the intensive but not the standard group.
Exposure to a TZD may increase cognitive decline in some patients with T2D. However, these results may be confounded by unexplained differences between participants.
PMCID: PMC3748242  PMID: 23680059
thiazolidinediones; insulin; diabetes; cognition
3.  Effect of intensive treatment of hyperglycemia on microvascular complications of type 2 diabetes in ACCORD: a randomized trial 
Lancet  2010;376(9739):419-430.
ACCORD is a parallel group, randomized trial designed to investigate whether intensive glycemic therapy with a target HbA1c of <6.0% versus standard therapy with a target of 7.0 to 7.9% reduces cardiovascular disease (CVD) morbidity, mortality, and microvascular complications in participants with type 2 diabetes.
Volunteers with established type 2 diabetes, HbA1c levels ≥ 7.5% and CVD or two or more CVD risk factors were recruited at 77 clinical sites across the U.S. and Canada. Instructional materials, behavioral counseling, glucose-lowering medications and self-monitoring supplies were provided by the study. Therapeutic regimens were individualized on the basis of randomized assignment and response to therapy. This investigation examines the effect of treatment to glycemic goals on occurrence of microvascular diabetes complications. Prespecified composite outcomes were: 1) dialysis or renal transplantation, or serum creatinine >291.7 micromol/L, or retinal photocoagulation or vitrectomy, and 2) these plus peripheral neuropathy. Thirteen prespecified secondary measures of kidney, eye, and peripheral nerve function were also evaluated. Randomization was performed at clinical sites using a central randomization routine available on the study website. Both investigators and participants were unmasked to treatment arm assignment.
A total of 10,251 participants were randomized (5,128 intensive and 5,123 standard) between January, 2001 and October, 2005. This analysis includes 10,234 patients (5,107 intensive and 5,108 standard). Intensive therapy was stopped before study end due to increased mortality, and patients were transitioned to standard therapy. Outcomes are reported at transition and at study end. At transition, the first composite outcome occurred in 443/5107 and 444/5108 participants in the intensive and standard arms, respectively (p= 0.99), and the second outcome in 1591/5107 and 1659/5108 participants in intensive and standard arms (p=0.20). Results were similar at study end. Secondary measures at study end favoring intensive therapy (p<0.05) included development of macroalbuminuria, cataract extraction, visual acuity, a score of >2.0 on the Michigan Neuropathy Screening Instrument, loss of ankle jerk and light touch.
Intensive glycemic treatment did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of macroalbuminuria and some measures of eye complications and neuropathy. These benefits must be weighed against the increase in total and CVD-related mortality, increased weight gain, and higher risk for severe hypoglycemia.
PMCID: PMC4123233  PMID: 20594588
4.  Determinants of Weight Gain in the Action to Control Cardiovascular Risk in Diabetes Trial 
Diabetes Care  2013;36(8):2162-2168.
Identify determinants of weight gain in people with type 2 diabetes mellitus (T2DM) allocated to intensive versus standard glycemic control in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.
We studied determinants of weight gain over 2 years in 8,929 participants (4,425 intensive arm and 4,504 standard arm) with T2DM in the ACCORD trial. We used general linear models to examine the association between each baseline characteristic and weight change at the 2-year visit. We fit a linear regression of change in weight and A1C and used general linear models to examine the association between each medication at baseline and weight change at the 2-year visit, stratified by glycemia allocation.
There was significantly more weight gain in the intensive glycemia arm of the trial compared with the standard arm (3.0 ± 7.0 vs. 0.3 ± 6.3 kg). On multivariate analysis, younger age, male sex, Asian race, no smoking history, high A1C, baseline BMI of 25–35, high waist circumference, baseline insulin use, and baseline metformin use were independently associated with weight gain over 2 years. Reduction of A1C from baseline was consistently associated with weight gain only when baseline A1C was elevated. Medication usage accounted for <15% of the variability of weight change, with initiation of thiazolidinedione (TZD) use the most prominent factor. Intensive participants who never took insulin or a TZD had an average weight loss of 2.9 kg during the first 2 years of the trial. In contrast, intensive participants who had never previously used insulin or TZD but began this combination after enrolling in the ACCORD trial had a weight gain of 4.6–5.3 kg at 2 years.
Weight gain in ACCORD was greater with intensive than with standard treatment and generally associated with reduction of A1C from elevated baseline values. Initiation of TZD and/or insulin therapy was the most important medication-related factor associated with weight gain.
PMCID: PMC3714487  PMID: 23412077
5.  Diabetic Retinopathy, Its Progression, and Incident Cardiovascular Events in the ACCORD Trial 
Diabetes Care  2013;36(5):1266-1271.
Both the presence of diabetic retinopathy and its severity are significantly associated with future cardiovascular (CV) events. Whether its progression is also linked to incident CV outcomes hasn’t been assessed.
The relationship between retinopathy, its 4-year progression, and CV outcomes (CV death or nonfatal myocardial infarction or stroke) was analyzed in participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial who also participated in the ACCORD Eye Study. Retinopathy was classified as either none, mild, moderate, or severe, and worsening was classified as a <2-step, 2–3-step, or >3-step change (that included incident laser therapy or vitrectomy).
Participants (n = 3,433) of mean age 61 years had baseline retinal photographs (seven stereoscopic fields). Compared with no retinopathy, the adjusted HRs (95% CI) for the CV outcome rose from 1.49 (1.12–1.97) for mild retinopathy to 2.35 (1.47–3.76) for severe retinopathy. A subset of 2,856 was evaluated for progression of diabetic retinopathy at 4 years. The hazard of the primary outcome increased by 38% (1.38 [1.10–1.74]) for every category of change in retinopathy severity. Additional adjustment for the baseline and follow-up levels of A1C, systolic blood pressure, and lipids either individually or together rendered the relationships between worsening and CV outcomes nonsignificant.
Both the severity of retinopathy and its progression are determinants of incident CV outcomes. The retina may provide an anatomical index of the effect of metabolic and hemodynamic factors on future CV outcomes.
PMCID: PMC3631868  PMID: 23238658
6.  Depressive Symptoms and Diabetes 
PMCID: PMC3904750  PMID: 19001617
7.  Hyperglycemia-induced stimulation of glucose transport in skeletal muscle measured by PET-[18F]6FDG and [18F]2FDG 
Physiological measurement  2012;33(10):1661-1673.
A physiologically based model proposed by our group has been developed to assess glucose transport and phosphorylation in skeletal muscle. In this study, we investigated whether our model has the ability to detect a glucose-induced increase in glucose transport in skeletal muscle. In particular, we used small-animal positron emission tomography (PET) data obtained from [18F]6-fluoro-6-deoxy-D-glucose ([18F]6FDG). A two-hour PET scan was acquired following a bolus injection of [18F]6FDG in rats currently under euglycemic or hyperglycemic conditions, while somatostatin was infused during both conditions in order to prevent a rise in the endogenous plasma insulin concentration. We were thus able to assess the effect of hyperglycemia per se. For a comparison of radiopharmaceuticals, additional rats were studied under the same conditions, using [18F]2-fluoro-2-deoxy-D-glucose ([18F]2FDG). When [18F]6FDG was used, the time-activity curves (TACs) for skeletal muscle had distinctly different shapes during euglycemic and hyperglycemic conditions. This was not the case with [18F]2FDG. For both [18F]6FDG and [18F]2FDG, the model detects increases in both interstitial and intracellular glucose concentrations, increases in the maximal velocity of glucose transport, and increases in the rate of glucose transport, all in response to hyperglycemia. In contrast, there was no increase in the maximum velocity of glucose phosphorylation or in the glucose phosphorylation rate. Our model-based analyses of the PET data, obtained with either [18F]6FDG or [18F]2FDG, detect physiologic changes consistent with established behaviors. Moreover, based on differences in the TAC shapes, [18F]6FDG appears to be superior to [18F]2FDG for evaluating the effect of hyperglycemia on glucose metabolism in skeletal muscle.
PMCID: PMC3486741  PMID: 22986442
glucose transport; kinetic model; PET; glucose clamp; hyperglycemia
8.  Role of Intensive Glucose Control in Development of Renal Endpoints in Type 2 Diabetes: Systematic Review and Meta-analysis 
Archives of internal medicine  2012;172(10):761-769.
Aggressive glycemic control has been hypothesized to prevent renal disease in type 2 diabetics. A systematic review was conducted to summarize the benefits of intensive versus conventional glucose control on kidney-related outcomes for adults with type 2 diabetes.
Three databases were systematically searched (January 1950 to December 2010) with no language restrictions to identify randomized trials that compared surrogate renal endpoints (micro and macroalbuminuria) and clinical renal endpoints (doubling of serum creatinine, End Stage Renal Disease [ESRD] and death from renal disease) in patients with type 2 diabetes receiving intensive glucose control versus receiving conventional glucose control.
Seven trials involving 28,065 adults who were followed-up for 2 to 15 years. Compared with conventional control, intensive glucose control reduced the risk for microalbuminuria (risk ratio [RR], 0.86 [95% CI, 0.76 to 0.96]) and macroalbuminuria (RR 0.74 [95% CI, 0.65–0.85]), but not doubling of serum creatinine (RR 1.06 [95% CI, 0.92 to 1.22]), ESRD (RR 0.69 [95% CI, 0.46–1.05]), or death from renal disease (RR 0.99 [95% CI 0.55–1.79]). Meta-regression revealed that larger differences in HbA1C between intensive and conventional therapy at the study level were associated with greater benefit for both micro- and macroalbuminuria. The pooled cumulative incidence of doubling of creatinine, ESRD, and death from renal disease was low (< 4%, <1.5%, and <0.5%, respectively) compared with the surrogate renal endpoints of micro- (23%) and macroalbuminuria (5%).
Intensive glucose control reduces the risk for microalbuminuria and macroalbuminuria but evidence is lacking that intensive glycemic control reduces the risk for significant clinical renal outcomes such as doubling of creatinine, ESRD or death from renal disease during the years of follow-up of the trials.
PMCID: PMC3688081  PMID: 22636820
Proteinuria; creatinine; chronic kidney disease; end-stage renal disease; prognosis
9.  Poor Cognitive Function and Risk of Severe Hypoglycemia in Type 2 Diabetes 
Diabetes Care  2012;35(4):787-793.
Self-management of type 2 diabetes including avoidance of hypoglycemia is complex, but the impact of cognition on safe self-management is not well understood. This study aimed to assess the effect of baseline cognitive function and cognitive decline on subsequent risk of severe hypoglycemia and to assess the effect of different glycemic strategies on these relationships.
Prospective cohort analysis of data from the ACCORD trial included 2,956 adults aged ≥55 years with type 2 diabetes and additional cardiovascular risk factors. Cognitive tests (Digit Symbol Substitution Test [DSST], Rey Auditory Verbal Learning Test, Stroop Test, and Mini Mental Status Examination) were conducted at baseline and 20 months. Study outcomes were incident confirmed severe hypoglycemia requiring medical assistance (HMA) and hypoglycemia requiring any assistance (HAA).
After a median 3.25-year follow-up, a 5-point-poorer baseline score on the DSST was predictive of a first episode of HMA (hazard ratio 1.13 [95% CI 1.08–1.18]). Analyses of the other cognitive tests and of HAA were consistent with the DSST results. Cognitive decline over 20 months increased the risk of subsequent hypoglycemia to a greater extent in those with lower baseline cognitive function (Pinteraction = 0.037). Randomization to an intensive versus standard glycemic strategy had no impact on the relationship between cognitive function and the risk of severe hypoglycemia.
Poor cognitive function increases the risk of severe hypoglycemia in patients with type 2 diabetes. Clinicians should consider cognitive function in assessing and guiding their patients regarding safe diabetes self-management regardless of their glycemic targets.
PMCID: PMC3308284  PMID: 22374637
10.  Insulin Fibrillation and Protein Design: Topological Resistance of Single-Chain Analogs to Thermal Degradation with Application to a Pump Reservoir 
Insulin is susceptible to thermal fibrillation, a misfolding process that leads to nonnative cross-b assembly analogous to pathological amyloid deposition. Pharmaceutical formulations are ordinarily protected from such degradation by sequestration of the susceptible monomer within native protein assemblies. With respect to the safety and efficacy of insulin pumps, however, this strategy imposes an intrinsic trade-off between pharmacokinetic goals (rapid absorption and clearance) and the requisite physical properties of a formulation (prolonged shelf life and stability within the reservoir). Available rapid-acting formulations are suboptimal in both respects; susceptibility to fibrillation is exacerbated even as absorption is delayed relative to the ideal specifications of a closed-loop system. To circumvent this molecular trade-off, we exploited structural models of insulin fibrils and amyloidogenic intermediates to define an alternative protective mechanism. Single-chain insulin (SCI) analogs were shown to be refractory to thermal fibrillation with maintenance of biological activity for more than 3 months under conditions that promote the rapid fibrillation and inactivation of insulin. The essential idea exploits an intrinsic incompatibility between SCI topology and the geometry of cross-b assembly. A peptide tether was thus interposed between the A- and B-chains whose length was (a) sufficiently long to provide the “play” needed for induced fit of the hormone on receptor binding and yet (b) sufficiently short to impose a topological barrier to fibrillation. Our findings suggest that ultrastable monomeric SCI analogs may be formulated without protective self-assembly and so permit simultaneous optimization of pharmacokinetics and reservoir life.
PMCID: PMC3380768  PMID: 22538136
amyloid; closed-loop system; insulin pump; intraperitoneal pump; pump reservoir
11.  Uptake of 18F-Labeled 6-Fluoro-6-Deoxy-d-Glucose by Skeletal Muscle Is Responsive to Insulin Stimulation 
We are developing a methodology for the noninvasive imaging of glucose transport in vivo with PET and 18F-labeled 6-fluoro-6-deoxy-d-glucose (18F-6FDG), a tracer that is transported but not phosphorylated. To validate the method, we evaluated the biodistribution of 18F-6FDG to test whether it is consistent with the known properties of glucose transport, particularly with regard to insulin stimulation of glucose transport.
Under glucose clamp conditions, rats were imaged at the baseline and under conditions of hyperinsulinemia.
The images showed that the radioactivity concentration in skeletal muscle was higher in the presence of insulin than at the baseline. We also found evidence that the metabolism of 18F-6FDG was negligible in several tissues.
18F-6FDG is a valid tracer that can be used in in vivo transport studies. PET studies performed under glucose clamp conditions demonstrated that the uptake of nonphosphorylated glucose transport tracer 18F-6FDG is sensitive to insulin stimulation.
PMCID: PMC3571725  PMID: 19443592
glucose transport; radiopharmaceutical; PET; glucose clamp
12.  Use of Insulin Sensitizers for the Treatment of Major Depressive Disorder: A Pilot Study of Pioglitazone for Major Depression Accompanied by Abdominal Obesity 
Journal of Affective Disorders  2011;136(3):1164-1173.
This study was conducted to examine the safety and efficacy of pioglitazone, a thiazolidinedione insulin sensitizer, in adult outpatients with major depressive disorder.
In a 12-week, open-label, flexible-dose study, 23 patients with major depressive disorder received pioglitazone monotherapy or adjunctive therapy initiated at 15mg daily. Subjects were required to meet criteria for abdominal obesity (waist circumference >35 in. in women and >40 in. in men) or metabolic syndrome. The primary efficacy measure was the change from baseline to Week 12 on the Inventory of Depressive Symptomatology (IDS) total score. Partial responders (≥25% decrease in IDS total score) were eligible to participate in an optional extension phase for an additional three months.
Pioglitazone decreased depression symptom severity from a total IDS score of 40.3 ± 1.8 to 19.2 ± 1.8 at week 12 (p<.001). Among partial responders (≥ 25% decrease in IDS total score), an improvement in depressive symptoms was maintained during an additional 3-month extension phase (total duration = 24 weeks) according to IDS total scores (p<.001). Patients experienced a reduction in insulin resistance from baseline to Week 12 according to the log homeostasis model assessment (−0.8 ± 0.75; p<.001) and a significant reduction in inflammation as measured by log highly- sensitive C-reactive protein (−0.87 ± 0.72; p<.001). During the current episode, the majority of participants (74%, n=17), had already failed at least one antidepressant trial. The most common side effects were headache and dizziness; no patient discontinued due to side effects.
These data are limited by a small sample size and an open-label study design with no placebo control.
Although preliminary, pioglitazone appears to reduce depression severity and improve several markers of cardiometabolic risk, including insulin resistance and inflammation. Larger, placebo-controlled studies are indicated.
PMCID: PMC3225727  PMID: 21782251
13.  Analysis of Metabolism of 6FDG: A PET Glucose Transport Tracer 
Nuclear medicine and biology  2011;38(5):667-674.
We are developing 18F-labeled 6-fluoro-6-deoxy-D-glucose ([18F]6FDG) as a tracer of glucose transport. As part of this process it is important to characterize and quantify putative metabolites. In contrast to the ubiquitous PET tracer 18F-labeled 2-fluoro-2-deoxy-D-glucose ([18F]2FDG) which is phosphorylated and trapped intracellularly, the substitution of fluorine for a hydroxyl group at carbon 6 in [18F]6FDG should prevent its phosphorylation. Consequently, [18F]6FDG has the potential to trace the transport step of glucose metabolism without the confounding effects of phosphorylation and subsequent steps of metabolism. Herein the focus is to determine whether, and the degree to which, [18F]6FDG remains unchanged following intravenous injection.
Biodistribution studies were performed using 6FDG labeled with 18F as well as the longer-lived radionuclides 3H and 14C. Tissues were harvested at 1, 6, and 24 h following intravenous administration and radioactivity was extracted from the tissues and analyzed using a combination of ion exchange columns, high-performance liquid chromatography, and chemical reactivity.
At the 1 h time-point, the vast majority of radioactivity in the liver, brain, heart, skeletal muscle, and blood was identified as 6FDG. At the 6- and 24-h time-points there was evidence of a minor amount of radioactive materials that appeared to be 6-fluoro-6-deoxy-D-sorbitol and possibly 6-fluoro-6-deoxy-D-gluconic acid.
On the time scale typical of PET imaging studies radioactive metabolites of [18F]6FDG are negligible.
PMCID: PMC3128789  PMID: 21718942
Glucose transport; 6-fluoro-6-deoxy-D-glucose
14.  Severe hypoglycemia symptoms, antecedent behaviors, immediate consequences and association with glycemia medication usage: Secondary analysis of the ACCORD clinical trial data 
Hypoglycemia is a common complication of diabetes treatment. This paper describes symptoms, predecessors, consequences and medications associated with the first episode of severe hypoglycemia among ACCORD participants with type 2 diabetes, and compares these between intensive (Int: goal A1C <6.0%) and standard (Std, goal A1C 7–7.9%) glycemia intervention groups.
Information about symptoms, antecedents, and consequences was collected at the time participants reported an episode of severe hypoglycemia. Data on medications prescribed during the clinical trial was used to determine the association of particular diabetes drug classes and severe hypoglycemia.
The most frequently reported symptoms in both glycemia group were weakness/fatigue (Int 29%; Std 30%) and sweating (Int 26%; Std 27%), followed by confusion/disorientation (Int 22%; Std 29%) and shakiness (Int 21%; Std 19%). Approximately half of all events were preceded by a variation in food intake (Int 48%; Std 58%). The most common consequences were confusion (Int 37%; Std 34%), loss of consciousness (Int 25%; Std 25%), and hospitalization (Int 18%; Std 24%). The highest rates of hypoglycemia were found among those participants treated with insulin only (Int 6.09/100 person yrs; Std 2.64/100 person yrs) while the lowest were among those prescribed oral agents only (Int 1.93/100 person yrs; Std 0.20/100 person yrs).
Severe hypoglycemia episodes were frequently preceded by a change in food intake, making many episodes potentially preventable. Symptoms of confusion/disorientation and loss of consciousness were frequently seen. The highest rates of hypoglycemia were seen with prescription of insulin, either alone or in combination with other medications.
Clinical Trial Registration
Number: NCT00000620
PMCID: PMC3433360  PMID: 22646230
Hypoglycemia; Type 2 diabetes
15.  Effect of Intensive Compared With Standard Glycemia Treatment Strategies on Mortality by Baseline Subgroup Characteristics 
Diabetes Care  2010;33(4):721-727.
To determine if baseline subgroups in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial can be identified for whom intensive compared with standard glycemia treatment had different effects on all-cause mortality.
Exploratory post hoc intention-to-treat comparisons were made between intensive and standard glycemia groups on all-cause mortality by subgroups defined by baseline characteristics.
There were few significant interactions between baseline characteristics and effects of intensive versus standard glycemia treatment on mortality: self-reported history of neuropathy (hazard ratio [HR] 1.95, 95% CI 1.41–2.69) versus no history of neuropathy (0.99, 0.79–1.26; P value for interaction 0.0008), higher A1C (A1C >8.5%: HR 1.64, 95% CI 1.22–2.22; A1C 7.5–8.4%: 1.00, 0.75–1.34; A1C <7.5%: 1.00, 0.67–1.50; P value for interaction 0.04), and aspirin use (HR 1.45, 95% CI 1.13–1.85, compared with 0.96, 0.72–1.27, in nonusers; P value for interaction 0.03).
We found a remarkable similarity of effect from intensive compared with standard glycemia treatment on mortality across most baseline subgroups. No differential effect was found in subgroups defined by variables anticipated to have an interaction: age, duration of diabetes, and previous history of cardiovascular disease. The three baseline characteristics that defined subgroups for which there was a differential effect on mortality may help identify patients with type 2 diabetes at higher risk of mortality from intensive regimens for glycemic control. Further research is warranted.
PMCID: PMC2845012  PMID: 20103550
16.  Near-Normalization of Glucose and Microvascular Diabetes Complications: Data from ACCORD and ADVANCE 
To compare results of clinical trials that assessed the impact of near-normalization of glucose on microvascular complications in type 2 diabetes.
ACCORD (N = 10,234) and ADVANCE (N = 11,140) tested the hypothesis that near-normalization of glucose reduces microvascular complications in adults with established type 2 diabetes. Differences in incidence rates (intensive versus standard glucose control) for specific microvascular complications are expressed as ‘number needed to treat’ (NNT) to prevent one microvascular complication. The impact of blood pressure (BP) control and fenofibrate use on microvascular complications was also assessed.
In ADVANCE, near-normalization of glucose reduced new or worsening nephropathy (NNT = 77 for 5 years to prevent one occurrence), but not eye or foot complications. In ACCORD, near-normalization of glucose did not reduce prespecified composite measures of advanced microvascular complications, and impact on secondary microvascular outcomes was mixed. The ancillary ACCORD Eye Study found reduced progression in retinopathy with near-normalization of glucose (NNT = 32 for 4 years), and with blinded fenofibrate therapy (NNT = 27 for 4 years), but neither intervention reduced vision loss. ADVANCE showed a benefit of intensive BP control (mean BP 133/70 mmHg) on microvascular complications, independent of glucose control.
End-stage microvascular complications were not altered by near-normalization of glucose. Some early manifestations of microvascular complications were reduced, with inconsistencies across studies in which were affected. These early and inconsistent micro-vascular effects must be weighed against significantly increased severe hypoglycemia, weight gain, and (in ACCORD) increased total mortality (NNT = 94 for 3.5 years for one excess death) consistently found in all prespecified patient subgroups. Alternative clinical strategies, such as moderate BP control or fenofibrate treatment may reduce microvascular complications independent of glucose control. The data strongly support personalized glucose control goals based on clinical factors and patient preferences for outcomes.
PMCID: PMC3474623  PMID: 23148169
clinical guidelines; clinical trials; glucose control; nephropathy; neuropathy; retinopathy; type 2 diabetes
18.  The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study  
Objective To determine whether there is a link between hypoglycaemia and mortality among participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.
Design Retrospective epidemiological analysis of data from the ACCORD trial.
Setting Diabetes clinics, research clinics, and primary care clinics.
Participants Patients were eligible for the ACCORD study if they had type 2 diabetes, a glycated haemoglobin (haemoglobin A1C) concentration of 7.5% or more during screening, and were aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of subclinical disease or two additional cardiovascular risk factors.
Intervention Intensive (haemoglobin A1C <6.0%) or standard (haemoglobin A1C 7.0-7.9%) glucose control.
Outcome measures Symptomatic, severe hypoglycaemia, manifest as either blood glucose concentration of less than 2.8 mmol/l (<50 mg/dl) or symptoms that resolved with treatment and that required either the assistance of another person or medical assistance, and all cause and cause specific mortality, including a specific assessment for involvement of hypoglycaemia.
Results 10 194 of the 10 251 participants enrolled in the ACCORD study who had at least one assessment for hypoglycaemia during regular follow-up for vital status were included in this analysis. Unadjusted annual mortality among patients in the intensive glucose control arm was 2.8% in those who had one or more episodes of hypoglycaemia requiring any assistance compared with 1.2% for those with no episodes (53 deaths per 1924 person years and 201 deaths per 16 315 person years, respectively; adjusted hazard ratio (HR) 1.41, 95% CI 1.03 to 1.93). A similar pattern was seen among participants in the standard glucose control arm (3.7% (21 deaths per 564 person years) v 1.0% (176 deaths per 17 297 person years); adjusted HR 2.30, 95% CI 1.46 to 3.65). On the other hand, among participants with at least one hypoglycaemic episode requiring any assistance, a non-significantly lower risk of death was seen in those in the intensive arm compared with those in the standard arm (adjusted HR 0.74, 95% 0.46 to 1.23). A significantly lower risk was observed in the intensive arm compared with the standard arm in participants who had experienced at least one hypoglycaemic episode requiring medical assistance (adjusted HR 0.55, 95% CI 0.31 to 0.99). Of the 451 deaths that occurred in ACCORD up to the time when the intensive treatment arm was closed, one death was adjudicated as definitely related to hypoglycaemia.
Conclusion Symptomatic, severe hypoglycaemia was associated with an increased risk of death within each study arm. However, among participants who experienced at least one episode of hypoglycaemia, the risk of death was lower in such participants in the intensive arm than in the standard arm. Symptomatic, severe hypoglycaemia does not appear to account for the difference in mortality between the two study arms up to the time when the ACCORD intensive glycaemia arm was discontinued.
Trial registration NCT00000620.
PMCID: PMC2803744  PMID: 20061358
19.  Effect of thyroid hormone on the distribution and activity of Na, K-ATPase in ventricular myocardium 
Employing detergent-free sucrose density gradient fractionation method we isolated cholesterol rich lighter membrane fractions containing ~ 10% of protein, ~ 30% of cholesterol in membranes of ventricular myocardium. Cholesterol- rich lighter membrane fractions contain > 70% of Na, K-ATPase, and caveolins 1 and 3, and < 10% of β-actin. Treatment of hypothyroid rats with T3 increased the relative abundance of both α1 and β1 Na, K-ATPase subunits in total membranes by 4–5-fold (with no change in caveolin 3), and resulted in 1.9-fold increase in enzyme activity. T3 induced Na, K-ATPase subunits were preferentially distributed to the lighter fractions (#s 4, 5 and 6); and increased abundance of α1 and β1 were 34% to 70% and 43% to 68% respectively. We conclude that the activity of Na, K-ATPase is not uniform in cardiac membranes, and while a significant amount of Na, K-ATPase is present in cardiac cholesterol-rich membrane fractions, the intrinsic activity is significantly less than the enzyme present in relatively cholesterol-poor membranes.
PMCID: PMC2474788  PMID: 18457653
Na; K-ATPase; cholesterol; rafts; detergent resistant membranes; membrane fractionation; caveolar membranes
20.  Rat liver adenyl cyclase activity in various thyroid states 
Journal of Clinical Investigation  1972;51(9):2498-2501.
Thyroidectomized and euthyroid rats were injected with three doses of triiodothyronine (T3) or of the diluent over a 6 day period, and liver homogenates were assayed for basal, epinephrine-stimulated, and NaF-stimulated adenyl cyclase activity. Based on NaF-stimulated levels, total adenyl cyclase activity, expressed per milligram of liver protein, was increased after thyroidectomy. Administration of T3 to either hypothyroid or euthyroid rats, however, had no effect on the NaF-stimulated levels. Basal and epinephrine-stimulated enzyme activities were the same in hypothyroid, euthyroid, and hyperthyroid (euthyroid + T3) liver homogenates. In contrast, injections of T3 in hypothyroid rats increased the activities of basal and epinephrine-stimulated adenyl cyclase. In view of the findings in euthyroid and hyperthyroid liver, it is possible that this effect is transient. In general, no correlation was found between the effects of thyroid hormone on respiration and on adenyl cyclase activity of the rat liver. These results imply that the hepatic thermogenic response to thyroid hormone is not mediated by stimulation of adenyl cyclase activity with the possible exception of the early effects of T3 in the athyroid rat.
PMCID: PMC292419  PMID: 4639030
21.  The Mechanism of the Calorigenic Action of Thyroid Hormone  
The Journal of General Physiology  1971;57(6):710-722.
In an earlier study, we proposed that thyroid hormone stimulation of energy utilization by the Na+ pump mediates the calorigenic response. In this study, the effects of triiodothyronine (T3) on total oxygen consumption (QOO2), the ouabain-sensitive oxygen consumption [QOO2(t)], and NaK-ATPase in liver, kidney, and cerebrum were measured. In liver, ∼90% of the increase in QOO2 produced by T3 in either thyroidectomized or euthyroid rats was attributable to the increase in QOO2(t). In kidney, the increase in QOO2(t) accounted for 29% of the increase in QOO2 in thyroidectomized and 46% of the increase in QOO2 in euthyroid rats. There was no demonstrable effect of T3 in euthyroid rats on QOO2 or QOO2(t) of cerebral slices. The effects of T3 on NaK-ATPase activity in homogenates were as follows: In liver +81% from euthyroid rats and +54% from hypothyroid rats. In kidney, +21% from euthyroid rats and +69% from hypothyroid rats. T3 in euthyroid rats produced no significant changes in NaK-ATPase or Mg-ATPase activity of cerebral homogenates. Liver plasma membrane fractions showed a 69% increase in NaK-ATPase and no significant changes in either Mg-ATPase or 5'-nucleotidase activities after T3 injection. These results indicate that thyroid hormones stimulate NaK-ATPase activity differentially. This effect may account, at least in part, for the calorigenic effects of these hormones.
PMCID: PMC2203122  PMID: 4252666

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