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1.  Insulin Dose and Cardiovascular Mortality in the ACCORD Trial 
Diabetes Care  2015;38(11):2000-2008.
In the ACCORD trial, intensive treatment of patients with type 2 diabetes and high cardiovascular (CV) risk was associated with higher all-cause and CV mortality. Post hoc analyses have failed to implicate rapid reduction of glucose, hypoglycemia, or specific drugs as the causes of this finding. We hypothesized that exposure to injected insulin was quantitatively associated with increased CV mortality.
We examined insulin exposure data from 10,163 participants with a mean follow-up of 5 years. Using Cox proportional hazards models, we explored associations between CV mortality and total, basal, and prandial insulin dose over time, adjusting for both baseline and on-treatment covariates including randomized intervention assignment.
More participants allocated to intensive treatment (79%) than standard treatment (62%) were ever prescribed insulin in ACCORD, with a higher mean updated total daily dose (0.41 vs. 0.30 units/kg) (P < 0.001). Before adjustment for covariates, higher insulin dose was associated with increased risk of CV death (hazard ratios [HRs] per 1 unit/kg/day 1.83 [1.45, 2.31], 2.29 [1.62, 3.23], and 3.36 [2.00, 5.66] for total, basal, and prandial insulin, respectively). However, after adjustment for baseline covariates, no significant association of insulin dose with CV death remained. Moreover, further adjustment for severe hypoglycemia, weight change, attained A1C, and randomized treatment assignment did not materially alter this observation.
These analyses provide no support for the hypothesis that insulin dose contributed to CV mortality in ACCORD.
PMCID: PMC4876773  PMID: 26464212
2.  Durable change in glycaemic control following intensive management of type 2 diabetes in the ACCORD clinical trial 
Diabetologia  2014;57(10):2030-2037.
We aimed to determine the persistence of glycaemic control 1 year after a limited period of intensive glycaemic management of type 2 diabetes.
4119 ACCORD Trial participants randomized to target HbA1c <6.0% (42 mmol/mol) for 4.0±1.2 years were systematically transitioned to target HbA1c 7.0–7.9% (53–63 mmol/mol) and followed for an additional 1.1±0.2 years. Characteristics of participants with HbA1c <6.5% (48 mmol/mol) or ≥6.5% at transition were compared. Changes in BMI and glucose-lowering medications were compared between those ending with HbA1c <6.5% vs ≥6.5%. Poisson models were used to assess the independent effect of attaining HbA1c <6.5% before transition on ending with HbA1c <6.5%.
Participants with pre-transition HbA1c <6.5% were older with shorter duration diabetes and took less insulin but more non-insulin glucose-lowering agents than those with higher HbA1c. A total of 823 participants achieved a final HbA1c <6.5%, and had greater post-transition reductions in BMI, insulin dose and secretagogue and acarbose use than those with higher HbA1c (p<0.0001). HbA1c <6.5% at transition predicted final HbA1c <6.5% (crude RR 4.9 [95% CI 4.0, 5.9]; RR 3.9 [95% CI 3.2, 4.8] adjusted for demographics, co-interventions, pre-intervention HbA1c, BMI and glucose-lowering medication, and post-transition change in both BMI and glucose-lowering medication). Progressively lower pre-transition HbA1c levels were associated with a greater likelihood of maintaining a final HbA1c of <6.5%. Follow-up duration was not associated with post-transition rise in HbA1c.
Time-limited intensive glycaemic management using a combination of agents that achieves HbA1c levels below 6.5% in established diabetes is associated with glycaemic control more than 1 year after therapy is relaxed.
PMCID: PMC4698982  PMID: 24985147
Intensive glucose lowering; Long-term glycaemic control; Post-intervention follow-up; Type 2 diabetes
3.  Effect of Hypoglycemia on Brain Structure in People With Type 2 Diabetes: Epidemiological Analysis of the ACCORD-MIND MRI Trial 
Diabetes Care  2014;37(12):3279-3285.
The effect of hypoglycemia related to treatment of type 2 diabetes mellitus (T2DM) on brain structure remains unclear. We aimed to assess whether symptomatic severe hypoglycemia is associated with brain atrophy and/or white matter abnormalities.
We included T2DM participants with brain MRI from the Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) trial. Symptomatic severe hypoglycemia was defined as blood glucose <2.8 mmol/L or symptoms resolved with treatments that required the assistance of another person or medical assistance (hypoglycemia requiring assistance [HA]). Standardized brain MRI was performed at baseline and at 40 months. Total brain volume (TBV) and abnormal white matter (AWM) volume were calculated using an automated computer algorithm. Brain MRI scans of hypoglycemic participants were also reviewed for local disease.
Of the 503 T2DM participants (mean age, 62 years) with successful baseline and 40-month brain MRI, 28 had at least one HA episode during the 40-month follow-up. Compared with participants without HA, those with HA had marginally significant less atrophy (less decrease in TBV) from baseline to 40 months (−9.55 [95% CI −15.21, −3.90] vs. −15.38 [95% CI −16.64, −14.12], P = 0.051), and no significant increase of AWM volume (2.06 [95% CI 1.71, 2.49] vs. 1.84 [95% CI 1.76, 1.91], P = 0.247). In addition, no unexpected local signal changes or volume loss were seen on hypoglycemic participants’ brain MRI scans.
Our study suggests that hypoglycemia related to T2DM treatment may not accentuate brain pathology, specifically brain atrophy or white matter abnormalities.
PMCID: PMC4237972  PMID: 25267796
4.  The Effects of Medical Management on the Progression of Diabetic Retinopathy in Persons with Type 2 Diabetes: The ACCORD Eye Study 
Ophthalmology  2014;121(12):2443-2451.
To report additional ocular outcomes of intensive treatment of hyperglycemia, elevated blood pressure, and dyslipidemia in the ACCORD Study.
Double 2 × 2 factorial multicenter randomized clinical trials in men and women with type 2 diabetes who had established cardiovascular disease and/or cardiovascular risk factors. In the glycemia trial targets of intensive and standard treatment were HbA1c <6.0% and 7.0-7.9%, respectively, and in the blood pressure trial systolic blood pressure of <120 mm Hg and <140 mm Hg, respectively. The dyslipidemia trial compared fenofibrate plus simvastatin vs. placebo plus simvastatin.
Of the 5273 ACCORD-Eye participants, 3,472 were enrolled and 2856 had 4-year data (85% of survivors).
Eye examinations and fundus photographs were taken at baseline and year 4. Photographs were graded centrally for retinopathy severity and features of macular edema using the Early Treatment Diabetic Retinopathy Study (ETDRS) methods.
Primary Outcome Measure
3 or more steps progression on the ETDRS person scale or treatment of retinopathy with photocoagulation or vitrectomy.
As previously reported, there were significant reductions in the primary outcome in the glycemia and dyslipidemia trials, but no significant effect in the blood pressure trial. Results were similar for retinopathy progression by 1, 2, and 4 or more steps on the person scale and for ≥2 steps on the eye scale. In the subgroup of patients with mild retinopathy at baseline, effect estimates were large (Odds Ratios ∼0.30, P<0.001), but did not reach nominal significance for participants with no retinopathy or for those with moderate to severe retinopathy at baseline.
Slowing of progression of retinopathy by intensive treatment of glycemia was observed in ACCORD participants, whose average age and diabetes duration were 62 and 10 years, respectively, and who had established cardiovascular disease and/or cardiovascular risk factors. The effect appeared stronger in patients with mild retinopathy. Similar slowing of progression was observed in patients treated with fenofibrate, while no effect was observed with intensive BP treatment. This is the second study to confirm the benefits of fenofibrate in reducing diabetic retinopathy progression and fenofibrate should be considered for treatment of diabetic retinopathy.
PMCID: PMC4252767  PMID: 25172198
5.  Effect of Intensive Glycemic Control on Ischemic Heart Disease 
Lancet  2014;384(9958):1936-1941.
The possibility that hyperglycemia accounts for the 2–3 fold higher risk of ischemic heart disease (IHD) in type 2 diabetes was explored by assessing the effect of intensive glucose lowering on IHD in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.
10,251 people (mean age = 62) with type 2 diabetes (mean duration = 10 years, mean A1c = 8.3%) were allocated to intensive or standard glycemic control targeting an A1c <6% or 7–7.9% respectively. This intervention’s effect on IHD (fatal or non-fatal myocardial infarction, coronary revascularization, unstable angina, and new angina) was assessed during a mean active treatment period of 3.7 years followed by an additional 1.2 years.
Fewer participants allocated to the intensive versus standard care group experienced a myocardial infarction during both active treatment (HR = 0.80; 95% CI 0.67 – 0.96; P = 0.015) and full (active and additional) follow-up (HR = 0.84; 95% CI 0.72 – 0.97; P = 0.02). Similar findings were observed for a composite IHD outcome of myocardial infarction, coronary revascularization or unstable angina (HR = 0.89; 95% CI 0.79–0.99 and HR = 0.87; 95% CI 0.79 – 0.96 during active treatment and full follow-up respectively)and for coronary revascularization (HR = 0.84; 95% CI 0.75–0.94), and unstable angina (HR = 0.81; 95% CI 0.67–0.97) during full follow-up. Adding A1C levels achieved during active treatment attenuated the significant hazard ratios to neutrality.
Glucose elevation is a modifiable risk factor for IHD in middle aged people with type 2 diabetes and other IHD risk factors.
PMCID: PMC4397008  PMID: 25088437
6.  Combined intensive blood pressure and glycemic control does not produce an additive benefit on microvascular outcomes in type 2 diabetic patients 
Kidney international  2011;81(6):586-594.
A reduction of either blood pressure or glycemia decreases some microvascular complications of type 2 diabetes, and we studied here their combined effects. In total, 4733 older adults with established type 2 diabetes and hypertension were randomly assigned to intensive (systolic blood pressure less than 120mmHg) or standard (systolic blood pressure less than 140mmHg) blood pressure control, and separately to intensive (HbA1c less than 0.060) or standard (HbA1c 0.070–0.079) glycemic control. Prespecified microvascular outcomes were a composite of renal failure and retinopathy and nine single outcomes. Proportional hazard regression models were used without correction for type I error due to multiple tests. During a mean follow-up of 4.7 years, the primary outcome occurred in 11.4% of intensive and 10.9% of standard blood pressure patients (hazard ratio 1.08), and in 11.1% of intensive and 11.2% of standard glycemia control patients. Intensive blood pressure control only reduced the incidence of microalbuminuria (hazard ratio 0.84), and intensive glycemic control reduced the incidence of macroalbuminuria and a few other microvascular outcomes. There was no interaction between blood pressure and glycemic control, and neither treatment prevented renal failure. Thus, in older patients with established type 2 diabetes and hypertension, intensive blood pressure control improved only 1 of 10 prespecified microvascular outcomes. None of the outcomes were significantly reduced by simultaneous intensive treatment of glycemia and blood pressure, signifying the lack of an additional beneficial effect from combined treatment.
PMCID: PMC4641306  PMID: 22166848
albuminuria; cardiovascular disease; macroalbuminuria; microalbuminuria; nephropathy; retinopathy
7.  The degree of retinopathy is equally predictive for renal and macrovascular outcomes in the ACCORD Trial 
Diabetic retinopathy (DR) is associated with a higher risk of renal and cardiovascular events. We sought to compare the risk for renal versus cardiovascular (CV) outcomes, stratified by retinopathy severity.
ACCORD was a randomized trial of people with type 2 diabetes, at high-risk for CV disease. A subgroup (n=3,369 from 71 clinics) had stereoscopic fundus photographs graded centrally. Participants were stratified at baseline to moderate/severe DR or no/mild DR and were monitored for renal and CV outcomes at follow-up visits over 4 years. The composite renal outcome was comprised of serum creatinine doubling, macroalbuminuria, or end-stage renal disease. The composite CV outcome was the ACCORD trial primary outcome. Competing risk techniques were used to estimate the relative risk (RR) of renal versus CV composite outcomes within each DR stratum.
The hazards ratio for doubling of serum creatinine and incident CV event in the moderate/severe DR versus no/mild DR strata were: 2.31 (95%CI: 1.25–4.26) and 1.98 (95%CI: 1.49–2.62), respectively. The RR of the two composite outcomes was highly similar in the no/mild DR stratum (adjusted RR at 4 years for CV versus renal events=0.96, 95%CI:0.72–1.28) and the moderate/severe DR stratum (adjusted RR=0.92, 95%CI:0.64–1.31).
Thus, in people with type 2 diabetes at high risk for cardiovascular disease, incident CV versus renal events was similar, irrespective of the severity of the DR. Further evaluation of the specificity of DR for microvascular versus macrovascular events in other populations is warranted.
PMCID: PMC4252726  PMID: 25123755
retinopathy; nephropathy; macrovascular; albuminuria
8.  Dexamethasone-Induced Insulin Resistance: Kinetic Modeling Using Novel PET Radiopharmaceutical 6-Deoxy-6-[18F]fluoro-D-glucose 
An insulin-resistant rat model, induced by dexamethasone, was used to evaluate a Michaelis–Menten-based kinetic model using 6-deoxy-6-[18F]fluoro-D-glucose (6-[18F]FDG) to quantify glucose transport with PET.
Seventeen, male, Sprague–Dawley rats were studied in three groups: control (Ctrl), control+insulin (Ctrl+I), and dexamethasone+insulin (Dex+I). PET scans were acquired for 2 h under euglycemic conditions in the Ctrl group and under hyperinsulinemic-euglycemic conditions in the Ctrl+I and Dex+I groups.
Glucose transport, assessed according to the 6-[18F]FDG concentration, was highest in skeletal muscle in the Ctrl+I, intermediate in the Dex+I, and lowest in the Ctrl group, while that in the brain was similar among the groups. Modeling analysis applied to the skeletal muscle uptake curves yielded values of parameters related to glucose transport that were greatest in the Ctrl+I group and increased to a lesser degree in the Dex+I group, compared to the Ctrl group.
6-[18F]FDG and the Michaelis–Menten-based model can be used to measure insulin-stimulated glucose transport under basal and an insulin resistant state in vivo.
PMCID: PMC4578717  PMID: 24819311
PET; Glucose clamp; Kinetic modeling; Insulin resistant; Skeletal muscle
9.  PPAR-γ Agonism as a Modulator of Mood: Proof-of-Concept for Pioglitazone in Bipolar Depression 
CNS drugs  2014;28(6):571-581.
Insulin resistance and other cardiometabolic risk factors predict increased risk of depression and decreased response to antidepressant and mood stabilizer treatments. This proof-of-concept study tested whether administration of an insulin-sensitizing peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist could reduce bipolar depression symptom severity. A secondary objective determined if levels of highly-sensitive C-reactive protein and Interleukin-6 (IL-6) predicted treatment outcome.
Thirty-four patients with bipolar disorder (I, II, or not otherwise specified) and metabolic syndrome/insulin resistance who were currently depressed (Quick Inventory of Depressive Symptoms (QIDS) total score ≥ 16) despite an adequate trial of a mood stabilizer received open-label, adjunctive treatment with the PPAR- γ agonist pioglitazone (15–30 mg/d) for 8 weeks. The majority of participants (76%, n=26) were experiencing treatment-resistant bipolar depression, having already failed two mood stabilizers or the combination of a mood stabilizer and a conventional antidepressant.
Supporting an association between insulin sensitization and depression severity, pioglitazone treatment was associated with a decrease in the total Inventory of Depressive Symptomatology (IDS-C30) score from 38.7±8.2 at baseline to 21.2±9.2 at week 8 (p<.001). Self-reported depressive symptom severity and clinician-rated anxiety symptom severity significantly improved over 8 weeks as measured by the QIDS (p<.001) and Structured Interview Guide for the Hamilton Anxiety Scale (p<.001), respectively. Functional improvement also occurred as measured by the change in total score on the Sheehan Disability Scale (−17.9±3.6; p<.001). Insulin sensitivity increased from baseline to week 8 as measured by the Insulin Sensitivity Index derived from an oral glucose tolerance test (0.98±0.3; p<.001). Higher baseline levels of IL-6 were associated with greater decrease in depression severity (parameter estimate β=−3.89, SE=1.47, p=0.015). A positive correlation was observed between improvement in IDS-C30 score and change in IL-6 (r=0.44, p<01).
Open-label administration of the PPAR-γ agonist, pioglitazone, was associated with improvement in depressive symptoms and reduced cardiometabolic risk. Reduction in inflammation may represent a novel mechanism by which pioglitazone modulates mood. ( Identifier: NCT00835120)
PMCID: PMC4113193  PMID: 24715548
10.  Triglyceride High-Density Lipoprotein Ratios Predict Glycemia-Lowering in Response to Insulin Sensitizing Drugs in Type 2 Diabetes: A Post Hoc Analysis of the BARI 2D 
Journal of Diabetes Research  2015;2015:129891.
Glycemic management is central in prevention of small vessel and cardiovascular complications in type 2 diabetes. With the plethora of newer medications and recommendations for a patient centered approach, more information is necessary to match the proper drug to each patient. We showed that BARI 2D, a five-year trial designed to compare two different glycemic treatment strategies, was suitable for assessing different responses according to different phenotypic characteristics. Treatment with insulin sensitizing medications such as thiazolidinediones and metformin was more effective in improving glycemic control, particularly in the more insulin resistant patient, when compared to the insulin provision strategy using insulin and or sulfonylureas. Triglyceride and high density lipoprotein ratio (TG/HDL-cholesterol ratio) was found to be a readily available and practical biomarker that helps to identify the insulin resistant patient. These results support the concept that not all medications for glycemic control work the same in all patients. Thus, tailored therapy can be done using phenotypic characteristics rather than a “one-size-fits-all approach.”
PMCID: PMC4461783  PMID: 26106623
11.  Paradoxical Reduction in HDL-C With Fenofibrate and Thiazolidinedione Therapy in Type 2 Diabetes: The ACCORD Lipid Trial 
Diabetes Care  2014;37(3):686-693.
To determine the occurrence of extremely low HDL cholesterol (HDL-C) among participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Trial and to examine the relationship of this finding with treatment with fenofibrate and thiazolidinedione (TZD).
The ACCORD Lipid Trial was a randomized, double-blind, placebo-controlled study conducted in patients with type 2 diabetes at 77 clinical centers across the U.S. and Canada in a 5,518-patient subset of the larger 10,251 ACCORD Glycemia Trial. Patients were enrolled from 11 January 2001 to 29 October 2005 and followed until the end of study visits between 1 March and 30 June 2009. Follow-up in the ACCORD Lipid Trial was 4–8 years (mean 4.7 years). Patients were treated with blinded fenofibrate or placebo on a background of simvastatin therapy. The main outcome measures for these descriptive, post hoc analyses was the occurrence of extremely low HDL-C (defined as <25 mg/dL [0.647 mmol/L]) during the trial.
Among ACCORD Lipid Trial participants, the occurrence of extremely low HDL-C ever during study follow-up was 106% higher among those randomized to fenofibrate (10.1% fenofibrate vs. 4.9% placebo, P < 0.001). The occurrence of low HDL-C was associated with concurrent treatment with fenofibrate and TZD (7.0% for both vs. 2.2% for neither at 48 months postrandomization).
Idiosyncratic and marked reduction in HDL-C can occur in some patients treated with both fenofibrate and TZD. Practitioners should recognize this important potential idiosyncratic reaction and take appropriate corrective action.
PMCID: PMC3931389  PMID: 24296848
12.  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
13.  +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
14.  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
15.  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
16.  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
17.  Depressive Symptoms and Diabetes 
PMCID: PMC3904750  PMID: 19001617
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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