Search tips
Search criteria

Results 1-25 (30)

Clipboard (0)

Select a Filter Below

Year of Publication
1.  Changes in human brain glutamate concentration during hypoglycemia: insights into cerebral adaptations in hypoglycemia-associated autonomic failure in type 1 diabetes 
Hypoglycemia-associated autonomic failure (HAAF) is a condition in which patients with type 1 diabetes (T1D) who experience frequent hypoglycemia develop defective glucose counter-regulation and become unable to sense hypoglycemia. Brain glutamate may be involved in the mechanism of HAAF. The goal of this study was to follow the human brain glutamate concentration during experimentally induced hypoglycemia in subjects with and without HAAF. 1H magnetic resonance spectroscopy was used to track the occipital cortex glutamate concentration throughout a euglycemic clamp followed immediately by a hypoglycemic clamp. T1D patients with HAAF were studied in comparison to two control groups, i.e., T1D patients without HAAF and healthy controls (n=5 per group). Human brain glutamate concentration decreased (P⩽0.01) after the initiation of hypoglycemia in the two control groups, but a smaller trend toward a decrease in patients with HAAF did not reach significance (P>0.05). These findings are consistent with a metabolic adaptation in HAAF to provide higher glucose and/or alternative fuel to the brain, eliminating the need to oxidize glutamate. In an exploratory analysis, we detected additional metabolite changes in response to hypoglycemia in the T1D patient without HAAF control group, namely, increased aspartate and decreased lactate.
PMCID: PMC4013769  PMID: 24549182
brain; diabetes; glutamate; hypoglycemia; unawareness
2.  Hypoglycemia as a driver of cardiovascular risk in diabetes 
Severe hypoglycemia in patients with diabetes is associated with increased risk of adverse cardiovascular events and death. Recent large randomized clinical trials in individuals with type 2 diabetes have shown that intensive glycemic control may result in increased mortality and hypoglycemia has been investigated as a possible cause. Acute hypoglycemia is a pro-arrhythmic, pro-inflammatory and pro-thrombotic state and several mechanisms have been proposed to explain how hypoglycemia might increase cardiovascular morbidity and mortality. However, data from large clinical trials do not provide strong evidence to establish hypoglycemia as cause of increase mortality. Severe hypoglycemia is also a marker of frailty and predictor of adverse outcomes in patients with diabetes. Individualized therapy should be the goal in patients with diabetes to avoid severe hypoglycemia and any related adverse outcomes.
PMCID: PMC3743541  PMID: 23881546
Hypoglycemia; diabetes mellitus; cardiovascular risk; HAAF; mortality; type 2 diabetes mellitus; type 1 diabetes mellitus; severe hypoglycemia
3.  +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
4.  The Effect of Non-surgical Periodontal Therapy on Hemoglobin A1c Levels in Persons with Type 2 Diabetes and Chronic Periodontitis: A Randomized Clinical Trial 
Chronic periodontitis, a destructive inflammatory disorder of the supporting structures of the teeth, is prevalent in patients with diabetes. Limited evidence suggests that periodontal therapy may improve glycemic control.
To determine if non-surgical periodontal treatment reduces hemoglobin A1c (HbA1c) in persons with type 2 diabetes (DM) and moderate to advanced chronic periodontitis.
Design, Setting and Participants
The Diabetes and Periodontal Therapy Trial (DPTT) is a 6-month, single-masked, randomized, multi-center clinical trial. Participants had DM, were taking stable doses of medications, had HbA1c ≥7% and <9%, and untreated periodontitis. Five hundred fourteen participants were enrolled between November 2009 and March 2012 from diabetes and dental clinics and communities affiliated with five academic medical centers.
The treatment group (n=257) received scaling and root planing plus chlorhexidine oral rinse at baseline, and supportive periodontal therapy at three and six months. The control group (n=257) received no treatment for six months.
Main Outcome Measure
Difference in HbA1c change from baseline between groups at six months. Secondary outcomes included changes in probing pocket depths, clinical attachment loss, bleeding on probing, gingival index, fasting glucose, and the Homeostasis Model Assessment (HOMA2).
Enrollment was stopped early due to futility. At 6 months, the periodontal therapy group increased HbA1c 0.17% (1.0) (mean (SD)) compared to 0.11% (1.0) in the control group, with no significant difference between groups based on a linear regression model adjusting for clinical site (mean difference = -0.05%; 95% Confidence Interval (CI): -0.23%, 0.12%; p=0.55). Probing depth, clinical attachment loss, bleeding on probing and gingival index measures improved in the treatment group compared to the control group at six months with adjusted between-group differences of 0.33mm (95% CI: 0.26, 0.39), 0.31mm (95% CI: 0.23, 0.39), 16.5% (95% CI: 12.9, 20.0) and 0.28 (95% CI: 0.21, 0.35), respectively; all p values <0.0001).
Conclusions and Relevance
Non-surgical periodontal therapy did not improve glycemic control in patients with DM and moderate to advanced chronic periodontitis. These findings do not support the use of nonsurgical periodontal treatment in patients with diabetes for the purpose of lowering HbA1c.
PMCID: PMC4089989  PMID: 24346989
Diabetes; Diabetes Mellitus; Type 2; Periodontal Disease; Periodontitis; Glycated Hemoglobin; HbA1c
5.  Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society 
Diabetes Care  2013;36(5):1384-1395.
To review the evidence about the impact of hypoglycemia on patients with diabetes that has become available since the past reviews of this subject by the American Diabetes Association and The Endocrine Society and to provide guidance about how this new information should be incorporated into clinical practice.
Five members of the American Diabetes Association and five members of The Endocrine Society with expertise in different aspects of hypoglycemia were invited by the Chair, who is a member of both, to participate in a planning conference call and a 2-day meeting that was also attended by staff from both organizations. Subsequent communications took place via e-mail and phone calls. The writing group consisted of those invitees who participated in the writing of the manuscript. The workgroup meeting was supported by educational grants to the American Diabetes Association from Lilly USA, LLC and Novo Nordisk and sponsorship to the American Diabetes Association from Sanofi. The sponsors had no input into the development of or content of the report.
The writing group considered data from recent clinical trials and other studies to update the prior workgroup report. Unpublished data were not used. Expert opinion was used to develop some conclusions.
Consensus was achieved by group discussion during conference calls and face-to-face meetings, as well as by iterative revisions of the written document. The document was reviewed and approved by the American Diabetes Association’s Professional Practice Committee in October 2012 and approved by the Executive Committee of the Board of Directors in November 2012 and was reviewed and approved by The Endocrine Society’s Clinical Affairs Core Committee in October 2012 and by Council in November 2012.
The workgroup reconfirmed the previous definitions of hypoglycemia in diabetes, reviewed the implications of hypoglycemia on both short- and long-term outcomes, considered the implications of hypoglycemia on treatment outcomes, presented strategies to prevent hypoglycemia, and identified knowledge gaps that should be addressed by future research. In addition, tools for patients to report hypoglycemia at each visit and for clinicians to document counseling are provided.
PMCID: PMC3631867  PMID: 23589542
6.  Neurochemical profile of patients with type 1 diabetes measured by 1H-MRS at 4 T 
The impact of type 1 diabetes mellitus (T1DM) on a comprehensive neurochemical profile of the human brain has not been reported yet. Our previous proton magnetic resonance spectroscopy (1H-MRS) studies on T1DM were focused exclusively on the assessment of brain glucose levels. In this study, we reexamined our previously acquired data to investigate concentration differences of a broad range of neurochemicals in T1DM subjects relative to nondiabetic controls. We selected MRS data from 13 subjects (4 F/9 M, age=41±11 years, body mass index=26±3 kg/m2) with well-controlled T1DM (disease duration=22±12 years, A1C=7.5%±2.0%) and 32 nondiabetic controls (14 F/18 M, age=36±10 years, body mass index=27±6 kg/m2) acquired during a hyperglycemic clamp (target [Glc]plasma=300±15 mg/dL). The 1H-MR spectra were collected from two 15.6-mL voxels localized in gray-matter-rich occipital lobe and in white-matter-rich parieto-occipital region using ultra-short echo-time STEAM at 4 T. LCModel analysis allowed reliable quantification of 17 brain metabolites. Lower levels of N-acetylaspartate (by 6%, P=0.007) and glutamate (by 6%, P=0.045) were observed in the gray matter of T1DM patients as compared with controls, which might indicate a partial neuronal loss or dysfunction as a consequence of long-term T1DM. No other differences in metabolites were observed between subjects with T1DM and controls.
PMCID: PMC3652707  PMID: 23403373
diabetes; glutamate; MR spectroscopy; neurochemistry; neurotransmitters
7.  Estimated plasma Stearoyl Co-A Desaturase-1 activity and risk of incident diabetes: the Atherosclerosis Risk in Communities (ARIC) study 
Evidence from pre-clinical studies suggests inhibition of Stearoyl Co-A Desaturase-1 (SCD-1) activity improves insulin sensitivity. Translation of these findings to humans remains less defined. The purpose of this research was to evaluate the association between different measures of SCD-1 activity and incident diabetes in a large, prospective human study.
In 2738 white participants (aged 45-64 yrs, 47% men) who were free of diabetes at baseline, SCD-1 activity was estimated at baseline by plasma fatty acid ratios in cholesterol esters (SCD16c=16:1n-7/16:0, SCD18c =18:1n-9/18:0) and in phospholipids (SCD16p=16:1n-7/16:0, SCD18p=18:1n-9/18:0). Incident diabetes was ascertained during 3 follow-up visits. Cox proportional hazards regression was used to determine the association between estimated SCD-1 activity and incident diabetes.
During follow-up (mean 8.0 ± SE 2.1 years), 207 (7.6%) participants developed diabetes. After adjusting for age and sex, higher SCD16c, higher SCD16p, and lower SCD18p were significantly associated with incident diabetes. After additional adjustment for education, parental history of diabetes, smoking, dietary intake (carbohydrate, fiber, saturated/monounsaturated/polyunsaturated fat), alcohol use, physical activity, body mass index (BMI), waist-hip ratio, blood pressure, and lipid composition – only SCD16c remained significantly associated with incident diabetes (Hazard Ratio=1.1 linearly across decreasing quintiles, 95% CI 1.01-1.30; p =0.03) which remained nominally associated after adjusting for insulin resistance (p=0.05).
In a large community-based prospective cohort study, the estimate of SCD-1 activity by SCD16c had the strongest association with incident diabetes. Refinement of SCD-1 measurement and replication of its association with incident diabetes in an independent cohort is recommended.
PMCID: PMC3518662  PMID: 22819528
fatty acid ratio; Type 2 Diabetes; prospective study
9.  Hypoglycemia-induced increases in thalamic cerebral blood flow are blunted in subjects with type 1 diabetes and hypoglycemia unawareness 
The thalamus has been found to be activated during the early phase of moderate hypoglycemia. Here, we tested the hypothesis that this region is less activated during hypoglycemia in subjects with type 1 diabetes (T1DM) and hypoglycemia unawareness relative to controls. Twelve controls (5 F/7 M, age 40±14 years, body mass index 24.2±2.7 kg/m2) and eleven patients (7 F/4 M, age 39±13 years, body mass index 26.5±4.4 kg/m2) with well-controlled T1DM (A1c 6.8±0.4%) underwent a two-step hyperinsulinemic (2.0 mU/kg per minute) clamp. Cerebral blood flow (CBF) weighted images were acquired using arterial spin labeling to monitor cerebral activation in the midbrain regions. Blood glucose was first held at 95 mg/dL and then allowed to decrease to 50 mg/dL. The CBF image acquisition during euglycemia and hypoglycemia began within a few minutes of when the target blood glucose values were reached. Hypoglycemia unaware T1DM subjects displayed blunting of the physiologic CBF increase that occurs in the thalamus of healthy individuals during the early phase of moderate hypoglycemia. A positive correlation was observed between thalamic response and epinephrine response to hypoglycemia, suggesting that this region may be involved in the coordination of the counter regulatory response to hypoglycemia.
PMCID: PMC3494000  PMID: 22892724
diabetes; glucose; hypoglycemia; imaging
10.  Sweet and Low: Measuring Brain Glucose During Hypoglycemia 
Diabetes  2012;61(8):1918-1919.
PMCID: PMC3402308  PMID: 22826309
11.  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
12.  Is silent myocardial infarction more common in women with type 2 diabetes than in men? 
Our aim was to determine if silent myocardial infarction (MI) is more common in women with type 2 diabetes than in men. Our secondary aim was to examine the relationships between silent MI and risk factors for cardiovascular disease.
Research Design and Methods
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) database was used to determine if women had more silent MI on baseline electrocardiograms (ECGs) than did men with a similar unremarkable cardiovascular history. MI was diagnosed using ECG analysis according to the Minnesota code. Multivariable logistic regression analysis was used to compare demographic and clinical associations. Interactive effects of risk factors by gender were tested using a forward selection algorithm.
Men were found to have a higher prevalence of silent MI on baseline ECGs than women (6% vs 4%, p=0.001). Women had lower odds of silent MI than men after adjusting for other risk factors (OR=0.80, p=0.04). Race and ethnicity were significantly associated with silent MI (p=0.02), with Asians having the highest and African Americans and Hispanics having lower odds relative to whites.
Our main findings provide no evidence that silent MI, as detected by the Minnesota code, was more common in women than in men in the ACCORD cohort. If, as in the general population, the women in ACCORD are found to have a higher heart disease mortality rate than the men, it seems unlikely that failure to recognize clinically silent heart disease in the years before study enrollment could be a major cause.
PMCID: PMC3348405  PMID: 22446034
silent myocardial infarction; type 2 diabetes; Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial; cardiovascular disease in women
13.  The Impact of Frequent and Unrecognized Hypoglycemia on Mortality in the ACCORD Study 
Diabetes Care  2012;35(2):409-414.
The aim of this study was to examine the relationship between frequent and unrecognized hypoglycemia and mortality in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study cohort.
A total of 10,096 ACCORD study participants with follow-up for both hypoglycemia and mortality were included. Hazard ratios (95% CIs) relating the risk of death to the updated annualized number of hypoglycemic episodes and the updated annualized number of intervals with unrecognized hypoglycemia were obtained using Cox proportional hazards regression models, allowing for these hypoglycemia variables as time-dependent covariates and controlling for the baseline covariates.
Participants in the intensive group reported a mean of 1.06 hypoglycemic episodes (self-monitored blood glucose <70 mg/dL or <3.9 mmol/L) in the 7 days preceding their regular 4-month visit, whereas participants in the standard group reported an average of 0.29 episodes. Unrecognized hypoglycemia was reported, on average, at 5.8% of the intensive group 4-month visits and 2.6% of the standard group visits. Hazard ratios for mortality in models including frequency of hypoglycemic episodes were 0.93 (95% CI 0.9–0.97; P < 0.001) for participants in the intensive group and 0.98 (0.91–1.06; P = 0.615) for participants in the standard group. The hazard ratios for mortality in models, including unrecognized hypoglycemia, were not statistically significant for either group.
Recognized and unrecognized hypoglycemia was more common in the intensive group than in the standard group. In the intensive group of the ACCORD study, a small but statistically significant inverse relationship of uncertain clinical importance was identified between the number of hypoglycemic episodes and the risk of death among participants.
PMCID: PMC3263892  PMID: 22179956
14.  Brain glycogen content and metabolism in subjects with type 1 diabetes and hypoglycemia unawareness 
Supercompensated brain glycogen may contribute to the development of hypoglycemia unawareness in patients with type 1 diabetes by providing energy for the brain during periods of hypoglycemia. Our goal was to determine if brain glycogen content is elevated in patients with type 1 diabetes and hypoglycemia unawareness. We used in vivo 13C nuclear magnetic resonance spectroscopy in conjunction with [1-13C]glucose administration in five patients with type 1 diabetes and hypoglycemia unawareness and five age-, gender-, and body mass index-matched healthy volunteers to measure brain glycogen content and metabolism. Glucose and insulin were administered intravenously over ∼51 hours at a rate titrated to maintain a blood glucose concentration of 7 mmol/L. 13C-glycogen levels in the occipital lobe were measured at ∼5, 8, 13, 23, 32, 37, and 50 hours, during label wash-in and wash-out. Newly synthesized glycogen levels were higher in controls than in patients (P<0.0001) for matched average blood glucose and insulin levels, which may be due to higher brain glycogen content or faster turnover in controls. Metabolic modeling indicated lower brain glycogen content in patients than in controls (P=0.07), implying that glycogen supercompensation does not contribute to the development of hypoglycemia unawareness in humans with type 1 diabetes.
PMCID: PMC3272603  PMID: 21971353
13C nuclear magnetic resonance spectroscopy; glucose; glycogen; hypoglycemia unawareness
15.  Non-invasive measurement of brain glycogen by NMR spectroscopy and its application to the study of brain metabolism 
Journal of neuroscience research  2011;89(12):1905-1912.
Glycogen is the reservoir for glucose in the brain. Beyond the general agreement that glycogen serves as an energy source in the central nervous system, its exact role in brain energy metabolism has yet to be elucidated. Experiments performed in cell and tissue culture and animals have shown that glycogen content is affected by several factors including glucose, insulin, neurotransmitters, and neuronal activation. The study of in vivo glycogen metabolism has been hindered by the inability to measure glycogen non-invasively, but in the past several years, the development of a non-invasive localized 13C nuclear magnetic resonance (NMR) spectroscopy method has enabled the study of glycogen metabolism in the conscious human. With this technique, 13C-glucose is administered intravenously and its incorporation into and wash-out from brain glycogen is tracked. One application of this method has been to the study of brain glycogen metabolism in humans during hypoglycemia: data have shown that mobilization of brain glycogen is augmented during hypoglycemia and, after a single episode of hypoglycemia, glycogen synthesis rate is increased, suggesting that glycogen stores rebound to levels greater than baseline. Such studies suggest glycogen may serve as a potential energy reservoir in hypoglycemia and may participate in the brain's adaptation to recurrent hypoglycemia and eventual development of hypoglycemia unawareness. Beyond this focused area of study, 13C NMR spectroscopy has a broad potential for application in the study of brain glycogen metabolism and carries the promise of a better understanding of the role of brain glycogen in diabetes and other conditions.
PMCID: PMC3189435  PMID: 21732401
Brain glycogen; 13C NMR spectroscopy; in vivo glycogen measurement
16.  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
17.  High Connectivity Between Reduced Cortical Thickness and Disrupted White Matter Tracts in Long-Standing Type 1 Diabetes 
Diabetes  2010;60(1):315-319.
Previous studies have observed disruptions in brain white and gray matter structure in individuals with type 1 diabetes, and these structural differences have been associated with neurocognitive testing deficiencies. This study investigated the relationship between cerebral cortical thickness reductions and white matter microstructural integrity loss in a group of patients with type 1 diabetes and in healthy control subjects using diffusion tensor imaging (DTI).
Twenty-five subjects with type 1 diabetes for at least 15 years and 25 age- and sex-matched control subjects underwent structural T1 and proton-density and DTI on a 3.0 Tesla scanner. Fractional anisotropy measurements were made on major cerebral white matter tracts, and DTI tractography was performed to identify cortical regions with high connectivity to these tracts.
Posterior white matter tracts with reduced fractional anisotropy (optic radiations, posterior corona radiata, and the splenium region of the corpus callosum) were found to have high connectivity with a number of posterior cortical regions, including the cuneus, precuneus, fusiform, and posterior parietal cortical regions. A significant reduction in cortical thickness in the diabetic group was observed in the regions with high connectivity to the optic radiations and posterior corona radiata tracts (P < 0.05).
The direct relationship between white and gray matter structural pathology has not been previously demonstrated in subjects with long-standing type 1 diabetes. The relationship between posterior white matter microstructural integrity disruption and lower cortical thickness demonstrated using a novel DTI connectivity technique suggests a common or interrelated pathophysiological mechanism in type 1 diabetes.
PMCID: PMC3012188  PMID: 20980455
18.  Neuroendocrine Responses to Hypoglycemia 
The counterregulatory response to hypoglycemia is a complex and well-coordinated process. As blood glucose concentration declines, peripheral and central glucose sensors relay this information to central integrative centers to coordinate neuroendocrine, autonomic, and behavioral responses and avert the progression of hypoglycemia. Diabetes, both type 1 and type 2, can perturb these counterregulatory responses. Moreover, defective counterregulation in the setting of diabetes can progress to hypoglycemia unawareness. While the mechanisms that underlie the development of hypoglycemia unawareness are not completely known, possible causes include altered sensing of hypoglycemia by the brain and/or impaired coordination of responses to hypoglycemia. Further study is needed to better understand the intricacies of the counterregulatory response and the mechanisms contributing to the development of hypoglycemia unawareness.
PMCID: PMC2991551  PMID: 21039590
Counterregulation; hypoglycemia; diabetes; hypoglycemia unawareness
19.  Epidemiologic Relationships Between A1C and All-Cause Mortality During a Median 3.4-Year Follow-up of Glycemic Treatment in the ACCORD Trial 
Diabetes Care  2010;33(5):983-990.
Randomized treatment comparing an intensive glycemic treatment strategy with a standard strategy in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was ended early because of an unexpected excess of mortality in the intensive arm. As part of ongoing post hoc analyses of potential mechanisms for this finding, we explored whether on-treatment A1C itself had an independent relationship with mortality.
Participants with type 2 diabetes (n = 10,251 with mean age 62 years, median duration of diabetes 10 years, and median A1C 8.1%) were randomly assigned to treatment strategies targeting either A1C <6.0% (intensive) or A1C 7.0–7.9% (standard). Data obtained during 3.4 (median) years of follow-up before cessation of intensive treatment were analyzed using several multivariable models.
Various characteristics of the participants and the study sites at baseline had significant associations with the risk of mortality. Before and after adjustment for these covariates, a higher average on-treatment A1C was a stronger predictor of mortality than the A1C for the last interval of follow-up or the decrease of A1C in the first year. Higher average A1C was associated with greater risk of death. The risk of death with the intensive strategy increased approximately linearly from 6–9% A1C and appeared to be greater with the intensive than with the standard strategy only when average A1C was >7%.
These analyses implicate factors associated with persisting higher A1C levels, rather than low A1C per se, as likely contributors to the increased mortality risk associated with the intensive glycemic treatment strategy in ACCORD.
PMCID: PMC2858202  PMID: 20427682
21.  Measurement of cerebral oxidative glucose consumption in patients with type 1 diabetes and hypoglycemia unawareness using 13C nuclear magnetic resonance spectroscopy 
The aim of the present study was to use 13C NMR to measure the cerebral oxidative metabolic rate of glucose (CMRglc(ox)) in patients with diabetes and to compare these measurements with those collected from matched controls. We elected to study a group with type 1 diabetes and hypoglycemia unawareness, since we had previously found such patients to have higher brain glucose concentrations than normal volunteers under steady state conditions. We sought to determine if this difference in steady-state brain concentrations could be explained by a difference in CMRglc(ox). Time courses of 13C label incorporation in brain amino acids were measured in occipital cortex during infusion of [1-13C]glucose. These time courses were fitted using a one-compartment metabolic model to determine CMRglc(ox). Our results show that the TCA cycle rate (VTCA, which is twice CMRglc(ox)) in subjects with type 1 diabetes was not significantly different from normal controls (0.84 ± 0.03 vs 0.79 ± 0.03 μmol/gm/min, n=5 in each group, mean ± SEM). We conclude that the changes in steady-state brain glucose concentrations that we observed in patients with type 1 diabetes in a previous study (1) cannot be explained by changes in oxidative glucose consumption
PMCID: PMC2789919  PMID: 19766263
22.  The Final Frontier: How Does Diabetes Affect the Brain? 
Diabetes  2010;59(1):4-5.
PMCID: PMC2797942  PMID: 20040482
23.  Human Brain Glycogen Metabolism During and After Hypoglycemia 
Diabetes  2009;58(9):1978-1985.
We tested the hypotheses that human brain glycogen is mobilized during hypoglycemia and its content increases above normal levels (“supercompensates”) after hypoglycemia.
We utilized in vivo 13C nuclear magnetic resonance spectroscopy in conjunction with intravenous infusions of [13C]glucose in healthy volunteers to measure brain glycogen metabolism during and after euglycemic and hypoglycemic clamps.
After an overnight intravenous infusion of 99% enriched [1-13C]glucose to prelabel glycogen, the rate of label wash-out from [1-13C]glycogen was higher (0.12 ± 0.05 vs. 0.03 ± 0.06 μmol · g−1 · h−1, means ± SD, P < 0.02, n = 5) during a 2-h hyperinsulinemic-hypoglycemic clamp (glucose concentration 57.2 ± 9.7 mg/dl) than during a hyperinsulinemic-euglycemic clamp (95.3 ± 3.3 mg/dl), indicating mobilization of glucose units from glycogen during moderate hypoglycemia. Five additional healthy volunteers received intravenous 25–50% enriched [1-13C]glucose over 22–54 h after undergoing hyperinsulinemic-euglycemic (glucose concentration 92.4 ± 2.3 mg/dl) and hyperinsulinemic-hypoglycemic (52.9 ± 4.8 mg/dl) clamps separated by at least 1 month. Levels of newly synthesized glycogen measured from 4 to 80 h were higher after hypoglycemia than after euglycemia (P ≤ 0.01 for each subject), indicating increased brain glycogen synthesis after moderate hypoglycemia.
These data indicate that brain glycogen supports energy metabolism when glucose supply from the blood is inadequate and that its levels rebound to levels higher than normal after a single episode of moderate hypoglycemia in humans.
PMCID: PMC2731528  PMID: 19502412
24.  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
25.  The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study 
Objectives To investigate potential determinants of severe hypoglycaemia, including baseline characteristics, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the association of severe hypoglycaemia with levels of glycated haemoglobin (haemoglobin A1C) achieved during therapy.
Design Post hoc epidemiological analysis of a double 2×2 factorial, randomised, controlled trial.
Setting Diabetes clinics, research clinics, and primary care clinics.
Participants 10 209 of the 10 251 participants enrolled in the ACCORD study with type 2 diabetes, a haemoglobin A1C concentration of 7.5% or more during screening, and aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of significant atherosclerosis, albuminuria, left ventricular hypertrophy, or two or more additional risk factors for cardiovascular disease (dyslipidaemia, hypertension, current smoker, or obese).
Interventions Intensive (haemoglobin A1C <6.0%) or standard (haemoglobin A1C 7.0-7.9%) glucose control.
Main outcome measures Severe hypoglycaemia was defined as episodes of “low blood glucose” requiring the assistance of another person and documentation of either a plasma glucose less than 2.8 mmol/l (<50 mg/dl) or symptoms that promptly resolved with oral carbohydrate, intravenous glucose, or glucagon.
Results The annual incidence of hypoglycaemia was 3.14% in the intensive treatment group and 1.03% in the standard glycaemia group. We found significantly increased risks for hypoglycaemia among women (P=0.0300), African-Americans (P<0.0001 compared with non-Hispanic whites), those with less than a high school education (P<0.0500 compared with college graduates), aged participants (P<0.0001 per 1 year increase), and those who used insulin at trial entry (P<0.0001). For every 1% unit decline in the haemoglobin A1C concentration from baseline to 4 month visit, there was a 28% (95% CI 19% to 37%) and 14% (4% to 23%) reduced risk of hypoglycaemia requiring medical assistance in the standard and intensive groups, respectively. In both treatment groups, the risk of hypoglycaemia requiring medical assistance increased with each 1% unit increment in the average updated haemoglobin A1C concentration (standard arm: hazard ratio 1.76, 95% CI 1.50 to 2.06; intensive arm: hazard ratio 1.15, 95% CI 1.02 to 1.21).
Conclusions A greater drop in haemoglobin A1C concentration from baseline to the 4 month visit was not associated with an increased risk for hypoglycaemia. Patients with poorer glycaemic control had a greater risk of hypoglycaemia, irrespective of treatment group. Identification of baseline subgroups with increased risk for severe hypoglycaemia can provide guidance to clinicians attempting to modify patient therapy on the basis of individual risk.
Trial registration number NCT00000620.
PMCID: PMC2803743  PMID: 20061360

Results 1-25 (30)