Amir Moheet

Thiazolidinediones and Risk of Heart Failure in Patients with or at High Risk of Type 2 Diabetes Mellitus

BackgroundRecent meta-analyses of randomized clinical trials (RCTs) demonstrated a higher risk of heart failure (HF) with the use of thiazolidinediones (TZDs). However, this effect may have been diluted by including active controls. Also, it is uncertain whether the risk of HF is similar with rosiglitazone and pioglitazone.ObjectivesThis study quantified the risks of HF with the use of TZDs in patients with or at high risk of developing type 2 diabetes mellitus (DM), and evaluated differential effects by type of TZD. Secondarily, we evaluated risks of peripheral edema.MethodsWe performed a systematic review and meta-analysis of placebo-controlled RCTs evaluating the effect of rosiglitazone or pioglitazone on investigator-reported HF and edema. Articles published before 31 December 2009 were searched in MEDLINE, The Web of Science, and Scopus, and the data were extracted by three investigators. RCTs with ≥100 patients and ≥3 months of follow-up were included. We quantified the effect of TZDs as odds ratios (ORs) by using the Mantel-Haenzel and alternative models. We further evaluated the risk of serious/severe HF, and the effect of several trial characteristics on HF risk by subgroup analysis and meta-regression analysis.Results29 trials (n = 20254) were evaluated. TZDs were significantly associated with HF (TZD 360/6807 [5.3%] vs placebo 234/6328 [3.7%], OR 1.59; 95% CI 1.34, 1.89; p<0.00001). The risk of HF was higher with rosiglitazone than with pioglitazone (2.73 [95% CI 1.46, 5.10] vs 1.51 [1.26, 1.81]; p = 0.06). TZDs were associated with a similar risk of serious/severe HF (OR 1.47; 95% CI 1.16, 1.87; p = 0.002). Use of TZDs was also associated with edema (OR 2.04; 95% CI 1.85, 2.26; p<0.00001). HF and edema risks were consistent using Peto and random effects models. Risks of HF were significantly high for the subgroups of trials including patients with or at high risk for type 2 DM, and for the subgroup of trials with ≥12 months of follow-up. Meta-regression analysis showed that trials with lower overall baseline risk had higher HF risks.ConclusionIn placebo-controlled trials of adult patients with or at high risk for type 2 DM, TZD therapy is significantly and consistently associated with a higher risk of HF. The risk of serious/severe HF is also increased with the use of TZDs. HF risks are similar to those of meta-analyses combining active- and placebo-controlled trials. The benefit/risk profile of TZDs should be considered when treating diabetic patients with or without prior HF.

Impact of diabetes on cognitive function and brain structure

Both type 1 and type 2 diabetes have been associated with reduced performance on multiple domains of cognitive function and with structural abnormalities in the brain. With an aging population and a growing epidemic of diabetes, central nervous system–related complications of diabetes are expected to rise and could have challenging future public health implications. In this review, we will discuss the brain structural and functional changes that have been associated with type 1 and type 2 diabetes. Diabetes duration and glycemic control may play important roles in the development of cognitive impairment in diabetes, but the exact underlying pathophysiological mechanisms causing these changes in cognition and structure are not well understood. Future research is needed to better understand the natural history and the underlying mechanisms, as well as to identify risk factors that predict who is at greatest risk of developing cognitive impairment. This information will lead to the development of new strategies to minimize the impact of diabetes on cognitive function.

Support for and aspects of use of educational games in family medicine and internal medicine residency programs in the US: a survey

BackgroundThe evidence supporting the effectiveness of educational games in graduate medical education is limited. Anecdotal reports suggest their popularity in that setting. The objective of this study was to explore the support for and the different aspects of use of educational games in family medicine and internal medicine residency programs in the United States.MethodsWe conducted a survey of family medicine and internal medicine residency program directors in the United States. The questionnaire asked the program directors whether they supported the use of educational games, their actual use of games, and the type of games being used and the purpose of that use.ResultsOf 434 responding program directors (52% response rate), 92% were in support of the use of games as an educational strategy, and 80% reported already using them in their programs. Jeopardy like games were the most frequently used games (78%). The use of games was equally popular in family medicine and internal medicine residency programs and popularity was inversely associated with more than 75% of residents in the program being International Medical Graduates. The percentage of program directors who reported using educational games as teaching tools, review tools, and evaluation tools were 62%, 47%, and 4% respectively.ConclusionsGiven a widespread use of educational games in the training of medical residents, in spite of limited evidence for efficacy, further evaluation of the best approaches to education games should be explored.

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.

Feasibility and reproducibility of neurochemical profile quantification in the human hippocampus at 3T

Hippocampal dysfunction is known to be associated with several neurological and neuropsychiatric disorders such as Alzheimers disease, epilepsy, schizophrenia and depression; therefore, there has been significant clinical interest in studying hippocampal neurochemistry. However, the hippocampus is a challenging region to study using 1H MRS, hence the use of MRS for clinical research in this region has been limited. Our goal was therefore to investigate the feasibility of obtaining high‐quality hippocampal spectra that allow reliable quantification of a neurochemical profile and to establish inter‐session reproducibility of hippocampal MRS, including reproducibility of voxel placement, spectral quality and neurochemical concentrations. Ten healthy volunteers were scanned in two consecutive sessions using a standard clinical 3 T MR scanner. Neurochemical profiles were obtained with a short‐echo (TE = 28 ms) semi‐LASER localization sequence from a relatively small (~4 mL) voxel that covered about 62% of the hippocampal volume as calculated from segmentation of T1‐weighted images. Voxel composition was highly reproducible between sessions, with test–retest coefficients of variation (CVs) of 3.5% and 7.5% for gray and white matter volume fraction, respectively. Excellent signal‐to‐noise ratio (~54 based on the N‐acetylaspartate (NAA) methyl peak in non‐apodized spectra) and linewidths (~9 Hz for water) were achieved reproducibly in all subjects. The spectral quality allowed quantification of NAA, total choline, total creatine, myo‐inositol and glutamate with high scan–rescan reproducibility (CV ≤ 6%) and quantification precision (Cramér–Rao lower bound, CRLB < 9%). Four other metabolites, including glutathione and glucose, were quantified with scan–rescan CV below 20%. Therefore, the highly optimized, short‐echo semi‐LASER sequence together with FASTMAP shimming substantially improved the reproducibility and number of quantifiable metabolites relative to prior reports. In addition, the between‐session variation in metabolite concentrations, as well as CRLB, was lower than the between‐subject variation of the concentrations for most metabolites, indicating that the method has the sensitivity to detect inter‐individual differences in the healthy brain. Copyright

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.

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 proarrhythmic, proinflammatory, and prothrombotic 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 a cause of increased mortality. Severe hypoglycemia is also a marker of frailty and a 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.

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.

Hypoglycemia-Associated Autonomic Failure in Healthy Humans: Comparison of Two vs Three Periods of Hypoglycemia on Hypoglycemia-Induced Counterregulatory and Symptom Response 5 Days Later

CONTEXT Hypoglycemia-associated autonomic failure (HAAF) limits the ability of patients with diabetes to achieve target glycemia. Animal models have provided insights into the pathogenesis of HAAF, but a robust human model of HAAF in which recurrent hypoglycemia impacts the counterregulatory responses to hypoglycemia days later is lacking. OBJECTIVE The aim of this study was to determine the impact of two or three episodes of moderate hypoglycemia on counterregulatory responses to subsequent hypoglycemia induced 5 days later. DESIGN AND SUBJECTS Six healthy subjects participated in each of the two study protocols. In both protocol 1 and 2, subjects underwent two 2-hour hypoglycemic clamp studies during the morning and afternoon of day 1. In protocol 2, subjects underwent an additional third hypoglycemic clamp during the morning of day 2. All subjects in both protocols underwent a final hypoglycemic clamp on the morning of day 5. RESULTS In protocol 1, there were no significant differences in the hypoglycemia-induced hormone response or in symptoms scores between the mornings of days 1 and 5. In protocol 2, hypoglycemia-induced epinephrine (P = .02) and cortisol (P = .04) secretions were significantly lower on day 5 compared with day 1, whereas glucagon (P = .08) and norepinephrine (P = .59) were not different. Also in protocol 2, neurogenic (P = .02) and neuroglycopenic (P = .04) symptoms during hypoglycemia were decreased on day 5 compared with day 1. CONCLUSION These results demonstrate that exposure of healthy humans to three 2-hour hypoglycemic episodes over 30 hours leads to significant blunting in counterregulatory and symptom response to subsequent hypoglycemia on day 5.

Initial experience with seven tesla magnetic resonance spectroscopy of hypothalamic GABA during hyperinsulinemic euglycemia and hypoglycemia in healthy humans.

Hypothalamic GABA signaling has been shown to regulate the hormonal response to hypoglycemia in animals. The hypothalamus is a challenging brain region for magnetic resonance spectroscopy (MRS) due to its small size and central location. To investigate the feasibility of measuring GABA in the hypothalamus in humans, ultra‐high field MRS was used.