Elizabeth Seaquist | University of Minnesota - Twin Cities (original) (raw)

Papers by Elizabeth Seaquist

NMR in biomedicine, Jan 22, 2015

Hippocampal dysfunction is known to be associated with several neurological and neuropsychiatric ... more Hippocampal dysfunction is known to be associated with several neurological and neuropsychiatric disorders such as Alzheimer's 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 (1) H 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) voxe...

Nature Reviews Endocrinology, 2014

Minnesota medicine, 2011

The University of Minnesota and Mayo Clinic have launched a 10-year effort called the Decade of D... more The University of Minnesota and Mayo Clinic have launched a 10-year effort called the Decade of Discovery: A Minnesota Partnership to Conquer Diabetes. The partnership harnesses the extensive research expertise at the two institutions in an effort to make discoveries that will transform prevention, management, and treatment of diabetes--a disease that affects one in three people in the state. The ultimate goal isto find a cure. This article describes the vision for this undertaking as well as research that might one day lead to a cure.

Nature Reviews Endocrinology, 2013

ABSTRACT At very low glucose levels, the cognitive function of patients with diabetes mellitus an... more ABSTRACT At very low glucose levels, the cognitive function of patients with diabetes mellitus and recurrent iatrogenic hypoglycaemia is often better than that of hypoglycaemia-naive individuals. A new study shows that the brain adapts to recurrent hypoglycaemia by increasing uptake of glucose and lactate, with preferential shuttling of glucose to neurons.

How endurance training alters muscle lipid metabolism while preserving insulin sensitivity remain... more How endurance training alters muscle lipid metabolism while preserving insulin sensitivity remains unclear. Because acute free fatty acid (FFA) elevation by lipid infusion reduces insulin sensitivity, we hypothesized that training status would alter accumulation of muscle triacylglycerol (TAG), diacylglycerol (DAG), ceramide, and acylcarnitine during acute FFA elevation. Trained (n = 15) and sedentary (n = 13) participants matched for age, sex, and BMI received either a 6-h infusion of lipid (20% Intralipid at 90 ml/h) or glycerol (2.25 g/100 ml at 90 ml/h) during a hyperinsulinemic euglycemic clamp. Muscle biopsies were taken at 0, 120, and 360 min after infusion initiation to measure intramyocellular concentrations of TAG, DAG, ceramides, and acylcarnitines by liquid chromatography-tandem mass spectrometry. Trained participants had a higher Vo2 max and insulin sensitivity than sedentary participants. The lipid infusion produced a comparable elevation of FFA (594 ± 90 μmol/l in trained, 721 ± 30 μmol/l in sedentary, P = 0.4) and a decline in insulin sensitivity (-44.7% trained vs. -47.2% sedentary, P = 0.89). In both groups, lipid infusion increased the linoleic and linolenic acid content of TAG without changing total TAG. In the sedentary group, lipid infusion increased total, oleic, and linoleic acid and linolenic acid content of DAG. Regardless of training status, lipid infusion did not alter total ceramide, saturated ceramide, palmitoyl-carnitine, or oleoyl-carnitine. We conclude that during acute FFA elevation, trained adults have a similar decline in insulin sensitivity with less accumulation of muscle DAG than sedentary adults, suggesting that lipid-induced insulin resistance can occur without elevation of total muscle DAG.

Magnetic Resonance Imaging, 2006

In vivo 13 C NMR spectroscopy has the unique capability to measure metabolic fluxes noninvasively... more In vivo 13 C NMR spectroscopy has the unique capability to measure metabolic fluxes noninvasively in the brain. Quantitative measurements of metabolic fluxes require analysis of the 13 C labeling time courses obtained experimentally with a metabolic model. The present work reviews the ingredients necessary for a dynamic metabolic modeling study, with particular emphasis on practical issues. D

Neuroendocrinology, 2006

Insulin receptors are found throughout the brain, particularly in the hippocampus, although the i... more Insulin receptors are found throughout the brain, particularly in the hippocampus, although the impact of insulin on memory is unclear. The purpose of this study was to examine the effect of insulin on event-related potentials in response to a standard memory task and visual evoked potentials (VEPs) during exposure to a reversing checkerboard. We hypothesized that insulin would decrease P300 magnitude and latency during the presentation of previously observed stimuli, but would have no effect on VEPs. Sixteen humans participated in two euglycemic clamp studies with somatostatin performed in random order in which serum insulin levels were either suppressed (14 +/- 1 pmol/l) or increased by insulin infusion (433 +/- 40 pmol/l). At steady state, event-related potentials and then VEPs were collected using a 32-electrode cap. The major finding was that the P300 amplitude measured during the identification of an object as old was significantly smaller over parietal regions when insulin was infused than when no insulin was provided. Insulin was without effect on the VEPs. We conclude that insulin has region- and task-specific effects on neuronal activation. While the P300 amplitude measured during the presentation of an old object was reduced during insulin infusion, the hormone was without effect on VEPs.

Neurochemistry international

The concentration and metabolism of the primary carbohydrate store in the brain, glycogen, is unk... more The concentration and metabolism of the primary carbohydrate store in the brain, glycogen, is unknown in the conscious human brain. This study reports the first direct detection and measurement of glycogen metabolism in the human brain, which was achieved using localized 13C NMR spectroscopy. To enhance the NMR signal, the isotopic enrichment of the glucosyl moieties was increased by administration of 80 g of 99% enriched [1-13C]glucose in four subjects. 3 h after the start of the label administration, the 13C NMR signal of brain glycogen C1 was detected (0.36+/-0.07 micromol/g, mean+/-S.D., n=4). Based on the rate of 13C label incorporation into glycogen and the isotopic enrichment of plasma glucose, the flux through glycogen synthase was estimated at 0.17+/-0.05 micromol/(gh). This study establishes that brain glycogen can be measured in humans and indicates that its metabolism is very slow in the conscious human. The noninvasive detection of human brain glycogen opens the prospec...

Metabolism, 2010

The aim of the present study was to use 13 C NMR to measure the cerebral oxidative metabolic rate... more The aim of the present study was to use 13 C 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 13 C label incorporation in brain amino acids were measured in occipital cortex during infusion of [1-13 C]glucose. These time courses were fitted using a one-compartment metabolic model to determine CMRglc(ox). Our results show that the TCA cycle rate (V TCA , 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 Diabetes mellitus is a devastating disease that affects the metabolism, structure, and function of many organs. It has been long recognized that diabetes has effects on the kidneys, eyes, peripheral nerves and vasculature, and there is a growing body of evidence that diabetes affects the brain as well (2) Patients with diabetes have an increased incidence of cognitive dysfunction and dementia (3-5), and have been found to have abnormalities in white matter structure and function (6,7) as well as reductions in gray matter volumes and densities . Such functional and structural abnormalities presumably result from the extremes in glycemia experienced by patients with the disease. However, the extent to which these functional and structural abnormalities are associated with or caused by alterations in glucose metabolism is uncertain.

Metabolism, 2005

Hyperglycemia and diabetes alter the function and metabolism of many tissues. The effect on the b... more Hyperglycemia and diabetes alter the function and metabolism of many tissues. The effect on the brain remains poorly defined, but some animal data suggest that chronic hyperglycemia reduces rates of brain glucose transport and/or metabolism. To address this question in human beings, we measured glucose in the occipital cortex of patients with poorly controlled diabetes and healthy volunteers at the same levels of plasma glucose using proton magnetic resonance spectroscopy. Fourteen patients with poorly controlled diabetes (hemoglobin A 1c = 9.8% F 1.7%, mean F SD) and 14 healthy volunteers similar with respect to age, sex, and body mass index were studied at a plasma glucose of 300 mg/dL. Brain glucose concentrations of patients with poorly controlled diabetes were lower but not statistically different from those of control subjects (4.7 F 0.9 vs 5.3 F 1.1 lmol/g wet wt; P = .1). Our sample size gave 80% power to detect a difference as small as 1.1 lmol/g wet wt.

Metabolic Brain Disease, 2014

Glycogen serves as an important energy reservoir in the human body. Despite the abundance of glyc... more Glycogen serves as an important energy reservoir in the human body. Despite the abundance of glycogen in the liver and skeletal muscles, its concentration in the brain is relatively low, hence its significance has been questioned. A major challenge in studying brain glycogen metabolism has been the lack of availability of non-invasive techniques for quantification of brain glycogen in vivo. Invasive methods for brain glycogen quantification such as post mortem extraction following high energy microwave irradiation are not applicable in the human brain. With the advent of (13)C Magnetic Resonance Spectroscopy (MRS), it has been possible to measure brain glycogen concentrations and turnover in physiological conditions, as well as under the influence of stressors such as hypoglycemia and visual stimulation. This review presents an overview of the principles of the (13)C MRS methodology and its applications in both animals and humans to further our understanding of glycogen metabolism under normal physiological and pathophysiological conditions such as hypoglycemia unawareness.

Magnetic Resonance in Medicine, 1998

The peak at 3.35 ppm in the 'H-NMR spectrum characteristic for scyllo-inositol may be a marker fo... more The peak at 3.35 ppm in the 'H-NMR spectrum characteristic for scyllo-inositol may be a marker for cerebral pathology, although it has a well-known constant concentration relative to myo-inositol. Such a peak was observed with an intensity at least 300% above normal in the brain of a healthy volunteer.

Magnetic Resonance in Medicine, 2001

The relationships between brain activity and accompanying hemodynamic and metabolic alterations, ... more The relationships between brain activity and accompanying hemodynamic and metabolic alterations, particularly between the cerebral metabolic rate of oxygen utilization (CMR O2 ) and cerebral blood flow (CBF), are not thoroughly established. CMR O2 is closely coupled to the rate of tricarboxylic acid (TCA) cycle flux. In this study, the changes in glutamate labeling during 13 C labeled glucose administration were determined in the human brain as an index of alterations in neuronal TCA cycle turnover during increased neuronal activity. Two-volume 1 H-{ 13 C} MR spectroscopy (MRS) of the visual cortex was combined with functional MRI (fMRI) at 4 Tesla. Hemifield visual stimulation was employed to obtain data simultaneously from activated and control regions located symmetrically in the two hemispheres of the brain. The results showed that the fractional change in the turnover rate of C4 carbon of glutamate was less than that of CBF during visual stimulation. The fractional changes in CMR O2 (⌬CMR O2 ) induced by activation must be equal to or less than the fractional change in glutamate labeling kinetics. Therefore, the results impose an upper limit of ϳ30% for ⌬CMR O2 and demonstrate: 1) that fractional CBF increases exceed ⌬CMR O2 during elevated activity in the visual cortex, and 2) that such an unequal change would explain the observed positive blood oxygenation level dependent (BOLD) effect in fMRI. Magn Reson Med 45:349 -355, 2001.

Magnetic Resonance in Medicine, 2014

Hypothalamic GABA signaling has been shown to regulate the hormonal response to hypoglycemia in a... more 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. GABA levels in the hypothalamus and occipital cortex (control region) were measured in healthy volunteers during euglycemia and hypoglycemia at 7 tesla using short-echo STEAM (TE = 8 ms, TR = 5 s). Hypothalamic GABA levels were quantified with a mean within-session test-retest coefficient of variance of 9%. Relatively high GABA levels were observed in the hypothalamus compared with other brain regions. Hypothalamic GABA levels were 3.5 ± 0.3 µmol/g during euglycemia (glucose 89 ± 6 mg/dL) vs. 3.0 ± 0.4 µmol/g during hypoglycemia (glucose 61 ± 3 mg/dL) (P = 0.06, N = 7). In the occipital cortex, GABA levels remained constant at 1.4 ± 0.4 vs.1.4 ± 0.3 µmol/g (P = 0.3, N = 5) as glucose fell from 91 ± 4 to 61 ± 4 mg/dL. GABA concentration can be quantified in the human hypothalamus and shows a trend toward decrease in response to an acute fall in blood glucose. These methods can be used to further investigate role of GABA signaling in the counterregulatory response to hypoglycemia in humans.

Magnetic Resonance in Medicine, 2005

A novel single-shot spectral editing technique for in vivo proton NMR is proposed to recover reso... more A novel single-shot spectral editing technique for in vivo proton NMR is proposed to recover resonances of low-concentration metabolites obscured by very strong resonances. With this new method, editing is performed by transferring transverse magnetization to J-coupled spins from selected coupling partners using a homonuclear Hartmann-Hahn polarization transfer with adiabatic pulses. The current implementation uses 1D-TOCSY with single-voxel localization based on LASER to recover the H1 proton of ␤-glucose at 4.63 ppm from under water and the lactate methyl resonances from beneath a strong lipid signal. The method can be extended to further spin systems where conventional editing methods are difficult to perform. Magn Reson Med 53:783-789, 2005.

Magnetic Resonance in Medicine, 1996

Measurement of the resonances of glucose between 3.2 and 3.9 ppm in 'H NMR spectra from the human... more Measurement of the resonances of glucose between 3.2 and 3.9 ppm in 'H NMR spectra from the human brain is diflicult due to spectral overlap with peaks from more concentrated metabolites. The H i resonance of cY-D-glucose at 5.23 ppm is resolved from other metabolite peaks, but potentially overlaps with the intense water signal at 4.72 ppm. This paper demonstrates that the increased resolution at 4 Tesla permits to suppress the water signal sufficiently to reliably detect glucose directly at 5.23 ppm by 'H MRS and the estimated peak intensity is consistent with previous I3C NMR quantification.

Journal of Neuroscience Research, 2011

Glycogen is the reservoir for glucose in the brain. Beyond the general agreement that glycogen se... more 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 noninvasively, but, in the past several years, the development of a noninvasive localized (13) C nuclear magnetic resonance (NMR) spectroscopy method has allowed the study of glycogen metabolism in the conscious human. With this technique, (13) C-glucose is administered intravenously, and its incorporation into and washout 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 that glycogen may serve as a potential energy reservoir in hypoglycemia and may participate in the brain&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s adaptation to recurrent hypoglycemia and eventual development of hypoglycemia unawareness. Beyond this focused area of study, (13) C 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.

Journal of Neuroscience Research, 2005

Although it is well established that recurrent hypoglycemia leads to hypoglycemia unawareness, th... more Although it is well established that recurrent hypoglycemia leads to hypoglycemia unawareness, the mechanisms responsible for this are unknown. One hypothesis is that recurrent hypoglycemia alters brain glucose transport or metabolism. We measured steady-state brain glucose concentrations during a glucose clamp to determine whether subjects with type 1 diabetes and hypoglycemia unawareness may have altered cerebral glucose transport or metabolism after exposure to recurrent hypoglycemia. We compared 14 subjects with diabetes and hypoglycemia unawareness to 27 healthy control subjects. Brain glucose concentrations were measured under similar metabolic conditions using in vivo (1)H nuclear magnetic resonance (NMR) spectroscopy at 4 Tesla during a hyperglycemic clamp (plasma glucose = 16.7 mmol/l) with somatostatin and insulin. Subjects with type 1 diabetes and hypoglycemia unawareness had significantly higher brain glucose concentrations compared to that in controls under the same conditions (5.5 +/- 0.3 vs. 4.7 +/- 0.1 micromol/g wet weight, P = 0.016). These data suggest that changes in brain glucose transport or metabolism may occur as a result of recurrent hypoglycemia.

Journal of Neuroscience Research, 2003

The brain contains a small but significant amount of glycogen, which has long been considered to ... more The brain contains a small but significant amount of glycogen, which has long been considered to play an insignificant role in the brain. In this study, brain glycogen metabolism was measured using 13 C NMR spectroscopy at 9.4 T. Brain glycogen metabolism was modulated by hyperinsulinemia resulting in a net accumulation. The role of glycogen in maintaining brain function is unknown; one possibility is that it may serve as an endogenous glucose reservoir to protect the brain against severe hypoglycemia. To address this possibility, rats were subjected to insulin-induced moderate hypoglycemia and when the level of brain glucose approached zero, brain glycogen content began to decrease gradually, demonstrating utilization of this glucose reservoir. The brain glycogen signal never became undetectable, however, even during 2 hr of hypoglycemia. When plasma and brain glucose concentrations were restored, glycogen increased and the concentration exceeded the prehypoglycemic level by several-fold. The data suggest that brain glycogen can provide fuel for extended periods of time when glucose supply is inadequate. Furthermore, brain glycogen can rebound (super-compensate) after a single episode of hypoglycemia. We postulate that brain glycogen serves as an energy store during hypoglycemia and that it may participate in the creation of reduced physiological responses to hypoglycemia that are involved in a symptom often observed in patients with diabetes, hypoglycemia unawareness.