Biomarker Evaluation for Low Blood Sugar
(E-VAL Trial)
Recruiting in Palo Alto (17 mi)
Age: 18 - 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Academic
Recruiting
Sponsor: Pennington Biomedical Research Center
Must not be taking: Benzodiazepines, Thiazides, Cortisone, others
Disqualifiers: Diabetes, Hypertension, Cardiovascular, others
No Placebo Group
Trial Summary
What is the purpose of this trial?
Hypoglycemic complications are a major impediment to the maintenance of healthy glucose levels in persons with diabetes. The investigators recently completed a clinical pilot and feasibility study (GLIMPSE, NCT02690168), which identified a novel biomarker, glial acetate metabolism, that appears to predict the susceptibility to hypoglycemia. By providing an assay to predict hypoglycemic events and therefore diabetic complications, the development of this biomarker could significantly improve the treatment of persons with diabetes. The goal of this study is to determine the efficacy of our biomarker for predicting susceptibility to insulin-induced hypoglycemia. In order to accomplish this goal the investigatiors will pair our 13C magnetic resonance spectroscopy procedure to assess glial acetate metabolism, developed in the GLIMPSE study, with a hyperinsulinemic-hypoglycemic clamp procedure, developed in the HYPOCLAMP study (NCT03839511). The two procedures will be separated by a three day interval. The investigators will then correlate the participants' rates of glial acetate metabolism with their neuroendocrine responses to the hypoglycemic clamp. This proof of concept study will test the hypothesis that glial acetate metabolism is inversely proportional to the neuroendocrine response to hypoglycemia, that is, as glial acetate metabolism increases the neuroendocrine response will decrease.
Will I have to stop taking my current medications?
Yes, you will need to stop taking medications that affect glucose metabolism, such as benzodiazepines, thiazide diuretics, cortisone, and prednisone, as well as beta-adrenergic antagonists.
What data supports the effectiveness of the treatment Glial Acetate Metabolism for low blood sugar?
Is the treatment for low blood sugar generally safe in humans?
Research shows that brain metabolism of acetate and lactate is increased during low blood sugar in both diabetic and non-diabetic individuals, suggesting that the body adapts to maintain brain function. However, specific safety data for humans using this treatment under the name Glial Acetate Metabolism is not directly provided in the studies.12367
How does this treatment for low blood sugar differ from other treatments?
This treatment may involve the use of acetate, which is unique because it targets glial cells in the brain and can influence energy metabolism differently than traditional glucose-based treatments. Acetate's role in brain metabolism and its potential to modulate cellular energy status through enzyme acetylation makes it a novel approach compared to standard treatments for low blood sugar.2891011
Eligibility Criteria
This trial is for healthy men and women aged 18-40 with a BMI of 20-30 kg/m2. Participants must be medically cleared to join, not pregnant or breastfeeding, consume less than 10 alcoholic drinks per week, have no MRI contraindications, no cardiovascular disease history, normal blood pressure and glucose levels, non-smokers or those who quit over 10 years ago.Inclusion Criteria
I am a healthy individual.
Medically cleared for participation in the study
I am between 18 and 40 years old.
See 1 more
Exclusion Criteria
You are not able to have an MRI scan.
I have diabetes or my fasting blood sugar is over 126 mg/dL.
I am taking medication that can affect my blood sugar levels.
See 7 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
13C Magnetic Resonance Spectroscopy
Participants undergo 13C magnetic resonance spectroscopy to assess glial acetate metabolism
120 minutes
1 visit (in-person)
Hyperinsulinemic-Hypoglycemic Clamp
Participants undergo a hyperinsulinemic-hypoglycemic clamp procedure to measure neuroendocrine response
135 minutes
1 visit (in-person)
Follow-up
Participants are monitored for safety and effectiveness after procedures
4 weeks
Treatment Details
Interventions
- Glial Acetate Metabolism (Metabolic Biomarker)
Trial OverviewThe study tests if glial acetate metabolism can predict low blood sugar events in diabetics. It uses a special brain scan (13C-MRS) after an acetate infusion and compares it to the body's response during controlled insulin-induced hypoglycemia using a hyperinsulinemic-hypoglycemic clamp procedure.
Participant Groups
1Treatment groups
Experimental Treatment
Group I: Arm 1Experimental Treatment2 Interventions
Participants will have their glial acetate metabolism measured by carbon-13 magnetic resonance spectroscopy as well as their neuroendocrine response to hypoglycemia 3 days later.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Pennington Biomedical Research CenterBaton Rouge, LA
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Who Is Running the Clinical Trial?
Pennington Biomedical Research CenterLead Sponsor
References
Increased brain lactate concentrations without increased lactate oxidation during hypoglycemia in type 1 diabetic individuals. [2021]Previous studies have reported that brain metabolism of acetate is increased more than twofold during hypoglycemia in type 1 diabetic (T1D) subjects with hypoglycemia unawareness. These data support the hypothesis that upregulation of blood-brain barrier monocarboxylic acid (MCA) transport may contribute to the maintenance of brain energetics during hypoglycemia in subjects with hypoglycemia unawareness. Plasma lactate concentrations are ∼10-fold higher than acetate concentrations, making lactate the most likely alternative MCA as brain fuel. We therefore examined transport of [3-(13)C]lactate across the blood-brain barrier and its metabolism in the brains of T1D patients and nondiabetic control subjects during a hypoglycemic clamp using (13)C magnetic resonance spectroscopy. Brain lactate concentrations were more than fivefold higher (P
Glial acetate metabolism is increased following a 72-h fast in metabolically healthy men and correlates with susceptibility to hypoglycemia. [2022]Prior exposure to insulin-induced hypoglycemia was shown to increase glial acetate metabolism (GAM) during subsequent exposure to hypoglycemia in diabetic individuals. However, it remained unclear whether this effect was dependent on the disease state or the antecedent cause of hypoglycemia. We aimed to establish whether exposure to fasting-induced hypoglycemia was sufficient to produce alterations in GAM in non-diabetic individuals.
Increased brain monocarboxylic acid transport and utilization in type 1 diabetes. [2019]We hypothesized that increased capacity for brain utilization of nonglucose substrates (monocarboxylic acids [MCAs]) by upregulation of the MCA transporters may contribute metabolic substrates during hypoglycemia. To test this hypothesis, we assessed brain acetate metabolism in five well-controlled type 1 diabetic subjects and six nondiabetic control subjects using 13C magnetic resonance spectroscopy during infusions of [2-(13)C]acetate during hypoglycemia (approximately 55 mg/dl). Acetate is transported into the brain through MCA transporters that are also used for lactate and ketones. Brain acetate concentrations were over twofold higher in the subjects with diabetes than the control subjects (P = 0.01). The fraction of oxidative metabolism from acetate (P = 0.015) and the rate of MCA transport (P = 0.01) were also approximately twofold higher in the diabetic subjects. We conclude that during hypoglycemia MCA transport in the brain was increased by approximately twofold in patients with well-controlled type 1 diabetes, as reflected by higher brain acetate concentrations and rates of acetate oxidation. This upregulation would potentially allow a similar twofold increase in the transport of other MCAs, including lactate, during insulin-induced hypoglycemia. These data are consistent with the hypothesis that upregulation of MCA transport may contribute to the maintenance of brain energetics during hypoglycemia in patients with type 1 diabetes.
Decreased astrocytic GFAP expression in streptozotocin-induced diabetes after gliotoxic lesion in the rat brainstem. [2019]The aim of this study was to evaluate the effect of diabetic hyperglycemia on astrocyte function, estimated by means of glial fibrillary acidic protein - GFAP - immunohistochemical expression.
Elevated brain glutamate levels in type 1 diabetes: correlations with glycaemic control and age of disease onset but not with hypoglycaemia awareness status. [2022]Chronic hyperglycaemia in type 1 diabetes affects the structure and functioning of the brain, but the impact of recurrent hypoglycaemia is unclear. Changes in the neurochemical profile have been linked to loss of neuronal function. We therefore aimed to investigate the impact of type 1 diabetes and burden of hypoglycaemia on brain metabolite levels, in which we assumed the burden to be high in individuals with impaired awareness of hypoglycaemia (IAH) and low in those with normal awareness of hypoglycaemia (NAH).
Correlation of clinical and biochemical findings with diabetic ketoacidosis-related cerebral edema in children using magnetic resonance diffusion-weighted imaging. [2008]To determine clinical and biochemical factors influencing cerebral edema formation during diabetic ketoacidosis (DKA) in children.
Lactate preserves neuronal metabolism and function following antecedent recurrent hypoglycemia. [2021]Hypoglycemia occurs frequently during intensive insulin therapy in patients with both type 1 and type 2 diabetes and remains the single most important obstacle in achieving tight glycemic control. Using a rodent model of hypoglycemia, we demonstrated that exposure to antecedent recurrent hypoglycemia leads to adaptations of brain metabolism so that modest increments in circulating lactate allow the brain to function normally under acute hypoglycemic conditions. We characterized 3 major factors underlying this effect. First, we measured enhanced transport of lactate both into as well as out of the brain that resulted in only a small increase of its contribution to total brain oxidative capacity, suggesting that it was not the major fuel. Second, we observed a doubling of the glucose contribution to brain metabolism under hypoglycemic conditions that restored metabolic activity to levels otherwise only observed at euglycemia. Third, we determined that elevated lactate is critical for maintaining glucose metabolism under hypoglycemia, which preserves neuronal function. These unexpected findings suggest that while lactate uptake was enhanced, it is insufficient to support metabolism as an alternate substrate to replace glucose. Lactate is, however, able to modulate metabolic and neuronal activity, serving as a "metabolic regulator" instead.
Acetate metabolism does not reflect astrocytic activity, contributes directly to GABA synthesis, and is increased by silent information regulator 1 activation. [2019][13 C]Acetate is known to label metabolites preferentially in astrocytes rather than neurons and it has consequently been used as a marker for astrocytic activity. Recent discoveries suggest that control of acetate metabolism and its contributions to the synthesis of metabolites in brain is not as simple as first thought. Here, using a Guinea pig brain cortical tissue slice model metabolizing [1-13 C]D-glucose and [1,2-13 C]acetate, we investigated control of acetate metabolism and the degree to which it reflects astrocytic activity. Using a range of [1,2-13 C]acetate concentrations, we found that acetate is a poor substrate for metabolism and will inhibit metabolism of itself and of glucose at concentrations in excess of 2 mmol/L. By activating astrocytes using potassium depolarization, we found that use of [1,2-13 C]acetate to synthesize glutamine decreases significantly under these conditions showing that acetate metabolism does not necessarily reflect astrocytic activity. By blocking synthesis of glutamine using methionine sulfoximine, we found that significant amount of [1,2-13 C]acetate are still incorporated into GABA and its metabolic precursors in neurons, with around 30% of the GABA synthesized from [1,2-13 C]acetate likely to be made directly in neurons rather than from glutamine supplied by astrocytes. Finally, to test whether activity of the acetate metabolizing enzyme acetyl-CoA synthetase is under acetylation control in the brain, we incubated slices with the AceCS1 deacetylase silent information regulator 1 (SIRT1) activator SRT 1720 and showed consequential increased incorporation of [1,2-13 C]acetate into metabolites. Taken together, these data show that acetate metabolism is not directly nor exclusively related to astrocytic metabolic activity, that use of acetate is related to enzyme acetylation and that acetate is directly metabolized to a significant degree in GABAergic neurons. Changes in acetate metabolism should be interpreted as modulation of metabolism through changes in cellular energetic status via altered enzyme acetylation levels rather than simply as an adjustment of glial-neuronal metabolic activity.
Visualizing reactive astrocyte-neuron interaction in Alzheimer's disease using 11C-acetate and 18F-FDG. [2023]Reactive astrogliosis is a hallmark of Alzheimer's disease (AD). However, a clinically validated neuroimaging probe to visualize the reactive astrogliosis is yet to be discovered. Here, we show that PET imaging with 11C-acetate and 18F-fluorodeoxyglucose (18F-FDG) functionally visualizes the reactive astrocyte-mediated neuronal hypometabolism in the brains with neuroinflammation and AD. To investigate the alterations of acetate and glucose metabolism in the diseased brains and their impact on the AD pathology, we adopted multifaceted approaches including microPET imaging, autoradiography, immunohistochemistry, metabolomics, and electrophysiology. Two AD rodent models, APP/PS1 and 5xFAD transgenic mice, one adenovirus-induced rat model of reactive astrogliosis, and post-mortem human brain tissues were used in this study. We further curated a proof-of-concept human study that included 11C-acetate and 18F-FDG PET imaging analyses along with neuropsychological assessments from 11 AD patients and 10 healthy control subjects. We demonstrate that reactive astrocytes excessively absorb acetate through elevated monocarboxylate transporter-1 (MCT1) in rodent models of both reactive astrogliosis and AD. The elevated acetate uptake is associated with reactive astrogliosis and boosts the aberrant astrocytic GABA synthesis when amyloid-β is present. The excessive astrocytic GABA subsequently suppresses neuronal activity, which could lead to glucose uptake through decreased glucose transporter-3 in the diseased brains. We further demonstrate that 11C-acetate uptake was significantly increased in the entorhinal cortex, hippocampus and temporo-parietal neocortex of the AD patients compared to the healthy controls, while 18F-FDG uptake was significantly reduced in the same regions. Additionally, we discover a strong correlation between the patients' cognitive function and the PET signals of both 11C-acetate and 18F-FDG. We demonstrate the potential value of PET imaging with 11C-acetate and 18F-FDG by visualizing reactive astrogliosis and the associated neuronal glucose hypometablosim for AD patients. Our findings further suggest that the acetate-boosted reactive astrocyte-neuron interaction could contribute to the cognitive decline in AD.
Acetate transport and utilization in the rat brain. [2021]Acetate, a glial-specific substrate, is an attractive alternative to glucose for the study of neuronal-glial interactions. The present study investigates the kinetics of acetate uptake and utilization in the rat brain in vivo during infusion of [2-13C]acetate using NMR spectroscopy. When plasma acetate concentration was increased, the rate of brain acetate utilization (CMR(ace)) increased progressively and reached close to saturation for plasma acetate concentration > 2-3 mM, whereas brain acetate concentration continued to increase. The Michaelis-Menten constant for brain acetate utilization (K(M)(util) = 0.01 +/- 0.14 mM) was much smaller than for acetate transport through the blood-brain barrier (BBB) (K(M)(t) = 4.18 +/- 0.83 mM). The maximum transport capacity of acetate through the BBB (V(max)(t) = 0.96 +/- 0.18 micromol/g/min) was nearly twofold higher than the maximum rate of brain acetate utilization (V(max)(util) = 0.50 +/- 0.08 micromol/g/min). We conclude that, under our experimental conditions, brain acetate utilization is saturated when plasma acetate concentrations increase above 2-3 mM. At such high plasma acetate concentration, the rate-limiting step for glial acetate metabolism is not the BBB, but occurs after entry of acetate into the brain.
Labeled acetate as a marker of astrocytic metabolism. [2021]Astrocytes have various important roles in brain physiology. To further elucidate the details of astrocytic functions under normal and pathological states, astrocyte-specific measurements are mandatory. For studying brain energy metabolism, the use of the astrocyte-specific energy substrate acetate has proven to be of great value. Since the first applications of labeled acetate for brain studies about 50 years ago, numerous methodologies have been developed and employed in compartment-specific investigations of brain metabolism. Here, we provide an overview of these different methodological approaches and review studies employing acetate labeled with the most commonly used carbon isotopes.