Increased Brain Monocarboxylic Acid Transport and Utilization in Type 1 Diabetes

Abstract

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 13 C magnetic resonance spectroscopy during infusions of [2-13 C]acetate during hypoglycemia (ϳ55 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 appoximately 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 insulininduced 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. Diabetes 55: 929 -934, 2006 U nder normal, nonfasting conditions, oxidation of glucose is the main source of energy for brain function (1). In intensively treated subjects with type 1 diabetes, there is often a loss of both the counterregulatory response and the mild cognitive symptoms before severe cognitive dysfunction (2,3). Both of these adaptations are believed to significantly contribute to hypoglycemic unawareness, which increases the risk of severe hypoglycemia, which may result in seizure or coma (4). The loss of cognitive symptoms is believed to be, at least in part, secondary to adaptations that allow brain energy metabolism to be maintained during moderate hypoglycemia (5). Several studies have found that intensively treated patients with type 1 diabetes have cortical metabolic adaptations during hypoglycemia. Positron emission tomography (PET) and arterio-venous difference studies have found that in contrast to control subjects who show a 20 -30% decrease in glucose uptake during moderate hypoglycemia (ϳ2.8 mmol/l), subjects with intensively treated type 1 diabetes show minimal reduction in glucose uptake (5-8).Several hypotheses have been proposed to explain this metabolic adaption, particularly increased brain glucose transport, based on studies in rat models that showed an increase in glucose transporter activity in rats exposed to prolonged hypoglycemia (rev. in 9), but this concept is controversial. Studies of humans with diabetes have generally not been able to establish a change in transport parameters in poorly controlled and well-controlled patients. The study ...

Alteration of Interaction Between Astrocytes and Neurons in Different Stages of Diabetes: a Nuclear Magnetic Resonance Study Using [1-13C]Glucose and [2-13C]Acetate

“…This result is consistent with a previous observation of the increased brain MCA transport activity in patients with well-controlled type 1 diabetes [23], which can possibly lead to decreased glucose utilization.…”

“…Decreased glutamine (Gln) supply to gamma-aminobutyric acid (GABA)ergic neurons has been observed in the cortex and subcortex of young epileptic rats, whereas astrocytic metabolism has been increased in adult epileptic rats [22]. Mason et al applied [2][3][4][5][6][7][8][9][10][11][12][13] C]acetate as a tracer to evaluate the hypothesis that patients with type 1 diabetes exhibit increased blood-brain transport and monocarboxylic acid (MCA) metabolism to sustain upregulated MCA transporters during hypoglycemia [23]. 13 C MRS is a primary technique for studying brain metabolism.…”

Brain Lactate Concentration Falls in Response to Hypoglycemia in Patients With Type 1 Diabetes and Impaired Awareness of Hypoglycemia

“…Our observation that plasma lactate levels fell in the IAH group argues against increased brain lactate export. Furthermore, it is unlikely that the lower brain lactate levels were the result of decreased cerebral lactate uptake, given that plasma lactate levels fell to a similar extent in both patient groups and that lactate transport capacity has been reported to be increased in patients with IAH (14). We cannot completely exclude that the fall in lactate reflected a decrease in glycolysis due to reduced neuronal activation (25).…”

“…Administration of lactate during hypoglycemia impairs hypoglycemic symptoms, attenuates counterregulatory hormone responses, and preserves cognitive function, mirroring the changes seen in subjects with IAH (11,12). Finally, brain lactate transport capacity through monocarboxylic acid transporters was found to be increased during hypoglycemia in patients with IAH (13,14).…”

Brain Glycogen Content and Metabolism in Subjects with Type 1 Diabetes and Hypoglycemia Unawareness

“…One possible mechanism is that recurrent hypoglycemia leads to upregulated fuel availability to the brain, either in the form of glucose (free or in glycogen reserves) or in the form of alternative fuels. Prior work suggested glucose uptake may increase (Boyle et al, 1994;Criego et al, 2005;McCall et al, 1986) or alternative fuels such as lactate may support a greater fraction of oxidative metabolism (Jiang et al, 2009;Mason et al, 2006) after recurrent hypoglycemia, both of which may serve to enhance fuel availability during subsequent periods of hypoglycemia. Another potential mechanism to enhance fuel availability during hypoglycemia is to increase brain glycogen content via a phenomenon termed 'supercompensation'.…”