Human Cerebral Blood Flow and Metabolism in Acute Insulin-Induced Hypoglycemia

Abstract

How the human brain functions under conditions of acute hypoglycemia remains a complex question by virtue of the potential simultaneous shifts in processes of perfusion, metabolism, and changing demand. We examined this issue by measuring cerebral blood flow (CBF) and oxidative metabolism (CMRO 2 ) in insulin-induced hypoglycemic (HG) and euglycemic (EG) conditions at rest and during motor activation in normal human subjects using magnetic resonance (MR). Experiments were performed on 12 subjects (9M, 3F). The protocol consisted of insulin-induced hypoglycemia (targeting a HG of 60 mg/dL) followed by euglycemia, or in reverse order, each phase lasting approximately 1.5 h. Euglycemia was performed with the same insulin infusion rate so as to match the hypoglycemic phase. Magnetic resonance data were acquired 30 mins after the target plasma glucose was achieved so as to minimize any acute effects. Although the depth of hypoglycemia achieved in the present study was relatively small, the present data found a significant increase in flow in motor cortex with mild hypoglycemia, from 56.4713.6 mL/100 g min (euglycemia) to 64.37 7.6 mL/100 g min (hypoglycemia). Using the Renkin-Crone exponential model of oxygen extraction with MR models of susceptibility-based relaxation, analysis of the flow measurements, relaxation and BOLD data also implied that throughout the studies, metabolism and flow remained coupled. Elementary motor task activation was not associated with any consistent larger activated flows. Thus it remains that although mild hypoglycemia induced an increase in basal flow and metabolism, a similar increase was not seen in task activation.

Small Decrements in Systemic Glucose Provoke Increases in Hypothalamic Blood Flow Prior to the Release of Counterregulatory Hormones

“…Our data are consistent with this hypothesis and with prior studies using fMRI-BOLD demonstrating that the hypothalamus is responsive to changes in systemic glucose levels (13)(14)(15)(16)(17). On the other hand, previous studies investigating the effects of hypoglycemia on regional CBF in nondiabetic subjects have not identified an increase in hypothalamic blood flow following insulin-induced hypoglycemia (22,24,25). This may be because the hypothalamus is a very small brain region, making it difficult to detect significant changes in blood flow when compared with larger brain regions.…”

“…PASL is an indirect measure of neuronal activity believed to reflect changes in metabolic state because there is a clear relationship between changes in the local rate of oxygen consumption and changes in local tissue blood flow (20). Although previous studies have investigated the effects of hypoglycemia on CBF in nondiabetic subjects, the current study examined the effects of small glucose decrements within the normal range, whereas earlier studies measured CBF after moderate hypoglycemic levels (plasma glucose Յ60 mg/dl) were achieved (22,24,25). As a result, we were able to investigate the time sequence relationship between hypothalamic activation and the initiation of the counterregulatory hormonal response.…”

“…Some studies, using PET (22), single-photon emission computed tomography (23), high-field magnetic resonance perfusion (24), and continuous arterial spin labeling (25), have shown region-specific increases in brain CBF in response to hypoglycemia. However, none of these studies specifically demonstrated changes in blood flow to the hypothalamus during hypoglycemia.…”

Changes in Human Brain Glutamate Concentration during Hypoglycemia: Insights into Cerebral Adaptations in Hypoglycemia-Associated Autonomic Failure in Type 1 Diabetes

“…2 Although the mechanisms of HAAF have not been fully elucidated, a picture is emerging in which a series of cerebral adaptations, including altered fuel transport and/or metabolism, lead to defective glucose counter-regulation and impaired hypoglycemia awareness. 3 The cerebral response to hypoglycemia in the healthy brain involves changes in regional blood flow 4,5 and sequential adjustments in cerebral metabolism in order to provide sufficient fuel for brain activity. As the levels of glucose, the principal cerebral energy substrate, drop from 5 to B3 mmol/L in plasma, cerebral metabolic rate of glucose (CMRglc) and cerebral metabolic rate of oxygen (CMRO 2 ) are preserved [6][7][8] despite lower brain glucose uptake.…”

Hypothalamic Nitric Oxide in Hypoglycemia Detection and Counterregulation: A Two-Edged Sword

“…Human and animal studies showed that insulin-induced hypoglycemia is associated with increased cerebral blood flow in different brain areas, including the hypothalamus (42,58). Hypoglycemia-induced increases in cerebral blood flow could increase nutrient availability to brain cells during energy deficit.…”