Steady-State Brain Glucose Concentrations During Hypoglycemia in Healthy Humans and Patients With Type 1 Diabetes

Kim C.C. van de Ven; Marinette van der Graaf; Cees J. Tack; Arend Heerschap; Bastiaan E. de Galan

Disclosures

Diabetes. 2012;61(8):1974-1977. 

In This Article

Abstract and Introduction

Abstract

The objective of this study was to investigate the relationship between plasma and brain glucose levels during euglycemia and hypoglycemia in healthy subjects and patients with type 1 diabetes mellitus (T1DM). Hyperinsulinemic euglycemic (5 mmol/L) and hypoglycemic (3 mmol/L) [1-13C]glucose clamps were performed in eight healthy subjects and nine patients with uncomplicated T1DM (HbA1c 7.7 ± 1.4%). Brain glucose levels were measured by 13C magnetic resonance spectroscopy. Linear regression analysis was used to fit the relationship between plasma and brain glucose levels and calculate reversible Michaelis-Menten (MM) kinetic parameters. Brain glucose values during euglycemia (1.1 ± 0.4 μmol/g vs. 1.1 ± 0.3 μmol/g; P = 0.95) and hypoglycemia (0.5 ± 0.2 μmol/g vs. 0.6 ± 0.3 μmol/g; P = 0.52) were comparable between healthy subjects and T1DM patients. MM kinetic parameters of combined data were calculated to be maximum transport rate/cerebral metabolic rate of glucose (Tmax/CMRglc) = 2.25 ± 0.32 and substrate concentration at half maximal transport (Kt) = 1.53 ± 0.88 mmol/L, which is in line with previously published data obtained under hyperglycemic conditions. In conclusion, the linear MM relationship between plasma and brain glucose can be extended to low plasma glucose levels. We found no evidence that the plasma to brain glucose relationship or the kinetics describing glucose transport over the blood–brain barrier differ between healthy subjects and patients with uncomplicated, reasonably well-controlled T1DM.

Introduction

Hypoglycemia frequently complicates (intensive) insulin treatment in patients with type 1 diabetes mellitus (T1DM). On average, T1DM patients experience two to three hypoglycemic events every week and one hypoglycemic event complicated by loss of consciousness or seizures, reflecting severe brain dysfunction, every 1 to 2 years.[1] Knowledge about glucose transport over the blood–brain barrier during hypoglycemia is important because the brain is dependent on continuous supply of glucose as its principal source of energy.

Glucose transport over the blood–brain barrier takes place through facilitated diffusion mediated by the glucose transporter GLUT1.[2] Cerebral glucose content depends on the plasma glucose concentration, transport of glucose in and out of the brain, and the cerebral metabolic rate of glucose (CMRglc). Several studies using magnetic resonance spectroscopy (MRS) have shown that over a range of plasma glucose from 4.6 to 30 mmol/L, brain glucose content is linearly related to the plasma glucose level.[3–5] However, whether the relationship between brain glucose content and plasma glucose concentration is altered during hypoglycemia, either in subjects without diabetes or in patients with T1DM, has not been investigated. Such alterations could have important implications for our understanding of brain glucose handling under conditions of deprivation in humans in general and in patients with diabetes who are at continuous risk of hypoglycemia.

Glucose transport under nonhypoglycemic conditions has been modeled by reversible Michaelis-Menten (MM) kinetics,[3] which predict a linear relationship between plasma and brain glucose. Whether such linearity persists into the hypoglycemic range, as has been shown in rats,[5] is currently unknown. In fact, the uncertainty of published values for reversible MM kinetics is so large that this leads to predictions for brain glucose value to approach 0 μmol/g when plasma glucose levels lie anywhere between 0 and 5 mmol/L.[3–6]

Applying 13C MRS to measure brain glucose content during hypoglycemia is challenging. Infusion of isotopically enriched glucose to improve the sensitivity of the MRS measurements conflicts with obtaining hypoglycemia. We recently developed a protocol to measure brain glucose metabolism under euglycemic and hypoglycemic conditions by 13C MRS in humans in vivo.[7] In this study, we applied this protocol to quantitatively assess brain glucose content and calculate kinetic parameters for brain glucose transport under these conditions. We performed this study in healthy human volunteers as well as in patients with uncomplicated T1DM.

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