Effect of hypoglycemia on brain glycogen metabolism in vivo

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 pre-hypoglycemic 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

Direct, noninvasive measurement of brain glycogen metabolism in humans

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 prospect of understanding the role and function of this important energy reserve under various physiological and pathophysiological conditions

Brain glucose concentrations in poorly controlled diabetes mellitus as measured by high-field magnetic resonance spectroscopy

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% +/- 1.7%, mean +/- 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 +/- 0.9 vs 5.3 +/- 1.1 micromol/g wet wt; P = .1). Our sample size gave 80% power to detect a difference as small as 1.1 micromol/g wet wt. We conclude that chronic hyperglycemia in diabetes does not alter brain glucose concentrations in human subjects

Brain glucose concentrations in healthy humans subjected to recurrent hypoglycemia

Mechanisms responsible for hypoglycemia unawareness remain unknown. Previously, we found that patients with type 1 diabetes and hypoglycemia unawareness had increased brain glucose concentrations as measured by (1)H-magnetic resonance spectroscopy (MRS) compared with controls measured under the same metabolic condition, suggesting that an alteration in brain glucose transport and/or metabolism may play a role in the pathogenesis of hypoglycemia unawareness. To determine whether the brain glucose concentration is altered in normal subjects subjected to recurrent hypoglycemia, we compared the brain glucose concentrations measured in healthy subjects after three episodes of hypoglycemia to blunt the counterregulatory response over 24 hr and compared this value with that measured at a time remote from the antecedent hypoglycemia protocol. Sixteen subjects (9 M/7 F, age 36 +/- 10 years, mean +/- SD) underwent three hypoglycemic clamps for 30 min at 8 AM (0 hr), 5 PM (9 hr), and 7 AM (24 hr). After the third hypoglycemic clamp, subjects underwent a hyperglycemic clamp during which brain glucose concentration was measured by MRS at 4 T. Brain glucose concentration after repeated hypoglycemia was not different from the brain glucose concentration measured in the same subjects during a control study (5.1 +/- 0.8 vs. 4.5 +/- 0.5 mumol/g wet weight, respectively, P = 0.05). These observations suggest that brain glucose transport or metabolism is not altered following short episodes of recurrent hypoglycemia in healthy human volunteers

Uncovering hidden in vivo resonances using editing based on localized TOCSY

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 beta-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

The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study

Objective To determine whether there is a link between hypoglycaemia and mortality among participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial

Estimated plasma stearoyl co-A desaturase-1 activity and risk of incident diabetes: The Atherosclerosis Risk in Communities (ARIC) study

Evidence from pre-clinical studies suggests inhibition of Stearoyl Co-A Desaturase-1 (SCD-1) activity improves insulin sensitivity. Translation of these findings to humans remains less defined. The purpose of this research was to evaluate the association between different measures of SCD-1 activity and incident diabetes in a large, prospective human study

The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study

Objectives To investigate potential determinants of severe hypoglycaemia, including baseline characteristics, in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the association of severe hypoglycaemia with levels of glycated haemoglobin (haemoglobin A1C) achieved during therapy