Dynamic response of cerebral blood flow to insulin-induced hypoglycemia

The dynamics of cerebral blood flow (CBF) at the onset of hypoglycemia may play a key role in hypoglycemia unawareness; however, there is currently a paucity of techniques that can monitor adult CBF with high temporal resolution. Herein, we investigated the use of diffuse correlation spectroscopy (DCS) to monitor the dynamics of CBF during insulin-induced hypoglycemia in adults. Plasma glucose concentrations, cortisol levels, and changes in CBF were measured before and during hypoglycemia in 8 healthy subjects. Cerebral blood flow increased by 42% following insulin injection with a delay of 17 ± 10 min, while the onset of hypoglycemia symptoms was delayed by 24 ± 11 min. The findings suggest that the onset of CBF increments precedes the appearance of hypoglycemia symptoms in nondiabetic subjects with normal awareness to hypoglycemia, and DCS could be a valuable tool for investigating the role of CBF in hypoglycemia unawareness

Ketone Body Metabolism Preserves Hepatic Function during Adaptation to Birth and in Overnutrition

Mammalian ketone body metabolism partially oxidizes hepatic acyl-chains to ketone body intermediates, which can serve as alternative fuels in extrahapetic tissues during carbohydrate restricted states. Ketone body production (ketogenesis) occurs primarily in liver, due to hepatocyte-specific expression of the fate committing ketogenic enzyme, mitochondrial 3-hydroxymethylglutaryl-CoA synthase (HMGCS2). In contrast, the fate committing enzyme of ketone body oxidation, mitochondrial Succinyl-CoA:3-oxoacid CoA Transferase (SCOT), is expressed ubiquitously, except in liver. Here I demonstrate novel roles for ketone body metabolism during a classically ketogenic period, the transition to birth, and in a classically `non-ketogenic\u27 state, overnutrition, using novel genetic mouse models, high-resolution measures of dynamic metabolism using 13C-labeled substrates, and systems physiology approaches. I show that germline SCOT-knockout (KO) mice cannot oxidize ketone bodies in any tissue. These mice developed lethal hyperketonemia and hypoglycemia within the first 48 hr of life and died in a manner that phenocopied human sudden infant death syndrome. Nonetheless, my studies of tissue-specific SCOT-KO mice revealed that ketone body oxidation is dispensable during the transition to birth and during starvation in the adult when individually eliminated in neurons, cardiomyocytes, or skeletal myocytes, which comprise the three largest consumers of ketone bodies. Surprisingly, the inability to dispose of ketone bodies in germline SCOT-KO mice drove derangements of carbohydrate and fatty acid metabolism, oxidized redox potential, and inhibited ketogenesis in liver. Moreover, I show that adult-onset loss of HMGCS2 ablated the liver\u27s capacity to effectively convert fat into ketone bodies, and thus induced ketogenesis insufficiency. Ketogenesis insufficient mice exhibited increased hepatic gluconeogenesis from pyruvate and mild hyperglycemia in the fed state. High-fat diet feeding of ketogenesis insufficient mice caused extensive hepatocyte injury and inflammation that was associated with decreased glycemia due to fatty acid-induced sequestration of free coenzyme A that caused secondary derangements of hepatic tricarboxylic acid (TCA) cycle intermediate concentrations and impaired gluconeogenesis. Together, my studies have revealed a critical and novel role for ketone body metabolism in preservation of the dynamic intermediary metabolic network in liver during the adaptation to birth and in overnutrition

The continuum of spreading depolarizations in acute cortical lesion development: Examining Leão's legacy.

A modern understanding of how cerebral cortical lesions develop after acute brain injury is based on Aristides Leão's historic discoveries of spreading depression and asphyxial/anoxic depolarization. Treated as separate entities for decades, we now appreciate that these events define a continuum of spreading mass depolarizations, a concept that is central to understanding their pathologic effects. Within minutes of acute severe ischemia, the onset of persistent depolarization triggers the breakdown of ion homeostasis and development of cytotoxic edema. These persistent changes are diagnosed as diffusion restriction in magnetic resonance imaging and define the ischemic core. In delayed lesion growth, transient spreading depolarizations arise spontaneously in the ischemic penumbra and induce further persistent depolarization and excitotoxic damage, progressively expanding the ischemic core. The causal role of these waves in lesion development has been proven by real-time monitoring of electrophysiology, blood flow, and cytotoxic edema. The spreading depolarization continuum further applies to other models of acute cortical lesions, suggesting that it is a universal principle of cortical lesion development. These pathophysiologic concepts establish a working hypothesis for translation to human disease, where complex patterns of depolarizations are observed in acute brain injury and appear to mediate and signal ongoing secondary damage

Hypoglycemia

Glucose is an essential metabolic substrate of all mammalian cells being the major carbohydrate presented to the cell for energy production and also many other anabolic requirements. Hypoglycemia is a disorder where the glucose serum concentration is usually low. The organism usually keeps the glucose serum concentration in a range of 70 to 110 mL/dL of blood. In hypoglycemia the glucose concentration normally remains lower than 50 mL/dL of blood. This book provides an abundance of information for all who need them in order to help many people worldwide