We recommend evaluation and management of hypoglycemia only in patients in whom Whipple's triad--symptoms, signs, or both consistent with hypoglycemia, a low plasma glucose concentration, and resolution of those symptoms or signs after the plasma glucose concentration is raised--is documented. In patients with hypoglycemia without diabetes mellitus, we recommend the following strategy. First, pursue clinical clues to potential hypoglycemic etiologies--drugs, critical illnesses, hormone deficiencies, nonislet cell tumors. In the absence of these causes, the differential diagnosis narrows to accidental, surreptitious, or even malicious hypoglycemia or endogenous hyperinsulinism. In patients suspected of having endogenous hyperinsulinism, measure plasma glucose, insulin, C-peptide, proinsulin, beta-hydroxybutyrate, and circulating oral hypoglycemic agents during an episode of hypoglycemia and measure insulin antibodies. Insulin or insulin secretagogue treatment of diabetes mellitus is the most common cause of hypoglycemia. We recommend the practice of hypoglycemia risk factor reduction--addressing the issue of hypoglycemia, applying the principles of intensive glycemic therapy, and considering both the conventional risk factors and those indicative of compromised defenses against falling plasma glucose concentrations--in persons with diabetes.

OBJECTIVETo review the evidence about the impact of hypoglycemia on patients with diabetes that has become available since the past reviews of this subject by the American Diabetes Association and The Endocrine Society and to provide guidance about how this new information should be incorporated into clinical practice.PARTICIPANTSFive members of the American Diabetes Association and five members of The Endocrine Society with expertise in different aspects of hypoglycemia were invited by the Chair, who is a member of both, to participate in a planning conference call and a 2-day meeting that was also attended by staff from both organizations. Subsequent communications took place via e-mail and phone calls. The writing group consisted of those invitees who participated in the writing of the manuscript. The workgroup meeting was supported by educational grants to the American Diabetes Association from Lilly USA, LLC and Novo Nordisk and sponsorship to the American Diabetes Association from Sanofi. The sponsors had no input into the development of or content of the report.EVIDENCEThe writing group considered data from recent clinical trials and other studies to update the prior workgroup report. Unpublished data were not used. Expert opinion was used to develop some conclusions.CONSENSUS PROCESSConsensus was achieved by group discussion during conference calls and face-to-face meetings, as well as by iterative revisions of the written document. The document was reviewed and approved by the American Diabetes Association’s Professional Practice Committee in October 2012 and approved by the Executive Committee of the Board of Directors in November 2012 and was reviewed and approved by The Endocrine Society’s Clinical Affairs Core Committee in October 2012 and by Council in November 2012.CONCLUSIONSThe workgroup reconfirmed the previous definitions of hypoglycemia in diabetes, reviewed the implications of hypoglycemia on both short- and long-term outcomes, considered the implications of hypoglycemia on treatment outcomes, presented strategies to prevent hypoglycemia, and identified knowledge gaps that should be addressed by future research. In addition, tools for patients to report hypoglycemia at each visit and for clinicians to document counseling are provided.

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. Design Retrospective epidemiological analysis of data from the ACCORD trial. Setting Diabetes clinics, research clinics, and primary care clinics. Participants Patients were eligible for the ACCORD study if they had type 2 diabetes, a glycated haemoglobin (haemoglobin A 1C ) concentration of 7.5% or more during screening, and were aged 40-79 years with established cardiovascular disease or 55-79 years with evidence of subclinical disease or two additional cardiovascular risk factors. Intervention Intensive (haemoglobin A 1C <6.0%) or standard (haemoglobin A 1C 7.0-7.9%) glucose control. Outcome measures Symptomatic, severe hypoglycaemia, manifest as either blood glucose concentration of less than 2.8 mmol/l (<50 mg/dl) or symptoms that resolved with treatment and that required either the assistance of another person or medical assistance, and all cause and cause specific mortality, including a specific assessment for involvement of hypoglycaemia. Results 10 194 of the 10 251 participants enrolled in the ACCORD study who had at least one assessment for hypoglycaemia during regular follow-up for vital status were included in this analysis. Unadjusted annual mortality among patients in the intensive glucose control arm was 2.8% in those who had one or more episodes of hypoglycaemia requiring any assistance compared with 1.2% for those with no episodes (53 deaths per 1924 person years and 201 deaths per 16 315 person years, respectively; adjusted hazard ratio (HR) 1.41, 95% CI 1.03 to 1.93). A similar pattern was seen among participants in the standard glucose control arm (3.7% (21 deaths per 564 person years) v 1.0% (176 deaths per 17 297 person years); adjusted HR 2.30, 95% CI 1.46 to 3.65). On the other hand, among participants with at least one hypoglycaemic episode requiring any assistance, a nonsignificantly lower risk of death was seen in those in the intensive arm compared with those in the standard arm (adjusted HR 0.74, 95% 0.46 to 1.23). A significantly lower risk was observed in the intensive arm compared with the standard arm in participants who had experienced at least one hypoglycaemic episode requiring medical assistance (adjusted HR 0.55, 95% CI 0.31 to 0.99). Of the 451 deaths that occurred in ACCORD up to the time when the intensive treatment arm was closed, one death was adjudicated as definitely related to hypoglycaemia. Conclusion Symptomatic, severe hypoglycaemia was associated with an increased risk of death within each study arm. However, among participants who experienced at least one episode of hypoglycaemia, the risk of death was lower in such participants in the intensive arm than in the standard arm. Symptomatic, severe hypoglycaemia does not appear to account for the difference in mortality between the two study arms up to the time when the ACCORD intensive glycaemia arm was discontinued. Trial registratio...

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Gruetter, Rolf, Elizabeth R. Seaquist, and Kâ mil Ugurbil. A mathematical model of compartmentalized neurotransmitter metabolism in the human brain. Am J Physiol Endocrinol Metab 281: E100-E112, 2001.-After administration of enriched [1-13 C]glucose, the rate of 13 C label incorporation into glutamate C4, C3, and C2, glutamine C4, C3, and C2, and aspartate C2 and C3 was simultaneously measured in six normal subjects by 13 C NMR at 4 Tesla in 45-ml volumes encompassing the visual cortex. The resulting eight time courses were simultaneously fitted to a mathematical model. The rate of (neuronal) tricarboxylic acid cycle flux (V PDH ), 0.57 Ϯ 0.06 mol ⅐ g Ϫ1 ⅐ min Ϫ1 , was comparable to the exchange rate between (mitochondrial) 2-oxoglutarate and (cytosolic) glutamate (V x , 0.57 Ϯ 0.19 mol ⅐ g Ϫ1 ⅐ min Ϫ1 ), which may reflect to a large extent malate-aspartate shuttle activity. At rest, oxidative glucose consumption [CMR Glc(ox) ] was 0.41 Ϯ 0.03 mol ⅐ g Ϫ1 ⅐ min Ϫ1 , and (glial) pyruvate carboxylation (V PC ) was 0.09 Ϯ 0.02 mol ⅐ g Ϫ1 ⅐ min Ϫ1. The flux through glutamine synthetase (V syn ) was 0.26 Ϯ 0.06 mol ⅐ g Ϫ1 ⅐ min Ϫ1 . A fraction of V syn was attributed to be from (neuronal) glutamate, and the corresponding rate of apparent glutamatergic neurotransmission (V NT ) was 0.17 Ϯ 0.05The ratio [V NT /CMR Glc(ox) ] was 0.41 Ϯ 0.14 and thus clearly different from a 1:1 stoichiometry, consistent with a significant fraction (ϳ90%) of ATP generated in astrocytes being oxidative. The study underlines the importance of assumptions made in modeling 13 C labeling data in brain.nuclear magnetic resonance; glutamate; neurotransmission; in vivo spectroscopy IN THE TRADITIONAL CONTEXT of neuroscience, the brain's tasks are mainly accomplished by the neurons, with the surrounding glial cells performing simple, passive tasks of maintaining the milieu required for optimal neurotransmission. However, the glial cells are more than just passive components in neuronal function, in that they are intimately involved in the process of neurotransmission through glial uptake of glutamate (Glu) from the synaptic cleft (64,77,78). Glu is the major excitatory neurotransmitter (62); it is present in the mammalian brain in high concentrations and is dynamically stored in presynaptic vesicles (73). Despite the high intracellular concentration of Glu, the extracellular concentration must be maintained very low (ϳ0.004 mM) to avoid excitotoxicity. Presynaptic release of Glu into the synaptic cleft therefore requires efficient uptake mechanisms, which are achieved by Glu transporters (2). Most of the metabolic evidence suggests that uptake by glia is the most important process. Most of the Glu is in neurons (51), as is most of the glutaminase activity (52), whereas astrocytes contain most of the glutamine (Gln) (51), all of the glutamine synthetase (42), and pyruvate carboxylase (63); they predominantly take up and metabolize acetate (74). Early studies showed that cerebral Glu metabolism is compartmentalized, involving two major metabolic po...