RESEARCH ARTICLE

The nature of the control of blood glucose in those with poorerglucose tolerance influences mood and cognition

Hayley Young & David Benton

Received: 29 August 2013 /Accepted: 12 February 2014# Springer Science+Business Media New York 2014

Abstract The ability to control the levels of blood glucosewas related to mood and cognition. 155 adults, aged 4585 years, without a diagnosis of diabetes, were given an oralglucose tolerance test and cognitive tests. Participants wereclassified according to age (4160/6185 years), whether theyhad better or poorer glucose tolerance and whether bloodglucose did or did not fall below baseline values. There weretwomain findings. Those with poorer glucose tolerance forgotmorewords and had slower decision times, but only if 61 yearsor older. Secondly as there are reports in animal studies thatinducing low levels of blood glucose values benefited cogni-tive performance, for the first time in humans, individualdifferences in the tendency to develop low levels of bloodglucose were considered. In those with poor glucose tolerancea tendency for blood glucose to fall below baseline values wasassociated with better mood and faster working memory.

Keywords Glucose intolerance . Hypoglycemia .Memory .

Mild cognitive impairment . Mood

AbbreviationsLBG Low blood glucoseGT Glucose tolerance

Introduction

As glucose is the primary fuel of the brain a continuous supplyis required to maintain cognitive functioning; both poorerglucose tolerance (Lamport et al. 2009) and low levels of

blood glucose (Warren and Frier 2005) are disruptive. Theaim was to relate, in a healthy older sample, individual differ-ences in glucoregulation, mood and cognitive functioning.

In those without diabetes a reduced ability to regulate bloodglucose is associated with poorer attention (Donohoe andBenton. 2000), slower reaction times (Yaffe et al. 2012) andpoorer memory (Yaffe et al. 2012). Although the mechanismsbehind the disruption of cognition in glucose intolerant indi-viduals are unclear, one suggestion is that they reflect areduced ability to transport glucose into the brain (Convit2005). There is evidence that the rate of peripheral glucosechange during cognitive testing is related to performance inboth healthy participants (De Feo et al. 1988; Benton et al.1996; Donohoe and Benton 2000; Scholey et al. 2001) andthose with diabetes (Perlmuter et al. 2009). It is possible that ahigher rate of decline in peripheral blood glucose reflectsgreater glucose uptake by the brain, facilitating cognition.Therefore, in conditions that hinder glucose uptake, such aspoorer glucose tolerance, the brain may be deprived of the fuelit requires. This view is consistent with reductions in cerebralglucose metabolism in those at risk of dementia (Mosconiet al. 2007).

Despite much research on the cognitive effects of chroni-cally raised plasma glucose levels, there has been little re-search on the impact of frequent low levels of blood glucose.Individuals in the early stage of glucose intolerance oftenexperience hyperinsulinemic compensation (Polonsky 2000);that is increased levels of plasma insulin. However, if toomuch insulin is produced blood glucose levels may fall tolow levels, resulting in substantial fluctuations in blood glu-cose levels and the possibility of developing mild hypoglyce-mia (Brun et al. 2000;

differences is that recurrent episodes of low blood glucoselead to subsequent brain adaptation, so that if hypoglycemiare-occurs cognition is preserved. For example, animals ex-posed to recurrent hypoglycemia (2.53.0 mmol/L or 4554mg/dl) have increased hippocampal glucose concentrationsonce glycemia is restored (McNay et al. 2006). In humans,Fruehwald-Schultes et al. (2000) using a hypoglycemicclamp, found that a single episode of antecedent hypoglyce-mia (3.1 mmol/L) preserved cognition during subsequenthypoglycemia.

Previous studies have tended to artificially lower bloodglucose to levels that will rarely be found in everyday life.As the levels of blood glucose needed to induce adaptation areunclear one aimwas to see if comparable effects occur in thosewhose physiology predisposes to the development of moder-ately low levels of blood glucose. A glucose profile oftenobserved in adults in the early stages of glucose intoleranceis the tendency for blood glucose to drop to low levels 2 to 3 hafter an OGTT (Brun et al. 2000;

one of the lamps illuminated. The subject then extinguishedthe light by depressing a button directly below the lamp, usingthe finger initially on the home key. Simple reaction timeswere measured for 20 trials using one lamp. Choice reactiontimes were thenmeasured over three sets of 20 trials when oneof 2, 4 or 8 lamps could potentially illuminate. Decision times,the time taken to lift the finger from the home key, wereanalyzed.

National adult reading test

The National Adult Reading Test (NART; Nelson 1982) iswidely used to retrospectively estimate the level of premorbidintellectual functioning, as unlike other aspects of cognitionthe ability to recognize words is relatively preserved with age(Bright et al. 2002). The test involves reading aloud of 50phonetically irregular words that occur progressively lessfrequently in English. Essentially it is a measure of vocabularythat correlates with measures of overall intelligence.

Statistical analysis

Subjects were divided into two groups according to theirblood glucose level after 2 h of the OGTT. To allow sufficientsample sizes as near a median split as possible was made. Iftheir blood glucose was 7.0 mmol/L or higher they weredescribed as having poorer glucose tolerance (GT), if theirblood glucose was less than 7 mmol/L they were described ashaving better GT. The World Health Organisation (WHO)defines glucose intolerance as blood glucose>7.8 mmol/L at2 h OGTT, although this definition does not reflect anymeasure of cognitive functioning. According to this definition32 % of the samples (n=49) were glucose intolerant.

Individuals were also divided into two groups dependingon the tendency for blood glucose to remain above or fallbelow fasting values. This cut-off was chosen as a convenient,albeit arbitrary, indication of the tendency of blood glucoselevels to fall. However, falling below the baseline value doesnot necessary result in problems as there are individual differ-ences in the response to low levels of blood glucose. Thosewhose levels fell below baseline at the end of the test(150 min) all had glucose levels at this time

Importantly, 50 % of these final values fell below 4.0 mmol/Land 30 % were

were examined the GT X LBG X Age interaction was non-significant (F(1,139)=0.33 n.s.).

Reaction times

With decision times the GT X Age interaction was significant(F(3,432)=2.84, p

adaptation to low levels of blood glucose has been littleconsidered in healthy subjects, similar phenomena have beendescribed in diabetics (Lobmann et al. 2000) and animals(McNay et al. 2006; McNay and Sherwin 2004). In animals,low blood sugar levels (2.53.0 mmol/l) have been reported toinduce brain adaptation such that cognitive functioning im-proved. For example, a single episode of low blood glucoseincreased hippocampal interstitial glucose concentrations(McNay et al. 2006; McNay and Sherwin 2004). You canspeculate that this increase in brain glucose levels enhancedsubsequent cognitive performance by providing a greatersupply of glucose. For example, maze learning by rats, a taskthat is associated with a drop in hippocampal interstitial glu-cose levels (McNay et al. 2000), was performed better after3 days of exposure to hypoglycemia (McNay and Sherwin2004): there were smaller falls in interstitial glucose whenanimals had been exposed to hypoglycemia. Although themechanisms underlying these findings remain unclear,GLUT 1 at the endothelium (Boado and Pardridge 1993)and the neuronal glucose transporter GLUT 3 (Uehara et al.1997) are both up regulated following hypoglycemia. It isinteresting that localized drops in brain interstitial glucose

during activation have been reported to be greater, and to lastlonger, in aged rather than young animals (McNay and Gold2001) and that exposure to hypoglycemic episodes modifiedthe effects of aging on cognitive decline (McNay 2005).

Whilst in adults with poorer GT the tendency for bloodglucose to fall was beneficial, this was not the case for thosewith better GT. It is possible that the beneficial effects associ-ated with LBG are more easily demonstrated in those withpoorer GT because performance had already deteriorated; areflection of lower levels of brain glucose (Convit 2005). Inaddition, it may be hypothesised that if LBG leads to anadaptive response that increases cerebral interstitial glucose,then this may offset the negative repercussions of reducedcerebral glucose uptake associated with poorer GT, thus facil-itating cognition.

A critical question is why did the blood glucose levels ofsome with poor GT remained high while in others there was asharp decline after 120 and 150 min (Fig. 1): it was this fall inblood glucose that was beneficial (Figs. 3 and 5). Althoughlevels were not measured it is probable that this effect reflecteda late increase in insulin secretion in those with the tendencyfor blood glucose to fall below baseline levels. The usualresponse to insul in res is tance is compensa toryhyperinsulinemia (Polonsky 2000), therefore hyperglycemiaand glucose intolerance do not occur until insulin secretion isimpaired (Triplitt 2012). Thus it is possible that adults withpoorer GT, whose blood glucose values subsequently fell,may have developed hyperinsulinemia to compensate forinsulin resistance. This consideration of the role played byinsulin in controlling blood glucose in those with poor GTraises the question whether it directly played a part in improv-ing the cognitive functioning of those with poorer GT whoselevels fell below baseline values. Although the current con-sensus is that glucose transport into the brain is not dependenton insulin, the hormone crosses the blood brain barrier and isthought to modulate memory (Zhao et al. 2004). As such, ahigher rate of insulin secretion could be the mechanism thatproduces both falling blood glucose levels and enhancedcognitive functioning.

The beneficial effect of a tendency of blood glucose to fallin those with poorer GT is an intriguing finding, although itraises questions. Is this glucose response a stage betweenglucose intolerance and later diabetes? In time would thosewhose glucose levels fell sharply turn into the group whoselevels remained high: a sample needs to be considered overtime? The question also arises as to whether cognitive declinemay be influenced by a prolonged dietary intervention basedon the glycemic response to meals?

Also noteworthy was that the negative effects of poor GTwere more pronounced in those over 61 years; in older ratherthan younger individuals poorer GT was associated withslower decision times and forgetting more words. Althoughpreviously when considering GT and cognition a stronger

p

association has been found in older (Messier et al. 2003) ratherthan young adults (Lamport et al. 2009), this is the first studyto directly compare younger and older adults with a similarlevel of impaired GT (Table 2). Although the exact mecha-nism is to be determined, there was a negative interactionbetween age and the metabolic consequences of impaired GT.

A recent study found that raised blood glucose levels, thatas defined by the WHO were still in the normal range, wereassociated with lower grey/white matter volumes in otherwisecognitively healthy older adults (Mortby et al. 2013). This is apotentially important observation as white matter plays animportant role in allowing messages to be sent quickly in thebrain and damage in white matter is frequently observed inpeople with dementia. There is clear relationship betweendamage to white matter and cognitive impairment. It seemsreasonable to suggest that in part at least that damage to whitematter might reflect problems with the ability of blood vesselsto supply glucose.

In conclusion, older rather than younger adults with poorerGT had poorer cognitive performance. In addition, the ten-dency to develop LBG was associated with better cognitiveperformance and mood in those with poorer glucose tolerance.Further research is required to establish the level at whichraised blood glucose becomes detrimental.

Acknowledgments The authors declare that they have no conflict ofinterest and that the work was not externally funded. We are grateful tothe Swansea University for supplying the necessary facilities.

References

Ahmadpour S, Kabadi U (1997) Pancreatic -cell function in idiopathicreactive hypoglycaemia. Metabolism 46:639643

Awad N, Gagnon M, Desrochers A, Tsiakas M, Messier C (2002) Impactof peripheral glucoregulation onmemory. Behav Neurosci 116:691702

Benton D, Parker PY, Donohoe RT (1996) The supply of glucose to thebrain and cognitive functioning. J Biosoc Sci 28:463479

Biessels GJ, Deary IJ, Ryan CM (2008) Cognition and diabetes: a lifespanperspective. Lancet Neurol 7:184190

Boado RJ, Pardridge WM (1993) Glucose deprivation causes posttran-scriptional enhancement of brain capillary endothelial glucose trans-porter gene expression via GLUT1 mRNA stabilization. JNeurochem 60:22902296

Bright P, Jaldow ELI, KopelmanMD (2002) The National Adult ReadingTest as a measure of premorbid intelligence: a comparison withestimates derived from demographic variables. J Int NeuropsycholSoc 8:847854

Brun JF, Fedou C,Mercier J (2000) Postprandial reactive hypoglycaemia.Diabetes Metab (Paris) 26:337351

Chan DW (1985) The Chinese version of the General HealthQuestionnaire: does language make a difference? Psychol Med 15:147155

Convit A (2005) Links between cognitive impairment in insulin resis-tance: an explanatory model. Neurobiol Aging 26(Suppl. 1):3135

De Feo P, Gallai V, Mazzotta G, Crispino G, Torlone E, Perriello G,Ventura MM, Santeusanio F, Brunetti P, Bolli GB (1988) Modest

decrements in plasma glucose concentration cause early impairmentin cognitive function and later activation of glucose counterregulationin the absence of hypoglycemic symptoms in normal man. J ClinInvestig 82:436444

Donohoe RT, Benton D (2000) Glucose tolerance predicts performanceon tests of memory and cognition. Physiol Behav 71:395401

Fruehwald-Schultes B, Born J, Kern W, Peters A, Fehm H (2000)Adaptation of cognitive function to hypoglycaemia in healthymen. Diabetes Care 23:10591066

Kaplan RJ, Greenwood CE, Winocur G, Wolever TM (2000) Cognitiveperformance is associated with glucose regulation in healthy elderlypersons and can be enhanced with glucose and dietary carbohy-drates. Am J Clin Nutr 72:825836

Lamport DJ, Lawton CL, Mansfield MW, Dye L (2009) Impairments inglucose tolerance can have a negative impact on cognitivefunction: a systematic research review. Neurosci Biobehav Rev 33:394413

Lobmann R, Smid HG, Pottag G, Wagner K, Heinze HJ, Lehnert H(2000) Impairment and recovery of elementary cognitive functioninduced by hypoglycaemia in type-1 diabetic patients and healthycontrols. J Clin Endocrinol Metab 85:27582766

Matthews DR, Holman RR, Bown E, Steenson J, Watson A, Hughes S(1987) Pen-sized digital 30-second blood glucose meter. Lancet 1:778779

McCrimmon RJ, Deary IJ, Frier BM (1997) Auditory information pro-cessing during acute insulin-induced hypoglycaemia in non-diabetichuman subjects. Neuropsychologia 35:15471553

McNay EC (2005) The impact of recurrent hypoglycaemia on cognitivefunction in aging. Neurobiol Aging 26:7679

McNay EC, Gold PE (2001) Age-related differences in hippocampalextracellular fluid glucose concentration during behavioral testingand following systemic glucose administration. J Gerontol A BiolSci Med Sci 56:B66B71

McNay EC, Sherwin RS (2004) Effect of recurrent hypoglycaemia onspatial cognition and cognitive metabolism in normal and diabeticrats. Diabetes 53:418425

McNay EC, Fries TM, Gold PE (2000) Decreases in rat extracel-lular hippocampal glucose concentration associated with cog-nitive demand during a spatial task. Proc Natl Acad Sci U S A 97:28812885

McNay EC, Williamson A, McCrimmon RJ, Sherwin RS (2006)Cognitive and neural hippocampal effects of long-term moderaterecurrent hypoglycaemia. Diabetes 55:10881095

Messier C, Tsiakas M, Gagnon M, Desrochers A, Awad N (2003) Effectof age and glucoregulation on cognitive performance. NeurobiolAging 24:9851003

Mortby M, Janke A, Anstey K, Sachdev P, Cherbuin N (2013) Highnormal blood glucose is associated with decreased brain volumeand cognitive performance in the 60s: the PATH through life study.PLoS ONE 8:e73697

Mosconi L, Brys M, Glodzik-Sobanska L, De Santi S, Rusinek H, deLeon MJ (2007) Early detection of Alzheimers disease using neu-roimaging. Exp Gerontol 42:129138

Nelson HE (1982) National Adult Reading Test: test manual. NFER-Nelson, Windsor

Perlmuter L, Shah P, Flanagan B, Surampudi V, Kosman Y, Singh S(2009) Rate of peripheral glucose change during cognitive testingpredicts performance in diabetes mellitus. J Diabetes 1:4349

Polonsky KS (2000) Dynamics of insulin secretion in obesity and diabe-tes. Int J Obes Relat Metab Disord 24:S29S31

Scholey A, Harper S, Kennedy D (2001) Cognitive demand and bloodglucose. Physiol Behav 73:585592

Stuart K, Field A, Raju J, Ramachandran S (2013) Postprandial reactivehypoglycaemia: varying presentation patterns on extended glucosetolerance tests and possible therapeutic approaches. Case Rep Med2013:273957. doi:10.1155/2013/273957

Metab Brain Dis

Triplitt CL (2012) Examining the mechanisms of glucose regulation. AmJ Manag Care 18:S4S10

Uehara Y, Nipper V, McCall AL (1997) Chronic insulin hypoglycaemiainduces GLUT-3 protein in rat brain neurons. Am J Physiol 272:716719

VeaH, Jorde R, Sager G, Vaaler S, Sundsfjord J (1992) Reproducibility ofglycaemic thresholds for activation of counterregulatory hormonesand hypoglycaemic symptoms in healthy subjects. Diabetologia 35:958961

Warren RE, Frier BM (2005) Hypoglycaemia and cognitive function.Diabetes Obes Metab 7:493503

Yaffe K, Falvey C, Hamilton N, Schwartz AV, Simonsick EM, SatterfieldS, Harris TB (2012) Diabetes, glucose control, and 9-year cognitivedecline among older adults without dementia. Arch Neurol 69:11701175

Zhao WQ, Chen H, Quon MJ, Alkon DL (2004) Insulin and the insulinreceptor in experimental models of learning and memory. Eur JPharmacol 490:7181

Metab Brain Dis

The nature of the control of blood glucose in those with poorer glucose tolerance influences mood and cognitionAbstractIntroductionMethodsSubjectsProcedureTest batteryEpisodic memoryWorking memoryReaction timesNational adult reading test

Statistical analysis

ResultsEpisodic memoryWorking memoryReaction timesDepression and anxiety

DiscussionReferences