‘Type 3 diabetes’: linking a brain insulin-resistant state with dementia … · 2016-03-14 ·...
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‘We propose the term Type 3 Diabetes to reflect this newly identified pathogenic mechanism of neurodegeneration.’ de la Monte, 2005. 1 A t the 60th (June 2000) Annual Scientific Sessions of the American Diabetes Association, on an otherwise dismal afternoon in San Antonio, attending delegates were enthralled by a presentation from Trevor Orchard (University of Pittsburgh) asking them to contemplate a concept of ‘Double Diabetes’, a combi- nation of type 1 diabetes and insulin resistance, so familiar with hindsight and even more so in this modern era. ‘Double Diabetes’ has since been described as type 3 diabetes (not to be confused with MODY3), and so the proposal of yet another different form of diabetes also labelled as type 3 does create some confusion while at the same time providing an intriguing insight into potential shared pathogenic mechanisms between type 2 diabetes and Alzheimer’s disease. 1 Further publication from the Rhode Island team last year 2 reiterated that there is ‘growing evidence support- ing the concept that Alzheimer’s disease is fundamen- tally a metabolic syndrome that leads to abnormalities linked to progressive brain insulin resistance’ with consequent impairment of central insulin signalling processes, accumulation of neuro toxins, neuronal stress and in due course neurodegeneration. The medical implications of this proposal received rapid and promi- nent coverage in the popular media, including New Scientist: ‘Food for thought: Eat your way to dementia’. 3 Having already noted interest in the New Scientist article, this author was then further motivated with the topic following challenge, while captive in the dentist’s chair, with: ‘What is your opinion on the recent Guardian newspaper article – “Alzheimer’s could be the most cata- strophic impact of junk food”?’ 4 Clearly, an important issue has been identified. But within these somewhat sensational speculations, it would appear that insulin does play a significant role within the brain, and that abnormalities of allied insulin function may contribute to cognitive decline. Much still remains of a controversial nature and largely derived from experimental investiga- tion, but the science so far does suggest that there is a syndrome of central insulin resistance, similar to that seen with type 2 diabetes, that may be associated with impaired cognitive function, including memory loss, learning difficulties and dementia. Accelerated cognitive decline is sadly a recognised long-term complication of diabetes, with causation likely to be of multifactorial nature including circulatory and metabolic considerations as well as the uncertain consequences of exposure to recurrent hypoglycaemia. Examining a possible association between serum insulin levels and cognitive function, the Rotterdam Study, 5 using mini-mental state scores in an elderly population, observed that raised insulin levels, such as typically seen in response to insulin resistance, were associated with decreased cognitive function and dementia in women, independent of other cardiovascular risk factors. Insulin-resistant brain state A decade ago, challenging the then accepted view that human brain glucose was entirely insulin-independent, Stephanie Amiel’s research group at King’s College Hospital, London, were able to demonstrate, employing autoradiographic technology in human volunteers, that insulin derived from the systemic circulation does access cerebral insulin receptors and exert a significant effect on glucose metabolism within the brain cortex. 6 This research work has continued, examining the relationship between brain glucose metabolism and cerebral function in various ways. In a recent review 7 of current understanding of insulin resistance and brain activity, Amiel observes that not only are there implications in respect of appetite con- trol and obesity, but with ‘the epidemiological evidence linking insulin resistance and type 2 diabetes with demen- tia, the role of insulin in cognitive function offers an excit- ing opportunity for potential new preventative strategies’. On the basis that Alzheimer’s disease and type 2 dia- betes ‘share many age related pathophysiological features’, researchers at the University of Pennsylvania 8 have found evidence of brain insulin resistance associated with reduced central insulin and IGF-1 responsiveness as an early feature in Alzheimer’s disease and cognitive decline, but expressed preference for the term ‘insulin-resistant brain state’ and not type 3 diabetes, as neither hypergly- caemia nor conventional diabetes are consistently found in Alzheimer’s disease, although still recognising that features of metabolic syndrome may be observed in up to two-thirds of Alzheimer’s disease cases. Communicating their findings with Science News, 9 the Pennsylvania team extended their conclusions, commenting that their research studies of post-mortem brain tissue from Alzheimer patients without diabetes had identified ‘exten- sive abnormalities in the [central] activity of two major signaling pathways for insulin and insulin-like growth factor’. They observed that these abnormalities showed significant correlation with episodic memory loss and a number of cognitive disabilities, and postulated that brain insulin resistance may directly contribute to cognitive decline in Alzheimer’s disease, thereby opening a poten- tial therapeutic role for the use of insulin-sensitising drugs in the treatment of Alzheimer’s disease. A toxic cycle The Rhode Island proposal 10 for the term type 3 dia- betes derives from experimental studies in rats with streptozotocin-induced diabetes, demonstrating an association between impaired central insulin signalling 102 PRACTICAL DIABETES VOL. 30 NO. 3 COPYRIGHT © 2013 JOHN WILEY & SONS Leader ‘Type 3 diabetes’: linking a brain insulin-resistant state with dementia and Alzheimer’s disease Ken Shaw
Transcript of ‘Type 3 diabetes’: linking a brain insulin-resistant state with dementia … · 2016-03-14 ·...
‘We propose the term Type 3 Diabetes to reflect this newly identifiedpathogenic mechanism of neurodegeneration.’ de la Monte, 2005.1
At the 60th (June 2000) Annual Scientific Sessions ofthe American Diabetes Association, on an otherwisedismal afternoon in San Antonio, attending
delegates were enthralled by a presentation from Trevor Orchard (University of Pittsburgh) asking themto contemplate a concept of ‘Double Diabetes’, a combi-nation of type 1 diabetes and insulin resistance, so familiar with hindsight and even more so in this modernera. ‘Double Diabetes’ has since been described as type3 diabetes (not to be confused with MODY3), and so theproposal of yet another different form of diabetes alsolabelled as type 3 does create some confusion while atthe same time providing an intriguing insight intopotential shared pathogenic mechanisms between type 2diabetes and Alzheimer’s disease.1
Further publication from the Rhode Island team lastyear2 reiterated that there is ‘growing evidence support-ing the concept that Alzheimer’s disease is fundamen-tally a metabolic syndrome that leads to abnormalitieslinked to progressive brain insulin resistance’ with consequent impairment of central insulin signallingprocesses, accumulation of neuro toxins, neuronal stressand in due course neurodegeneration. The medicalimplications of this proposal received rapid and promi-nent coverage in the popular media, including NewScientist: ‘Food for thought: Eat your way to dementia’.3Having already noted interest in the New Scientist article,this author was then further motivated with the topic following challenge, while captive in the dentist’s chair,with: ‘What is your opinion on the recent Guardiannewspaper article – “Alzheimer’s could be the most cata-strophic impact of junk food”?’4 Clearly, an importantissue has been identified. But within these somewhat sensational speculations, it would appear that insulindoes play a significant role within the brain, and thatabnormalities of allied insulin function may contributeto cognitive decline. Much still remains of a controversialnature and largely derived from experimental investiga-tion, but the science so far does suggest that there is asyndrome of central insulin resistance, similar to thatseen with type 2 diabetes, that may be associated withimpaired cognitive function, including memory loss,learning difficulties and dementia.
Accelerated cognitive decline is sadly a recognisedlong-term complication of diabetes, with causation likelyto be of multifactorial nature including circulatory and metabolic considerations as well as the uncertain consequences of exposure to recurrent hypoglycaemia.Examining a possible association between serum insulinlevels and cognitive function, the Rotterdam Study,5using mini-mental state scores in an elderly population,
observed that raised insulin levels, such as typically seenin response to insulin resistance, were associated withdecreased cognitive function and dementia in women,independent of other cardiovascular risk factors.
Insulin-resistant brain stateA decade ago, challenging the then accepted view thathuman brain glucose was entirely insulin-independent,Stephanie Amiel’s research group at King’s CollegeHospital, London, were able to demonstrate, employingautoradiographic technology in human volunteers, thatinsulin derived from the systemic circulation does accesscerebral insulin receptors and exert a significant effect onglucose metabolism within the brain cortex.6 This researchwork has continued, examining the relationship betweenbrain glucose metabolism and cerebral function in various ways. In a recent review7 of current understandingof insulin resistance and brain activity, Amiel observes thatnot only are there implications in respect of appetite con-trol and obesity, but with ‘the epidemiological evidencelinking insulin resistance and type 2 diabetes with demen-tia, the role of insulin in cognitive function offers an excit-ing opportunity for potential new preventative strategies’.
On the basis that Alzheimer’s disease and type 2 dia-betes ‘share many age related pathophysiological features’,researchers at the University of Pennsylvania8 have foundevidence of brain insulin resistance associated withreduced central insulin and IGF-1 responsiveness as anearly feature in Alzheimer’s disease and cognitive decline,but expressed preference for the term ‘insulin-resistantbrain state’ and not type 3 diabetes, as neither hypergly-caemia nor conventional diabetes are consistently found in Alzheimer’s disease, although still recognising that features of metabolic syndrome may be observed in up totwo-thirds of Alzheimer’s disease cases. Communicatingtheir findings with Science News,9 the Pennsylvania teamextended their conclusions, commenting that theirresearch studies of post-mortem brain tissue fromAlzheimer patients without diabetes had identified ‘exten-sive abnormalities in the [central] activity of two major signaling pathways for insulin and insulin-like growth factor’. They observed that these abnormalities showed significant correlation with episodic memory loss and anumber of cognitive disabilities, and postulated that braininsulin resistance may directly contribute to cognitivedecline in Alzheimer’s disease, thereby opening a poten-tial therapeutic role for the use of insulin-sensitising drugsin the treatment of Alzheimer’s disease.
A toxic cycleThe Rhode Island proposal10 for the term type 3 dia-betes derives from experimental studies in rats withstreptozotocin-induced diabetes, demonstrating an association between impaired central insulin signalling
102 PRACTICAL DIABETES VOL. 30 NO. 3 COPYRIGHT © 2013 JOHN WILEY & SONS
Leader
‘Type 3 diabetes’: linking a brain insulin-resistant state with dementia and Alzheimer’s disease Ken Shaw
PRACTICAL DIABETES VOL. 30 NO. 3 COPYRIGHT © 2013 JOHN WILEY & SONS 103
Leader
mechanisms and altered behaviour in the rats underobservation. Other studies in alloxan-treated diabeticrabbits11 have linked incremental hyperglycaemia withbuild up of beta amyloid proteins, characteristic of theneuropathology seen with Alzheimer’s disease. Indeed,considerable basic science application is currentlyaddressing these complex metabolic inter-relationshipsin this important clinical domain. Drawing from thiscomplexity, and quoting a paper from research workersin Chicago,12 Bijal Trivedi (New Scientist ) describes thedevelopment of a ‘toxic cycle’ with the brain respondingto undue insulin exposure by inducing neuronal insulinresistance and an accumulation of excess beta amyloidprotein, which further increases central insulin resist-ance.3 Again further experimental work,13 observingthat abnormal accumulation of beta amyloid is associ-ated with impairment of neuronal insulin receptor function and central insulin responsiveness, providesadded confirmation of a vicious cycle linking the keypathogenic processes of insulin resistance, neurodegen-eration and dementia.
Therapeutic opportunitiesSo where are these experimental observations leading? Itwould seem that there is now an established body of reasonable evidence indicating a link between braininsulin resistance and the neurodegeneration that char-acterises Alzheimer’s disease. Insulin would appear pivotal and of physiological importance in terms of brainfunction. Insulin does enter the brain and benefits bothlearning and memory, and probably a number of otherimportant cerebral functions as well. Both insulin deficiency and excess insulin exposure are seeminglydetrimental. Much further research work still needs to bedone to extrapolate these implications to clinical prac-tice. The similarities or association with type 2 diabetesare there to be elucidated, but potential therapeuticavenues, including treatment with insulin-sensitisingagents and GLP-1 agonists, are being explored. The popular media placed their prime emphasis on the
modern diet with increased consumption of refined carbohydrate of high glycaemic index being particularlyprovocative of what they have termed ‘insulin surges’.The science linking insulin resistance and dementia isstill work in progress but as the media highlight, there iscertainly ‘Food for Thought’.
Professor Ken Shaw, MA, MD, FRCP, EmeritusProfessor of Medicine, University of Portsmouth, UK; Editor-in-Chief, Practical Diabetes
Declaration of interestsThere are no conflicts of interest declared.
References1. Steen E, et al. Impaired insulin and insulin-like growth factor expression and
signaling mechanisms in Alzheimer’s disease – is this type 3 diabetes? J AlzheimersDis 2005;7(1):63–80.
2. de la Monte SM, et al. Dysfunctional pro-ceramide, ER stress, and insulin/IGF sig-naling networks with progression of Alzheimer’s disease. J Alzheimers Dis 2012;30(Suppl 2):S217–29.
3. Trivedi B. Food for thought: Eat your way to dementia. New Scientist 3 Sept 2012;issue 2880.
4. Monbiot G. Alzheimer's could be the most catastrophic impact of junk food.Guardian 10 Sept 2012.
5. Stolk RP, et al. Insulin and cognitive function in an elderly population. TheRotterdam Study. Diabetes Care 1997;20(5):792–5.
6. Bingham EM, et al. The role of insulin in human brain glucose metabolism: an 18fluoro-deoxyglucose positron emission tomography study. Diabetes2002;51(12): 3384–90.
7. Hunt KF, et al. Brain Insulin Resistance. In The Metabolic Syndrome, 2nd edn. ByrneCD, Wild SH (eds). Blackwell Publishing Ltd, 2011. Chapter 9.
8. Talbot K, et al. Demonstrated brain insulin resistance in Alzheimer’s diseasepatients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitivedecline. J Clin Invest 2012;122(4):1316–38.
9. Brain insulin resistance contributes to cognitive decline in Alzheimer’s disease.Science News 23 March 2012.
10. de la Monte SM, Wands RJ. Alzheimer’s disease is type 3 diabetes – evidencereviewed. J Diabetes Sci Technol 2008;2(6):1101–13.
11. Bitel CL, et al. Amyloid-β and tau pathology of Alzheimer’s disease induced by diabetes in a rabbit animal model. J Alzheimers Dis 2012;32(2):291–305.
12. Farris W, et al. Insulin-degrading enzyme regulates the levels of insulin, amyloidbeta-protein, and the beta-amyloid precursor protein intracellular domain in vivo.Proc Natl Acad Sci U S A 2003;100(7):4162–7.
13. Chen Y-H, et al. Amyloid beta oligomers induce impairment of neuronal insulinreceptors. FASEB J 2008;22(1):246–60.
Diabetic Foot Master Class Weston Education Centre, King’s College Hospital, LondonFriday 14th June, 2013
The Modern Approach to the Diabetic Foot Patient with Vascular Compromise In this Masterclass, we emphasise both the treatment of the ischaemic foot/lower limb, as well as the control of theother risk factors for ischaemia. There will be a combined focus on reducing the mortality of the patient as well as themorbidity of the foot.
This conference is free to attend, with CPD points available. For further information or for details of how to register, please contact Christian Pankhurst on: [email protected] or [email protected]
King’s College HospitalNHS Foundation Trust
Guy’s and St Thomas’NHS Foundation Trust
The sessions will address: ● Clinical tests and diagnostics ● Vascular lab assessment ● Acute and Community management ● Casting the ischaemic foot
● Vascular intervention ● Recent NICE guidelines on Peripheral Vascular Disease ● General medical management of the ischaemic patient ● The management of ischaemic pain ● Antibiotic management of the infected ischaemic foot
