Type 3 diabetes: Do you have diabetes on the brain?

Posted on Sun, 15 Jan 12

Emerging evidence suggests that depression, cognitive decline with age and Alzheimer’s disease may actually be symptoms of a new kind of diabetes that affects the brain; type 3 diabetes.

The term type 3 diabetes was first coined by Suzanne de la Monte, MD, MPH, Associate Professor of Pathology and Medicine at Brown Medical School after her team discovered that sufferers of Alzheimer’s disease had an 80% decrease in the hormone insulin in the brain compared to otherwise healthy subjects (1).

Until relatively recently it was thought that the brain was in a privileged position whereby it could simply obtain sugar (glucose) for energy production as needed. However, it is now know that like other areas of the body the brain can develop insulin resistance, the same phenomena that underlies type 2 diabetes, which in turn affects energy supply and may have more serious deleterious consequences over time.

Diabetes on the brain

For some time there has been an association between diabetes and cognitive function. For example type 2 diabetes has been associated with behavioural problems such as depression and cognitive deficits, including learning and memory, intelligence, and executive functioning (2). And the link between type 2 diabetes and behavioural and cognitive function appears to be more than just an association; the same metabolic changes that underlie diabetes may be directly damaging the brain.

Magnetic imaging resonance (MRI) studies have found that even well controlled type 2 diabetes is associated with destruction of the hippocampus (3). The hippocampus is a brain region involved in higher cognitive functions such as memory so perhaps not surprisingly MRI results also correlated with poor memory function. 

And remarkably, type 3 diabetes may occur in the absence of type 2, as a unique and independent disease entity (7). What is going on in the type 3 diabetic brain then?

Insulin as a neurotransmitter

Insulin is not simply a regulator of blood glucose, in the central nervous system (CNS) insulin is better categorised as a neurotransmitter much like serotonin or dopamine. The insulin receptor is found in the CNS, including the areas of the brain such as the cerebellum, hypothalamus and the hippocampus where it is proposed to participate in a variety of functional activities including cognition (4).

Interestingly administration of insulin has been shown to improve cognitive performance in humans and animals in a wide variety of settings, including healthy subjects, aged subjects, Alzheimer's disease patients and in experimental models of insulin resistance.

Considering the role of insulin in cognition it should not be entirely surprising to learn that insulin resistance develops during the early course of cognitive decline and Alzheimer’s disease and is directly related to the severity of neurodegeneration (5).

Sugar coated but toxic

One of the primary consequences of insulin resistance is hyperglycaemia which when present in the brain is particularly toxic. Elevated levels of glucose in the brain impair the ability of nerve cells to function, repair and regenerate, all fundamental determinants of cognitive health (4).

Elevated brain glucose as a consequence of insulin resistance increases oxidative stress which can damage brain tissue and glucose itself may act as a direct neurotoxin. A recent review in Nature Reviews in Neuroscience summarised this well;

“Neurons have a constantly high glucose demand, and unlike muscle cells they cannot accommodate episodic glucose uptake under the influence of insulin. Neuronal glucose uptake depends on the extracellular concentration of glucose, and cellular damage can ensue after persistent episodes of hyperglycaemia — a phenomenon referred to as glucose neurotoxicity (6).”

So insulin resistance in the brain may impair cognitive function which is further exacerbated by elevated glucose which is directly neurotoxic. This understanding then opens a unique opportunity for improving behaviour, mood, memory and cognitive function by improving brain glucose control.

Sensitive mind 

Preliminary evidence suggests that medicines that improve insulin sensitivity may improve cognitive function in Alzheimer’s disease (7). A primary candidate for improving brain glucose control and cognitive function is the nutritional supplement Lipoic acid.

Lipoic acid readily crossed the blood brain barrier, has antioxidant effects, may play a role in repair of neuronal damage by stimulating brain growth factors as well as improving insulin resistance (8). Human clinical studies suggest lipoic acid improves insulin sensitivity in type 2  diabetes and although evidence is limited preliminary studies suggest lipoic acid may also improve cognitive function (9).

A small pilot study in nine patients with Alzheimer’s disease or other dementias found that lipoic acid at a dose of 600 mg per day for one year appeared to improve cognitive function or slowed disease progression (10). In a follow up study with forty three patients it was found that lipoic acid therapy for 48 months stabilized cognitive function and slowed dementia progression at a rate far greater than currently available medications (11).

Brain food

In addition to insulin sensitizing agents like lipoic acid it is entirely plausibly that dietary approaches designed to improve insulin resistance could improve brain insulin sensitivity, cognitive function and prevent type 3 diabetes.

Experimentally a western highly refined diet has been shown to be toxic to the brain. Rats fed with a diet high in saturated fats and simple sugars, and water supplemented with high-fructose corn syrup (to mimic soft drink and sweetened fruit juice) exhibited increased fasting blood glucose levels, impaired learning and neurological function and reduced levels of brain growth factors (12). This suggests potent effects of poor dietary patterns on brain function.

Accordingly people with type 2 diabetes have been shown to have reduced mental and cognitive function after high glycaemic index meals suggesting diet does indeed play a role in humans too (13).

Lower glycaemic index foods may thus help stabilize brain glucose levels and improve type 3 diabetes. Further, foods that are rich in vitamins, minerals and phytochemicals, such as minimally processed plant foods, may also enhance brain glucose metabolism and insulin signalling (14).

For example, supplementation with foods particularly rich in phytochemicals such as wild blueberries and apple juice have shown promise as ways to clinically improve cognition, memory, behaviour and mood in human studies (15-16). 

A new perspective

The discovery that cognitive decline, memory impairment and changes in mood and behaviour are characterised and may be a direct consequence of impaired brain insulin sensitivity opens the door for new therapeutic approaches. Insulin sensitizing agents such as lipoic acid, low glycaemic index dietary regimes and enrichment of the diet with foods particularly high in phytochemicals may emerge as effective ways to combat type 3 diabetes.

But perhaps even more important is the finding that impaired glucose tolerance may be risk factor for (and cause of) cognitive and behavioural changes with age, This discovery should pave the way for the new approaches to the early detection and prevention of dementia and Alzheimer’s disease centred on healthy blood glucose control.

References:

1. Kroner Z. The relationship between Alzheimer's disease and diabetes: Type 3 diabetes? Altern Med Rev. 2009 Dec;14(4):373-9.

2. Starr VL, Convit A. Diabetes, sugar-coated but harmful to the brain. Curr Opin Pharmacol. 2007 Dec;7(6):638-42.

3. Gold SM, Dziobek I, Sweat V, Tirsi A, Rogers K, Bruehl H, Tsui W, Richardson S, Javier E, Convit A. Hippocampal damage and memory impairments as possible early brain complications of type 2 diabetes. Diabetologia. 2007 Apr;50(4):711-9.

4. Reagan LP, Grillo CA, Piroli GG. The As and Ds of stress: metabolic, morphological and behavioral consequences. Eur J Pharmacol. 2008 May 6;585(1):64-75.

5. Rivera EJ, Goldin A, Fulmer N, Tavares R, Wands JR, de la Monte SM. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer's disease: link to brain reductions in acetylcholine. J  Alzheimers Dis. 2005 Dec;8(3):247-68.

6. Tomlinson DR, Gardiner NJ. Glucose neurotoxicity. Nat Rev Neurosci. 2008 Jan;9(1):36-45.

7. de la Monte SM, Wands JR. Alzheimer's disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol. 2008 Nov;2(6):1101-13.

8. Maczurek A, Hager K, Kenklies M, Sharman M, Martins R, Engel J, Carlson DA, Münch G. Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer's disease. Adv Drug Deliv Rev. 2008 Oct-Nov;60(13-14):1463-70.

9. Singh U, Jialal I. Alpha-lipoic acid supplementation and diabetes. Nutr Rev. 2008 Nov;66(11):646-57.

10.Hager K, Marahrens A, Kenklies M, Riederer P, Münch G. Alpha-lipoic acid as a  new treatment option for Alzheimer [corrected] type dementia. Arch Gerontol Geriatr. 2001 Jun;32(3):275-82. Erratum in: Arch Gerontol Geriatr. 2010 Jul-Aug;51(1):110.

11.Hager K, Kenklies M, McAfoose J, Engel J, Münch G. Alpha-lipoic acid as a new  treatment option for Alzheimer's disease--a 48 months follow-up analysis. J Neural Transm Suppl. 2007;(72):189-93.

12.Stranahan AM, Norman ED, Lee K, Cutler RG, Telljohann RS, Egan JM, Mattson MP. Diet-induced insulin resistance impairs hippocampal synaptic plasticity and cognition in middle-aged rats. Hippocampus. 2008;18(11):1085-8.

13.Papanikolaou Y, Palmer H, Binns MA, Jenkins DJ, Greenwood CE. Better cognitive performance following a low-glycaemic-index compared with a high glycaemic-index  carbohydrate meal in adults with type 2 diabetes. Diabetologia. 2006 May;49(5):855-62.

14.Gómez-Pinilla F. Brain foods: the effects of nutrients on brain function. Nat Rev Neurosci. 2008 Jul;9(7):568-78.

15.Remington R, Chan A, Lepore A, Kotlya E, Shea TB. Apple juice improved behavioral but not cognitive symptoms in moderate-to-late stage Alzheimer's disease in an open-label pilot study. Am J Alzheimers Dis Other Demen. 2010 Jun;25(4):367-71.

16. Joseph JA, Shukitt-Hale B, Willis LM. Grape juice, berries, and walnuts affect brain aging and behavior. J Nutr. 2009 Sep;139(9):1813S-7S.