INSULIN RESISTANT BRAIN STATE AND DIABETES MELLITUS − Rakyat Biologi

Type 2 diabetes mellitus is associated with dysfunction of insulin intracellular signal transduction due to the cell does not couple insulin binding to IR with activation of the particular cell function, i.e. cell becomes resistant to the action of insulin. The intriguing question is whether peripheral insulin resistant state (type 2 diabetes) and central insulin resistant states (presented here as e.g. aging and sporadic Alzheimer’s disease) are two different, separated entities or just one condition that, like in the physics “Law of connected containers”, metaphorically speaking, can “overflow” from one container to another. In other words, does peripheral insulin resistance lead to development of central insulin resistance and vice versa? Due to insufficient level of current knowledge, answers to these questions could only be speculative ones.

Growing evidence indicates that these conditions may be connected; effects of diabetes and aging on the brain may interact, and both conditions may interact with the appearance of sporadic late-onset Alzheimer’s disease (8). Summarizing the aforementioned data, brain glucose metabolism and insulin signal transduction in the brain seem to be the interconnecting link. Decreased brain glucose metabolism and decreased brain insulin content have been demonstrated in diabetes (1) as well as in aging and in the sporadic Alzheimer’s disease, accompanied by dysfunction of brain IR signalling cascade (31). Disturbances in transducing the signal from IR to the intraneuronal structures in the brain can be caused by various factors that may inhibit the tyrosine phosphorylation of IRSs and PI3 kinase subunits, among which advanced glycation end products (AGEs) and oxidative stress were frequently mentioned (10,27,70). AGEs have been generated by glucose-induced reaction of glycation of long-lived macromolecules and tend to accumulate both in the periphery and in the brain with aging, as well as in diabetes and in Alzheimer’s disease (52,81,87). During the formation of AGEs free radicals are produced, and they all may interfere with the IR functioning and signal transduction by diminishing the tyrosine phosphorylation of IRS-1/2, which then is unable to activate PI3 kinase – PKB/Act pathway, leading to altered glucose/glycogen metabolism and insulin resistance (32). Contributing factor could also be oxidative stress mediated by free radicals (10). Preclinical and clinical data demonstrate that aging, diabetes and Alzheimer’s disease are all associated with increased oxidative stress both at the periphery and in the CNS (41,53,70). Chronic oxidative stress may cause chronic oxidizing of tyrosine phosphatase PTP-1B, enzyme that dephosphorylates IR tyrosine residues and reduces its activity, leading thus to insulin resistance (32). In the context of human aging, an association between the IR and the longevity can be drawn, since altered IR signaling and marked insulin resistance are associated with physiological aging. This may suggest that not only aging increases the risk for type 2 diabetes, but also that type 2 diabetes may lead to premature aging (32).

Increasing evidence supports the hypothesis that type 2 diabetes may increase the risk for Alzheimer’s disease. This involves not only those at the signal transduction level representing insulin resistance and those at the behavioural level representing cognitive deficits, but also at the morphological level demonstrating hippocampal and amygdalar atrophy on magnetic resonance imaging (which is a good, early marker of the degree of Alzheimer’s neuropathology) in type 2 diabetic patients (23), and at the structural level, demonstrating deposits of islet amyloid polypeptide in pancreas of diabetic patients, that share a 90% structural similarity with APP which forms deposits in brain of patients with Alzheimer’s disease. Conversely, patients with Alzheimer’s disease have an increased risk for aberrations in peripheral glucose metabolism exhibiting less efficient glucoregulation with slightly but significantly decreased basal arterial glucose concentration and increased plasma insulin concentration resembling partly to the type 2 diabetes condition (15,20). Another study also suggested that patients with Alzheimer’s disease may have abnormal insulin activity in the CNS as well as at the periphery (21).

Regardless the cause, insulin resistance in the brain leads to brain insulin dysfunction. Cognitive deficits, particularly manifested as memory and learning deficits, are well known and documented in relation to age and Alzheimer’s disease as well, and it has been demonstrated that insulin administration can facilitate memory in such individuals (100). Cognitive impairments associated with diabetes mellitus have been reported more consistently in type 2 diabetes characterised by increased insulin resistance, and individuals suffering from type 2 diabetes show an increased prevalence of dementia (19,79). Memory deficits are not usually evident in insulin-dependent type 1 diabetes in humans, and if they occur, are often associated with hypoglycaemia (80,88). In experimental type 1 (streptozotocin-induced) diabetes cognitive deficits have not been consistently reported (9). However, duration and severity dependent distinct changes in hippocampal synaptic plasticity, associated with deficits in NMDA-dependent long-term potentiation probably related to insulin dysfunction, have been reported in streptozotocin-diabetic animals (40).

Beside cognitive deficit discrepancies between type 1 and type 2 diabetes, in general similar changes of monoaminergic neurotransmission at the neurochemical level were observed in streptozotocin-diabetic animals (representing type 1 diabetes) and in streptozotocin-intracerebroventricularly (icv) treated animals (representing an experimental model for sporadic Alzheimer’s disease and brain type 2 diabetes) (54,55,93-96). However, while changes of monoamines and their metabolite content, monoamine turnover rate, as well of monoamine synaptic transporters and dopaminergic receptors were irreversible and tend to progress with the duration of streptozotocin-induced diabetes, in streptozotocin icv-treated animals they seem to be reversible. Bearing in mind that streptozotocin is selectively toxic for insulin producing/secreting cells (92), and that insulin (possibly co-localised in catecholamine-containing neurons) has a neuromodulatory role in synaptic monoaminergic transmission (83,102), these results may suggest similar, insulin-related mechanism of induction the neurochemical changes in brain (at least at the level of monoamine transmission), regardless whether peripheral or central insulin-producing cells have been affecting. The tendency of reversibility of streptozotocin icv-induced changes may suggest that either the damage of brain producing/secreting cells alone is not enough for brain insulin dysfunction to be persistent, or that brain cell damage can somehow be compensated (reversibility depending possibly on streptozotocin dose, or other mechanisms including molecules that share the signalling pathway with insulin, like IGF-1).

Molecular biology and genetic studies give support to the hypothesis that brain insulin dysfunction could have consequences spreading to the periphery, as well. Neuron-specific disruption of the IR gene in mice results in development of diet-sensitive obesity with increases in body fat and plasma leptin levels, insulin resistance, hyperinsulinemia and hypertriglyceridemia, features seen in type 2 diabetes (14). The phenotype of a knock-out mouse model lacking the IRS-2 is similar to model with neuron-specific deletion of IR characterized by increased food intake, body fat content and impaired hypothalamic control of reproduction (16,36). Very recent data indicated that conditional knockout of IRS-2 in mouse pancreas β cells and parts of brain including hypothalamus caused obesity and insulin resistance that progressed to diabetes (58).However, diabetes resolved when functional β cells expressing IRS-2 repopulated the pancreas, restoring sufficient β cell function to compensate for insulin resistance, supporting the aforementioned hypothesis about possible compensation of function/structure of damaged insulin producing/secreting cells in the brain. Furthermore, insulin infusion in the third cerebral ventricle suppresses glucose production at the periphery independent of circulating levels of insulin, which suggests that hypothalamic insulin resistance can contribute to hyperglycemia that may lead to type 2 diabetes (36,73). This indicates that a decrease in the IR number, defects in IR function and signaling, and insulin lack or resistance in the brain may lead to the development of type 2 diabetes even when pancreatic β-cells are normal.