| HOME | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|---|
| ||||||||||||||
COMMENTARY |
GRECC, Veterans Affairs Medical Center–St. Louis.Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, Missouri.
DEPRESSION, cognitive impairments, and diabetes mellitus are increasingly recognized to be associated (1–3). The hypothesis of Rasgon and Jarvik (4) attempts to link these conditions through the mechanisms of insulin resistance and impaired glucose utilization. Specifically, the theory gives center stage not to the peripheral pools of insulin and glucose, but to those of the central nervous system (CNS). This theory, then, resonates with a number of other theories for various disease states that emphasize a role for peptides or regulatory proteins produced in one compartment (e.g., by peripheral tissues) affecting the function of the other compartment (i.e., the brain). Such theories date back to at least the mid-seventies when peptides first discovered in one compartment were later found in another. The first of these discoveries related to cholecystokinin. First discovered in the gastrointestinal tract as a stimulus for gallbladder contraction, it was later discovered in the brain (at first misidentified as gastrin). This led to the postulation of gut–brain axes in which these molecules somehow interacted (5,6). However, acceptance of such theories was a long time in coming, in part because it was unclear by what mechanism such an axis would act. The idea that peptides might cross the blood–brain barrier, proposed by Kastin for small peptides in 1975 and by Woods for insulin in 1977 (7,8), was largely rejected. Today, it is well established that many small peptides and regulatory proteins, including insulin (9), are transported across the blood–brain barrier in relevant amounts. It is also clear that other mechanisms, such as stimulation of afferent vagal fibers, can be used by peripheral peptides and regulatory proteins to affect brain function (10).
One of the intriguing aspects of the Rasgon–Jarvik hypothesis is that it points out how little we know about how the brain works. For example, although type 2 diabetes is associated with resistance at the peripheral insulin receptor, it is unknown whether the CNS insulin receptor is also dysfunctional. A related question is where exactly would CNS resistance to insulin occur. In traditional resistance syndromes affecting peripheral tissues, the problem is at the receptor or postreceptor level of the target tissue. But in the CNS, two other levels can be involved. Because the blood–brain barrier must transport insulin into the brain, failure of the transporter would produce a resistance-like syndrome. Indeed, as recently reviewed, the leptin resistance of obesity is likely partially caused by a failure of the blood–brain barrier transporter for leptin (11). Another level of failure that would look very "postreceptor" would be a lesion anywhere along the cascade of events leading to the final endpoint. In peripheral resistance syndromes, often only two or three tissues are involved in the regulatory portion of the feedback loop (e.g., in the hypothalamic-pituitary-adrenal axis). But in the CNS, whole networks can be involved in that process. For example, failure of the melanocortin-4 receptor can produce an obesity that looks like a leptin resistance (12).
Whether insulin resistance occurs in the CNS is a critical question for the interpretation of the "impaired glucose utilization" aspect of the Rasgon and Jarvik hypothesis. The paradox of diabetes mellitus is that, although a state of hyperglycemia exists, the insulin-sensitive cells are essentially responding as if they are in a hypoglycemic state. Therefore, whether insulin-sensitive CNS tissues are responding to the hyperglycorrhachia, which truly exists, or a perceived hypoglycorrhachia depends on the extent to which they are insulin resistant. No matter the situation for the receptor proteins, the other proteins in contact with brain interstitial fluid and cerebrospinal fluid are exposed to elevated glucose levels. Glycosylation of CNS proteins is a real concern.
Whether alterations in CNS insulin and glucose levels would result in depression is unclear. Lack of glucose in the CNS is lethal, thus no natural conditions as such exist. Harik and colleagues have described a family with reduced activity of GLUT-1, the protein that transports glucose across the blood–brain barrier, that have mental retardation (13). CNS insulin has actions that are paradoxic to those of blood-borne insulin, such as increasing serum glucose and suppressing feeding. Insulin, by producing within the brain actions opposite to those it produces at peripheral tissues, may act as its own counter-regulatory hormone (14). Insulin also shares a catabolic enzyme with amyloid beta protein, the substance thought to play a causal role in Alzheimer's disease. By competitive inhibition of enzyme activity, elevations of CNS insulin may lead to elevations of amyloid beta protein.
Several other mechanisms could be considered in light of the Rasgon–Jarvik hypothesis, but space must allow reflection upon at least one more. Persons with type 2 diabetes mellitus are often obese. Fat is no longer considered a silent tissue, but is now known to release numerous substances. Leptin, adiponectin, resistin, adipsin, agouti protein, and proinflammatory cytokines are among those substances. Depression, inflammatory molecules, and obesity have been linked with one another and with another common problem: cardiovascular disease (15).
In summary, the Rasgon–Jarvik hypothesis illustrates that we now know that many things once thought to be separate are really interconnected. The task before us is to learn how they are connected and how to use that knowledge to improve health.
Acknowledgments
Address correspondence to William A. Banks, MD, Division of Geriatric Medicine, Saint Louis University School of Medicine, 915 N. Grand Blvd., St. Louis, MO 63106. E-mail: bankswa{at}slu.edu
REFERENCES
| ||||||||||||||
| HOME | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|---|
