Saturday, October 10, 2009

3. The Basic Problem: Impaired Glucose Uptake

My research on homeostasis, the process by which the body manages its energy needs, leads me to conclude that a person who suffers from calcium and vitamin D deficiency is operating under an unusual set of rules for energy management. Energy management is a crucial component of all cell metabolism. Any work that a cell does consumes energy, and this energy is supplied by either fatty acids, in the form of triglycerides (derived from dietary fat or supplied by fat cells on the body) or from glucose (derived from carbohydrates and proteins or supplied from temporary stores in the liver). While muscle cells can typically store a small amount of fuel locally, these local stores are quickly depleted during intense exercise. New supplies of nutrients are then extracted from the blood stream. The levels of glucose and triglycerides in the blood are constantly monitored and adjusted based on complex chemical signaling, to maintain sufficient supplies to all the body's cells.

The basic problem that a person with metabolic syndrome faces is an impaired ability for glucose to enter muscle cells [13] (Details) . Critically, this includes the heart muscle. Glucose transport is inhibited because the cell has an inadequate supply of calcium [27] and vitamin D [2][3][28] (Details) . These two nutrients are both critical for the pancreas to release insulin into the blood. Insulin in turn stimulates glucose uptake in the muscle cells [7]. Calcium is also critical for the migration of the catalyst GLUT4 to the membrane of the cell [21][36], where it orchestrates the transfer of glucose across the membrane, providing energy to the cell.

The muscle cell consumes energy when it contracts. The source of this energy is adenosine triphosphate (ATP), which releases energy through a chemical process that converts it to adenosine monophosphate (AMP). The energy that is released when the ATP is converted to AMP fuels muscle contraction. The cell's mitochondria are able to convert AMP back to ATP (to be recycled) by consuming either glucose or fat. When there is not enough fuel to convert AMP back to ATP, the ratio of AMP to ATP builds up. The ratio of AMP to ATP within the cell is a measure of its energy state, and is used by many different types of cells in the body to detect energy shortages and trigger corrective measures.

As the muscle cell exhausts its internal stores of energy, it attempts to draw in more glucose from the blood. An impaired glucose transport mechanism inhibits this process. As a consequence, the ratio of AMP to ATP in the cell steadily rises, activating a powerful regulating peptide secreted by the cell, known as AMPK. AMPK in the muscle cell promotes the movement of GLUT4 to the membrane, even in reduced insulin contexts [33]. With GLUT4 at the cell membrane the cell can now begin to draw upon the glucose and insulin supplies in the blood.

At this point, several things happen to counteract the falling level of blood glucose, which is detected by the pancreas and hypothalamus. They emit hormones and peptides that signal the body to replenish glucose levels in the blood. The alpha cells in the pancreas react by secreting glucagon, a hormone that triggers the liver to convert its stores of glycogen into glucose and release it into the blood stream. Similar glucose-sensing cells in the hypothalamus increase the appetite and stimulate the person to consume food, in order to replenish the supplies being drawn down in the liver.

Both of these glucose sensing mechanisms (in the hypothalamus and in the pancreas) depend on AMPK, and both involve a rush of calcium into the cell as part of their signaling cascade [27] (Details) . I hypothesize that deficiencies in calcium cause these glucose sensing mechanisms to detect low glucose levels internally even when glucose levels in the blood are still reasonably high. This is in fact an intelligent design, to tie their glucose-sensing mechanisms to those of the muscle cells, because, if the muscle cells can't absorb glucose efficiently, it is in some sense equivalent to having low blood glucose.

Thus, due to poor glucose uptake, the set point for the blood levels of glucose is maintained at an artificially high level. This is because poor uptake can be somewhat compensated for by elevating the concentration in the blood. Eating easily processed sugars and starches is the most effective way to quickly satisfy the cravings caused by poor glucose uptake. While the higher levels of glucose help to satisfy the muscles' needs, the glucose is also available to the fat cells, which feed on the excess sugars and store them as fats. Over time, sustained high blood sugar leads to chronic weight gain, diabetes, and heart disease.

Correcting the underlying glucose uptake problem will require long-term dietary changes which I will later describe. But first, I would like to explain some of the biological processes involved in food metabolism and weight, and show how the body tries to compensate for malfunctioning glucose uptake.

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