The Triad of Diet, Obesity, and Insulin Resistance: Molecular and Cellular Mechanisms
Andrew S. Greenberg, Susan K Fried
JM-USDA HNRCA at Tufts University, Boston, MA and University of Maryland, Baltimore, MD
One of the major metabolic problems facing aging individuals is the
regulation of glucose homeostasis. Both insulin sensitivity and
adequacy of insulin secretion can be affected during the aging process.
Insulin sensitivity may be regulated and/or decreased by alterations in
body composition. Increases in fat mass and/or fat redistribution may
promote insulin resistance. Insulin resistance appears to be a central
component of the metabolic syndrome, which appears to affect
approximately 40% of individuals over the age of 60 years. The
metabolic syndrome is increasing at an alarming rate and is a major
risk factor for heart disease. As a result of alterations in body
composition, adipocyte metabolism may become dysregulated. Enlarged fat
cells produce less perilipin and adiponectin but increased quantities
of interleukin-6 (IL-6) and tumor necrosis factor (TNF). Perilipin,
which coats the surface of intracellular triacylglycerol in adipocytes,
blocks the lipolytic actions of lipases. Enlarged adipocytes have
reduced perilipin protein levels, which may facilitate increases in
fatty acid release (FA). Increased circulating FA promotes insulin
resistance in skeletal muscle and liver. Both adiponectin and IL-6 act
as hormones released by adipocytes. Adiponectin increases oxidation of
fatty acids in peripheral tissues. IL-6 increases adipocyte lipolysis
and block insulin actions in peripheral tissues. Thus a reduction in
adiponectin and increased production of IL-6 both promote insulin
resistance. TNF appears to act locally in adipose tissue and increases
adipocyte lipolysis. Regulation of fatty acid metabolism appears to be
a critical regulator of insulin sensitivity. The mechanisms that
underlie the reduction in insulin secretion with aging remain unclear.
Thus actions to maintain fatty acid homeostasis are critical in
preventing insulin resistance and countering any reduced insulin
secretory capacity that may be associated with aging.
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