Type 2 diabetes and heart disease: all roads lead through altered insulin signaling

Townsend Letter for Doctors and Patients,  May, 2007  by Jeffrey Bland

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Type 2 diabetes presents itself as a clear example of a disease that is defined by the individual's dysfunctional relationship between their genes and their diet, lifestyle, and environmental exposures. (1) Type 2 diabetes is a progressive disorder that starts as dysfunctional insulin signaling and progresses through various stages of metabolic syndrome/hyperinsulemia/insulin resistance until it finally results in loss of endocrine pancreatic beta cell function and insulin secretory ability. As it progresses to greater states of impairment of insulin signaling, multiple pathophysiological processes can develop including cardiovascular disease, hypertension, neurological deficits, fatty liver disease (i.e., NASH), chronic renal disease, and even the risk to certain cancers such as those of the colon, breast, and prostate. The clinical manifestations of the early signs of this progression include not only elevated fasting and postprandial insulin levels, but also elevated fasting triglycerides, low HDL cholesterol, hypertension, hyperuricemia, and increased visceral obesity.

Recently, SM Grundy at the University of Texas Southwestern Medical Center has commented that most current recommendations for the management of cardiovascular risk factors focus on relatively short-term risks. Metabolic syndrome represents a longer-term risk factor for cardiovascular disease that lies outside the traditionally accepted cardiovascular disease risk factors. He states, "Approximately one-third of an apparently healthy population is sufficiently insulin-resistant to be at increased risk to develop a variety of adverse clinical outcomes that now include Type 2 diabetes, CVD, essential hypertension, polycystic ovary disease, nonalcoholic liver disease, several forms of cancer, and sleep-disordered breathing." (2) He goes on to state that the greatest potential for progress in reducing the risk for cardiovascular disease is related to a clinical focus on metabolic syndrome and a complex multicomponent disorder, rather than a primary focus on the treatment of the each of the specific signs and symptoms associated with insulin resistance and compensatory hyperinsulemia.

The question then becomes how to recognize the presence of metabolic syndrome and dysfunctional insulin signaling before it results in end-organ pathology and a definitive disease. Recently, it has been suggested that the best prognostic marker for early-stage physiological dysfunction associated with insulin resistance is the alteration of the apolipoprotein B and apoliprotein A-1 levels in the serum. (3) Atherogenic dyslipidemia associated with dysfunctional insulin signaling is an important early marker for metabolic syndrome. It is not only related to elevated fasting triglycerides and a lowered HDL cholesterol, but also an alteration in apolipoprotein B and A-1 levels.

Apolipoprotein B is the transport protein manufactured in the liver in response to various hormonal messages. It is the protein scaffold that makes up the potentially atherogenic dense LDL particles, whereas apolipoprotein A-1, which is also manufactured in the liver, serves as the lipoprotein that makes up HDL and is involved with cholesterol efflux out of the arterial wall and tissues. (4) Both these lipoproteins are under both genetic and diet, lifestyle, and environmental controls. It has been well-established that an elevated apolipoprotein B to apolipoprotein A-1 ratio is an important determinant of cardiovascular disease risk independent of total serum cholesterol levels. (5)

The rationale for using apolipoprotein B to apolipoprotein A-1 ratios as indicators of cardiac and dysfunctional insulin signaling risks results from recently published prospective risk studies. (6) These lipid-lowering trials indicate that the apo B/apo A-1 ratio is a useful summary index of risk and that it is better than the conventionally used LDL-cholesterol measurements and various other lipid ratios. The apo B/apo A-1 ratio can be determined in non-fasting blood, which provides some additional advantage over the use of LDL, HDL, and total cholesterol as CVD risk factors that require the patient to be fasted to obtain accurate values. There is now compelling evidence that the apo B/apo A-1 ratio is a strong risk factor for cardiovascular disease and that the lower the ratio, the lower the risk to CVD. (7) A ratio of apoB/apo A-1 of 0.7 or lower would be considered lower risk, whereas a ratio of 0.8 or higher would represent an elevated risk. (5)

More importantly, the apoB/apo A-1 is a very sensitive indicator of the alteration in insulin signaling and provides an early warning prognosis of risk associated with metabolic syndrome that may be superior to any other common biochemical marker. (8)

The alterations in apo B levels have been identified as associated with dysfunctions in insulin that are modulated through alterations in insulin receptor substrate 1 (IRS-1) and phosphoinositol-3-kinase (PI3k) activity. (9) There is evidence that agents that can partially inhibit PI3k activity in states of dysfunctional insulin signaling result in lower apo B levels and a reduction in the pathology associated with metabolic syndrome. (10)