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Adeli Lab


Mechanisms of Diabetic Dyslipidemia: Animal Models of Obesity & Diabetes

Insulin resistance is an extremely common pathophysiological trait that is implicated in the development of a number of important human diseases including type 2 diabetes, obesity, atherosclerosis, hypertension, and dyslipidemia. The atherogenic dyslipidemia commonly associated with insulin resistant states consists of hypertriglyceridemia, high levels of very low density lipoproteins, low levels of HDL cholesterol, and small, dense LDL.

Metabolic dyslipidemia associated with insulin resistant states such as type 2 diabetes is a key contributing factor in the significantly higher rate of cardiovascular complications in these patients. Our laboratory has recently developed and characterized a diet induced animal model of insulin resistance, the fructose-fed Syrian golden hamster.

Over the past two years, our laboratory has been investigating the mechanisms of lipoprotein (very low density lipoprotein, VLDL) overproduction in the fructose-fed Syrian golden hamster. This animal model has allowed us to gain considerable insight into the molecular and cellular mechanisms that may mediate the VLDL overproduction observed in insulin resistant states. Details of our findings can be found in the attached publications/manuscripts and in the progress report. Fructose feeding for a two week period induced significant hypertriglyceridemia and hyperinsulinemia, and the development of whole body insulin resistance. Induction of insulin resistance was accompanied by a considerable rise in hepatic VLDL-apoB and VLDL-triglyceride production. Enhanced apoB secretion appeared to be caused by increased intracellular stability of apoB, elevated levels of MTP (microsomal triglyceride transfer protein), and enhanced assembly of VLDL particles.

Control studies showed that these changes were induced by insulin resistance rather than being direct effects of fructose itself. More recently, we investigated hepatic insulin signaling in the fructose-fed hamster model to establish whether hepatic insulin resistance was present and the potential contribution of attenuated insulin signaling to the VLDL overproduction in this model. In brief, we obtained considerable evidence for hepatic insulin resistance including reduced tyrosine phosphorylation of the insulin receptor and insulin receptor substrate (IRS-1), elevated protein mass and activity of PTP-1B (a protein tyrosine phosphatase that inhibits insulin signaling), and suppressed activity of PI 3-kinase (a lipid kinase mediating the metabolic actions of insulin) associated with IRS proteins.

Importantly, changes in the insulin signaling pathway coincided with drastic suppression of ER-60, a cysteine protease previously shown to be associated with apoB in HepG2 cells. These changes were also accompanied by an increase in the synthesis and secretion of apoB.

Based on the above studies, we now have a better understanding of the mechanisms underlying the overproduction of VLDL in insulin resistant states. These findings were recently published in J. Biol. Chem. and have received considerable attention in the lipoprotein community. This work is funding by an operating grants from the Canadian Institutes of Health Research (CIHR) and the Heart and Stroke Foundation of Ontario).