Background

Non-human primates are valuable models for the study of insulin resistance and human obesity. In baboons, insulin sensitivity levels can be evaluated directly with the euglycemic clamp and is highly predicted by adiposity, metabolic markers of obesity and impaired glucose metabolism (i.e. percent body fat by DXA and HbA1c). However, a simple method to screen and identify obese insulin resistant baboons for inclusion in interventional studies is not available.

Methods

We studied a population of twenty baboons with the euglycemic clamp technique to characterize a population of obese nondiabetic, insulin resistant baboons, and used a multivariate linear regression analysis (adjusted for gender) to test different predictive models of insulin sensitivity (insulin-stimulated glucose uptake = Rd) using abdominal circumference and fasting plasma insulin. Alternatively, we tested in a separate baboon population (n = 159), a simpler model based on body weight and fasting plasma glucose to predict the whole-body insulin sensitivity (Rd/SSPI) derived from the clamp.

Results

In the first model, abdominal circumference explained 59% of total insulin mediated glucose uptake (Rd). A second model, which included fasting plasma insulin (log transformed) and abdominal circumference, explained 64% of Rd. Finally, the model using body weight and fasting plasma glucose explained 51% of Rd/SSPI. Interestingly, we found that percent body fat was directly correlated with the adipocyte insulin resistance index (r = 0.755, p < 0.0001).

Conclusion

In baboons, simple morphometric measurements of adiposity/obesity, (i.e. abdominal circumference), plus baseline markers of glucose/lipid metabolism, (i.e. fasting plasma glucose and insulin) provide a feasible method to screen and identify overweight/obese insulin resistant baboons for inclusion in interventional studies aimed to study human obesity, insulin resistance and type 2 diabetes mellitus.

Metabolic syndrome is a cluster of risk factors that predispose to major cardiovascular diseases, liver steatosis and fibrosis, as well as reduced renal function. Metabolic syndrome and its early hepatic manifestation, non-alcoholic fatty liver disease, are prevalent both among the general population and in pre- and posttransplantation settings. Because indications for solid-organ transplantation are gradually increasing, attention should focus on the incidence of metabolic syndrome among transplanted patients, defined as posttransplant metabolic syndrome (PTMS). Subjects with worse metabolic profiles with two or more criteria of the syndrome show lower survival rates and greater co-morbidities.

However, it is still unclear whether the pathophysiology of posttransplantation metabolic syndrome differ from that of the general population and may be determined by the primary disease affecting the liver or kidney, or amplified or altered by the immunosuppressive treatment, as it has already been established that corticosteroids and calcineurin inhibitors cause metabolic disarrangements. Although there is controversy regarding the definition and the impact of PTMS on overall survival rates following transplantation, these patients are at increased risk for cardiovascular morbidity and mortality. Early recognition, prevention, and treatment of these conditions may impact long-term survival after transplantation. Thus, even if metabolic syndrome in transplant patients remains an unclear definition, an insulin resistance is present in these patients. The treatment of this condition represents a health problem that requires intervention by clinicians before and after transplantation.

Metabolic syndrome (MS) is a cluster of risk factors that predispose to major cardiovascular diseases and its complications, determining liver and kidney impairment. In the last decade, the indications to transplantation are increasing, with a linear incidence of the complications of the procedure. MS represents one of the commonest, being in turn may the consequence of the underlying disease that required the transplantation, or the result of the medical treatment, as well as one of the most important factor influencing the morbidity and mortality of the transplanted patients. Due to the growing incidence of the MS in these patients, it is crucial to focus and clarify the leading causes determining the onset of the metabolic disarrangement, its outcome and the hypothetical mechanism through which the clinicians could reduce the impact of the disease. In fact, prevention, early recognition, and treatment of the factor that could predict the onset or progression of the MS after the transplantation may impact long term survival of patients, that is again the scope of the same transplant. This review will update the different mechanisMS of the pathogenesis of MS in this population, the clinical effects of the presence of the MS, observing the risk factors to be treated before and after the transplantation and suggesting the management of the follow-up.

Aims/hypothesis

Chemokines and their receptors such as chemokine (C-C motif) receptor 2 (CCR2) may contribute to the pathogenesis of the metabolic syndrome via their effects on inflammatory monocytes. Increased accumulation of CCR2-driven inflammatory monocytes in epididymal fat pads is thought to favour the development of insulin resistance. Ultimately, the resulting hyperglycaemia and dyslipidaemia contribute to development of the metabolic syndrome complications such as cardiovascular disease and diabetic nephropathy. Our goal was to elucidate the role of CCR2 and inflammatory monocytes in a mouse model that resembles the human metabolic syndrome.

Methods

We generated a model of the metabolic syndrome by backcrossing KKAy+ with Apoe−/− mice (KKAy+Apoe−/−) and studied the role of CCR2 in this model system.

Results

KKAy+Apoe−/− mice were characterised by the presence of obesity, insulin resistance, dyslipidaemia and increased systemic inflammation. This model also manifested two complications of the metabolic syndrome: atherosclerosis and diabetic nephropathy. Inactivation of Ccr2 in KKAy+Apoe−/− mice protected against the metabolic syndrome, as well as atherosclerosis and diabetic nephropathy. This protective phenotype was associated with a reduced number of inflammatory monocytes in the liver and muscle, but not in the epididymal fat pads; circulating levels of adipokines such as leptin, resistin and adiponectin were also not reduced. Interestingly, the proportion of inflammatory monocytes in the liver, pancreas and muscle, but not in the epididymal fat pads, correlated significantly with peripheral glucose levels.

Conclusions/interpretation

CCR2-driven inflammatory monocyte accumulation in the liver and muscle may be a critical pathogenic factor in the development of the metabolic syndrome.

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