Body Fat Distribution Contributes to Defining the Relationship between Insulin Resistance and Obesity in Human Diseases.

The risk for metabolic and cardiovascular complications of obesity is defined by body fat distribution rather than global adiposity. Unlike subcutaneous fat, visceral fat (including hepatic steatosis) reflects insulin resistance and predicts type 2 diabetes and cardiovascular disease. In humans, available evidence indicates that the ability to store triglycerides in the subcutaneous adipose tissue reflects enhanced insulin sensitivity. Prospective studies document an association between larger subcutaneous fat mass at baseline and reduced incidence of impaired glucose tolerance. Case-control studies reveal an association between genetic predisposition to insulin resistance and a lower amount of subcutaneous adipose tissue. Human peroxisome proliferator-activated receptor-gamma (PPAR-γ) promotes subcutaneous adipocyte differentiation and subcutaneous fat deposition, improving insulin resistance and reducing visceral fat. Thiazolidinediones reproduce the effects of PPAR-γ activation and therefore increase the amount of subcutaneous fat while enhancing insulin sensitivity and reducing visceral fat. Partial or virtually complete lack of adipose tissue (lipodystrophy) is associated with insulin resistance and its clinical manifestations, including essential hypertension, hypertriglyceridemia, reduced HDL-c, type 2 diabetes, cardiovascular disease, and kidney disease. Patients with Prader Willi syndrome manifest severe subcutaneous obesity without insulin resistance. The impaired ability to accumulate fat in the subcutaneous adipose tissue may be due to deficient triglyceride synthesis, inadequate formation of lipid droplets, or defective adipocyte differentiation. Lean and obese humans develop insulin resistance when the capacity to store fat in the subcutaneous adipose tissue is exhausted and deposition of triglycerides is no longer attainable at that location. Existing adipocytes become large and reflect the presence of insulin resistance.

Cardiovascular Protection Associated With Cilostazol, Colchicine, and Target of Rapamycin Inhibitors.

ABSTRACT: An alteration in extracellular matrix (ECM) production by vascular smooth muscle cells is a crucial event in the pathogenesis of vascular diseases such as aging-related, atherosclerosis and allograft vasculopathy. The human target of rapamycin (TOR) is involved in the synthesis of ECM by vascular smooth muscle cells. TOR inhibitors reduce arterial stiffness, blood pressure, and left ventricle hypertrophy and decrease cardiovascular risk in kidney graft recipients and patients with coronary artery disease and heart allograft vasculopathy. Other drugs that modulate ECM production such as cilostazol and colchicine have also demonstrated a beneficial cardiovascular effect. Clinical studies have consistently shown that cilostazol confers cardiovascular protection in peripheral vascular disease, coronary artery disease, and cerebrovascular disease. In patients with type 2 diabetes, cilostazol prevents the progression of subclinical coronary atherosclerosis. Colchicine reduces arterial stiffness in patients with familial Mediterranean fever and patients with coronary artery disease. Pathophysiological mechanisms underlying the cardioprotective effect of these drugs may be related to interactions between the cytoskeleton, TOR signaling, and cyclic adenosine monophosphate (cAMP) synthesis that remain to be fully elucidated. Adult vascular smooth muscle cells exhibit a contractile phenotype and produce little ECM. Conditions that upregulate ECM synthesis induce a phenotypic switch toward a synthetic phenotype. TOR inhibition with rapamycin reduces ECM production by promoting the change to the contractile phenotype. Cilostazol increases the cytosolic level of cAMP, which in turn leads to a reduction in ECM synthesis. Colchicine is a microtubule-destabilizing agent that may enhance the synthesis of cAMP.

Elastic tissue disruption is a major pathogenic factor to human vascular disease.

Elastic fibers are essential components of the arterial extracellular matrix. They consist of the protein elastin and an array of microfibrils that support the protein and connect it to the surrounding matrix. The elastin gene encodes tropoelastin, a protein that requires extensive cross-linking to become elastin. Tropoelastin is expressed throughout human life, but its expression levels decrease with age, suggesting that the potential to synthesize elastin persists during lifetime although declines with aging. The initial abnormality documented in human atherosclerosis is fragmentation and loss of the elastic network in the medial layer of the arterial wall, suggesting an imbalance between elastic fiber injury and restoration. Damaged elastic structures are not adequately repaired by synthesis of new elastic elements. Progressive collagen accumulation follows medial elastic fiber disruption and fibrous plaques are formed, but advanced atherosclerosis lesions do not develop in the absence of prior elastic injury. Aging is associated with arterial extracellular matrix anomalies that evoke those present in early atherosclerosis. The reduction of elastic fibers with subsequent collagen accumulation leads to arterial stiffening and intima-media thickening, which are independent predictors of incident hypertension in prospective community-based studies. Arterial stiffening precedes the development of hypertension. The fundamental role of the vascular elastic network to arterial structure and function is emphasized by congenital disorders caused by mutations that disrupt normal elastic fiber production. Molecular changes in the genes coding tropoelastin, lysyl oxidase (tropoelastin cross-linking), and elastin-associated microfibrils, including fibrillin-1, fibulin-4, and fibulin-5 produce severe vascular injury due to absence of functional elastin.

Effect of diet composition on insulin sensitivity in humans.

Diet composition has a marked impact on the risk of developing type 2 diabetes and cardiovascular disease. Prospective studies show that dietary patterns with elevated amount of animal products and low quantity of vegetable food items raise the risk of these diseases. In healthy subjects, animal protein intake intensifies insulin resistance whereas plant-based foods enhance insulin sensitivity. Similar effects have been documented in patients with diabetes. Accordingly, pre-pregnancy intake of meat (processed and unprocessed) has been strongly associated with a higher risk of gestational diabetes whereas greater pre-pregnancy vegetable protein consumption is associated with a lower risk of gestational diabetes. Population groups that modify their traditional dietary habit increasing the amount of animal products while reducing plant-based foods experience a remarkable rise in the frequency of type 2 diabetes. The association of animal protein intake with insulin resistance is independent of body mass index. In obese individuals that consume high animal protein diets, insulin sensitivity does not improve following weight loss. Diets aimed to lose weight that encourage restriction of carbohydrates and elevated consumption of animal protein intensify insulin resistance increasing the risk of developing type 2 diabetes and cardiovascular disease. The effect of dietary components on insulin sensitivity may contribute to explain the striking impact of eating habits on the risk of type 2 diabetes and cardiovascular disease. Insulin resistance predisposes to type 2 diabetes in healthy subjects and deteriorates metabolic control in patients with diabetes. In nondiabetic and diabetic individuals, insulin resistance is a major cardiovascular risk factor.

Insulin resistance is a cardiovascular risk factor in humans.

Diabetes is a common metabolic disorder associated to elevated cardiovascular morbidity and mortality that is not explained by hyperglycemia or traditional cardiovascular risk factors such as smoking or hypercholesterolemia. Intensive glycemic control with insulin that achieves near-normal glycemia does not reduce significantly macrovascular complications compared with conventional glycemic control. Cardiovascular disease continues to develop in patients with diabetes despite adequate glycemic control. In contrast, intensive control with metformin (leading to insulin resistance improvement) reduces diabetes complications, including cardiovascular events, suggesting that enhancement of insulin sensitivity rather than plasma glucose level has a major role improving diabetes outcomes. Accordingly, insulin resistance estimated by glucose tolerance tests is better predictor of future cardiovascular events than fasting glucose level in nondiabetic individuals. Insulin resistance precedes for decades the clinical onset of type 2 diabetes and deteriorates metabolic control of type 1 diabetes. Numerous investigations including cross-sectional and prospective studies, meta-analyses, and systematic reviews provide compelling evidence that insulin resistance by itself is a cardiovascular risk factor in a variety of population groups, including the general population and patients with diabetes. Several estimations of insulin resistance have been consistently associated with elevated rate of cardiovascular events independently of other cardiovascular risk factors and diabetes status. The clinical expression of insulin resistance (the metabolic syndrome or any of its components including obesity, hyperinsulinemia, hypertension, and dyslipemia) has been related to cardiovascular disease as well. An estimation conducted by the Archimedes model confirms that insulin resistance is the most important single cause of coronary artery disease.

Glycogen metabolism in humans.

In the human body, glycogen is a branched polymer of glucose stored mainly in the liver and the skeletal muscle that supplies glucose to the blood stream during fasting periods and to the muscle cells during muscle contraction. Glycogen has been identified in other tissues such as brain, heart, kidney, adipose tissue, and erythrocytes, but glycogen function in these tissues is mostly unknown. Glycogen synthesis requires a series of reactions that include glucose entrance into the cell through transporters, phosphorylation of glucose to glucose 6-phosphate, isomerization to glucose 1-phosphate, and formation of uridine 5'-diphosphate-glucose, which is the direct glucose donor for glycogen synthesis. Glycogenin catalyzes the formation of a short glucose polymer that is extended by the action of glycogen synthase. Glycogen branching enzyme introduces branch points in the glycogen particle at even intervals. Laforin and malin are proteins involved in glycogen assembly but their specific function remains elusive in humans. Glycogen is accumulated in the liver primarily during the postprandial period and in the skeletal muscle predominantly after exercise. In the cytosol, glycogen breakdown or glycogenolysis is carried out by two enzymes, glycogen phosphorylase which releases glucose 1-phosphate from the linear chains of glycogen, and glycogen debranching enzyme which untangles the branch points. In the lysosomes, glycogen degradation is catalyzed by α-glucosidase. The glucose 6-phosphatase system catalyzes the dephosphorylation of glucose 6-phosphate to glucose, a necessary step for free glucose to leave the cell. Mutations in the genes encoding the enzymes involved in glycogen metabolism cause glycogen storage diseases.