Every time I read a news-feed it has something about how we are losing the battle against diabetes, pre-diabetes, and metabolic syndrome. Phil Wood DVM, MS, PhD focuses on Adiponectin: An Ally In Reducing Cardiometabolic Risk Factors and shows that there is a growing interest in understanding the role of adiponectin in insulin resistance, metabolic syndrome and type 2 diabetes.
Adiponectin: An Ally In Reducing Cardiometabolic Risk Factors
Philip A. Wood
There is a growing interest in understanding the role of adiponectin in insulin resistance, metabolic syndrome and type 2 diabetes. Hypoadiponectinemia has been highly correlated with development of insulin resistance, diabetes and cardiovascular disease (1, 2). Adiponectin is an adipocyte-derived cytokine, or adipokine, that promotes for normal insulin sensitivity and fat clearance from tissues, along with maintaining a reduced inflammatory state (1-4). Although it is made by fat cells, adiponectin is actually found to be abnormally low in obese, insulin-resistant patients (2).
One possibility is that this inverse relationship between adiponectin concentrations and body fat mass indicates a negative feedback mechanism on adiponectin synthesis (2) by other adipokines. That is, production of adiponectin may be inhibited when there is excessive production of one or more other adipokines such as resistin, tumor necrosis factor-α, interleukins-1 and 6, and plasminogen activator inhibitor-1, commonly known as PAI-1 (2). Other than adiponectin, all of the others promote for or further aggravate insulin resistance, as well as inducing proinflammatory and prothrombotic states.
Another possibility is that reduced adiponectin secretion by adipocytes represents a manifestation of insulin-resistant adipocytes because, as demonstrated in at least one study (3), adiponectin was inversely correlated more closely with insulin resistance than with obesity. Adiponectin circulates in the blood in multiple molecular forms, basically low molecular weight forms, predominately hexamers and high molecular weight forms (multimer forms) (1, 2, 4). When measured clinically, the high molecular weight form appears to be the active form and most informative (4) as far as correlating with metabolic improvement. Women tend to have higher adiponectin concentrations than men (2).
Obese, insulin-resistant individuals often have a condition known as hepatic steatosis, in which the liver stores excess fat and, as a result, produces excess glucose (2). With hepatic steatosis, the liver synthesizes and secretes excessive very low density lipoprotein (VLDL) particles. These particles, which are rich in triglycerides, further promote for increased proportions of small dense, low density lipoprotein (LDL) particles and decreased concentrations of high-density lipoprotein-cholesterol (HDL-C) particles. Collectively, these effects result in the common clinical finding of elevated blood triglyceride concentrations and abnormally low HDL-C concentrations. Low adiponectin, likewise, is associated with increased insulin resistance and fat storage in liver. Both of these findings—hepatic steatosis and low adiponectin—are part of a common constellation of cardiometabolic risk factors found in obese, insulin resistant individuals (4). In both animal and human studies, it appears that increasing adiponectin concentrations improves many of these metabolic processes by promoting clearance of excessive hepatic fat. Once the liver is cleared of excess fat, there is a reduction of glucose output and the problems of high triglycerides and low HDL-C in the blood (2).
Muscle also receives signals from adiponectin that are important for maintaining normal insulin sensitivity. Adiponectin appears to promote for fat clearance from muscle much as it does for the liver. In obese individuals, this clearance of fat, in turn, promotes for improved insulin sensitivity. The heart muscle is also directly protected by adiponectin, as it reduces the effects of myocardial infarction and appears to be antiatherogenic (1).
Since it appears increasing adiponectin has many benefits, let’s now consider how that can be accomplished. Clinically, it may difficult to administer adiponectin directly in patients because it has a large and complicated structure, as well as a short half life in the blood (1). Therefore, we are dependent on indirect means of increasing it. Weight loss by reducing adiposity, especially visceral adiposity, is the standard recommendation for reducing many of these cardiometabolic risk factors. It also applies to raising adiponectin concentrations. Weight loss has been associated with increased adiponectin concentrations, but it has required weight loss of >10%, and increasing exercise without losing weight was not a major help (2). Significant increases in adiponectin concentrations, in both diabetic and nondiabetic patients (1, 2), have been demonstrated in studies of thiazolidinediones (TZDs) such as rosiglitazone and piglitazone. In contrast, metformin did not change the adiponectin concentrations (2).
In summary, adiponectin is an ally in maintaining normal insulin sensitivity and in reducing the proinflammatory and prothrombotic states commonly found in obese, insulin-resistant patients. Increasing the concentration of adiponectin appears to be intricately involved in decreasing the common cardiometabolic risks associated with the development of diabetes and cardiovascular disease in these patients.
- Trujillo ME, Scherer PE. Adipose tissue-derived factors: Impact on health and disease. Endocrine Reviews 27: 762-778, 2006.
- Oh DK, Ciaraldi T, Henry RR. Adiponectin in health and disease. Diabetes, Obesity and Metabolism 9:282-289, 2007.
- Abbasi F, Chu JW, Lamendola C, McLaughlin T, Hayden J, Reaven GM, Reaven PD. Discrimination between obesity and insulin resistance in the relationship with adiponectin. Diabetes 53:585-590, 2004.
- Lara-Castro C, Luo N, Wallace P, Klein RL, Garvey WT. Adiponectin multimeric complexes and the metabolic syndrome trait cluster. Diabetes 55:249-259, 2006.