Wednesday, October 4, 2023
This activity is intended for endocrinologists, diabetologists, family physicians, and primary care physicians.
The goal of the conference coverage from the 62nd Scientific Sessions of the American Diabetes Association is to provide clinicians with the most current information on the basic science of diabetes and how this science informs the treatment of the disease. By presenting cutting-edge advances in the study of diabetes, conferences summaries aim to encourage the evaluation of current practice methods and to support clinicians who treat patients with diabetes and its ensuing complications.
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Associate Professor of Medicine, Baylor College of Medicine, Houston, Texas; Chief, Endocrine Service, Ben Taub General Hospital, Houston, Texas
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The notion that adipocyte depots comprise a key endocrine organ is by now incontestable -- only the number, regulation, and functions of the hormonal secretions remain to be determined. One of the latest of these hormones to take its place in the pantheon of energy-regulating factors is adiponectin (also known as adipoQ or ACRP30). The importance of adiponectin as an adipocyte-secreted insulin-sensitizing and anti-atherosclerotic hormone was emphasized in a number of symposia and poster presentations at the 62nd Scientific Sessions of the American Diabetes Association.
The gene for adiponectin is one of many encoding adipocyte hormones and cytokines that are induced in the process of cellular differentiation from pre-adipocytes to adipocytes. The protein product of this gene resembles complement factor C1q, with a "head domain" resembling that of tumor necrosis factor-alpha (TNF-alpha). It acquires posttranslational modifications and complex secondary structures, including calcium binding in its head region and the formation of homodimers and higher-order polymers.
Knowledge of its potential clinical significance has preceded understanding of its function. For example, the group of Dr. Antonio Tataranni at the National Institutes of Health unit in Phoenix, Arizona, has shown that plasma adiponectin levels correlate inversely with adiposity and fasting blood glucose levels, and that low adiponectin levels may precede declines in insulin sensitivity in humans.[1] Furthermore, clinically used thiazolidinedione agents can induce adiponectin gene expression.[2]
Speaking at a symposium entitled "Adipose Tissue As a Secretory Organ,"[3] Philipp E. Scherer, PhD, Albert Einstein School of Medicine, New York, NY, summarized what is currently known about adiponectin's function and regulation, and integrated these data with the results of his own group's recent studies.
Administration of recombinant adiponectin to mice under conditions of a hyperinsulinemic, euglycemic clamp resulted in dramatic improvement in hepatic insulin sensitivity, with a decreased rate of plasma glucose entry and reduction in the activity of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PCK). Corresponding changes in hepatocyte metabolic signaling molecules occurred, with activation of adenosine monophosphate-activated kinase (AMPK), a sensor of cellular energy stores (see "Exercise: How Does It Promote Insulin Sensitivity?"), and protein kinase B, a key intermediate of insulin action. This effect of adiponectin resembles the effects of the thiazolidinediones and metformin. Indeed, treatment of diabetic mice with thiazolidinediones does modulate circulating levels of adiponectin.
As described by Dr. Scherer, a piquant feature of adiponectin's regulation may relate to the connection between insulin sensitivity and the distribution (as opposed to the absolute amount) of body fat. There is differential expression of adiponectin in different fat depots. In rodents, it is highest in the abdominal and perigonadal regions and lowest in subcutaneous fat. Adiponectin expression is also more highly regulated in abdominal fat, the amount of which is inversely related to insulin sensitivity in many human epidemiologic studies. Increasing abdominal obesity is also associated inversely with plasma adiponectin levels. Diurnal variations in adiponectin secretion are roughly inverse to those of leptin and insulin, peaking at early hours of the morning and declining during the midafternoon. There is marked sexual dimorphism in plasma adiponectin levels, which are significantly higher in women than in men. In mice -- but apparently not in humans -- adiponectin levels increase in the immediate prepubertal period. Known hormonal and biochemical regulation of adiponectin secretion may be summarized as follows: secretion is increased by glucocorticoids and proliferator-activated receptor gamma (PPARgamma) agonists, potentiated by testosterone, and decreased by estrogen and prolactin.
The integration of these factors results in cycles of production and degradation of circulating adiponectin in various polymeric forms. A proposed model suggests that adiponectin is initially synthesized by adipocytes in an inactive, high-molecular-weight form. Subsequent insulin action may be needed to modify the protein to a secreted, hexameric form. In the circulation, a putative serum reductase may alter the protein to a trimer, which, at its target cells, may be proteolytically cleaved to its most bioactive form. The final cleavage step may determine varying levels of activity in different target tissues. For instance, the globular head domain alone is highly bioactive in muscle cells but not in hepatocytes. The presence of a cysteine residue at amino acid position 39 appears to be critical to achieve these functionally important modifications, as mutations of this residue can markedly alter bioactivity.
Dr. Scherer then described the whole-body functional effects of adiponectin in a transgenic overexpressing mouse. Such mice have increased hepatic insulin sensitivity with respect to glucose metabolism, together with lower plasma insulin levels. A peculiar concomitant to this beneficial effect was an increase in total body fat, with a concentration in the back as a "hump." The reason for this phenotypic change is unclear, but it appears to be associated with an improvement rather than a deterioration in plasma triglyceride and free fatty acid levels. The significance of this antilipidemic effect was underscored by the fact that administration of recombinant adiponectin to mice lacking caveolin (which had low plasma adiponectin and increased triglyceride levels) resulted in a significant decrease in the plasma triglyceride concentration. Conversely, the group of Dr. Takashi Kadowaki at Tokyo University, Japan, has shown that adiponectin deficiency induces insulin resistance in mice.[4]
Two important issues immediately come to mind regarding adiponectin as an adipocyte product that is associated with leanness as well as one that can function as an insulin "sensitizer":
Philippe Froguel, MD, PhD,[5] St. Bartholomew's Hospital Medical School, London, United Kingdom, presented his group's data on links between molecular defects in adiponectin and insulin resistance. These investigators have been genotyping and phenotyping large French cohorts, in whom they found that plasma adiponectin levels increased with age, decreased with adiposity, decreased during puberty, and were higher in women. A haplotype of 2 single nucleotide polymorphisms (SNPs) in the adiponectin gene -- one of them in the promoter region of the gene -- was strongly associated with plasma adiponectin levels, suggesting an effect of these polymorphisms on the expression of this gene. In particular, in a subset of morbidly obese subjects in the French cohort, there was a very significant effect of the SNPs on adiponectin levels.
It is important that the adiponectin gene polymorphisms were also linked to type 2 diabetes in French, German, Japanese, and Swedish population groups. Thus, this is quite a robust link, in diverse ethnic groups, between an "adipokine" gene polymorphism and insulin resistance. In Dr. Froguel's analysis, it appears to occur much more frequently than with mutations in other adipocyte-secreted factors, such as leptin or resistin. There is also a hint of a mechanism whereby the adiponectin gene polymorphism is linked to lower circulating adiponectin levels, thus diminishing the permissive effect of the hormone on insulin sensitivity in muscle and liver. There is also some evidence of linkage between the adiponectin polymorphism and coronary artery disease in the French population, although this finding remains to be confirmed.
These studies represent burgeoning interest in adipocyte-secreted factors as clinically relevant actors in the drama of insulin resistance and the metabolic syndrome. There are many such factors -- resistin, adipsin, TNF-alpha, plasminogen activator inhibitor-1 (PAI-1), adiponectin -- and they are likely to interact among themselves and with such "exogenous" factors as diet and physical activity to determine the expression of the metabolic syndrome. Of these, adiponectin appears to be the current "hot" item -- with good reason. Both its gene expression and the function of the protein are highly regulated, and both correlate with insulin sensitivity. Its function as an insulin sensitizer has been clearly demonstrated. Furthermore, the adiponectin gene is a strong candidate for an important contributor to the metabolic syndrome. We can clearly anticipate rapid progress in understanding the mechanisms of adiponectin action in normal and abnormal metabolic states, and its use -- either as the complete hormone or as an active fragment (eg, the active globular head domain) -- in the management of insulin resistance.
