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Introduction/Overview

The high prevalence of obesity, which is associated with insulin resistance, type 2 diabetes and cardiovascular disease,¹ has made understanding the biological mechanisms involved in feeding behavior and metabolic regulation an important focus of biomedical research.² In insulin-resistant conditions, the insulin target tissues do not properly respond to insulin, resulting in a dysregulation of energy metabolism. Perturbations of the endocannabinoid system (ECS) may contribute to the etiology of insulin resistance and type 2 diabetes. The cannabinoid (CB) receptor type 1 is expressed in a number of peripheral sites involved in the control of glucose homeostasis, including the mouse pancreas.³

Energy Balance and Metabolic Regulation

Peripheral Metabolic Regulation: Role of ECS

Matias et al assessed the function and possible dysregulation of endocannabinoids in an insulinoma model of pancreatic β cells.⁴ They found that these cells express both CB₁ and CB₂ receptors and the enzymes required for endocannabinoid biosynthesis and metabolism.⁴ In addition, endocannabinoid levels in these β cell-like cells appear to be under the negative control of insulin, and CB₁ receptor stimulation increased intracellular calcium and insulin release from pancreatic cells cultured in a high-glucose concentration.⁴ The investigators also found that mice with diet-induced obesity had higher endocannabinoid levels in the pancreas than did lean mice.⁴

Implications

Currently, data on the effects of the ECS in the pancreas are less extensive than data collected on other tissues and organs. Recent evidence indicates, however, that blockade of CB₁ receptors may exert direct effects on the pancreas that modulate energy homeostasis.⁴

Glucose Homeostasis

Glucose Metabolism: Role of the ECS

Insulin is the key hormone involved in glucose homeostasis. Understanding the role of the ECS on β-cells, therefore, may provide additional insights into the effects of this system on glucose metabolism. Juan-Picó et al showed that both CB₁ and CB₂ receptors are expressed in intact pancreatic islets of Langerhans isolated from mice.³ CB₁ receptors were most abundant in the glucagon-containing α-cells, whereas CB₂ receptors were present in both α-cells and the insulin-containing β-cells (Figure).³ CB₁ receptor mRNA and protein were expressed in rat islet cells and in the exocrine pancreas.⁵ Data from two studies suggested that pharmacological activation of CB₁ receptors in vitro stimulates insulin secretion.^{4, 5} In these studies, MIN6 or RIN m5F insulin-secreting cells were stimulated with CB₁ receptor agonists and CB₁ receptor antagonists. The CB₁ receptor agonists caused a significant potentiation of glucose-stimulated insulin secretion from the cells, although the CB₁ receptor antagonists did not inhibit insulin secretion, but blocked the effect of the agonists.

Implications

Further studies are needed to determine the impact of CB₁ receptor blockade and stimulation on pancreatic islet physiology and to establish a link between the ECS and β-cell function.

Figures

Figure. Location of CB₁ and CB₂ receptors in islet cells in mice. (A) Transmission image of islet cells. (B) Immunostaining of cells in (A) with an antiserum against insulin. Cells stained in green are insulin containing β-cells. (C) Immunostaining with anti-CB₁ receptor antibody. Note that only non-β-cells are stained. These cells have the typical morphology of α-cells, small diameter and big nucleus. (D) Double staining with insulin (green) and CB₁ receptor antibodies (red). (E) Transmission image of islet cells. (F) Immunostaining of cells in (E) with an antiserum against insulin. Cells stained in green are insulin-containing β-cells. (G) Immunostaining with anti-CB₂ receptor antibody. Note that both β- and non-β-cells (see arrows) are positive for CB₂ receptor staining. Again, non-β-cells have the typical morphology of α-cells, small diameter and big nucleus. (H) Double staining with insulin (green) and CB₂ receptor antibodies (red). From Juan-Picó et al.³

References

1. NHLBI Obesity Education Initiative Expert Panel on the Identification E, and Treatment of Overweight and Obesity in Adults. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults--The Evidence Report. National Institutes of Health. Obes Res. Sep 1998;6 Suppl 2:51S-209S.
2. Fricke O, Lehmkuhl G, Pfaff DW. Cybernetic principles in the systematic concept of hypothalamic feeding control. Eur J Endocrinol. Feb 2006;154(2):167-173.
3. Juan-Pico P, Fuentes E, Javier Bermudez-Silva F, et al. Cannabinoid receptors regulate Ca(2⁺) signals and insulin secretion in pancreatic beta-cell. Cell Calcium. Feb 2006;39(2):155-162.
4. Matias I, Gonthier MP, Orlando P, et al. Regulation, Function, and Dysregulation of Endocannabinoids in Models of Adipose and {beta}-Pancreatic Cells and in Obesity and Hyperglycemia. J Clin Endocrinol Metab. Aug 2006;91(8):3171-3180.
5. Liu B, Hobbs C, Doherty P, Jones P, Persaud S. Diacylglycerol lipase and cannabinoid receptor expression and function in pancreatic beta-cells (abstract 443). Paper presented at: 41st European Association for the Study of Diabetes (EASD) Annual Meeting; September 10-15, 2005, 2005; Athens, Greece.