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Glucose Homeostasis—Basic Science

ECSN Faculty

Henry N. Ginsberg, MD
Irving Professor of Medicine
College of Physicians and Surgeons of Columbia University
Director, Irving Center for Clinical Research
New York–Presbyterian Hospital
New York, New York

Samuel Klein, MD
William H. Danforth Professor of Medicine and Nutritional Science
Director, Center for Human Nutrition
Washington University School of Medicine
St. Louis, Missouri

Timothy E. McGraw, PhD
Professor of Biochemistry
Weill Medical College of Cornell University
New York, New York

Overview to Glucose Homeostasis

Overweight and obesity are reaching epidemic proportions in the United States.1 Data from the National Health and Nutrition Examination Survey (NHANES) indicated that the prevalence of overweight (body mass index [BMI] 25-29.9 kg/m2) and obesity (BMI ≥30 kg/m2) among adults increased from 55.9% to 64.5% between the late 1980s and 2000.2 The prevalence of obesity alone increased by almost 8 percentage points, from 22.9% to 30.5% during the same period.

Obesity compromises glucose homeostasis, particularly when it is associated with fat accumulation in the abdominal cavity, liver, or skeletal muscle compartment.3 The induction of insulin resistance is the primary mechanism of altered glucose homeostasis in obese subjects, and it may be partially related to increased levels of free fatty acids (FFAs) delivered to those sites.3, 4 Obesity is associated with an increased risk for insulin resistance, type 2 diabetes, and cardiovascular disease.5, 6 In persons with type 2 diabetes without known coronary heart disease, the absolute risk of major coronary events may approach that of nondiabetic persons with coronary heart disease.7

Insulin is a major regulator of whole-body energy homeostasis. Insulin inhibits hepatic gluconeogenesis, and it stimulates glucose uptake into adipose tissue and muscle. These effects result in postprandial blood glucose lowering. Insulin also regulates fatty-acid metabolism by inhibiting lipolysis and stimulating lipogenesis in adipose tissue.

Dr. Ginsberg’s video clip on the ECS and basic science data on diet-induced obesity.
Click play for Dr. Ginsberg’s comments on the ECS and basic science data on diet-induced obesity.

Insulin target tissues do not properly respond to insulin in insulin-resistant conditions such as obesity and type 2 diabetes mellitus, resulting in a dysregulation of energy metabolism. Evidence indicates that alterations in fatty-acid metabolism contribute to the higher risk of insulin resistance in obesity, although the exact mechanism linking obesity to insulin resistance is unknown.

Perturbations of the endocannabinoid system (ECS) may contribute to the development of insulin resistance and type 2 diabetes. The cannabinoid receptor type 1 (CB1) is expressed in a number of peripheral sites involved in the control of glucose homeostasis, including pancreas, liver, adipose tissue, skeletal muscle, and GI tract.8-11 The potential modulation of glucose homeostasis by the ECS in peripheral tissues is explored in the following sections.



Liver

Role of the ECS

The CB1 receptor is expressed in mouse hepatocytes and in primary cultures of human hepatic cells.10, 12 Levels of the endocannabinoid anandamide and the density of CB1 receptors are increased in the livers of diet-induced obese mice.10

The liver is the major source of endogenous glucose production.4 As noted above, insulin suppresses hepatic gluconeogenesis.3 Increased FFA flux to the liver from visceral adiposity and other adipose tissue depots results in hepatic insulin resistance and a failure of insulin to properly suppress glucose output.3 In addition, increased levels of circulating FFAs correlate with reduced insulin sensitivity in muscle and adipose tissue.13

Implications

FFA release from adipose tissue is increased in the presence of obesity, type 2 diabetes, and other insulin-resistant states.14 Increased flux of FFA to the liver reduces insulin sensitivity.3 Additional studies are needed to determine the importance of increased CB1 receptor density and the clinical effects of CB1 receptor blockade on hepatic insulin clearance and glucose production.

Adipocyte

Role of the ECS

Adipose tissue is no longer considered a passive energy-storage reservoir.15, 16 Rather, it is recognized as the source of signals involved in the integration of energy homeostasis. CB1 receptors and the main endocannabinoid degrading enzyme, fatty acid amide hydrolase (FAAH), are expressed in human adipocytes, and endocannabinoids are found in both mouse and human adipose tissue.11, 17, 18 Oral treatment with the CB1 receptor antagonist SR141716 enhanced the expression of genes that are critical regulators of glucose metabolism in diet-induced obese mice with significantly increased levels of endocannabinoid (2-arachidonoyl-glycerol) in the epididymal fat.11, 19 Global gene expression analyses demonstrated that SR141716 enhanced the expression of 4 of the 8 glycolytic enzymes found in adipose tissue: phosphofructokinase, glyceraldehydes-3-phosphate dehydrogenase, phosphoglycerate mutase, and b enolase.18 Thus, CB1 receptor stimulation is associated with increased expression of genes involved in glucose metabolism.

Adiponectin, a hormone that is derived primarily from adipocytes,15, 20 inhibits both the expression of hepatic gluconeogenic enzymes and the rate of endogenous glucose production.21 Studies in mice have shown that central administration (intracerebroventricular) of adiponectin leads to reductions in body weight and improvements in glucose metabolism.22 Adiponectin levels predict glucose tolerance in a manner that is partly independent of visceral adiposity.23 The ECS and adiponectin appear to be closely linked. First, CB1 receptor stimulation may decrease adiponectin expression in adipocytes.11 Second, CB1 receptor blockade with SR141716 increased adiponectin levels in both diet-induced obese mice24 and genetically obese rats.25 Importantly, these changes in adiponectin levels were associated with favorable changes in serum insulin and glucose levels.24, 25 It is unclear if the increased adiponectin levels were independent of weight loss in the animals treated with SR141716. However, in vitro treatment of mouse adipocyte cells with SR141716 was associated with significantly increased levels of adiponectin mRNA compared with control cells.25 Additional studies are needed to determine if changes in adiponectin are related to ECS effects on glucose metabolism.

Obesity is present in many persons with type 2 diabetes and other insulin-resistant states, and it is associated with excess circulating FFAs.3, 4, 26 High levels of circulating FFAs may impair insulin sensitivity by modifying signaling events downstream from the insulin receptor.13

Oral treatment with the CB1 receptor antagonist SR141716 increased gene expression of the insulin-sensitive glucose transporter GLUT4 in adipose tissue of diet-induced obese mice with elevated levels of endocannabinoid (2-AG) in the epididymal fat.11, 19 Increased expression of GLUT4 can lead to increased insulin-stimulated glucose uptake by adipocytes. Thus, CB1 receptor blockade may be involved in regulating insulin sensitivity in adipose tissue.

Implications

Preclinical data indicate that CB1 receptor blockade may produce gene-expression changes in adipose tissue that are associated with increased glucose uptake and metabolism.19 Additional studies are needed to determine if 1) CB1 receptor blockade changes the expression of these genes and their protein products in human adipose tissue, 2) these changes are associated with clinically significant effects on glucose metabolism, and 3) there is a relationship between CB1 receptors and insulin sensitivity in adipose tissue.

Pancreas

Role of the ECS

Figure 1
Click to Enlarge Figure 1

Insulin is the key hormone involved in glucose homeostasis. In addition, insulin is integrally involved in lipogenesis and adiposity, and it signals satiety in the brain.14, 27, 28 Therefore, understanding the role of the ECS on β--cell function 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 (Figure 1).29 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.29 CB1 receptor mRNA and protein were expressed in rat islet cells and in the exocrine pancreas.30 Data from two studies suggested that pharmacological activation of CB1 receptors in vitro stimulates insulin secretion.11, 30 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, they 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.

GI Tract

Role of the ECS

The GI tract plays a key role in the physiology of energy balance and glucose homeostasis, predominately by communicating with the central nervous system through both neural and endocrine pathways.31 Peripheral signals from the GI tract generally take the form of absorbed nutrients, neural signals, and peptide release. Neuronal pathways relate information about stomach distention and the chemical and hormonal environment of the GI tract to specific areas in the brain that control short-term eating behavior.31

Gastrointestinal CB1 receptors are present in neurons of the enteric nervous system and in sensory terminals of vagal and spinal neurons.32 Endogenous and synthetic cannabinoids have been shown to inhibit electrically evoked contractions in the isolated pig small intestine.32 Administration of a naturally occurring cannabinoid slowed gastric emptying and intestinal motility in both humans and rodents.32 These results were duplicated with the administration of a CB1 receptor agonist, and they were reversed with the administration of a CB1 receptor antagonist.

Implications

The clinical implications of the ECS in the GI tract for glycemic control are under investigation.

Skeletal Muscle

Role of the ECS

Figure 2
Click to Enlarge Figure 2

The modulation of glycemic control by the ECS may be mediated, in part, by effects on skeletal muscle. Liu et al showed that the rate of glucose uptake by isolated soleus muscle was significantly increased in mice treated with SR141716 for 7 days compared with vehicle-treated mice (Figure 2).33 However, it is unclear whether this effect was independent of changes in body weight. Pagotto et al showed that expression of CB1 receptor mRNA in soleus muscle from dietary-induced obese mice was increased compared with soleus muscle from lean control mice.9 Additional studies are needed to determine the relevance of this observation to the impaired glucose uptake by muscle found in experimental models of insulin resistance.

Implications

The insulin sensitivity of skeletal muscle plays a critical role in regulating glycemic control. Limited preclinical data indicate that CB1 receptors are expressed in skeletal muscle, and CB1 receptor blockade may enhance glucose uptake.9, 33 Although speculative, the clinical implications of these data are that CB1 receptor blockade may have therapeutic utility for increasing insulin sensitivity in type 2 diabetes and other insulin-resistant states.

Summary

Role of ECS—Interrelated Integrated Pathways

Glucose homeostasis is mediated, in part, by metabolic and hormonal interactions among adipose tissue, liver, pancreas, skeletal muscle, and GI tract, all of which express the CB1 receptor. Animal models of obesity have provided important evidence supporting the clinical potential for CB1 receptor blockade. Ravinet Trillou et al studied wild-type and CB1 receptor knockout mice fed a high-fat diet. Both types demonstrated an increase in fasting glycemia. The glucose-lowering effect of an intraperitoneal insulin injection was reduced in the wild-type mice, but it was maintained in the CB1 receptor knockout mice at the level of control mice fed standard laboratory chow. Thus, with high-fat feeding, the CB1 receptor knockout mice did not develop the insulin resistance that was observed in the wild-type mice.34 In addition, the CB1 receptor knockout mice maintained their lean phenotype despite consuming a high-fat diet. Whether protection from insulin resistance in the CB1 receptor knockout mouse is independent of protection from obesity on the high-fat diet is unclear.

Figure 3
Click to Enlarge Figure 3

Preclinical data also demonstrate that selective blockade of the CB1 receptor with SR141716 ameliorates abnormalities in glucose metabolism associated with diet-induced obesity. This response was studied in the diet-induced obesity model. Treatment with SR141716 (10 mg/kg/day) for 5 weeks led to a transient reduction of food intake (−48% on week 1) and a marked but sustained reduction of body weight (−20%) in obese mice fed a high-fat diet. The fasting insulin and glucose levels of the high-fat-fed mice treated with SR141716 were reduced to the levels observed in the mice fed standard chow. In contrast, the non-treated mice fed the high-fat diet had elevated fasting insulin and glucose levels (Figure 3).35

Dr. Cota’s video clip on the ECS and Glycemic Control.
Click play for Dr. Cota’s comment on the ECS and Glycemic Control.

Adiponectin expression is increased in adipocytes, which may lead to increased insulin sensitivity. Therefore, adipocytes are peripheral targets of CB1 blockade.The parallel reduction in blood glucose and insulin levels by CB1 receptor blockade observed in preclinical studies suggests improved glucose tolerance through increased insulin sensitivity, possibly through a direct action on skeletal muscle.

Implications

Preclinical data suggest that CB1 receptor blockade may hold promise for the treatment of obesity and its associated comorbid conditions such as type 2 diabetes and other insulin-resistant states.

Figures

Figure 1. 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.29

Figure 2. CB1 receptor blockade enhances glucose uptake in isolated soleus muscle. Genetically obese (Lepob/Lepob) mice received once daily intraperitoneal injection of SR141716 (10 mg/kg) or control (0.1% Tween 80 in saline; 2 mL/kg) for 7 days. The rate of glucose uptake was measured by the formation of [3H]2-deoxyglucose-6-phosphate in isolated soleus muscle. From Liu YL et al.33

Figure 3. CB1 receptor blockade is associated with decreased fasting glycemia and enhanced sensitivity in obese mice on a high-fat diet. Wild-type (+/+) and CB1 receptor knockout (−/−) mice were fed a standard diet (STD) or a high-fat diet (HFD) for 12 weeks. Insulin sensitivity was assessed by calculating the area under the curve (AUC) of glycemia during the 3 hours after intraperitoneal insulin (0.6 U/kg) injection in fasted mice. Values are means ± SEM. *P <0.05, **P <0.01. 35

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