The role of socioeconomic stress in the risk for obesity and diabetes: potential new targets of treatment

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Humans through evolutionary design have been pro- grammed to store energy in times of adequate food avail- ability to protect themselves from starvation when food is less readily available. However, today in times of relative abundance of food, there is still a tendency to store excess calories, which has resulted in an increase in the prevalence of obesity and type 2 diabetes mellitus (T2DM). Although the existence of starvation has virtually been eliminated in the United States, less severe forms of hunger and food insecurity (fear of hunger) are still found within the United States, and this food insecurity has been linked to increased rates of obesity, T2DM, and premature cardiovascular dis- ease.

Type 2 Diabetes Mellitus

Type 2 diabetes mellitus is a chronic disease associated with obesity, insulin resistance, compensatory hyperinsulinemia, eventual beta cell failure, and consequent hyperglycemia.There is a general consensus that acquisition of visceral obesity (intraabdominal) plays a pivotal role in the development of insulin resistance, T2DM, and atherosclerosis.Visceral adipocytes, which function to store dietary fat, once saturated, begin to produce excess amounts of various biologically active cytokines such as tumor necrosis factor-alpha (TNF-
) and interleukin-6 (IL-6), which directly induce insulin resistance.1In insulin target tissues such a sliver and muscle, TNF-
induces insulin resistance by de-creasing serine phosphorylation of the insulin receptor ki-nase, whereas IL-6 induces insulin resistance by inhibiting glucose transport 4 (GLUT4) synthesis. In addition, satu-rated visceral adipocytes release excess free fatty acids(FFAs)/nonesterifed fatty acids. Excessive FFAs in the cir-culation also contribute directly to the development of insulin resistance through ectopic deposition in insulin-sensi- tive tissues (liver and muscle), where they also release these same inflammatory cytokines.1-6 We have demonstrated that free fatty acids such as palmitate also directly activate the innate immune system through pathologic expression of toll-like receptor (TLR) expression and signaling in nonim- mune cells such as 3T3L1 adipocytes. TLRs are a family of cell surface receptors normally found on immune cells that recognize microbial or cellular products and initiate our innate immune response to environmental pathogens.1 TLR3, for example, recognizes double-stranded ribonucleic acid (dsRNA) from viral-damaged cells, then activates MHC genes important for immune cell interactions and an antiviral gene response.2 Harii et al. were the first to de- scribe functional TLR3 in nonimmune cells (thyrocytes) and show that TLR3 is overexpressed in thyrocytes from patients with Hashimoto’s thyroiditis.3 TLR3 has also been demonstrated in beta cells from individuals with new-onset type 1 diabetes mellitus.4 TLR4 normally function recog- nize bacterial lipopolysaccharides in immune cells and, like TLR3, activate genes important for immune cell interac- tions and an antibacterial response.5 We have shown that palmitate similar to lipopolysaccharides directly activates TLR4 signaling in nonimmune cells such as 3T3L1 adipo- cytes, and that this activation of TLR4 increases expression of IL-6 and TNF-a, which are the same cytokines that induce insulin resistance. This suggests that the innate im- mune system via pathologic activation of TLR4 in nonim- mune cells may also play a role in the pathogenesis of T2DM (Fig. 1).

Chronic stress

The disproportionately higher prevalence rates of depres- sion, obesity, T2DM, and cardiovascular disease observed within socioeconomically at-risk populations, where food sources are often inadequate, seemed initially to conflict with this hypothesis.7-9 However, socioeconomic stress it- self is now thought to be a major contributor to the in- creased prevalence of many chronic diseases. Chronic stress can have a cumulative negative impact on health over time. Stress has been shown to upregulate the sympathetic adrenal medullary axis to increase the secretion of epinephrine and norepinephrine, and the hypothalamic pituitary adrenal cor- tical axis to release cortisol (Fig. 2). Stress-induced in- creases in epinephrine, norepinephrine, and cortisol secre- tion result in increases in heart rate and blood pressure, and changes in carbohydrate and fat metabolism, triggering in- creased glucose mobilization that contributes directly to the development of insulin resistance. In response to these hor- mones, visceral adipocytes produce the same inflammatory cytokines, TNF-a and IL-6, which contribute to the induc- tion of insulin resistance. Thus, stress can contribute to the development of diabetes acutely via mobilization of glucose and FFAs and chronically by stimulating the acquisition of visceral obesity.

‌Socioeconomic stress

Socioeconomic stress is the chronic strain of attempting to meet basic survival needs without enough resources to do so or living up to the expectations set by others in the same social arena. Socioeconomic status is defined primarily by education and income levels. People in lower socioeco- nomic status brackets have higher prevalence rates of most chronic diseases, including obesity, diabetes, cardiovascular disease, and cancer, as well as higher morbidity and mor- tality rates from these diseases. In addition, the psychosocial stress of poverty itself may contribute directly to the in- creased risk for chronic illness.

Studies correlating socioeconomic stress with urine me- tabolites of epinephrine and norepinephrine, such as va- nillylmandelic acid or serum cortisol levels, have shown the highest stress hormone levels in lowest income quartiles. Lower socioeconomic status is also associated with in- creased central adiposity10,11 and decreased leptin, which is a major satiety hormone involved in decreasing food intake control.12 Stress eating is a common observation and stress hormones can result in decreases in serum levels of leptin, which is a major satiety signal. This might explain how chronic emotional stress leads to overeating and weight gain.12 Food insecurity and fear of hunger have also been linked to increased rates of obesity, diabetes, and poorer glucose control.‌

Chronic stress promotes adverse changes in mood and cognition, all of which can affect food intake, both total calories and food choices. During times of stress, it is part of typical human behavior to choose foods that are higher in calories and carbohydrates. These types of food also tend to be cheaper and more convenient, which makes them more appealing when on a budget with respect to time or money. The combination of stress and poor eating contribute to the development of visceral obesity and the risk for develop- ment of T2DM. More research needs to be done to deter- mine the precise mechanisms by which psychosocial stress associated with poverty and economic disparity contribute to the pathogenesis of chronic diseases like diabetes.

Food insecurity and fear of hunger have also been linked to increased rates of obesity, diabetes, and poorer glucose control. In at-risk communities, individuals with T2DM were also more likely to live in food-insecure households compared with those without T2DM, and persons with diabetes who exhibited glycosylated hemoglobin levels higher than 7% were more likely to come from food-inse- cure households compared with diabetics with levels lower than 7%. These observations taken together suggest that poverty, food insecurity, and economic disparity are strongly linked to the risk for obesity and T2DM. A study conducted in monkeys showed that in groups of monkeys that were insecure in obtaining food developed obesity and hyperinsulinemia13 compared with control animals. Food insecurity is a form of socioeconomic stress, and although monkeys do not directly experience socioeconomic stress, this study demonstrates that the stress of meeting basic needs can lead to obesity and hyperinsulinemia. This study in primates demonstrated that food insecurity leads to changes in eating behavior, leading to changes in carbohy- drate and fat metabolism, which results in increased glucose mobilization and insulin resistance.

The obvious solution to reduce the negative impact of poverty and socioeconomic stress on the prevalence of obe- sity, T2DM, and other chronic diseases would be to elimi- nate it. However, this is a very complex problem with multiple political, cultural, and economic barriers. Most interventions designed for stress management, including support groups, individual psychological therapy or coun- seling, stress management, or relaxation techniques, are limited with respect to access in these at-risk populations. Several new therapeutic targets designed to combat obesity and insulin resistance are currently in development includ- ing 11�-hydroxysteroid dehydrogenase (11�-HSD) inhibi- tors, leptin, ghrelin, insulin-like growth factor-1 (IGF-1), and specific TLR inhibitors. The physiology of each com- pound and their potential role in the treatment of obesity and T2DM are discussed here.

New Treatment Targets

11�-HSD inhibitors

Cortisol is one of the stress hormones previously de- scribed that is chronically elevated in at-risk populations and individuals in the lowest socioeconomic quartile. Cor- tisol is a major regulator of hepatic gluconeogenesis and adipocyte lipolysis. Its secretion is elevated during periods of stress, acute illness, or trauma, resulting in excessive glucose production, increased lipolysis, increased inflam- matory cytokine release (TNF-a and IL-6), and insulin resistance. Cortisol is the hormone principally responsible for the stress-induced hyperglycemia observed in these con- ditions. Cushing’s syndrome is a disease characterized by increased cortisol secretion, and it also results in excessive glucose production, increased lipolysis, central adiposity, insulin resistance, and glucose intolerance or overt T2DM. Cortisol is mildly elevated in obese patients, but there is also an increase in peripheral metabolism that involves increased conversion of cortisol to reduced derivatives as well as decreased hepatic conversion of cortisone to cortisol.14-16 The enzyme 11�-HSD is in the glucocorticoid hormone synthesis pathway. Both 11�-HSD type 1 and type 2 are located in the liver, whereas only 11�-HSD type 1 is ex- pressed primarily in adipocytes. In the liver, 11�-HSD type 2 functions as a reductase enzyme and metabolizes cortisol to cortisone, which is inactive glucocorticoid, whereas 11�- HSD type 1 metabolizes cortisone back to cortisol. Thus, these enzymes work together to regulate the amount of cortisol within the liver.

‌Expressed primarily in adipocytes, 11�-HSD type 1 me- tabolizes inactive cortisone back into the active cortisol molecule. This 11�-HSD type 1 enzyme activity can be induced by glucocorticoids or proinflammatory cytokines17 in adipocytes, and it has been hypothesized that the en- hanced conversion of cortisone to cortisol in adipose tissue is important in the induction of visceral adipogenesis char- acteristic of central obesity.14,17 It has also been hypothe- sized that decreased hepatic cortisol 11�-HSD type 1 ex- pression is a compensatory mechanism to decrease fasting hyperglycemia and improve insulin sensitivity in individu- als with visceral obesity and T2DM.17 Wake et al.18 state that increased 11�-HSD activity causes an increase in obe- sity and hyperinsulinemia. Stewart et al. have hypothesized that an imbalance of the 11�-HSD type 1 and type 2 enzyme activity leads to “hepatic and adipocytes glucocorticoid ex- cess,” which contributes to excess gluconeogenesis and insulin resistance associated with visceral obesity and T2DM. In either capacity, 11�-HSD has a role in T2DM and visceral obesity.

Levels of 11�-HSD1 are increased in adipose tissue and decreased in liver in obese patients. In contrast, lean patients with T2DM have normal adipose 11�-HSD1 and less marked down regulation of hepatic conversion of cortisone to cortisol. Theoretically, selective inhibition of 11�-HSD1 and/or the upregulation of 11�-HSD2 could prove benefi- cial in the treatment of T2DM because increased endoge- nous cortisol may be a factor in the development of insulin resistance.

‌Other compounds have also been shown to affect 11�- HSD activity as well. For example, both caffeinated and decaffeinated coffee extracts inhibit 11�-HSD and inhibit reduction of cortisol to cortisone.19 Licorice derivatives glycyrrhizic acid and glycyrrhetinic acid are also potent inhibitors of 11�-HSD, and their proposed mechanism of action is inhibition of the mRNA coding for 11�-HSD, which has been shown to increase the activity of glucocor- ticoids in rats (Fig. 3).20 Carbenoxolone, a drug derived from licorice, is a nonselective inhibitor of 11�-HSD1.21,22 One study demonstrated that carbenoxolone decreases the generation of bioactive cortisol22; however, a subsequent study demonstrated that carbenoxolone did not significantly alter glucose and insulin concentrations.21 However, by also inhibiting renal 11�-HSD2, carbenoxolone has unaccept- able long-term side effects including raising blood pressure. Clinical effectiveness of this compound will require selec- tive 11�-HSD1 inhibitors that lower intra-adipose cortisol levels and enhance peripheral glucose uptake.‌

Leptin

Leptin is an adipokine produced by visceral adipocytes previously mentioned and has been shown to be very im- portant in regulating food intake in the hypothalamus as well as energy balance peripherally23 via the HPA axis in the adrenal gland.24 Specific leptin receptors have been demonstrated in various regions of the brain and peripheral tissues such as the adrenal gland. However, use of leptin to suppress appetite was shown to be ineffective in patients with visceral obesity because they exhibited elevated leptin levels secondary to down-regulation of leptin receptors in the hypothalamus. The cellular mechanism of leptin recep- tor resistance in the hypothalamus is similar to insulin resistance and is mediated through cytokine-induced factors that directly affect both insulin and leptin signaling at the receptor level including the suppressor of cytokine signaling 3 (SOCS3) in the Janus kinase/signal transducer and acti- vation transcription protein (Jak/STAT) pathway.2 Activa- tion of the Jak/STAT pathway leads to an inhibitory feed- back loop of leptin signaling.25 These observations imply that the same inflammatory cytokines, TNF-a and interfer- on-�, which induce insulin resistance, may be mediating the leptin resistance. Leptin resistance is also a common finding in T2DM.26,27 The presence of leptin resistance has pre- cluded its use in most forms of obesity and T2DM.28 How- ever, inhibitors of pathologic TLR expression in adipocytes may also decrease both insulin and leptin resistance (see section on TLRs).

Ghrelin

Ghrelin is a peptide hormone that is orexigenic, meaning that it promotes appetite. It is secreted primarily in the fundus of the stomach and in the small intestine, with smaller concentrations in the lungs, pancreatic islets, adre- nal glands, gonads, thyroid, placenta, kidney, and brain.28 Similar to leptin, ghrelin’s opposite effects on appetite and effects on energy metabolism have made it a substance of great research interest. Secretion of ghrelin occurs in a pulsatile manner, where it is highest before eating and then decreases with food intake. It is also involved in regulation of energy balance and communicates the status of energy stores in the body to the brain.30,31 The effects of ghrelin on food intake and energy storage have been linked to obesity.

Ghrelin causes people to consume and store more calories than they need, and these calories are stored as fat.31 Ghrelin levels are lower in persons with obesity and are increased in lean individuals or in persons who lose weight.32,33 Central injections of ghrelin lead to an increase in glucose and fat storing enzymes, whereas peripheral injection of ghrelin causes weight gain without increase in food intake.34 In- creased ghrelin levels in response to diet-induced weight loss promote increased food intake and make weight loss more difficult.35 Ghrelin increases gastric emptying leading to an increase in food intake, so it is possible that a ghrelin antagonist could be used to slow down gastric emptying,35 cause earlier satiety, and reduce food consumption. Peptide YY, which is found in L cells of the gastrointestinal tract— especially in the ileum and colon—is stimulated by eating, inhibits gastric motility, and decreases ghrelin secretion. Together, ghrelin and peptide YY also act on the arcuate nucleus to regulate appetite.34

The relationship between insulin, glucose, ghrelin, and T2DM is unclear. Both oral and intravenous glucose de- crease ghrelin levels.29 Studies have shown that low circu- lating ghrelin levels are proportional to insulin sensitivity30; that is, insulin and ghrelin levels are inversely related in T2DM.29,31 The effect of the oral antidiabetic compound metformin, which exhibits modest weight-reducing activity clinically, has been shown to suppress postprandial plasma on ghrelin concentrations longer than diet alone in individ- uals with T2DM.35 The development of a specific ghrelin antagonist might be beneficial to suppress appetite in obe- sity and T2DM treatment.

‌IGF-1

IGF-1 is a peptide hormone produced primarily by the liver that has properties similar to insulin to decrease glu- cose output by the liver. Its synthesis and secretion is reg- ulated primarily by growth hormone, and it is a potent stimulator of cell growth and multiplication, and a potent inhibitor of programmed cell death. IGF-1 is also an endog- enous insulin sensitizer, and IGF-1 administration normal- izes insulin resistance in obese individuals and is effective at reducing glucose and hemoglobin A1c levels, as well as insulin requirements in both type 1 diabetes and T2DM. However, in trials where it was administered to patients with diabetes and preexisting retinopathy, it caused progres- sion of the retinopathy and the studies were suspended.36

TLR inhibitors

TLRs are pattern recognition receptors that recognize environmental elements of bacteria and viruses and appear to be important components of the innate immune system. Inappropriate TLR expression in nonimmune cells has now been associated with disease expression.1-6,37-44 Pathologic expression of TLR3 in nonimmune activated genes that increase inflammatory cytokines and costimulatory molecules which are important in the pathogenesis of many autoimmune diseases including Hashimoto’s thyroiditis and type1 diabetes. They are also involved in the growth and migration of certain cancers such as papillary thyroid can- cer; malignant melanoma; and carcinoma of the pancreas, colon, breast, and prostate. As mentioned previously, FFAs such as palmitate directly activate pathologic expression of TLR4 expression in 3T3L1 adipocytes and that TLR4 acti- vation increases the expression of IL-6 and TNF-a. These are the same cytokines that induce insulin resistance and contribute to the development of T2DM. The development of a compound that would selectively inhibit pathologic expression of TLR signaling without affecting normal TLR function in immune cells would be an important new ther- apy. Phenylmethimazole (C10) is a derivative of methima- zole, a drug used to treat autoimmune Graves’ disease and suppress thyrotrophin receptor antibody formation. Leonard Kohn and colleagues developed C10, which has been shown to inhibit pathologic TLR expression and signaling in a variety of disease models including diabetes and cancer.

TLR4 signaling has been hypothesized to regulate the inflammatory markers through the Jak/STAT pathway where SOCS3 is upregulated. Secretion of inflammatory markers decreases insulin sensitivity in fat cells; SOCS3 blocks insulin by impairing phosphorylation of insulin re- ceptors.37,39,40 A treatment that would inhibit TLR signaling could be beneficial in preventing or improving insulin re- sistance.41 C10 has already been proven to inhibit TLR3 signaling in Hashimoto’s thyroiditis.3 Phenylmethimazole (C10) inhibits the TLR4 signaling pathway, making it a promising novel therapeutic for reversing both leptin and insulin resistance and thus possibly in the treatment of obesity and T2DM.42,43

Discussion

There are already multiple pharmacologic compounds used to treat T2DM. Each acts to overcome some part of the pathophysiology of T2DM (Table 1). Often these com- pounds are used in combination to attack the various ab- normalities seen with T2DM. The newer compounds dis- cussed in this paper have the potential to be used in the treatment of obesity and T2DM, but unfortunately they will not be available in the near future. Specific ghrelin antago- nists, 11�-HSD1 inhibitors, and TLR receptor inhibitors may also prove to be safe and effective for the treatment of obesity and T2DM. However, in addition to clinical effi- cacy, the cost of these newer drugs will be a major limiting factor in their clinical use, especially in the economically at-risk populations discussed here. Keeping this in mind, Glucophage (generic, metformin; Bristol-Myers Squibb, Princeton, NJ), one of the most commonly used oral agents is on the $4 generic list at many pharmacies but is still too expensive for some budgets. Thus, affording diabetes med- ications is another stressor coupled with food insecurity, which promotes the cycle of socioeconomic stress.

Table 1 Examples of some of the existing drugs for T2DM Class Therapy target

Biguanides Gluconeogenesis

Thiazolinediones PPAR--y

Sulfonylureas

Examples

Glucophage Rosiglitazone* Pioglitazone

Beta cells—insulin Glipizide secretion Glyburide

Glimepiride

a-glucosidase a-glucosidase in the Acarbose

inhibitors brush border of the small intestines

DPP-4 inhibitors Dipeptidal peptidase Sitagliptin

type 4

Glucagon-like peptide-1 Synthetic glucagon- Exenatide† mimetic like peptide-1

Meglinitides Beta cells—insulin Repaglinide secretion Nateglinide

*Rosiglitizone (Avandia, GlaxoSmithKline, London, UK) has had bad press recently and is not frequently used as of this writing.

†Exenatide (Byetta, Amylin Pharmaceuticals, San Diego, CA) is injected, whereas the rest of these medications are taken orally.

‌Conclusion‌

‌Visceral obesity, T2DM, and their associated cardiovascular complications are major health care concerns. Lower socio- economic status, stress from poverty, and food insecurity are major contributors to the development of obesity and T2DM. In addition to adequate food for nutritional requirements, find- ing affordable interventions for these at-risk populations must be a national priority to avoid the personal crisis of poor or declining health and the stress of trying to afford healthy foods and medications. As more is discovered about the physiology of stress and its role in the development of chronic diseases like diabetes, perhaps more therapy can be targeted at the under- lying causes along with preventive medicine measures such as diet and exercise.

Acknowledgments

‌We acknowledge Kelly McCall, PhD, Leonard Kohn, MD, and Shelby Mullins.

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