Obesity, diabetes mellitus, and cardiometabolic risk: An Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) 2023

Figures

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  Fig. 1. How does obesity (adiposopathy) contribute to type 2 diabetes mellitus? In addition to biomechanical abnormalities leading to “fat mass disease” [2] obesity may cause adiposopathy, or “sick fat disease [34].” Adipose tissue immunopathies, endocrinopathies, and increased circulating free fatty acids may lead to insulin resistance and beta cell dysfunction [[5], [6], [7], [8],32,33]. The degree by which the adiposopathic consequences of obesity promotes hyperglycemia depends on the crosstalk, interactions, and biometabolic responses of other body organs such as liver, muscle, pancreas, kidney and brain.

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  Fig. 2. Insulin and insulin receptor functions. Diminished insulin activity can be due to an absolute or relative decrease in circulating insulin and/or impaired insulin signaling via reduced number of insulin receptors and/or impaired post-receptor insulin signaling [22,28]. Normoglycemia can be maintained in the early stages of insulin resistance by increased basal insulin (i.e., hyperinsulinemia), as often occurs in patients with obesity. However, over time, insulin secretion may no longer be sufficient to overcome insulin resistance, resulting in hyperglycemia. Obesity and the hyperglycemia of type 2 diabetes mellitus (T2DM) may result in a relative decrease in pancreatic insulin secretion, potentially due to elevations in leptin levels [35] as well as due to apoptosis with decreased pancreatic beta cell mass [4] as the result of: (a) beta cell exhaustion/overload [36], (b) glucolipotoxicity [4,37], (c) increase in pro-inflammatory factors, and (d) decrease in anti-inflammatory factors (e.g., adiponectin) [38]. Insulin is a peptide hormone released by pancreatic beta cells in response to a rise in blood glucose (e.g., postprandial response to carbohydrate ingestion). Fructose, some…

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  Fig. 3. Mechanisms how adiposopathic processes lead to insulin resistance. If obesity-mediated adipocyte hypertrophy and adipose tissue accumulation outgrows vascular supply, then the insufficient delivery of oxygen may contribute to adipocyte and adipose tissue hypoxia and increased adipocyte death. Adipocyte and adipose tissue hypoxia may adversely affect multiple metabolic processes regarding angiogenesis, adipocyte proliferation, adipocyte differentiation, reactive oxygen species generation, inflammation, and fibrosis. Beyond adipocyte and adipose tissue hypoxia, excessive intracellular lipids in the form of fatty acids may lead to ceramide (i.e., a unit of sphingolipids) and diacylglycerol (DAG) formation in adipocytes, where similar to adverse effect of increased fatty acid influx and ceramide and DAG accumulation in liver and muscle, may cause lipotoxicity leading to adipocyte dysfunction [47], such as: (a) inhibiting AKT Protein Kinase B and thus decreasing glucose uptake via GLUT 4, (b) inhibiting hormone sensitive lipase and thus decreasing adrenergic-mediated lipolysis, and (c) impairing mitochondrial function [47], all contributing to insulin resistance. Mechanotransduction…

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  Fig. 4. Illustrative adipose tissue functions potentially altered by obesity-mediated immunopathies. Adipose tissue is an active immune (and endocrine organ) that regulates multiple body processes critical to body homeostasis and body health. Disruption of adipose immune functions (i.e., adiposopathy) contributes to metabolic diseases and adverse cardiac and cancer outcomes. Many of the cytokines released with obesity may act locally. Systemic cytokine effects depend upon individual responses of non-adipose tissue organs [4].

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  Fig. 5. Obesity and the adiposopathic inflammatory cycle. Adipocyte hypertrophy and adipose tissue accumulation may lead to relative or absolute hypoxia, lipotoxicity, altered mechanotransduction, and intraorganellar dysfunction prompting release of cytokines (e.g., tumor necrosis factor) and chemokines [e.g., monocyte chemoattractant protein-1 (MCP-1)]. Adipocyte secreted MCP-1 attracts monocytes to adipose tissue that differentiate into macrophages. Adipose tissue macrophages produce additional MCP-1, that recruits more inflammatory cells to adipose tissue. Adipose tissue macrophages also produce proinflammatory cytokines such as tumor necrosis factor, that among pathogenic effects, includes the promotion of MCP-1 production from adipocytes, recruiting yet more immune cells to adipose tissue.

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  Fig. 6. Illustrative adipose endocrine functions. Adipose tissue is an active endocrine (and immune) organ that regulates multiple body processes critical to body homeostasis and health. Adipocytes have cellular receptors for traditional hormones, nuclear receptors for other hormones, receptors for cytokines or adipokines, receptors for neuronal hormones, as well as receptors for adenosine, lipoproteins, neuropeptide Y1 and Y5, prostaglandins, vascular endothelial growth factor and endocannabinoids. Dysfunction of adipose tissue (adiposopathy) may lead to adverse endocrinopathies and immunopathies leading to adverse clinical outcomes (e.g., diabetes mellitus, hypertension, dyslipidemia, alterations in reproductive hormones, cardiovascular disease, and cancer).

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  Fig. 7. Importance of non-adipose tissue in obesity-related glucose dysregulation (and other cardiometabolic diseases). The degree the immunopathies and endocrinopathies of adiposopathy result in adverse clinical consequences (e.g., abnormalities in glucose metabolism) largely depend on crosstalk, interactions, and biometabolic responses from non-adipose body tissues. Prediabetes and type 2 diabetes mellitus (T2DM) are mostly caused by multi-organ insulin resistance in conjunction with a decline in pancreatic beta cell insulin secretory function [4] The degree that weight reduction improves body organ function (e.g., adipose tissue, liver, muscle, pancreas, kidney, brain) varies among different individuals and among different organs within the individual. For example, insulin sensitivity in the liver (insulin-mediated suppression of glucose production) and adipose tissue (insulin-mediated suppression of lipolysis) may be maximally improved with 5%–8% weight reduction, while greater amounts of weight reduction may further improve skeletal muscle insulin sensitivity [4].

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  Fig. 8. Obesity, adiposopathy, energy overflow, and fat deposition within and around body organs. If during positive caloric balance, energy is stored in peripheral subcutaneous adipose tissue through unfettered adipocyte proliferation and differentiation, then while this may still result in biomechanical obesity complications described by “fat mass disease,” this may mitigate the adiposopathic “sick fat disease” immunopathies and endocrinopathies. However, if during positive caloric balance, either adipocyte proliferation or differentiation is impaired, then this may cause adipose tissue dysfunction (See Fig. 3) and limit energy storage in adipose tissue. This may result in immunopathies (See Fig. 4), endocrinopathies (See Fig. 6), and energy overflow with fat that may be deposited within and around body organs (i.e., fatty liver, fatty muscle, fatty heart), potentially resulting in “lipotoxicity” (See Fig. 3), depending on the susceptibility of the non-adipose tissue organ (See Fig. 7). The determination of energy (i.e., fat) storage distribution during positive caloric balance within the individual is dependent upon such factors as age [14], sex [14], race [14], genetics, medications…

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  Fig. 9. Navigating potential adiposopathic health consequences of adipocyte hypertrophy and visceral adiposity. Obesity, adipocyte hypertrophy, and accumulation of adipose tissue in the visceral and android regions often reflects pathogenic adipose tissue immune and endocrine responses, as well as increased circulating free fatty acids, that may be lipotoxic to peripheral organs. The pathogenic potential of adipose tissue to cause clinical disease largely depends on crosstalk, interactions, and responses of multiple body tissues. The liver, muscle, and other body organs among unique individuals may elicit unique responses to physiological/pathophysiological interaction and crosstalk with their adipose tissue (e.g., the adiposopathic immune, endocrine, and fatty acid onslaught that often occurs with obesity). Body organ metabolic flexibility is the ability of the organ to respond or adapt to changes in metabolic substrates. Adipokines influence metabolic flexibility in adipocytes. Similarly, myokines and hepatokines act on metabolism in muscle and liver, respectively, through paracrine and endocrine signaling [100]. Thus, the predisposition towards developing nonalcoholic fatty liver…

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  Fig. 10. Basic healthful nutrition principles [112,113]. Dietary principles that apply to patients with obesity without diabetes mellitus are similar to nutritional recommendations for patients with obesity and type 2 diabetes mellitus (T2DM), as well as similar to nutritional interventions for patients with other potential adiposopathic conditions such as high blood pressure, dyslipidemia, and/or cardiovascular disease and cancer. Prescriptive dietary recommendations should be evidenced-based [3] and be healthful both qualitatively and quantitatively. Nutritional recommendation should be sufficiently patient-centered and culturally sensitive as to facilitate patient agreement and adherence [113,[124], [125], [126]]. In general, patients should avoid ultra-processed, high energy-dense foods, limit sodium, alcohol, and simple carbohydrates. Conversely, it is generally more healthful to prioritize whole foods that are high in fiber and micronutrients (e.g., whole fruits and vegetables). Especially in patients with diabetes mellitus, complex carbohydrates are preferred over simple carbohydrates, which often have a higher glycemic index/load. ∗ Many natural foods contain varying amounts of…

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  Fig. 11. Obesity Medicine Association (OMA) physical activity [112] recommendations. The OMA physical activity recommendations may differ from other physical activity recommendations by explicitly including daily steps as an acceptable goal for dynamic/aerobic physical activity. Averaging around 5000 steps per day may be a good starting point for many patients with obesity who have limited mobility, or who were previously physically inactive. Evidence supports that 5000 steps or more per day may reduce mortality compared to 2700 steps per day [127]. Among those who engage in over 10,000 steps per day, the risk of incident type 2 diabetes mellitus (T2DM) is substantially reduced [128]. The health benefits of increasing steps per day appear to be linear up to 10,000 steps per day, with each 2000-step increment above inactivity associated with 6% lower risk of progression toward T2DM [129]. Similarly, especially among those ≥60 years of age, the reduction in risk for cardiovascular disease events is generally linear from minimal to 7000/10,000 steps per day [130]. It is unclear that step intensity is associated with mortality after adjusting for total steps per day [131].

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  Fig. 12. Summary of resistance training recommendations for patients with obesity [14,112]. The #1 priority in resistance training is primum non nocere (“first do no harm”), which is best achieved by a pre-physical-exercise health assessment (e.g., cardiovascular, pulmonary, musculoskeletal, and neurologic body systems) and patient education on safe resistance training techniques. Further, it is often advantageous to focus on the basic principles of this figure, with the use of an individual physical exercise prescription, rather than pursue a “quick fix” strategy via unproven and potentially interventions such as unsafe training practices and use of unproven supplements. Resistance training progress may best include muscle tape measurements and body composition, as opposed to body weight or the amount of weight lifted. Among the more efficient ways to increase total muscle mass is to train large muscle groups. Healthy posture, balance stabilization, back muscle strength, and endurance might best be achieved with physical exercise directed at developing “core” muscles. In most cases, both low load training (i.e., lower weights per set with more repetitions) and high load training (i.e.,…