Obesity and Diabetes: A Dangerous Duo - What You Need to Know
Understand the link between obesity and type 2 diabetes, and discover effective strategies to manage both conditions and reduce your risk of heart disease.
DR T S DID WAL MD
1/29/202414 min read
This Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) 2023 dives deep into the link between obesity and type 2 diabetes. It sheds light on how, beyond just storing energy, dysfunctional fat tissue ("adiposopathy") fuels metabolic problems like high blood sugar. This can lead to prediabetes and full-blown diabetes, which significantly raise the risk of heart disease, the leading cause of death in these patients. To protect their hearts, the statement calls for comprehensive measures like healthy habits, weight management, and controlling blood sugar, pressure, and lipids. Certain diabetes medications, like GLP-1 RAs and SGLT2 inhibitors, might help with weight and lower heart disease risk, but their effects vary. New drugs are being studied to see if they can offer broader protection. Remember, treating obesity comes first, and the goal is to find therapies that not only help patients lose weight but also protect their overall health from conditions like heart disease and cancer.
Key Points:
This statement aims to help clinicians understand the link between obesity and T2DM.
Obesity is recognized as a disease beyond just energy storage, with dysfunctional adipose tissue (adiposopathy) contributing to metabolic issues like hyperglycemia.
Adiposopathy can lead to prediabetes and T2DM, which are major risk factors for cardiovascular disease (CVD) and the leading causes of death in patients with obesity and T2DM.
Global CVD risk reduction is crucial for patients with obesity and T2DM, focusing on healthy lifestyle choices, weight management, and optimal control of blood sugar, pressure, and lipids.
Some anti-diabetes medications, like GLP-1 RAs and SGLT2 inhibitors, can offer benefits beyond blood sugar control by potentially reducing body weight and CVD risk. However, their effectiveness varies, and some may even increase weight or CVD risk.
New GLP-1 RAs and SGLT2 inhibitors are being studied for their potential to improve CVD outcomes in broader patient groups, including those with T2DM and obesity without T2DM.
While metformin may modestly reduce weight and might decrease CVD risk in some patients, further research is needed to confirm its overall impact on CVD events.
Some anti-diabetes medications specifically used for weight management (at higher doses) lack sufficient CVD outcome data to recommend them for improved CVD risk reduction.
Detailed Breakdown:
Introduction:
Highlights the OMA's "Obesity Algorithm" as a resource for clinicians managing obesity.
Emphasizes the importance of recognizing adipose tissue beyond its energy storage function and the role of adiposopathy in metabolic disruptions.
Adiposopathy and hyperglycemia:
Explains how the adiposopathic consequences of obesity can elevate blood glucose, leading to prediabetes and T2DM.
Underscoring the high prevalence of T2DM among individuals with obesity and its association with increased CVD risk.
CVD Risk Reduction:
Stresses the importance of comprehensive CVD risk reduction strategies for patients with obesity and T2DM, including lifestyle modifications, weight management, and optimal control of metabolic parameters.
Anti-Diabetes Medications and CVD Outcomes:
Discusses the varied effects of different anti-diabetes medications on body weight and CVD risk.
Highlights GLP-1 RAs and SGLT2 inhibitors as potentially beneficial for weight reduction and CVD risk reduction in some patients.
Cautions against the use of certain medications based on their potential to increase weight or CVD risk.
Future Directions:
Emphasizes ongoing research evaluating new GLP-1 RAs, SGLT2 inhibitors, and other medications for their potential to improve CVD outcomes in patients with obesity and T2DM.
Conclusion:
It reiterates the importance of understanding the link between obesity and T2DM for effective patient care.
Provides an algorithmic approach to treatment with "treating obesity first" as a priority.
Encourages clinicians to consider therapies that not only improve weight but also address broader health outcomes like CVD and cancer in patients with obesity and T2DM.
Overall, this OMA Clinical Practice Statement provides a comprehensive overview of the complex relationship between obesity, T2DM, and CVD, offering valuable insights and practical recommendations for clinicians managing these conditions.
In recent years, the prevalence of type 2 diabetes mellitus (T2DM) has been on the rise, becoming a global health concern. While various factors contribute to the development of T2DM, one significant risk factor often overlooked is obesity. This article will delve into the complex relationship between obesity and T2DM, shedding light on the mechanisms behind this link, the impact on patients, and the importance of addressing obesity as a priority in the management of T2DM.
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Obesity as More Than Just Excess Fat
To truly understand the connection between obesity and T2DM, we must first acknowledge that obesity is not merely the accumulation of excess body fat. It's a chronic, progressive, multifactorial neurobehavioral disease that leads to the dysfunction of adipose tissue and triggers abnormal metabolic, biomechanical, and psychosocial responses in the body This dysfunction of adipose tissue, often referred to as adiposopathy or "sick fat disease," results from an imbalance between energy intake and expenditure, which can vary among individuals due to genetic and environmental factors. It sets in motion a series of adverse metabolic and immune responses, contributing to conditions such as T2DM, hypertension, dyslipidemia, cardiovascular disease, and even cancer
The Role of Adipokines in Diabetes Development
Adipose tissue is not just a passive storage site for excess energy; it's an active endocrine organ that secretes a variety of signaling molecules known as adipokines. These adipokines play a pivotal role in regulating energy balance, metabolic processes, and inflammation. Among them, one of the most well-known is leptin, which influences appetite and energy expenditure. Another crucial adipokine is adiponectin, a hormone that has anti-inflammatory properties and improves insulin sensitivity Low levels of adiponectin are associated with diabetes, central obesity, insulin resistance, and metabolic syndrome. This deficiency leads to decreased fatty acid oxidation, increased hepatic glucose production, and diminished pancreatic β cell function, all contributing to the development of T2DM
The Link Between Obesity, Inflammation, and Insulin Resistance
One of the key pathways through which obesity contributes to T2DM is through the promotion of inflammation and insulin resistance. Excessive adipose tissue can lead to hypertrophy of existing adipocytes, immune cell infiltration, fibrosis, and changes in vascular architecture. This results in mechanical stress on adipose cells and disrupts their adaptive mechanotransduction, leading to adiposopathy. Adiposopathy not only generates local proinflammatory effects but also releases pro-inflammatory factors, pathogenic hormones, and free fatty acids into the circulation. These substances can impair insulin signaling in peripheral organs like the liver and skeletal muscle, contributing to insulin resistance. Essentially, the body becomes "inflexible" in managing, responding, or adapting to changes in metabolic substrates
The Role of Free Fatty Acids and Lipotoxicity
Free fatty acids, liberated from triglycerides stored in adipocytes, are another piece of the puzzle in the obesity-T2DM connection. While insulin promotes the uptake of fatty acids and their conversion into triglycerides in adipocytes, chronic elevation of circulating fatty acids can lead to lipotoxicity when they accumulate in non-adipose tissues like the liver and muscles In the post-absorptive fasting state, hormones like cortisol and catecholamines promote adipose tissue lipolysis, increasing free fatty acid levels in the circulation. In patients with obesity and nonalcoholic fatty liver disease, the origin of hepatic triglycerides is mainly from circulating non-esterified free fatty acids. This fatty liver is a significant cause of insulin resistance, further emphasizing the interplay between obesity and T2DM
Unveiling the Roles of HSL
Hormone-sensitive lipase (HSL) and adipose triacylglycerol lipase (ATGL) are two key players responsible for over 95% of lipolytic triglyceride hydrolase activity in white adipose tissue. Lipolysis, the process of breaking down triglycerides into free fatty acids and glycerol, is a vital metabolic process that provides the body with energy during fasting or physical exertion. HSL, located in adipocytes, plays a central role in this process.
The Influence of Catecholamines
HSL's activity is primarily stimulated by catecholamines, a group of neurotransmitters and hormones that include adrenaline and noradrenaline. When your body needs an energy boost, such as during exercise or stressful situations, catecholamines bind to specific receptors on the surface of adipocytes. This binding triggers a cascade of events that ultimately leads to the activation of HSL. As HSL becomes active, it breaks down triglycerides into free fatty acids and glycerol, making them available for energy production.
Insulin's Role in Inhibition
Conversely, insulin, a hormone produced by pancreatic beta cells, plays a crucial role in regulating blood glucose levels and inhibiting HSL activity. When you consume a meal, your blood glucose levels rise, prompting the release of insulin. Insulin receptors (IR) are found in various body tissues, including adipocytes. When insulin binds to these receptors, it initiates a series of reactions that reduce HSL activity.
Insulin-Mediated Signaling
In muscle, heart, and adipose tissue, insulin-mediated signaling leads to several key effects:
Promotes Glucose Uptake: Insulin facilitates the translocation of glucose transporters (GLUT-4) to the cell membrane, increasing glucose uptake.
Lipogenesis: It enhances the production of acetyl-CoA through cytoplasmic glycolysis, leading to fatty acid and triglyceride synthesis.
Decreased Lipolysis: Insulin reduces adipocyte hormone-sensitive lipase (HSL) activity, decreasing triglyceride hydrolysis.
Increased Fat Mass: The net result of these actions is an increase in fat mass.
In the liver, insulin promotes glycogen synthesis and inhibits gluconeogenesis, contributing to glucose regulation. However, insulin-independent GLUT transporters play a primary role in glucose transport in the liver, pancreatic beta cells, and brain, where glucose transport is not directly dependent on insulin.
Understanding the Insulin Receptor Substrates (IRS)
Insulin receptor substrates (IRS) are intracellular adapter proteins crucial for insulin signaling. When insulin binds to the insulin receptor, it activates both the receptor and IRS through phosphorylation. IRS, in turn, transmits signals through various intracellular pathways, influencing glucose uptake and cell growth. The phosphorylation of specific tyrosine and serine residues on IRS determines its activity.
The Conundrum of Insulin Resistance
Insulin resistance is a major concern in the context of obesity and type 2 diabetes. It refers to the diminished response of body tissues to insulin. Beyond a reduction in the number of insulin receptors, post-receptor insulin signaling abnormalities, such as inflammation, lipotoxicity, and mechanotransduction alterations, contribute to insulin resistance. Various methods, including insulin suppression tests and fasting glucose levels, can be used to measure insulin resistance.
The Role of Interleukins in Immune Responses
Interleukins (IL) are glycoprotein cytokines produced by leukocytes that regulate immune responses. Some interleukins are pro-inflammatory (e.g., IL-1), while others have anti-inflammatory properties (e.g., IL-10). Interleukin 6 (IL-6) can exhibit both pro-inflammatory and anti-inflammatory effects, depending on the context.
Leptin: The Regulator of Food Intake
Leptin, predominantly produced by adipocytes, plays a critical role in regulating food intake, body mass, and various physiological processes. It also influences fetal growth, proinflammatory immune responses, angiogenesis, and lipolysis. However, the complex interactions of leptin with various physiological systems make its effects a subject of ongoing research.
Lipotoxicity: The Consequences of Excessive Lipid Influx
An excessive intracellular lipid influx of circulating free fatty acids can lead to the formation of ceramide and diacylglycerol in various body tissues, including adipocytes, muscles, and the liver. Ceramides are a group of bioactive membrane sphingolipids that can accumulate and disrupt metabolic homeostasis, leading to cardiometabolic diseases. Lipotoxicity is a phenomenon where intracellular lipids, specifically in mitochondria and other organelles, lead to cellular dysfunction.
Metabolic Inflexibility and Its Impact
Metabolic flexibility is the ability of organs to adapt to changes in metabolic substrates, which is crucial during cycles of eating and fasting. Adiposopathy, characterized by hypertrophied adipocytes, may result in metabolic inflexibility, where the body struggles to adequately metabolize increased circulating free fatty acids, contributing to nonalcoholic fatty liver disease and insulin resistance in skeletal muscle.
Adipose Tissue as an Endocrine Organ
Adipose tissue is more than just a storage depot for fat; it is a dynamic endocrine and immune organ. It plays a crucial role in regulating several processes necessary for the body's homeostasis and overall health. Adipocytes, the individual cells within adipose tissue, possess receptors for various hormones, nuclear receptors, and receptors for cytokines and adipokines. Additionally, they are sensitive to neuronal hormones, adenosine, lipoproteins, neuropeptides Y1 and Y5, prostaglandins, vascular endothelial growth factors, and endocannabinoids. When adipose tissue dysfunction occurs, known as adiposopathy, it can lead to adverse endocrinopathies and immunopathies. These conditions, in turn, contribute to several clinical outcomes, including diabetes mellitus, hypertension, alterations in reproductive hormones, cardiovascular disease, and even cancer
The Interplay of Adiposopathy
Adiposopathy's influence doesn't end with adipose tissue; it extends its reach to various body organs, affecting them in different ways. For instance, it can result in abnormalities in glucose metabolism, notably prediabetes and type 2 diabetes mellitus (T2DM). The primary cause of these conditions is multi-organ insulin resistance combined with a decline in the insulin secretory function of pancreatic beta cells. The improvement of organ function through weight reduction is not uniform. Different organs respond differently to weight loss. For example, insulin sensitivity in the liver and adipose tissue can be maximally improved with a 5% to 8% reduction in weight, while greater weight reduction can further enhance skeletal muscle insulin sensitivity
The Role of 11β-HSD1 in Obesity
11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an enzyme produced in adipose tissue and the liver. It converts inactive cortisone to active cortisol and is increased in cases of obesity, often referred to as "local Cushing's syndrome.". This increased activity of 11β-HSD1 can amplify local glucocorticoid effects within the affected tissues, even when circulating glucocorticoid levels remain normal The consequences of elevated 11β-HSD1 activity are far-reaching. They include increased lipolysis, enhanced lipotoxic release of free fatty acids, increased gluconeogenesis in the liver, and decreased glucose uptake in muscles. Furthermore, adipocyte hypertrophy, often seen in obesity, is associated with increased expression levels of 11β-HSD1, which can reduce the synthesis of adiponectin, a hormone with protective metabolic effects. Given that excessive glucocorticoid activity can contribute to metabolic diseases like T2DM, hypertension, and cardiovascular diseases, targeting 11β-HSD1 becomes a potential avenue for pharmacotherapy to address obesity-related metabolic disorders.
Lipotoxicity and Obesity
The metabolic complications of obesity are intricate and multifaceted, largely driven by how various body organs respond to the immunopathies and endocrinopathies brought about by adiposopathy. Positive caloric balance and obesity lead to impaired energy uptake in unhealthy adipose tissue. This results in increased levels of circulating free fatty acids, which then get deposited in different body locations and organs Notably, the adverse effects of this fat deposition aren't limited to adipose tissue. Fat can accumulate in visceral, pericardial, and perivascular adipose tissue, as well as in the liver, muscle, heart, pancreas, and kidney. In the liver and muscle, the increased influx of free fatty acids from circulation triggers the formation of metabolically bioactive lipids, such as ceramides and diacylglycerols, which can cause insulin resistance by inhibiting insulin signaling
The Skeletal Muscle's Role in Energy Balance
Skeletal muscle plays a pivotal role in energy balance. During basal conditions, it primarily utilizes free fatty acids as fuel. However, after consuming glucose or mixed meals, the pancreas releases insulin into the bloodstream, which suppresses the lipolysis of adipose tissue triglycerides. This leads to a decrease in circulating free fatty acid levels and an increase in muscle glucose uptake through insulin-stimulated GLUT4 receptors. Consequently, the predominant fuel source for muscle shifts from fatty acids to glucose. Individuals with obesity and type 2 diabetes often experience "lipotoxic" impairments of the insulin receptor, leading to decreased insulin sensitivity
Impact on Pancreatic Beta Cells
Pancreatic beta cells, responsible for insulin secretion, are not immune to the effects of adiposopathy. Excessive exposure to glucose due to hyperglycemia and certain lipids derived from increased circulating free fatty acids can reduce insulin secretion due to gluco-lipotoxicity The formation of metabolically bioactive lipids, such as ceramides, promotes pancreatic beta cell apoptosis Managing glucose levels and reducing fat content in the liver and pancreas through weight loss may aid in the recovery of beta cell function, especially in patients with a shorter duration of type 2 diabetes
Evidence-Based Nutrition
Key Dietary Recommendations
Avoid Ultra-Processed Foods: Patients should steer clear of ultra-processed, high-energy-dense foods. These items often contain excess sugar, unhealthy fats, and artificial additives, which can contribute to obesity and other health issues.
Limit Sodium Intake: Reducing sodium intake is crucial for managing high blood pressure. Excessive sodium consumption can lead to hypertension, which is a significant risk factor for cardiovascular disease.
Moderate Alcohol Consumption: Patients should exercise moderation when it comes to alcohol. Excessive alcohol consumption can contribute to weight gain and other health problems.
Choose Whole Foods: Prioritize whole foods rich in fiber and essential micronutrients, such as whole fruits and vegetables. These foods provide important nutrients while helping control weight and blood sugar levels.
Complex Carbohydrates Over Simple Carbs: In patients with diabetes mellitus, complex carbohydrates are preferred over simple carbs due to their lower glycemic index and load. They provide a more sustained source of energy and help regulate blood sugar.
Physical Activity Recommendations
Physical activity is a cornerstone of health for individuals dealing with obesity and related conditions. The Obesity Medicine Association (OMA) offers valuable recommendations to help patients improve their physical fitness.
Daily Steps as Dynamic/Aerobic Activity
The OMA's approach includes explicitly considering daily steps as a form of dynamic or aerobic physical activity. Starting with an average of around 5000 steps per day can be a practical goal, especially for patients with limited mobility or those who were previously physically inactive. Research shows that taking 5000 steps or more daily can reduce mortality compared to a lower step count. Among individuals who engage in over 10,000 steps per day, the risk of developing type 2 diabetes mellitus is substantially reduced. The health benefits of increasing daily step counts appear to be linear up to 10,000 steps per day, with each 2000-step increment above inactivity associated with a 6% lower risk of progression toward type 2 diabetes.
Step Intensity and Mortality
While step count is important, the intensity of steps may not significantly impact mortality after adjusting for total steps per day. Thus, consistent physical activity, regardless of step intensity, remains a key goal.
Resistance Training Recommendations Resistance training is a vital component of physical fitness, especially for individuals dealing with obesity. It promotes muscle strength, endurance, and overall well-being. However, it's crucial to approach resistance training safely and effectively.
Balance Low-load and high-load Load Training
Both low-load training (lower weights per set with more repetitions) and high-load training (heavier weights with fewer repetitions) can promote muscle fiber hypertrophy. What matters most is the effort put into the workout, as muscle hypertrophy mainly occurs with sufficient overload. Consistency is vital for achieving positive outcomes in resistance training. Establishing a routine and adhering to it is crucial for long-term success. It's important to note that resistance training should be considered complementary to, rather than a substitute for, dynamic/aerobic exercise training. A balanced approach to both types of exercise is ideal.
Priority of Treatment: "Treat Obesity First"
When patients with obesity and diabetes mellitus face acute medical conditions, such as uncontrolled high blood pressure or severe hyperglycemia, addressing these issues takes precedence. Otherwise, comprehensive treatment of obesity remains the top priority for most patients.
Strong Evidence Supports Obesity Management
Evidence strongly supports the role of obesity management in impeding the transition from prediabetes to T2DM. Notably, managing obesity delays T2DM progression, enhances glycemia in T2DM patients, reduces the need for glucose-lowering medications, and aids in sustaining diabetes remission over extended periods of at least 2 years Studies highlight the profound impact of weight reduction on T2DM. Even modest weight loss, within the range of 3–7% of baseline weight, shows improvements in glycemia and intermediate cardiovascular risk factors. Larger and sustained weight loss, exceeding 10%, exhibits disease-modifying effects, potentially leading to the remission of type 2 diabetes. Weight reduction above 15% significantly correlates with reduced cardiovascular disease outcomes and mortality
Predictors of T2DM Remission
Identifying factors predicting T2DM remission include shorter duration of T2DM (under 2 years), requiring fewer anti-diabetes medications to achieve euglycemia and clinically substantial weight reduction
Dietary Contributions and Weight Reduction
Research underlines weight reduction as the primary dietary contributor to diabetes remission, regardless of macronutrients. Very low-energy diets and formula meal replacements emerge as effective strategies. Notably, low-carbohydrate diets, accompanied by weight reduction, display increased effectiveness in T2DM remission at the 6-month mark in comparison to low-fat diets.
Structured Weight Management Programs and Diabetes Remission
Structured weight management programs significantly contribute to sustained T2DM remission, emphasizing the strong correlation between remission and the degree of weight reduction. National health record reviews and meta-analyses support these findings Studies support the likelihood of achieving T2DM remission after bariatric surgery, primarily linked to substantial weight loss. However, it's essential to note that the mechanisms behind diabetes remission after bariatric surgery might extend beyond weight reduction alone (Refs. It's important to understand that the health benefits of reducing body fat are contingent upon promoting favourable health effects on adipose tissue function. Simply surgically removing functional body fat might not necessarily yield metabolic health benefits.
Medications and T2DM Remission
While approved medications might not exclusively target hepatic fat reduction in patients with nonalcoholic fatty liver disease (NAFLD), anti-obesity medications like glucagon-like peptide receptor agonists could potentially have beneficial effects on hepatic steatosis and inflammation
Conclusion
In conclusion, this comprehensive overview from the Obesity Medicine Association (OMA) highlights the interlinked nature of obesity and T2DM. The significance of obesity treatment in managing T2DM cannot be understated. Targeting obesity with appropriate therapies not only aids in weight reduction but also enhances glycemic control, potentially leading to improved cardiovascular outcomes. In understanding the intricacies of T2DM remission and the role of weight reduction, the wealth of evidence points towards the central role of managing obesity in addressing T2DM complications.
Reference Article
Harold Edward Bays, Shagun Bindlish, Tiffany Lowe Clayton,Obesity, diabetes mellitus, and cardiometabolic risk: An Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) 2023,https://doi.org/10.1016/j.obpill.2023.100056.
Image credit : Wikimedia Commons
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https://healthnewstrend.com/circadian-rhythm-and-obesity-how-your-sleep-cycle-affects-your-weight
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