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The prevalence of type 2 diabetes and obesity worldwide is increasing, and these two conditions have a bidirectional and linear relationship.
Obesity worsens the development of type 2 diabetes by increasing insulin resistance. Insulin resistance is commonly associated with obesity and is a key factor in the development of type 2 diabetes.
As noted in the review in , type 2 diabetes is a complex chronic illness characterized by high blood sugar levels, resulting from deficiencies in insulin secretion, action, or both. The link between obesity and type 2 diabetes involves complex cellular and physiological mechanisms, including changes in β-cell function, adipose tissue biology, and insulin resistance in multiple organs. These changes can often be improved and even reversed with significant weight loss.
Pathogenic adipose tissue and its functional abnormalities cause chronic low-grade inflammation, leading to insulin resistance. In addition to high blood sugar levels, adipose tissue dysfunction can produce reactive oxygen species due to mitochondrial and endoplasmic reticulum stress.
Apart from releasing proinflammatory substances into the bloodstream, adipose tissue also releases these substances through extracellular vesicles. In individuals with genetic or environmental susceptibility, these mechanisms can contribute to various metabolic abnormalities such as type 2 diabetes, hypertension, dyslipidemia, metabolic-associated fatty liver disease, cardiovascular disease, and cancer.
Potential Mechanisms
Factors that influence impaired weight reduction among patients with increased adiposity and insulin resistance can be multifactorial in diverse sets of populations. These social, economic, environmental, and genetic factors impact the individual and prevent weight reduction.
In patients with type 2 diabetes mellitus, clinical mechanisms that can cause micro- and macro-vascular complications can cause an increase in adiposity. Insulin resistance is a sentinel pathogenic mechanism, especially in early-onset disease. However, the relationship between hyperinsulinemia and obesity is complex.
Skeletal muscle is the major organ responsible for post-meal glucose clearance. Before the onset of type 2 diabetes mellitus, skeletal muscle appears to be more sensitive to insulin than the liver and adipose tissue. In the early development of type 2 diabetes mellitus, insulin resistance in skeletal muscle may occur before insulin resistance in the liver and adipose tissue.
When the insulin resistance in muscle exceeds that of adipose tissue, then adipocyte responsiveness to high insulin levels may be maintained in a comparative sense, with the possibility to promote lipogenesis, suppress lipolysis, and increase lipid storage in adipocytes. These effects of hyperinsulinemia that directly promotes fat deposition are known to be a mechanism that counteracts efforts at body fat reduction.
In patients with poorly controlled diabetes mellitus, the energy conservation mechanism is impaired due to high blood sugars that can result in spot urine glucose levels as high as ≥ 1,000 mg/d. Additionally, poorly controlled diabetes mellitus causes glucosuria by caloric/energy loss, osmotic water weight loss, and weight reduction due to loss of water-associated glycogen in muscle.
Another clinical mechanism impairing weight decline is the use of obesogenic anti-diabetes medications such as insulin, sulfonylureas, meglitinides, and thiazolidinediones. It is also important to address that therapeutic inertia in de-escalating insulin or anti-diabetes medication in a clinical setting is very prominent. The use of these medications that increase insulin exposure often promote hypoglycemia (particularly during times of weight reduction), requiring increased caloric consumption to treat low blood sugars. Increased caloric consumption to avoid or treat hypoglycemia counteracts the effectiveness of weight reduction efforts.
Other clinical complications impacting weight loss in patients with diabetes are endocrine dysfunction (low testosterone in males and polycystic ovarian syndrome in females), musculoskeletal and neurological complications such as sarcopenia and peripheral neuropathy that limits physical activity, sleep apnea that impacts pulmonary function, and diabetes retinopathy. These can all affect daily living activities, and the micro- and macro-vascular complications lead to acceleration of inflammation and cardiovascular disease.
Age, Sex, Genetic/Epigenetic, and Environmental Mechanisms
Over the years with the aging process, patients with type 2 diabetes mellitus, have a decrease in insulin sensitivity that leads to pathologic dysfunction in body composition. Limited physical activity leads to an increase in body fat and a decrease in muscle mass, which directly impacts weight reduction.
Female sex versus male sex can also have a diverse impact on weight reduction. With lifestyle modification, males tend to lose more weight than females, unlike the situation with pharmacological agents: glucagon-like peptide 1 receptor agonists have shown more weight reduction in females versus males.
Alternately, genetics and environmental factors play a major role in patients with type 2 diabetes and obesity. Although reduced caloric intake or time-restricted eating has gained popularity in patients without diabetes, it can be challenging for patients with type 2 diabetes who are on multiple medications, who may not be able to follow various dietary time-restricted regimens. Other factors and promoters of weight gain can be psychosocial factors, bias, and socioeconomic status.
Conclusion
Obesity and type 2 diabetes mellitus are diseases that are often correlated, making it sometimes challenging to determine the degree to which each independently contributes to adverse clinical consequences. In patients with type 2 diabetes and obesity, it is often challenging to unfold and understand the variable factors that impact weight reduction depending on the degree of insulin resistance.
It is evident from multiple data that the cause is multifactorial and includes but is not limited to clinical mechanisms, body system mechanisms, and environmental mechanisms. The focus of healthcare clinicians should be geared towards understanding the potential mechanisms and the individual driving forces for each patient.
In a nutshell, clinically meaningful weight reduction can be achieved in patients with increased adiposity and type 2 diabetes mellitus via healthful nutrition, physical activity, behavior modification, and pharmacologic therapy (i.e., anti-obesity medications and bariatric surgery).
In some cases, these interventions have the potential to promote diabetes remission. Among patients with obesity and type 2 diabetes mellitus, the focus of management should be geared towards choosing anti-diabetes medications that increase insulin sensitivity and promote weight loss and deprioritize the use of anti-diabetes medications that increase insulin exposure and promote weight gain.
This approach will help clinicians to manage patients with type 2 diabetes mellitus and concurrent pre-obesity/overweight and/or obesity to achieve optimum weight management with results.
Shagun Bindlish, MD, is a Diabetologist/Internal Medicine Physician in Dublin, California; she is also Medical and Scientific Committee Chair for the American Diabetes Association of Northern California and a Wellness Champion for the American College of Physicians.
Read the review here and an interview about it here.
Primary Source
Obesity Pillars
Bays HE "Why does type 2 diabetes mellitus impair weight reduction in patients with obesity? A review" Obes Pillars 2023; DOI: 10.1016/j.obpill.2023.100.