Diabetes mellitus is a heterogeneous metabolic syndrome characterized by hyperglycemia, mainly including type 1 diabetes (T1DM), type 2 diabetes (T2DM), specific types of diabetes, and gestational diabetes. Among them, type 2 diabetes (T2DM) accounts for 96% of all cases. Its core features are non-autoimmune progressive impairment of pancreatic β-cell function, often accompanied by insulin resistance (IR) and metabolic syndrome (MS). It has been recognized as a severe chronic non-communicable disease, posing a major threat to global public health.
Behind this increasingly severe health crisis, unhealthy dietary habits — especially high-fat and high-sugar intake — have become key drivers.Specifically, saturated fats in high-fat diets (e.g., red meat, full-fat dairy products) raise “bad cholesterol”, induce chronic inflammation, interfere with insulin signaling, and cause insulin resistance. Trans fats (common in fried foods and processed snacks) further increase the risk of cardiovascular diseases and metabolic disorders.Meanwhile, high-sugar diets — especially beverages and processed foods containing sucrose and fructose — stimulate the liver to synthesize more fat, leading to elevated triglycerides and non-alcoholic fatty liver disease. Through oxidative stress, chronic inflammation, and visceral fat accumulation, they further reduce insulin sensitivity.
In daily life, combinations of “high-fat + high-sugar” are common: fried chicken with cola, cake with milk tea, pizza with soda, etc. This “double dietary attack” is not a simple superposition, but synergistically disrupts the body’s metabolic homeostasis through multiple mechanisms, significantly accelerating the occurrence and progression of T2DM.
Insulin Resistance: The Collusion of High Fat and High Sugar
Insulin resistance (IR) is the core pathological basis of type 2 diabetes. When body cells become insensitive to insulin, glucose cannot efficiently enter cells for energy, leading to persistently elevated blood glucose levels.Studies have shown that saturated fatty acids in high-fat diets interfere with insulin signaling pathways (such as the IRS-1/PI3K/AKT pathway) in the liver, muscle, and adipose tissue, directly inducing insulin resistance.At the same time, high sucrose intake — especially fructose — is rapidly converted into triglycerides in the liver, causing fat accumulation (i.e., non-alcoholic fatty liver disease), impairing insulin signaling and worsening IR.
Glucagon plays a key role in maintaining blood glucose stability, forming a negative feedback regulation with insulin. However, long-term high-fat and high-sugar diets disrupt this balance.In addition, intestinal hormones such as GLP-1 and GIP participate in regulating insulin secretion and sensitivity. Obesity-induced reduction in GLP-1 and chronic inflammation further impair insulin function.Overall, high-fat diets (HFD) and sucrose jointly promote insulin resistance and T2DM by interfering with insulin signaling pathways, disrupting glucose homeostasis, and affecting the gut-pancreatic axis and liver-brain axis.
Pancreatic β-Cells: Collapse Under the Attack of “Glucotoxicity” and “Lipotoxicity”
If insulin resistance is the fuse of diabetes, then pancreatic β-cell failure is the tipping point for the full onset of the disease.β-cells are responsible for secreting insulin, but they become overwhelmed under the dual stress of long-term hyperglycemia (“glucotoxicity”) and high free fatty acids (“lipotoxicity”).
Chronic hyperglycemia caused by high sucrose promotes the accumulation of advanced glycation end products (AGEs) and oxidative stress, directly damaging β-cells. High-fat diets accelerate β-cell death by activating endoplasmic reticulum (ER) stress and pro-apoptotic pathways.Meanwhile, long-term hyperglycemia promotes the accumulation of misfolded proinsulin and IAAP, exacerbates oxidative damage, disturbs ER calcium homeostasis, and impairs insulin processing and release.In addition, decreased expression of the GLUT2 transporter weakens glucose-sensing ability, further damaging β-cell function.These mechanisms indicate that both high-fat and high-sugar intake damage the structure and function of β-cells through synergistic multi-pathway effects, ultimately driving the progression of T2DM.
Systemic Inflammatory Storm and Mitochondrial Paralysis
The harm of high-fat and high-sugar diets goes far beyond glucose and lipid metabolic disorders. They also trigger a low-grade but persistent “systemic inflammatory storm”.
High-fat diets promote adipose tissue to release large amounts of pro-inflammatory factors (such as TNF-α, IL-6), inducing systemic inflammation and impairing insulin signaling pathways. Excessive sugar intake also aggravates inflammation and metabolic damage, especially in the liver and adipose tissue, further promoting insulin resistance (IR).High fructose intake worsens liver inflammation, damages the intestinal barrier, causes endotoxins (LPS) to enter the bloodstream, and triggers metabolic endotoxemia. This chronic inflammatory state further interferes with insulin signaling, forming a vicious cycle.
At the same time, mitochondria — the cell’s “powerhouses” — also suffer damage. High-fat and high-sugar intake impairs mitochondrial oxidative phosphorylation, leading to excessive production of reactive oxygen species (ROS), which not only exacerbates oxidative damage but also directly inhibits insulin action.Studies have found that skeletal muscle mitochondrial dysfunction is common in T2DM patients and their first-degree relatives, which may be an early marker of disease development.
Gut Microbiota Imbalance: The Overlooked “Second Brain”
In recent years, the gut microbiome has been hailed as the body’s “second brain”, and its balance profoundly affects metabolic health.High-fat and high-sugar diets significantly alter gut microbiota composition: the number of beneficial bacteria (such as Akkermansia muciniphila, Bifidobacteria) decreases sharply, while the proportion of pro-inflammatory bacteria increases, leading to reduced short-chain fatty acids (SCFAs) and increased endotoxins.
This “microbial imbalance” not only weakens the intestinal barrier but also remotely regulates systemic inflammation and insulin sensitivity through the “gut-liver axis” and “gut-brain axis”, becoming an important driver of diabetes.