Decoding Type 2 Diabetes Mellitus: Mechanisms, Treatment Strategies, and Modeling Approaches

The Mechanisms of Type 2 Diabetes (T2D)

T2D is characterized by a non-autoimmune, heterogeneously progressive decline in adequate insulin secretion from pancreatic β cells. Insulin resistance (IR) and β cell dysfunction are the two core pathophysiological mechanisms^[2].Chronic exposure to overnutrition-related metabolites (e.g., elevated glucose, non-esterified fatty acids) disrupts insulin receptor activation and IRS-1/PI3K/Akt2 signaling, triggering chronic adipose inflammation, ectopic lipid deposition (in the liver/muscle), endoplasmic reticulum stress (ERS), oxidative stress, etc. These alterations contribute to the development and progression of T2D and target organ damage (TOD). These pathological processes impair insulin sensitivity and β-cell function, while reciprocally interacting with metabolic disorders^[2].

Given the complex pathophysiology of T2D, several therapeutic targets have been identified to address insulin resistance and β-cell dysfunction.

The classic therapeutic targets for T2D include GLP-1, DPP-4, and SGLT2, which play pivotal roles in regulating glucose homeostasis and enhancing insulin sensitivity. The most prominent physiological effect of GLP-1 is its insulinotropic activity: GLP-1 enhances insulin secretion exclusively during hyperglycemia, thereby minimizing the risk of hypoglycemia. Additionally, it inhibits glucagon secretion from α-cells—a process potentially regulated by local δ-cell-derived somatostatin. Extensive research has leveraged the hypoglycemic effects of GLP-1 for T2D treatment, however, the therapeutic potential of native GLP-1 is constrained by its short half-life and the need for parenteral administration^[3]. To overcome these constraints, two pharmacological strategies have been developed: DPP-4 inhibitors (elevate endogenous GLP-1 levels by inhibiting its proteolytic degradation) and GLP-1 receptor agonists (structurally analogous peptides activating the GLP-1 receptor but exhibiting prolonged in vivo activity after subcutaneous injection)^[3]. In contrast, SGLT2 inhibitors act through renal mechanisms by blocking glucose reabsorption in renal proximal tubules, leading to increased glycosuria and reduced blood glucose concentrations^[4]. Recent cardiovascular outcome trials have demonstrated that select SGLT2 inhibitors and GLP-1 receptor agonists significantly lower the risk of cardiorenal events.

While these established targets have revolutionized T2D management, additional pathways are gaining attention for their therapeutic potential. Among these, AMPK (AMP-activated protein kinase) plays a pivotal role in the development and progression of T2D by functioning as a cellular energy sensor and regulator. AMPK, an energy-sensitive enzyme, orchestrates metabolic responses to cellular energy deficits by enhancing glucose uptake in skeletal muscles, increasing fatty acid oxidation in tissues, and suppressing hepatic glucose production. Research has confirmed AMPK dysregulation in both metabolic syndrome and T2D models, as well as in humans, with its activation consistently enhancing insulin sensitivity and metabolic function^[6].

Given the multifaceted pathophysiology of T2D—characterized by insulin resistance, β-cell dysfunction, and complex metabolic disturbances—therapeutic approaches must be comprehensive and individualized. Targeting the underlying mechanisms not only improves glycemic control but also mitigates the risk of complications. The following sections outline current treatment strategies that incorporate lifestyle interventions and pharmacological therapies tailored to patient-specific needs.

The Current Treatment Strategies of T2D

Effective glycemic control can reduce the risk of TOD and cardiovascular diseases. Blood glucose targets should be individualized based on patient-specific factors (such as duration of diabetes, age, presence of cardiovascular diseases, life expectancy, and social factors, etc.). Treatment plans should be stratified according to both the current and target HbA1c levels. In the absence of pharmacologic intervention, lifestyle modifications—including physical activity, metabolic nutrition therapy (MNT), and weight management—can reduce HbA1c levels by 0.3% to 2%, and in some cases, even achieve diabetes remission^[2].

Following Paul Langerhans’ initial description of the pancreatic islets in Berlin in 1869, a series of innovative studies emerged, including insightful clinical observations and some controversial findings that collectively established the connection between the pancreas and diabetes. The number of classes of antidiabetic medications has increased substantially since the 1990s^[7].

Patients with T2D often suffer from multiple comorbidities, including dyslipidemia, pre-obesity or obesity, chronic kidney disease (CKD), and cardiovascular diseases, along with TOD resulting from metabolic dysfunction syndrome(MDS)^[2]. The 2022 consensus report from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommends more comprehensive and individualized management for individuals with T2D. This approach should consider patients' specific circumstances and preferences^[8].

For patients without established cardiovascular diseases, CKD or multiple high-risk factors, metformin or other glucose-lowering agents should be prioritized. These agents provide sufficient glycemic control and can help achieve and maintain treatment goals^[2]. Clinical trials of SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP-1 RA) have demonstrated that, in addition to improving blood sugar control, these agents provide additional cardioprotective and renoprotective benefits^[2,8]. A real-world prospective cohort study involving 2.2 million participants demonstrated superior outcomes with combination therapy using SGLT2i and GLP-1 RAs compared with monotherapy, including reductions in all-cause mortality, myocardial infarction (MI), and hospital admission rates^[2,9]. Combination regimens should be individualized based on patient characteristics, in alignment with the principles applied to monotherapy.

In addition to clinical treatment strategies, preclinical modeling plays a critical role in understanding T2D and evaluating new therapies.

Experimental Modeling Approaches for T2D

Based on the principles of model establishment, diabetes models can be classified as spontaneous, induced, or genetically engineered mouse models. Currently, among diabetes models, the induced models are widely used due to their well-established methodologies and ease of implementation. Physical interventions (e.g., pancreatectomy), dietary modifications (e.g., high-sugar and high-fat diets), and chemical agents can all effectively induce diabetes in animal models.

The chemical induction models are often the preferred choice for evaluating new antidiabetic agents or novel insulin formulations. Numerous substances exhibit diabetogenic properties, including alloxan(ALX), streptozotocin(STZ), ferric nitrilotriacetate, dithizone, etc. Among these, STZ and ALX are the most commonly used chemical inducers for creating diabetes models^[10]. STZ is a glucose analogue that, when administered intraperitoneally or intravenously, is primarily transported to pancreatic β-cells via glucose transporter subtype 2 (GLUT-2), inducing cytotoxicity through DNA alkylation. Unlike STZ, ALX selectively destroys insulin-producing pancreatic β-cells through mechanisms mediated by reactive oxygen species (ROS), making it suitable for inducing diabetes in experimental animals^[11].

Currently, there is no standardized consensus for diagnosing diabetes in animal models.
(1) In general, random blood glucose levels are used as the primary criterion for diagnosing diabetes in animal models. Animals with blood glucose levels exceeding 300 mg/dL (16.7 mmol/L) are considered diabetic. When fasting blood glucose levels are used, values above 150 mg/dL (8.3 mmol/L) or 200 mg/dL (11 mmol/L) may be adopted as indicators of hyperglycemia, depending on the research objective. When repeated blood sampling is impractical, the presence of glucosuria in NOD mice is regarded as a sign of diabetes^[16].
(2) Additional indicators: In diabetic animal models, increased water intake, urine output, and weight loss are commonly observed. Serum biochemical parameters, including total cholesterol, aspartate aminotransferase, triglycerides, and low-density lipoprotein (LDL), also show significant elevations as diabetes develops^[15,17].

The prevalence of type 2 diabetes (T2D) continues to rise substantially, positioning it as a major risk factor for both microvascular complications (e.g., retinopathy, nephropathy) and macrovascular complications (e.g., stroke, myocardial infarction). Effective management requires individualized strategies that integrate lifestyle interventions—such as physical activity and metabolic nutrition therapy (MNT)—with pharmacologic therapies, including metformin, SGLT2 inhibitors, and GLP-1 receptor agonists, which have demonstrated protective effects on organs beyond glycemic control. Animal modeling approaches, particularly chemically induced models employing streptozotocin (STZ) or alloxan (ALX), remain essential for elucidating disease pathophysiology and facilitating drug development. As the global burden of T2D continues to escalate, advances in mechanistic understanding, individualized treatment strategies, and preclinical modeling collectively drive innovation in clinical care, leading to improved therapeutic outcomes and reduced disease-related morbidity.