Diabetes mellitus (DM) is a chronic endocrine disorder characterized by persistent hyperglycemia resulting from absolute insulin deficiency, insulin resistance, or a combination of both mechanisms. Type 1 diabetes (DM1) is characterized by autoimmune destruction of pancreatic β-cells leading to absolute insulin deficiency, whereas type 2 diabetes (DM2) develops on the basis of peripheral insulin resistance associated with progressive β-cell dysfunction and insufficient insulin secretion (Sapra, Bhandari, 2023). Hyperglycemia leads to disturbances in carbohydrate, lipid, and protein metabolism and creates the foundation for the development of various metabolic complications (Dilworth et al., 2021).
Global diabetes prevalence is rising dramatically. According to International Diabetes Federation (IDF) data, the number of people with diabetes in 2021 exceeded 537 million, and by 2045 it is projected to rise to 783 million (Sun et al., 2022). This trend is observed across all age groups, with increasing obesity, sedentary lifestyle, and population aging among the main contributing factors. In addition, gestational diabetes is affecting an increasing number of women and represents an important risk factor for later development of DM2 (Zhu, Zhang, 2016).
Epidemiological data indicate that DM is not only more common but also increasingly severe in terms of complications. High prevalence of vascular and metabolic disorders, including dyslipidemia, hypertension, and cardiovascular disease, substantially worsens patient prognosis (Russo et al., 2023). At the same time, however, access to treatment and prevention remains uneven across many regions, underscoring the need for global and local interventions (Fralick et al., 2022).
Pathophysiology of diabetes
Mechanisms of DM1 and DM2
DM1 is an autoimmune disease characterized by the destruction of pancreatic β-cells, which leads to absolute insulin deficiency. Pathogenesis involves genetic predisposition (especially HLA genes), autoimmune factors, and environmental triggers. The result is the pancreas’s inability to produce insulin, leading to acute hyperglycemia (Zaccardi et al., 2016).
DM2 is a multifactorial metabolic disorder that develops through a combination of insulin resistance and progressive β-cell insulin secretory dysfunction (Fig. 1). Unlike DM1, DM2 has a stronger association with lifestyle factors, including excess caloric intake, physical inactivity, and obesity, which contribute to the development of pathological changes in insulin signaling (Ojo et al., 2023).
Fig. 1 Pathogenesis of Type 2 Diabetes Mellitus
The scheme illustrates eight key pathophysiological mechanisms responsible for the development and persistence of hyperglycemia in type 2 diabetes mellitus. These are reduced insulin secretion by pancreatic β-cells, increased glucagon secretion by α-cells, increased hepatic glucose production, impaired central regulation of glucose metabolism (neurotransmitter dysfunction), reduced glucose uptake by peripheral tissues (especially skeletal muscle), increased renal glucose reabsorption, increased lipolysis in adipose tissue, and reduced incretin effect. These disturbances together contribute to the chronic hyperglycemia typical of type 2 diabetes. Source: Slovenská diabetologická spoločnosť.
Insulin resistance
Insulin resistance is the central pathophysiological mechanism in the development of DM2. It is defined as the reduced ability of cells—especially hepatocytes, myocytes, and adipocytes—to respond to insulin action. The consequence is reduced glucose uptake from blood, increased hepatic gluconeogenesis, and a global loss of metabolic homeostasis (Lee et al., 2022).
Among the main mechanisms contributing to the development of insulin resistance are elevated free fatty acid (FFA) levels and ectopic fat deposition in non-adipose tissues, which adversely affect intracellular insulin signaling pathways. Another major factor is chronic low-grade inflammation mediated by cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), which disrupt insulin signaling and contribute to reduced sensitivity of target tissues. In addition, oxidative stress and endoplasmic reticulum stress play a significant role by worsening the balance between insulin synthesis, storage, and secretion (Banday et al., 2020).
These pathophysiological changes lead to reduced expression of the glucose transporter GLUT4 in skeletal muscle and defects in IRS-1 phosphorylation (insulin receptor substrate 1), resulting in an inadequate cellular response to insulin signaling. The result is persistent hyperglycemia, which accelerates diabetes progression (Galicia-Garcia et al., 2020).
β-cell failure and insulin secretion
A key role in DM2 pathophysiology is played by pancreatic β-cell failure. After an initial phase characterized by compensatory hyperinsulinemia, which is a response to peripheral insulin resistance, there is progressive decline in β-cell function and viability. This process is the result of several pathogenic mechanisms.
One of the main factors is glucotoxicity—chronically elevated blood glucose levels leading to oxidative stress and mitochondrial dysfunction in β-cells, adversely affecting their ability to synthesize and secrete insulin. Lipotoxicity also occurs simultaneously, in which accumulation of free fatty acids and triglycerides in the pancreas disrupts cellular architecture and signaling pathways. In addition, patients with DM2 often develop a chronic inflammatory state mediated by pro-inflammatory cytokines that induces β-cell apoptosis (Ojo et al., 2023; Banday et al., 2020).
The combination of these factors leads to reduced numbers of functional β-cells and decreased secretory capacity. Subsequent relative or absolute insulin deficiency makes it impossible to adequately compensate for insulin resistance, leading to overt hyperglycemia. In advanced stages, DM2 can have a clinical course very similar to DM1, often requiring initiation of insulin replacement therapy (Zaccardi et al., 2016; Freeman et al., 2023).
Acute metabolic complications
Diabetic ketoacidosis
Diabetic ketoacidosis (DKA) is among the most serious acute metabolic complications of diabetes, especially type 1. It arises from absolute or relative insulin deficiency, leading to decompensated glucose metabolism and increased lipolysis. This condition is most typical for younger patients with DM1, but it can also occur in DM2, especially in cases of infection, inadequate treatment, or stress (Dhatariya et al., 2020).
The pathophysiological basis of diabetic ketoacidosis is profound insulin deficiency, which prevents cells from using glucose as the primary energy source. This leads to activation of alternative energy pathways, especially lipolysis. Released free fatty acids are then metabolized in the liver into ketone bodies, such as acetoacetate and β-hydroxybutyrate. Accumulation of these ketone bodies results in metabolic acidosis with lowered blood pH and the characteristic ketoacidotic symptomatology (Elendu et al., 2023).
Fig. 2: Symptoms of diabetic ketoacidosis
The scheme shows the major clinical manifestations of diabetic ketoacidosis, an acute metabolic complication of diabetes mellitus. It affects multiple organ systems, including the central nervous system (polydipsia, polyphagia, lethargy, stupor), visual system (blurred vision), respiratory system (Kussmaul respiration, acetone breath), urinary system (polyuria, glucosuria, ketonuria), and gastrointestinal tract (nausea, vomiting, abdominal pain). Source: Nature Reviews Disease Primers
Typical clinical features of DKA include polyuria, polydipsia, dehydration, nausea, vomiting, abdominal pain, and Kussmaul breathing (Fig. 2). In severe cases, altered consciousness may progress to diabetic coma. Lab findings are characterized by hyperglycemia, acidosis (pH < 7.3), increased anion gap, and the presence of ketones in serum or urine. DKA is associated with life-threatening complications such as cerebral edema, arrhythmias, acute kidney injury, and hypoglycemia due to incorrect treatment. Despite modern management, DKA remains associated with substantial morbidity, especially in children, older patients, and in developing countries (Dhatariya et al., 2020).
Hyperglycemic hyperosmolar syndrome
Hyperglycemic hyperosmolar state (HHS) is a severe acute complication of DM2, characterized by extreme hyperglycemia (often > 33 mmol/l), plasma hyperosmolality (> 320 mOsm/kg), severe dehydration, and absent or minimal ketosis. This clinical condition develops gradually over several days and is typically seen especially in older patients with poorly controlled or undiagnosed diabetes (Mustafa et al., 2023).
The basis of HHS pathophysiology is relative insulin deficiency—insulin levels are sufficient to inhibit lipolysis and therefore prevent ketogenesis, but insufficient to inhibit hepatic gluconeogenesis and glucose production. As a result, extreme hyperglycemia develops, inducing osmotic diuresis, severe dehydration, and electrolyte disturbances (Rodriguez Alvarez et al., 2025).
The clinical picture of HHS is often subtle and nonspecific, including polyuria, polydipsia, dry mucous membranes, muscle weakness, orthostatic hypotension, and, in advanced stages, altered mental status from lethargy to coma. Laboratory findings are dominated by glucose > 600 mg/dl, osmolality > 320 mOsm/kg, normal pH (> 7.3), low or absent ketones, and often hypernatremia. Neurological symptoms closely correlate with the degree of hyperosmolality (Rosager et al., 2024).
HHS management focuses on controlled rehydration with isotonic fluid, subsequent insulin administration, electrolyte correction—especially potassium—and treatment of the precipitating cause (e.g., infection, heart failure, disruption of treatment regimen). Careful glucose reduction is essential to avoid the risk of cerebral edema. Despite advances in management, HHS mortality remains high, estimated at 10–50%, depending on patient age, comorbidities, and speed of therapeutic intervention. Older patients and those without access to healthcare are at greatest risk (Shaka et al., 2022).
HHS requires a multidisciplinary approach emphasizing continuous monitoring of vital signs, osmolality, glucose, and neurologic status. Thromboprophylaxis should also be considered, since the condition is often associated with a hypercoagulable state (Milanesi, Weinreb, 2018).
Chronic metabolic complications
Diabetic dyslipidemia
DM leads to diabetic dyslipidemia, which includes elevated triglycerides, reduced HDL cholesterol, and the presence of atherogenic LDL particles. These changes substantially increase the risk of atherosclerotic complications and cardiovascular disease in patients with both types of diabetes. Dyslipidemia is present in more than 30% of patients with type 2 diabetes mellitus and is associated with approximately a two-fold increase in atherosclerotic cardiovascular disease (ASCVD) risk (Goldberg, 2022).
Non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD) is a common comorbidity in patients with obesity and DM2, with prevalence around 25%; in people with diabetes it is even higher. This disease includes a spectrum from simple lipid accumulation to non-alcoholic steatohepatitis (NASH) and fibrosis. Pathophysiologically, it involves impaired insulin signaling, inflammatory processes, and endoplasmic reticulum stress, which contribute to disease progression and increase cardiometabolic risk (Pouwels et al., 2022).
Metabolic syndrome and oxidative stress
Metabolic syndrome, which includes abdominal obesity, insulin resistance, hypertension, and dyslipidemia, leads to pronounced oxidative stress. Reactive oxygen species generated by mitochondrial pathways damage proteins, lipids, and mitochondria, further worsening metabolic homeostasis. This cycle contributes to progression of organ complications, including cardiovascular and renal diseases (Masenga et al., 2023).
Sarcopenic obesity
Sarcopenic obesity, defined as concurrent loss of muscle mass and increased body fat, represents a significant metabolic complication in older adults with diabetes. The ESPEN/EASO consensus statement identifies it as a risk factor for worsening glucose regulation and increased risk of cardiometabolic diseases (Donini et al., 2022).
Cardiovascular risk
Patients with diabetes and metabolic syndrome show higher prevalence of hypertension, dyslipidemia, and obesity, leading to much greater risk of coronary artery disease, stroke, and heart failure. A cohort study from Rafsanjan in Iran reports up to 30% higher cardiovascular event risk in patients with metabolic syndrome (Bazmandegan et al., 2023).
Metabolic acidosis in chronic kidney disease (CKD)
In patients with diabetes and coexisting chronic kidney disease, metabolic acidosis frequently develops, worsening catabolism, promoting muscle loss, and increasing the risk of CKD progression. Acidosis triggers activation of the renin-angiotensin-aldosterone system (RAAS), inflammation, and disturbances in bone metabolism. Targeted correction of acidosis may slow kidney function decline and reduce mortality risk (Raphael, 2024).
Metabolic cardiomyopathies
Chronic hyperglycemia and carbohydrate metabolism disturbances lead to an energy deficit and accumulation of toxic intermediates (e.g., AGEs), which damage cardiac muscle. Patients with DM2 may develop so-called diabetic cardiomyopathy, characterized by diastolic dysfunction and left ventricular hypertrophy, often without prior myocardial infarction. These changes are linked to mitochondrial bioenergetic dysfunction and oxidative stress (Conte et al., 2023).
Treatment-related complications
Drug-induced hypoglycemia
Hypoglycemia is the most common treatment-related complication in patients with diabetes and occurs with overuse of insulin or secretagogues. Insulin lowers blood glucose by increasing peripheral glucose uptake, while sulfonylureas and meglitinides stimulate insulin release regardless of current glycemic level. In real-world data, the study by Lyu et al. (2023) showed that patients treated with sulfonylureas had up to double the risk of severe hypoglycemic episodes compared with patients using newer antihyperglycemic agents affecting glucose metabolism, such as GLP-1 receptor agonists and SGLT2 inhibitors (Lyu et al., 2023). The Endotext consensus report recommends thorough patient education on hypoglycemia symptoms, medication dose adjustment according to diet and activity, regular glucose monitoring, and the availability of a glucagon autoinjector for emergencies (Davis et al., 2024).
Metabolic changes from insulin and sulfonylurea use
Insulin acts as a potent anabolic hormone that promotes glucose storage as glycogen and increases fatty acid synthesis, which commonly leads to weight gain. A review by McGill and colleagues (2024) emphasizes that at initiation of insulin therapy, a patient may gain on average 2–5 kg during the first year of treatment, with mechanisms including improved glucose utilization efficiency and increased lipogenesis (McGill et al., 2024).
Sulfonylureas strongly stimulate insulin release and increase insulin activity independently of glycemia; in addition to hypoglycemia, this contributes to fat retention and worsening insulin resistance. StatPearls recommendations also address this issue, suggesting consideration of discontinuing or reassessing sulfonylurea therapy in patients with persistent weight gain and frequent hypoglycemic episodes, or switching to agents with lower risk of weight gain (Costello et al., 2023).
Discussion
Assessment of the diabetes-metabolic disorders relationship
Diabetes mellitus is a chronic metabolic disease that, beyond glucose metabolism disturbances, causes complex systemic changes leading to the development of multiple chronic complications. New research shows that in addition to classic complications such as retinopathy, nephropathy, and neuropathy, we are increasingly diagnosing conditions such as NAFLD, cognitive impairment, osteoporosis, and sarcopenia. These conditions are the result of combined effects of chronic hyperglycemia, inflammatory pathways, insulin resistance, and metabolic memory (Tomic et al., 2022).
Significance in clinical practice
Current diabetes management requires more than glucose control—it is a comprehensive approach to reducing cardiovascular and metabolic complications. A combination of GLP-1 receptor agonists and SGLT2 inhibitors has been identified as an effective strategy that not only improves glycemic control but also lowers body weight and blood pressure, while positively influencing the progression of renal and cardiac damage. This approach is increasingly used in personalized DM2 treatment (Yepes-Cortés et al., 2025).
In the 2022 ADA and EASD consensus report, the importance of individualized therapeutic strategy is emphasized, taking into account comorbidities, patient preferences, and risk factors. In practice, this means actively involving patients in decision making, rigorous monitoring of metabolic parameters, and favoring drugs with cardiometabolic benefit (Davies et al., 2022).
Challenges in treatment and prevention
Despite the availability of effective therapeutic options, major practical challenges remain. One of the greatest barriers is financial toxicity, namely the economic burden associated with modern diabetes treatment. Studies show that high out-of-pocket costs and the indirect burden on patients’ budgets often prevent timely treatment intensification, thereby worsening long-term outcomes (Patel, 2025). Reducing these barriers requires not only system-level changes in reimbursement and drug availability but also greater patient education, integration of technologies (e.g., CGM, telemedicine), and cross-disciplinary collaboration. Successfully addressing these challenges is crucial for reducing complications and improving quality of life in patients with DM.
Conclusion
DM represents a complex disease whose management requires a multidisciplinary approach focused not only on glycemic control but also on early recognition and treatment of metabolic complications. Current scientific evidence demonstrates a close relationship between diabetes and multiple metabolic disorders that significantly increase patient morbidity and mortality. Personalized treatment has a key role, reflecting individual risk factors and comorbidities. A major challenge remains the availability of innovative treatment approaches and ensuring their sustainability in practice. Systematic prevention and patient education are key tools for reducing the overall impact of this disease on public health.
Authors: Mgr. Anastasiia Ostafiichuk, Ústav verejného zdravotníctva a hygieny, Lekárska fakulta UPJŠ, Košice prof. Mgr. MUDr. Erik Dorko, Phd., MPH, MBA, Ústav verejného zdravotníctva a hygieny, Lekárska fakulta UPJŠ, Košice doc. MUDr. Ingrid Dravecká PhD., I. interná klinika UPJŠ LF a UNLP, Košice prof. MUDr. Kvetoslava Rimárová CSc., Ústav verejného zdravotníctva a hygieny, Lekárska fakulta UPJŠ, Košice
The work was supported by KEGA grants 001UPJŠ-4/2024 and 003UPJŠ-4/2024 Ministerstva školstva, výskumu, vývoja a mládeže SR.
List of bibliographic references
BANDAY, Mujeeb Z. – SAMEER, Aga S. – NISSAR, Saniya. 2020. Pathophysiology of diabetes: An overview. Avicenna J Med, 2231-0770, 2020, 10, 4, 174–188.
BAZMANDEGAN, Gholamreza, et al. 2023. Cardiovascular risk factors in diabetic patients with and without metabolic syndrome: A cohort-based study in Rafsanjan. Sci Rep, 2045-2322, 2023, 13, —, 559.
COSTELLO, Ryan A. – NICOLAS, Samar – SHIVKUMAR, Abhijit. 2023. Sulfonylureas. 2023 Jul 12. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan–. PMID: 30020597.
CONTE, Federica, et al. 2023. Metabolic Cardiomyopathies and Cardiac Defects in Inherited Disorders of Carbohydrate Metabolism: A Systematic Review. Int J Mol Sci, 1422-0067, 2023, 24, 10, 8632.
DAVIS, Hugh A. et al. 2024. Hypoglycemia During Therapy of Diabetes. 2024 Jul 7. In: Feingold KR, Ahmed SF, Anawalt B, et al. (eds.) Endotext. South Dartmouth (MA): MDText.com, Inc.; 2000 –. PMID: 25905325.
DAVIES, Melanie J. et al. 2022. Management of hyperglycaemia in type 2 diabetes: a consensus report by the ADA and the EASD. Diabetologia, 0012-186X, 2022, 65, 12, 1925–1966.
DHATARIYA, Ketan K. et al. 2020. Diabetic ketoacidosis. Nat Rev Dis Primers, 2056-676X, 2020, 6, —, 40.
DILWORTH, Lowell – FACEY, Aldeam – OMORUYI, Felix. 2021. Diabetes Mellitus and Its Metabolic Complications: The Role of Adipose Tissues. Int J Mol Sci, 1422-0067, 2021, 22, 14, 7644.
DONINI, Lorenzo M. et al. 2022. Definition and Diagnostic Criteria for Sarcopenic Obesity: ESPEN and EASO Consensus Statement. Obes Facts, 1662-4025, 2022, 15, 3, 321–335.
ELENDU, Chukwuka, et al. 2023. Comprehensive review of diabetic ketoacidosis: an update. Ann Med Surg (Lond), 2049-0801, 2023, 85, 6, 2802–2807.
FRALICK, Michael, et al. 2022. Global accessibility of therapeutics for diabetes mellitus. Nat Rev Endocrinol, 1759-5029, 2022, 18, 4, 199–204.
FREEMAN, Andrew M. – ACEVEDO, Luis A. – PENNINGS, Nicholas. 2023. Insulin Resistance. 2023 Aug 17. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2025 Jan–. PMID: 29939616.
GALICIA-GARCIA, Unai, et al. 2020. Pathophysiology of Type 2 Diabetes Mellitus. Int J Mol Sci, 1422-0067, 2020, 21, 17, 6275.
GOLDBERG, Ronald B. 2022. Dyslipidemia in Diabetes: When and How to Treat? Endocrinol Metab Clin North Am, 0889-8529, 2022, 51, 3, 603–624.
LOU, Jing, et al. 2023. Evaluation of Out-of-Pocket Costs and Treatment Intensification With an SGLT2 Inhibitor or GLP-1 RA in Patients With Type 2 Diabetes and Cardiovascular Disease. JAMA Network Open, 2574-3805, 2023, 6, 6, e2317886.
LYU, Beini, et al. 2023. Glucose-Lowering Agents and the Risk of Hypoglycemia: a Real-world Study. J Gen Intern Med, 0884-8734, 2023, 38, 1, 107–114.
MASENGA, Sepiso K. et al. 2023. Mechanisms of Oxidative Stress in Metabolic Syndrome. Int J Mol Sci, 1422-0067, 2023, 24, 9, 7898.
MCGILL, Janet B. et al. 2024. The Current and Future Role of Insulin Therapy in the Management of Type 2 Diabetes: A Narrative Review. Diabetes Ther, 1869-6953, 2024, 15, 5, 1085–1098.
MILANESI, Anna – WEINREB, Jane E. 2018. Hyperglycemic Hyperosmolar State. 2018 Aug 1. In: Feingold KR, Ahmed SF, Anawalt B, et al. (eds.) Endotext. South Dartmouth (MA): MDText.com, Inc.; 2000–. PMID: 25905210.
MUSTAFA, Omar G. et al. 2023. Management of Hyperosmolar Hyperglycaemic State (HHS) in Adults: An updated guideline from JBDS. Diabet Med, 0742-3071, 2023, 40, 3, e15005.
OJO, Oluwafemi A. et al. 2023. Diabetes mellitus: From molecular mechanism to pathophysiology and pharmacology. Med Novel Technol Devices, 2023, 19, 100247.
PATEL, Minal R. 2025. Financial Toxicity in Diabetes: The State of What We Know. Curr Diab Rep, 1534-4827, 2025, 25, 1, 32.
POUWELS, Sjaak, et al. 2022. Non-alcoholic fatty liver disease (NAFLD): a review of pathophysiology, clinical management and effects of weight loss. BMC Endocr Disord, 1472-6823, 2022, 22, —, 63.
RAPHAEL, Kalani L. 2024. Metabolic Acidosis in CKD: Pathogenesis, Adverse Effects, and Treatment Effects. Int J Mol Sci, 1422-0067, 2024, 25, 10, 5187.
RODRIGUEZ ALVAREZ, Paloma – SAN MARTIN, Vicente T. – MOREY-VARGAS Oscar L. 2025. Hyperglycemic crises in adults: A look at the 2024 consensus report. Cleve Clin J Med, 0891-1150, 2025, 92, 3, 152–158.
ROSAGER, Emilie V. et al. 2024. Incidence and Characteristics of the Hyperosmolar Hyperglycemic State: A Danish Cohort Study. Diabetes Care, 0149-5992, 2024, 47, 2, 272–279.
RUSSO, María P. et al. 2023. Prevalence of diabetes, epidemiological characteristics and vascular complications. Arch Cardiol Mex, 0187-464X, 2023, 93, 1, 30–36.
SHAKA, Hafeez, et al. 2022. Hospitalizations and inpatient mortality for hyperosmolar hyperglycemic state over a decade. Diabetes Res Clin Pract, 0168-8227, 2022, 185, —, 109230.
SUN, Hong, et al. 2022. IDF Diabetes Atlas: Global prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract, 0168-8227, 2022, 183, —, 109119.
TOMIC, Dunya – SHAW, Jonathan E. – MAGLIANO, Dianna J. 2022. The burden and risks of emerging complications of diabetes mellitus. Nat Rev Endocrinol, 1759-5029, 2022, 18, 9, 525–539.
YEPES-CORTÉS, Carlos A. et al. 2025. Combining GLP-1 RA and SGLT2 inhibitors in T2DM: A scoping review. Diabetes Ther, 1869-6953, 2025, 16, 5, 813–849.
ZACCARDI, Francesco, et al. 2016. Pathophysiology of type 1 and type 2 diabetes mellitus: a 90-year perspective. Postgrad Med J, 0032-5473, 2016, 92, 1084, 63–69.
ZHU, Yeyi, ZHANG, Cuilin. 2016. Prevalence of Gestational Diabetes and Risk of Progression to T2DM: a Global Perspective. Curr Diab Rep, 1534-4827, 2016, 16, 1, 7.