Type 2 diabetes mellitus

Type 2 diabetes is a disorder of carbohydrate metabolism in which tissue cells lose sensitivity to insulin (insulin resistance), while the pancreas gradually exhausts, failing to compensate with hormone production. According to the International Diabetes Federation, there are over 537 million adults with diabetes worldwide, and this number doubles every 15–20 years. T2D is associated with serious complications: diabetic nephropathy, retinopathy, neuropathy, diabetic foot syndrome, accelerated atherosclerosis, and cardiovascular events. Standard therapy — diet, metformin, DPP-4 inhibitors, GLP-1 receptor agonists, SGLT-2 inhibitors, insulin — controls glycaemia but does not address the key mechanism: chronic low-grade inflammation underlying insulin resistance. Cell therapy is considered a way to act on this inflammatory background and to preserve β-cell function in early stages of the disease.

The epidemiology of T2D reflects the 21st-century epidemic of metabolic disease. It accounts for 90–95% of all diabetes cases. In Russia the State Diabetes Registry exceeds 4.9 million patients, with a real estimate including undiagnosed of 8–10 million. The principal modifiable factors are visceral obesity, sedentary lifestyle, a diet high in refined carbohydrates and saturated fats, sleep deprivation, and chronic stress. Non-modifiable factors include age over 45 years, family history (TCF7L2, KCNQ1, PPARG polymorphisms), and ethnicity (elevated risk in South Asian, Latino, and Middle Eastern populations). A separate condition is prediabetes: fasting glucose 5.6–6.9 mmol/L, 2-hour OGTT glucose 7.8–11.0 mmol/L, or HbA1c 5.7–6.4%; at this stage reversal probability with lifestyle change is high.

Pathophysiologically, T2D results from a combination of insulin resistance and progressive β-cell secretory dysfunction. In skeletal muscle, liver, and adipose tissue, insulin signalling through the IRS-1/PI3K/Akt cascade fails because of serine phosphorylation of IRS-1 by pro-inflammatory kinases (JNK, IKK). The source of these kinases is chronic low-grade inflammation in visceral adipose tissue: hypertrophic adipocytes recruit macrophages polarised to a pro-inflammatory M1 phenotype that secrete TNF-α, IL-6, and MCP-1, sustaining systemic background. Lipotoxicity (accumulation of ceramides and diacylglycerols in muscle and liver) and glucotoxicity (chronic hyperglycaemia damaging β-cells via oxidative and ER stress) develop in parallel. With disease progression, β-cells transition into a dedifferentiated state, lose the capacity for glucose-stimulated insulin secretion, reflected by falling C-peptide. The end result is relative or absolute insulin deficiency and dependence on exogenous insulin therapy.

Contemporary T2D pharmacotherapy (ADA/EASD 2023) follows a risk-stratified approach. Metformin remains first-line for most patients as a drug with proven cardiovascular safety, minimal hypoglycaemia risk, and weight-neutral or favourable effect. In patients with established atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease, SGLT2 inhibitors (dapagliflozin, empagliflozin) and GLP-1 receptor agonists (semaglutide, liraglutide) become first-line or add-on therapy — reducing cardiovascular mortality and slowing CKD progression independently of HbA1c reduction. Second-line options include DPP-4 inhibitors (sitagliptin), sulphonylureas (gliclazide), and pioglitazone. With HbA1c >9% or marked catabolic symptoms, early insulin is initiated. Despite this arsenal, only 50–60% of patients reach HbA1c targets in real-world data, and β-cell function continues to decline by approximately 5% per year, ultimately requiring intensification and insulin dependence.

Mesenchymal cell therapy targets pathogenic mechanisms inaccessible to standard pharmacotherapy. Following intravenous infusion, UC-MSCs and placenta-derived MSCs migrate into zones of chronic inflammation (visceral adipose tissue, islets of Langerhans) and via paracrine factors switch macrophages from a pro-inflammatory M1 to a regenerative M2 phenotype, lowering local TNF-α and IL-6. Insulin signalling along the IRS-1/PI3K/Akt axis is restored; β-cells receive protection from apoptosis through paracrine HGF, FGF-2, and IGF-1; oxidative stress in endothelium falls, indirectly limiting microvascular complications. The double-blind placebo-controlled phase II RCT of Hu and colleagues (2022) in 91 Chinese patients showed that after three intravenous UC-MSC infusions at 4-week intervals, 20% in the cell therapy arm achieved HbA1c <7.0% with insulin dose reduction ≥50%, against 4.55% in placebo at 48 weeks. A meta-analysis of 8 clinical trials with 334 patients confirmed reproducibility of the effect, with mean HbA1c reduction of 1.06% (95% CI 0.85–1.27).

The Hanshi United programme for T2D builds on these data. The standard course is three intravenous procedures of UC-MSC or placenta-derived MSCs at 15–20 day intervals. Optimal candidates are patients with T2D duration up to 5–7 years, preserved C-peptide, and no terminal complications. Standard glucose-lowering therapy (metformin, GLP-1 RA, SGLT2 inhibitors, insulin) is maintained at full dose throughout the course. Lifestyle modification is mandatory in parallel — 5–10% weight loss produces an independent significant effect that amplifies cell therapy. At 3 and 6 months the treating endocrinologist reviews drug doses on the basis of HbA1c, home glucose monitoring, HOMA-IR, and C-peptide. In patients with longer history and insulin dependence, the course may be extended to 4–5 procedures, with the principal aim of improving tissue insulin sensitivity and slowing complications rather than discontinuing insulin.