Advancing diabetes management: Exploring pancreatic beta-cell restoration’s potential and challenges

Table 1 Key pathophysiological pathways in type 1, type 2, and type 3 diabetes

Pathway	Type 1 diabetes	Type 2 diabetes	Type 3 diabetes (Alzheimer’s disease)
Insulin production	Autoimmune destruction of pancreatic beta cells leads to absolute insulin deficiency	Insulin resistance in peripheral tissues leads to compensatory hyperinsulinemia, followed by beta-cell dysfunction and relative insulin deficiency	Insulin resistance and deficiency in the brain contribute to impaired glucose metabolism and cognitive decline
Immune system involvement	Autoimmune response targeting beta cells, involving T cell-mediated destruction	Chronic low-grade inflammation contributes to insulin resistance and beta-cell dysfunction	Possible involvement of neuroinflammation and immune dysregulation contributing to neurodegeneration
Glucose metabolism	Hyperglycemia due to lack of insulin, resulting in impaired glucose uptake by cells	Hyperglycemia due to insulin resistance and inadequate compensatory insulin secretion by beta cells	Impaired glucose metabolism in the brain leads to reduced energy supply and cognitive impairment
Beta-cell function	Progressive loss of beta-cell mass due to autoimmune attack	Gradual decline in beta-cell function due to chronic insulin resistance, oxidative stress, and inflammation	Not directly related to beta cells, but brain insulin signaling impairment is a key factor
Associated complications	Ketoacidosis, retinopathy, nephropathy, neuropathy, cardiovascular disease	Retinopathy, nephropathy, neuropathy, cardiovascular disease, non-alcoholic fatty liver disease	Cognitive decline, memory loss, dementia, potential overlap with Alzheimer’s disease
Therapeutic targets	Insulin replacement therapy, immunomodulation, beta-cell regeneration	Insulin sensitizers, lifestyle modifications, beta-cell support and regeneration, and anti-inflammatory agents	Improving brain insulin sensitivity, neuroprotective agents, and management of cognitive decline

Table 2 Comparison of regenerative approaches for diabetes treatment

Regenerative approach	Mechanism of action	Advantages	Challenges	Examples	Ref.
Beta-cell regeneration and novel regenerative molecules	Stimulates proliferation, enhances function, and supports survival of existing beta cells	Potential for restoring endogenous insulin production and enhancing beta-cell mass	Reproducibility, safety concerns, and challenges in achieving efficient beta-cell proliferation	GLP-1 analogs, EGF, gastrin, Harmine (DYRK1A inhibitor)	[111,114-116,119]
Stem cell therapy	Differentiates stem cells into beta-like cells	Can potentially replace lost beta cells	Ethical concerns, risk of tumorigenesis, and immune rejection	hESCs, iPSCs	[89,124,125]
Gene editing	Corrects genetic defects in beta cells	Precise genetic modifications	Off-target effects, ethical concerns	CRISPR-Cas9, TALENs, ZFNs	[116,121,123]
Reprogramming molecules	Converts other pancreatic cell types into beta-like cells	Increases beta-cell mass	Efficiency and stability of reprogrammed cells remain areas of investigation	PDX1, NGN3, MAFA	[113]

CRISPR-Cas9: Clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9; DYRK1A: Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A; EGF: Epidermal growth factor; GLP-1: Glucagon-like peptide 1; hESCs: Human embryonic stem cells; iPSCs: Induced pluripotent stem cells; MAFA: V-Maf musculoaponeurotic fibrosarcoma oncogene homolog A; NGN3: Neurogenin 3; PDX1: Pancreatic and duodenal homeobox 1; TALENs: Transcription activator-like effector nucleases; ZFNs: Zinc finger nucleases.