Hepatic Glucokinase Activators versus Sulfonylureas: Hypoglycemia Risk Reduction in Type 2 Diabetes Management

Mpora Kakwanzi Evelyn

Department of Pharmacognosy Kampala International University Uganda

Email: evelyne.mpora@studwc.kiu.ac.ug

ABSTRACT

Type 2 diabetes mellitus (T2DM) was characterized by impaired glucose homeostasis and insulin resistance, necessitating pharmacologic interventions to maintain glycemic control. Sulfonylureas (SUs) had been widely used to stimulate insulin secretion but were associated with a significant risk of hypoglycemia. Hepatic glucokinase activators (GKAs) are emerging agents that enhance hepatic glucose uptake and metabolism, potentially reducing hypoglycemia risk by acting insulin-independently. This review critically examined the comparative hypoglycemia risk profiles of hepatic glucokinase activators versus sulfonylureas in T2DM management. A comprehensive literature search was conducted using major scientific databases to identify preclinical and clinical studies evaluating hypoglycemia incidence associated with GKAs and SUs, focusing on randomized controlled trials, mechanistic studies, and meta-analyses. Sulfonylureas induce hypoglycemia predominantly by stimulating pancreatic β-cell insulin secretion regardless of ambient glucose levels. In contrast, hepatic GKAs amplify glucose phosphorylation in hepatocytes, enhancing glycogen synthesis and glucose clearance without direct insulin stimulation. Clinical evidence indicated that GKAs reduced fasting and postprandial glucose effectively with a lower incidence of hypoglycemia compared to SUs. Nevertheless, hepatic GKAs’ efficacy varied depending on their isoform selectivity and pharmacokinetic profiles. Limitations included the relatively recent clinical trial data on GKAs and the long-term safety concerns related to liver metabolism modulation. Hepatic glucokinase activators represented a promising therapeutic alternative to sulfonylureas, with a more favorable hypoglycemia risk profile in the management of T2DM. However, further longitudinal studies were required to establish sustained efficacy, safety, and optimal dosing.

Keywords: Type 2 diabetes mellitus, Hepatic glucokinase activators, Sulfonylureas, hypoglycemia, Glucose metabolism, Pancreatic β-cell.

CITE AS: Mpora Kakwanzi Evelyn (2026). Hepatic Glucokinase Activators versus Sulfonylureas: Hypoglycemia Risk Reduction in Type 2 Diabetes Management. RESEARCH INVENTION JOURNAL OF BIOLOGICAL AND APPLIED SCIENCES 6(1):38-42. https://doi.org/10.59298/RIJBAS/2026/613842