What enzyme with high Km (Michaelis constant) and high Vmax (maximum velocity) regulates insulin secretion?

From the Guidelines

Glucokinase is the enzyme with high Km and high Vmax that regulates insulin secretion in pancreatic beta cells. This enzyme serves as a glucose sensor in beta cells because its high Km (low affinity) for glucose means it only becomes active when blood glucose levels rise significantly above normal fasting levels [ 1 ]. When blood glucose increases after a meal, glucokinase accelerates glucose phosphorylation, generating glucose-6-phosphate at a rate proportional to blood glucose concentration. This increases ATP production, which closes ATP-sensitive potassium channels, depolarizes the cell membrane, opens calcium channels, and triggers insulin release.

Key Characteristics of Glucokinase

• High Km: allows the enzyme to only become active at high glucose levels
• High Vmax: enables the enzyme to rapidly increase its activity as glucose levels rise
• Serves as a glucose sensor in beta cells
• Critical for glucose homeostasis, as mutations in the glucokinase gene can cause both hyperglycemia and hypoglycemia [ 1 ]. Some key points to consider when evaluating the role of glucokinase in insulin secretion include:
• The enzyme's unique kinetic properties prevent hypoglycemia by limiting insulin secretion at low glucose levels
• Glucokinase enables appropriate insulin release during hyperglycemia
• Mutations in the glucokinase gene can cause maturity-onset diabetes of the young type 2, highlighting its critical role in glucose homeostasis [ 1 ].

From the Research

Enzyme Kinetics and Insulin Secretion

• The enzyme glucokinase (GCK) plays a crucial role in glucose homeostasis and is considered the glucose sensor for regulating insulin release by pancreatic β-cells 2.
• GCK has a high Km (Michaelis constant) and high Vmax (maximum velocity), which allows it to effectively phosphorylate glucose to glucose-6-phosphate throughout the physiological range of glucose concentrations 2.
• The high Km of GCK enables it to respond to changes in glucose levels, while the high Vmax ensures that glucose phosphorylation occurs rapidly and efficiently 2.

Regulation of Insulin Secretion

• Insulin secretion is regulated by the energy state of the pancreatic β-cells, which is influenced by the metabolism of glucose 2.
• The increase in intramitochondrial [NADH]/[NAD+] and [ATP]/[ADP][Pi] ratios, and the decrease in [Mg2+ADP] and [AMP] levels, play a crucial role in regulating insulin secretion 2.
• Sulfonylureas and meglitinides are oral hypoglycemic agents that increase insulin secretion by closing ATP-sensitive potassium channels in pancreatic β-cells, thereby stimulating insulin release 3, 4, 5.

Treatment of Type 2 Diabetes

• Metformin is the first-line treatment for type 2 diabetes mellitus, and it inhibits hepatic gluconeogenesis by suppressing the expression of genes involved in glucose production 6.
• Sulfonylureas and meglitinides are commonly used as second-line agents for treating type 2 diabetes mellitus, and they offer an alternative to metformin for patients who are intolerant or have contraindications to metformin 3, 4, 5.
• The combination of metformin and nitric oxide may offer a potential therapeutic strategy for managing type 2 diabetes mellitus by enhancing the inhibition of hepatic gluconeogenesis and decreasing the required dose of metformin 6.