medwireNews: Dorzagliatin treatment has increased insulin secretion and improved beta-cell function in patients with glucokinase maturity-onset diabetes of the young (GK-MODY), also known as MODY2, in a small phase 1 trial.
Elaine Chow (The Chinese University of Hong Kong), who presented the study at the 82nd ADA Scientific Sessions in New Orleans, Louisiana, explained that dorzagliatin achieved this by restoring the enzyme activity of select GK variants in addition to enhancing normal GK activity.
GK is important for glucose metabolism because it serves as a kind of glucose sensor for the pancreatic beta cells, explained Chow. “Within the pancreatic beta cells, glucokinase phosphorylates glucose to Glucose-6-P, and the latter participates in glycolysis and produces a large amount of ATP to stimulate insulin secretion. In the liver, glucokinase also enhances hepatic glucose uptake and glycogenesis.”
In patients with GK-MODY, a range of different dominant mutations in the GK gene reduce the enzyme’s affinity for glucose, leading to mild, but persistent, hyperglycemia in those who carry only one copy of the mutation. For those with two copies, the symptoms are generally worse and require more treatment, noted Chow.
Dorzagliatin has achieved good phase 3 results for treating type 2 diabetes over the past couple of years in the SEED and DAWN studies, among others. To investigate its potential for treating GK-MODY, Chow and colleagues carried out a small exploratory study including eight GK-MODY patients and 10 newly diagnosed type 2 diabetes patients.
The participants were adults younger than 65 years old who had a BMI in the healthy to overweight range. During the study, participants underwent 2-hour 12 mmol/L hyperglycemic clamps with either placebo or dorzagliatin 75 mg, followed by a 2-week washout period and then another hyperglycemic clamp and the alternate treatment option with a follow-up 7 days later.
The results showed that dorzagliatin was able to restore glucokinase activity in individuals with GK-MODY, correcting the inherited glucose sensing defect. Insulin secretion rates improved significantly after 100 minutes of the clamp with dorzagliatin compared with placebo, at absolute rates of 413.6 versus 271.7 pmol/min per m2 and incremental rates of 341.8 versus 214.3 pmol/min per m2.
Beta cell function was also significantly improved, with patients achieving a glucose sensitivity of 51.0 pmol/min per m2 with dorzagliatin treatment, compared with 33.4 pmol/min per m2 with placebo.
Both of these improvements were greater among those with GK-MODY than among the group with type 2 diabetes, observed Chow.
She suggested that, while people with GK-MODY who only have one GK mutation may not require this level of treatment, dorzagliatin shows promise for homozygous individuals with GK-MODY and others who develop more severe symptoms.
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ADA Scientific Sessions; New Orleans, Louisiana: 3–7 June 2022