Exploring Phenotype-Genotype Correlations Using Interstitial Glucose Results in a Family With a Glucokinase Mutation

Interstitial glucose measurements may be of clinical utility, when trying to differentiate mild glucose dysregulation from normoglycemia.¹ GCK (glucokinase) gene mutations, present in approximately 1:1,000 of the population,² are usually associated with mild glucose dysregulation. The glucose set point for heterozygotes with an inactivating mutation is shifted upward by around 30-50 mg/dL. In contrast to most other forms of hyperglycemia, glucose homeostasis is however maintained.² The term GCK-MODY (glucokinase maturity onset diabetes of youth, or MODY 2) refers to individuals with these inactivating mutations. Because hyperglycemia is mild, affected individuals rarely develop diabetes complications.²

The Case

A slim European male aged 56 years underwent community diabetes screening. He was diagnosed with T2DM (type 2 diabetes) based on (1) HbA1c values of 45-51 mmol/mol, measured over several years, and (2) the presence of comorbidities, including symptomatic axonal sensory peripheral neuropathy and mild background diabetic retinopathy. He was then referred to a diabetes specialist. Findings included a history of long-standing slim body habitus, a family history of “mild” diabetes, negative diabetes related antibodies, and no impact of metformin therapy on glucose or HbA1c. The diagnosis of T2DM was queried and GCK-MODY was considered. Subsequent genetic analysis showed heterozygosity for GCK:c.523G>A, p.(Gly175Arg), which is a genetic variant known to be associated with GCK-MODY, thus a diagnosis of GCK-MODY was confirmed.

Familial HbA1c prescreening of the proband’s two teenage sons showed HbA1cs (mmol/mol) of 33 and 47. The second son screened positive for the same genetic mutation as his father.

The next clinical question was, did the proband have additional concurrent etiology such as T2DM, explaining the presence of neuropathy and retinopathy, or was his metabolic status consistent with classical MODY 2?

We hypothesized that if the proband had GCK-MODY as the only etiology for elevated glucose levels, then the following would be observed: Concordance of absolute glucose values, in family members concordant for GK-MODY. Also, both positive and negative family members would show similar levels of glucose variability, demonstrating maintenance of glucose homeostasis in GK-MODY. Variability was assessed using MAGE (mean amplitude of glycemic excursions), calculated using EasyGV.³ Interstitial glucose results from the sons were in effect being used as control values (negative and positive), for comparison with results from the proband. Written consent was obtained for the measurement of interstitial glucose, using Abbott Libre.

Results (see Figure 1) demonstrate similar glucose values for the father and son with GCK-MODY, also MAGE for all three family members was similar and was within the normative range.⁴

Figure 1.

GCK-MODY family’s Abbott Libre downloads. Results collected contemporaneously over two weeks using the same batch of interstitial glucose sensors.

The proband’s elevated glucose was therefore considered to be due to GCK-MODY alone. His comorbidities were reassigned as follows: idiopathic axonal peripheral neuropathy, plus an incidental finding of a single small nondiabetic retinal lesion.

One other study has explored phenotype-genotype correlations in GCK-MODY using interstitial glucose monitoring.⁵ This study took place in a research setting, using CGM (continuous glucose monitoring).⁵ In the current study, factory-calibrated flash glucose monitoring was chosen for its ease of use and low cost.

In conclusion, our case study shows that interstitial glucose measurements may have an adjunctive role, when done together with standard laboratory testing, on the routine outpatient assessment of phenotype-genotype correlations in GCK-MODY.