Identification of pathogenic GCK variants in patients with common type 2 diabetes can lead to discontinuation of pharmacological treatment

Thuesen, Anne Cathrine Baun; Jensen, Rasmus Tanderup; Maagensen, Henrik; Kristiansen, Maja Refshauge; Sørensen, Henrik Toft; Vaag, Allan; Beck‐Nielsen, Henning; Pedersen, Oluf; Grarup, Niels; Nielsen, Jens Steen; Rungby, Jørgen; Gjesing, Anette P.; Storgaard, Heidi; Vilsbøll, Tina; Hansen, Torben

doi:10.1016/j.ymgmr.2023.100972

Cited by 3 publications

(5 citation statements)

References 51 publications

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“…On the surface, it may appear as if our results oppose other studies describing the MODY GCK phenotype as an isolated, stable hyperglycemia 18,19 . Instead, it is important to consider the combination of penetrance in glucose elevations with lifetime risk of both T2D diagnosis and diabetic outcomes in individuals harboring qualifying GCK variants.…”

Section: Discussioncontrasting

confidence: 75%

“…While glucose and HbA1c are linked to T2D diagnosis, these measures are an incomplete representation of clinically significant outcomes themselves. Research suggests not all individuals harboring pathogenic GCK variants are truly diabetic in the sense of their likelihood to develop microvascular and macrovascular outcomes 12,18,19 . In order to assess whether individuals with qualifying MODY or Novel GCK qualifying variants diagnosed with T2D had different outcomes compared to other T2D patients, we used the adapted Diabetes Complication Severity Index (DCSI), a 14-point scale, derived from the ICD codes obtained from patient medical records, organized into seven disease categories that are considered secondary complications of T2D (see methods for details, Table S1 for ICD codes and severity scores for each category) 29,30 .…”

Section: Resultsmentioning

confidence: 99%

“…Penetrance estimates for GCK and T2D are in line with some of the most well established CDC Tier-1 gene-disease associations, such as BRCA1 / BRCA2 with Breast and Ovarian Cancers and LDLR / APOB with Familial Hypercholesterolemia 13 . Early work focused on outcomes suggests that those harboring GCK variants and standalone mild, stable hyperglycemia are not at increased risk for the typical array of long-range complications associated with T2D, especially microvascular complications 14,18–22 . In addition, treating patients with damaging GCK variants with first-line pharmacological interventions such as insulin or oral hypoglycaemic agents (metformin and glibenclamide) has been shown to have little to no effect on HbA1c levels, and it may be difficult or impossible to reduce glucose levels below standard risk thresholds 18,23 .…”

mentioning

confidence: 99%

“…Early work focused on outcomes suggests that those harboring GCK variants and standalone mild, stable hyperglycemia are not at increased risk for the typical array of long-range complications associated with T2D, especially microvascular complications 14,18–22 . In addition, treating patients with damaging GCK variants with first-line pharmacological interventions such as insulin or oral hypoglycaemic agents (metformin and glibenclamide) has been shown to have little to no effect on HbA1c levels, and it may be difficult or impossible to reduce glucose levels below standard risk thresholds 18,23 . Taken together, the excess of T2D diagnoses in individuals harboring damaging GCK variants may represent some degree of misdiagnosis in adulthood of what are instead asymptomatic, mild and stable hyperglycemias in these individuals 11,18,24 .…”

mentioning

confidence: 99%

“…In addition, treating patients with damaging GCK variants with first-line pharmacological interventions such as insulin or oral hypoglycaemic agents (metformin and glibenclamide) has been shown to have little to no effect on HbA1c levels, and it may be difficult or impossible to reduce glucose levels below standard risk thresholds 18,23 . Taken together, the excess of T2D diagnoses in individuals harboring damaging GCK variants may represent some degree of misdiagnosis in adulthood of what are instead asymptomatic, mild and stable hyperglycemias in these individuals 11,18,24 . Untangling benign glucose elevations from accurately assigned T2D diagnoses in those with GCK variants represents a great opportunity for precision medicine 12 .…”

mentioning

confidence: 99%

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Patients with Type 2 Diabetes and aGCKvariant are still at risk for T2D-related secondary complications

Schiabor Barrett,

Telis,

McEwen

et al. 2023

Preprint

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Natural HbA1c levels inGCK-MODY patients often sit above the diagnostic threshold for type 2 diabetes (T2D). Standard treatments to lower HbA1c levels are ineffective in these individuals, yet in case studies to date,GCK-MODY patients often evade secondary T2D complications. Given these deviations from a more typical T2D disease course, genetic screening ofGCKmay be clinically useful, but population studies are needed to more precisely quantify T2D-related outcomes inGCKvariant carriers. Using a state-of-the-art variant interpretation strategy based on glucose elevations, we genotyped all individuals in two real-world cohorts (n~535,000) forGCKrisk variants and examined rates of T2D and T2D-complications from seven disease categories.We identified 439 individuals withGCKvariants predicted to increase glucose (~1/1200). Aligning with their glucose elevations,GCK-MODY variant carriers were 12x as likely, and all otherGCKrisk carriers 4x as likely, to receive a T2D diagnosis, compared to non-GCKcarriers. Surprisingly,GCKrisk carriers with T2D develop a range of T2D-related complications at rates comparable to non-GCKT2D patients. Although the penetrance for secondary complications is lower than that for glucose elevations,GCKrisk carriers remain at elevated risk of T2D and secondary complications.

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Section: Discussioncontrasting

confidence: 75%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Patients with Type 2 Diabetes and aGCKvariant are still at risk for T2D-related secondary complications

Schiabor Barrett,

Telis,

McEwen

et al. 2023

Preprint

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Underestimated risk of secondary complications in pathogenic and glucose-elevating GCK variant carriers with type 2 diabetes

Schiabor Barrett,

Telis,

McEwen

et al. 2024

Commun Med

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Background Natural HbA1c levels in GCK Maturity-onset diabetes of the young ( GCK -MODY) patients often sit above the diagnostic threshold for type 2 diabetes (T2D). Treatments to lower HbA1c levels show reduced effectiveness in these individuals, yet in case studies to date, GCK -MODY patients often evade secondary T2D complications. Given these deviations, genetic screening of GCK may be clinically useful, but population studies are needed to more broadly understand T2D-related complications in GCK variant carriers. Methods To identify GCK variant carriers at the population level, we used both ACMG/AMP variant interpretation for GCK-MODY pathogenicity and a state-of-the-art variant interpretation strategy based on functional and statistical evidence to predict glucose elevations. Presence of pathogenic and glucose-elevating GCK variants was assessed in two cohorts ( n ~535,000). We identified 442 individuals with GCK variants predicted to increase glucose (~1/1200), with 150 (34%) of these individuals harboring variants reaching a pathogenic interpretation. Results In a retrospective analysis, we show that in addition to elevated HbA1c, pathogenic variant carriers are 10x as likely, and all other glucose-elevating GCK variant carriers are 3x as likely, to receive a T2D diagnosis compared to non- GCK carriers. Surprisingly, carriers of pathogenic and glucose-elevating GCK variants with T2D develop T2D-related complications at rates more than double that of individuals without T2D, comparable to non- GCK individuals with T2D. Conclusions This population-level assessment shows secondary complications in individuals with pathogenic and glucose-elevating GCK variants and T2D and suggests that genotyping for these variants should be considered in a precision medicine approach for T2D treatment and prevention.

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The Danish Centre for Strategic Research in Type 2 Diabetes (DD2) Project Cohort and Biobank from 2010 Through 2023—A Cohort Profile Update

Kristensen,

Nicolaisen,

Nielsen

et al. 2024

CLEP

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Purpose This paper provides an overview of the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) cohort and biobank, including baseline characteristics of participants enrolled up to 2023, and post-enrollment rates of cardiovascular disease outcomes and mortality. Methods Since 2010, the DD2 project has enrolled individuals with type 2 diabetes mellitus (T2DM) recently diagnosed by general practitioners and by hospital-based clinicians across Denmark. Data from questionnaires, clinical examinations, and biological samples are collected at enrollment. Additional baseline and longitudinal follow-up data are accessed via linkage to health registries. Results Between 2010 and 2023, the DD2 project enrolled 11,369 participants (41.3% women, median age 61.4 years). Median T2DM duration at enrollment was 1.3 years, and median BMI was 31.6 kg/m 2 for women and 30.5 kg/m 2 for men. 18.3% were smokers, 5.7% consumed more than 14/21 units of alcohol weekly (women/men), and 17.9% reported leisure-time physical inactivity. Original midwife records dating back >80 years revealed that 20.2% of cohort participants had birth weights <3000 g. Based on complete hospital contact history 10 years before enrollment, 20.7% of cohort participants had macrovascular complications, 17.0% had microvascular complications, and 21.7% had kidney disease based on eGFR or urine albumin-creatinine measurements. At enrollment, statins were used by 68.2%, antihypertensive drugs by 69.9%, and glucose-lowering drugs by 86.5% of individuals. Median HbA1c was 48 mmol/mol and median LDL cholesterol 2.2 mmol/L. Genome-wide genotyping and biomarker data have been analyzed for over 9000 individuals. During the current follow-up time from the enrollment date (median 7.9 years), incident cardiovascular disease rate has been 13.8 per 1000 person-years and the mortality rate has been 17.6 per 1000 person-years. Conclusion The DD2 cohort, with its detailed information and long-term follow up, can improve our understanding of the progression and prevention of complications among individuals with newly diagnosed T2DM.

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Identification of pathogenic GCK variants in patients with common type 2 diabetes can lead to discontinuation of pharmacological treatment

Cited by 3 publications

References 51 publications

Patients with Type 2 Diabetes and aGCKvariant are still at risk for T2D-related secondary complications

Patients with Type 2 Diabetes and aGCKvariant are still at risk for T2D-related secondary complications

Underestimated risk of secondary complications in pathogenic and glucose-elevating GCK variant carriers with type 2 diabetes

The Danish Centre for Strategic Research in Type 2 Diabetes (DD2) Project Cohort and Biobank from 2010 Through 2023—A Cohort Profile Update

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