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A retrospective in-depth analysis of continuous glucose monitoring datasets for patients with hepatic glycogen storage disease: Recommended outcome parameters for glucose management.

ABSTRACT: Continuous glucose monitoring (CGM) systems have great potential for real-time assessment of glycemic variation in patients with hepatic glycogen storage disease (GSD). However, detailed descriptions and in-depth analysis of CGM data from hepatic GSD patients during interventions are scarce. This is a retrospective in-depth analysis of CGM parameters, acquired in a continuous, real-time fashion describing glucose management in 15 individual GSD patients. CGM subsets are obtained both in-hospital and at home, upon nocturnal dietary intervention (n = 1), starch loads (n = 11) and treatment of GSD Ib patients with empagliflozin (n = 3). Descriptive CGM parameters, and parameters reflecting glycemic variation and glycemic control are considered useful CGM outcome parameters. Furthermore, the combination of first and second order derivatives, cumulative sum and Fourier analysis identified both subtle and sudden changes in glucose management; hence, aiding assessment of dietary and medical interventions. CGM data interpolation for nocturnal intervals reduced confounding by physical activity and diet. Based on these analyses, we conclude that in-depth CGM analysis can be a powerful tool to assess glucose management and optimize treatment in individual hepatic GSD patients.

SUBMITTER: Peeks F

PROVIDER: S-EPMC8519135 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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A retrospective in-depth analysis of continuous glucose monitoring datasets for patients with hepatic glycogen storage disease: Recommended outcome parameters for glucose management.

Peeks Fabian F Hoogeveen Irene J IJ Feldbrugge R Lude RL Burghard Rob R de Boer Foekje F Fokkert-Wilts Marieke J MJ van der Klauw Melanie M MM Oosterveer Maaike H MH Derks Terry G J TGJ

Journal of inherited metabolic disease 20210505 5

Continuous glucose monitoring (CGM) systems have great potential for real-time assessment of glycemic variation in patients with hepatic glycogen storage disease (GSD). However, detailed descriptions and in-depth analysis of CGM data from hepatic GSD patients during interventions are scarce. This is a retrospective in-depth analysis of CGM parameters, acquired in a continuous, real-time fashion describing glucose management in 15 individual GSD patients. CGM subsets are obtained both in-hospital ...[more]

PMID: 33834518

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Project description:ContextAlthough previous research has shown the benefit of continuous glucose monitoring (CGM) for hepatic glycogen storage diseases (GSDs), current lack of prospectively collected CGM metrics and glycemic targets for CGM-derived outcomes in the hepatic GSD population limits its use.ObjectiveTo assess CGM metrics for glycemic variation and glycemic control in adult patients with GSDIa as compared to matched healthy volunteers.DesignProspective CGM data were collected during the ENGLUPRO GSDIa trial (NCT04311307) in which a Dexcom G6 device was used. Ten adult patients with GSDIa and 10 age-, sex- and body mass index-matched healthy volunteers were enrolled. Capillary blood glucose was concurrently measured during 2 standardized 2-hour time intervals. Descriptive [eg, glycemic variability (GV), time below range, time in range (TIR), time above range (TAR)] and advanced (ie, first- and second-order derivatives, Fourier analysis) CGM outcomes were calculated. For each descriptive CGM outcome measure, 95% CIs were computed in patients with GSDIa and healthy volunteers, respectively.ResultsCGM overestimation was higher under preprandial and level 1 hypoglycemia (ie, capillary glucose values ≥ 3.0 mmol/L and < 3.9 mmol/L) conditions. GV and TAR were higher while TIR was lower in patients with GSDIa compared to healthy volunteers (P < 0.05). Three patients with GSDIa showed descriptive CGM outcomes outside the calculated 95% CI in GSDIa patients. Advanced CGM analysis revealed a distinct pattern (ie, first- and second-order derivatives and glucose curve amplitude) in each of these 3 patients within the patients group.ConclusionsThis is the first study to prospectively compare CGM outcomes between adult patients with GSDIa and matched healthy volunteers. The generation of a set of CGM metrics will provide guidance in using and interpreting CGM data in GSDIa and will be useful for the definition of glycemic targets for CGM in patients with GSDIa. Future studies should investigate the prognostic value of CGM outcomes and their major determinants in patients with GSDIa.

Project description:ObjectiveCarbohydrate Response Element Binding Protein (ChREBP) is a glucose 6-phosphate (G6P)-sensitive transcription factor that acts as a metabolic switch to maintain intracellular glucose and phosphate homeostasis. Hepatic ChREBP is well-known for its regulatory role in glycolysis, the pentose phosphate pathway, and de novo lipogenesis. The physiological role of ChREBP in hepatic glycogen metabolism and blood glucose regulation has not been assessed in detail, and ChREBP's contribution to carbohydrate flux adaptations in hepatic Glycogen Storage Disease type 1 (GSD I) requires further investigation.MethodsThe current study aimed to investigate the role of ChREBP as a regulator of glycogen metabolism in response to hepatic G6P accumulation, using a model for acute hepatic GSD type Ib. The immediate biochemical and regulatory responses to hepatic G6P accumulation were evaluated upon G6P transporter inhibition by the chlorogenic acid S4048 in mice that were either treated with a short hairpin RNA (shRNA) directed against ChREBP (shChREBP) or a scrambled shRNA (shSCR). Complementary stable isotope experiments were performed to quantify hepatic carbohydrate fluxes in vivo.ResultsShChREBP treatment normalized the S4048-mediated induction of hepatic ChREBP target genes to levels observed in vehicle- and shSCR-treated controls. In parallel, hepatic shChREBP treatment in S4048-infused mice resulted in a more pronounced accumulation of hepatic glycogen and further reduction of blood glucose levels compared to shSCR treatment. Hepatic ChREBP knockdown modestly increased glucokinase (GCK) flux in S4048-treated mice while it enhanced UDP-glucose turnover as well as glycogen synthase and phosphorylase fluxes. Hepatic GCK mRNA and protein levels were induced by shChREBP treatment in both vehicle- and S4048-treated mice, while glycogen synthase 2 (GYS2) and glycogen phosphorylase (PYGL) mRNA and protein levels were reduced. Finally, knockdown of hepatic ChREBP expression reduced starch domain binding protein 1 (STBD1) mRNA and protein levels while it inhibited acid alpha-glucosidase (GAA) activity, suggesting reduced capacity for lysosomal glycogen breakdown.ConclusionsOur data show that ChREBP activation controls hepatic glycogen and blood glucose levels in acute hepatic GSD Ib through concomitant regulation of glucose phosphorylation, glycogenesis, and glycogenolysis. ChREBP-mediated control of GCK enzyme levels aligns with corresponding adaptations in GCK flux. In contrast, ChREBP activation in response to acute hepatic GSD Ib exerts opposite effects on GYS2/PYGL enzyme levels and their corresponding fluxes, indicating that GYS2/PYGL expression levels are not limiting to their respective fluxes under these conditions.

Dataset Information

A retrospective in-depth analysis of continuous glucose monitoring datasets for patients with hepatic glycogen storage disease: Recommended outcome parameters for glucose management.

Publications

A retrospective in-depth analysis of continuous glucose monitoring datasets for patients with hepatic glycogen storage disease: Recommended outcome parameters for glucose management.

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