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Attenuated incretin effect after glucose loading in monogenic HNF1A diabetes

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11 diapositives · 217 Views · Aug 24, 2014
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Attenuated incretin effect after glucose loading in monogenic HNF1A diabetes
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  1. Attenuated incretin effect after glucose loading in monogenic HNF1A diabetes Diabetes doi:10.2337/db13-1878

  2. Introduction • Maturity onset diabetes of the young (MODY) represents monogenic forms of nonautoimmune diabetes characterized by autosomal dominant inheritance, non-insulin dependent diabetes at onset, and diagnosis often before 25 years of age • The two most common forms result from mutations in the genes encoding glucokinase (GCK) (GCK-diabetes: MODY2; 10 to 20% of all MODY patients) and hepatocyte nuclear factor 1α (HNF1A) (HNF1Adiabetes: MODY3; 36 to 60% of all MODY patients • In a new study, Signe Østoft and colleagues report that patients with MODY3 exhibit a diminished incretin effect

  3. Research Design And Methods • Ten patients with HNF1A-diabetes and 9 patients with GCK-diabetes were included • Six patients with HNF1A-diabetes were treated with oral blood glucose lowering drugs. The remaining MODY patients (n = 13) were treated with diet only • Controls (CTRLs) (n = 9) were without family history of diabetes and had normal glucose tolerance

  4. Research Design And Methods • Participants were studied on two separate experimental days: 1) a 4h 50g-oral glucose tolerance test (OGTT) and 2) a 4h isoglycemic intravenous glucose infusion (IIGI) • The two days were separated by at least 48 hours and each day was preceded by 1-week wash-out of blood glucose lowering drugs and an overnight 10h fast • Acetaminophen (1.5g) was added the OGTT to estimate gastric emptying • The IIGI was performed with sterile 20% w/v glucose infusion adjusted to duplicate the PG profile of the OGTT

  5. Research Design And Methods • Blood samples were drawn at predefined time points before, during and after glucose administration • Baseline, peak, area under the curve (AUC) and incretin effect values are expressed as mean±standard error of the mean (SEM) • Differences resulting in P values <0.05 were considered significant • Linear mixed effect modeling was used for analysis of longitudinal and repeated measures using statistical software R • Insulinogenic index was used to assess beta cell secretory function, and was calculated based on plasma insulin (PI) as (PI30min-PIbaseline)/ (PG30 min-PGbaseline)

  6. Results Plasma glucose (Panel A), plasma insulin (Panel B) Means ± SEM during 50g-oral glucose tolerance test (OGTT) (closed symbols) and isoglycemic intravenous glucose infusion (IIGI) (open symbols) in healthy individuals (CTRL) (purple symbols) and in patients with GCK-diabetes (blue symbols) and HNF1A-diabetes (green symbols)

  7. Plasma C peptide concentrations (Panel C) and ISR (Panel D) Results Means ± SEM during 50g-oral glucose tolerance test (OGTT) (closed symbols) and isoglycemic intravenous glucose infusion (IIGI) (open symbols) in healthy individuals (CTRL) (purple symbols) and in patients with GCK-diabetes (blue symbols) and HNF1A-diabetes (green symbols)

  8. Results • The incretin effect, calculated from insulin release, was similar in CTRLs and patients with GCK-diabetes (CTRL: 48 ± 5%; GCK-diabetes: 44 ± 3%; P = 0.587) • Whereas patients with HNF1A-diabetes exhibited a lower incretin effect (HNF1A-diabetes: 19 ± 8%) compared to the other groups (vs. CTRL: P = 0.008; vs. GCK-diabetes: P = 0.011) • When calculating the incretin effect from C-peptide and ISR patients with HNF1A-diabetes exhibited lower incretin effect compared to CTRLs but not to patients with GCK-diabetes

  9. Results Glucagon, GIP and GLP-1. Plasma glucagon (Panel A), GIP (Panel B) and GLP-1 concentrations (Panel C) (means ± SEM) during 50g-oral glucose tolerance test (OGTT) (closed symbols) and isoglycemic intravenous glucose infusion (IIGI) (open symbols) in healthy individuals (CTRL) (purple symbols) and in patients with GCK-diabetes (blue symbols) and HNF1A-diabetes (green symbols). Glucagon data are baseline-subtracted

  10. Results • The incretin effect, calculated from insulin release, was similar in CTRLs and patients with GCK-diabetes (CTRL: 48 ± 5%; GCK-diabetes: 44 ± 3%; P = 0.587) • Whereas patients with HNF1A-diabetes exhibited a lower incretin effect (HNF1A-diabetes: 19 ± 8%) compared to the other groups (vs. CTRL: P = 0.008; vs. GCK-diabetes: P = 0.011) • When calculating the incretin effect from C-peptide and ISR patients with HNF1A-diabetes exhibited lower incretin effect compared to CTRLs but not to patients with GCK-diabetes

  11. Conclusion • Patients with GCK-diabetes exhibit preserved incretin physiology • While patients with HNF1A-diabetes are characterized by • A reduced incretin effect • A marked beta cell dysfunction • An inappropriate glucagon response to OGTT, but have normal insulin sensitivity