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Assessment of insulin sensitivity in glucokinase-deficient subjects

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Summary

The chronic hyperglycaemia of glucokinase-deficient diabetes results from a glucose-sensing defect in pancreatic beta cells and abnormal hepatic glucose phosphorylation. We have evaluated the contribution of insulin resistance to this form of chronic hyperglycaemia. Insulin sensitivity, assessed by the homeostasis model assessment (HOMA) method in 35 kindreds with glucokinase mutations, was found to be significantly decreased in 125 glucokinase-deficient subjects as compared to 141 unaffected first-degree relatives. Logistic regression analysis showed that in glucokinase-deficient subjects a decrease in insulin sensitivity was associated with deterioration of the glucose tolerance status. A euglycaemic hyperin-sulinaemic clamp was performed in 14 glucokinase-deficient subjects and 12 unrelated control subjects. In six patients and six control subjects the clamp was coupled to dideutero-glucose infusion to measure glucose turnover. Average glucose infusion rates (GIR) at 1 and 5 mU · kg body weight · min−1 insulin infusion rates were significantly lower in (the glucokinase-deficient) patients than in control subjects. Although heterogeneous results were observed, in 8 out of the 14 patients GIRs throughout the experiment were lower than 1 SD below the mean of the control subjects. Hepatic glucose production at 1 mU · kg body weight−1 · min−1 insulin-infusion rate was significantly higher in patients than in control subjects. In conclusion, insulin resistance correlates with the deterioration of glucose tolerance and contributes to the hyperglycaemia of glucokinase-deficient diabetes. Taken together, our results are most consistent with insulin resistance being considered secondary to the chronic hyperglycaemia and/or hypoinsulinaemia of glucokinase-deficiency. Insulin resistance might also result from interactions between the unbalanced glucose metabolism and susceptibility gene(s) to low insulin sensitivity likely to be present in this population.

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Abbreviations

NIDDM:

Non-insulin-dependent diabetes mellitus

HGP:

hepatic glucose production

GCK:

glucokinase

IIR:

insulin infusion rate

GIR:

glucose infusion rate

MFH:

mild fasting hyperglycaemia

NGT:

normal glucose tolerance

IGT:

impaired glucose tolerance

HOMA:

homeostasis model assessment

ANOVA:

analysis of variance

MODY:

maturity-onset diabetes of the young

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Authors and Affiliations

  1. CNRS EP-10, Institut Pasteur de Lille, Lille, France

    K. Clément, M. Vaxillaire & Ph. Froguel

  2. INSERM U-358, HÔpital Saint Louis, 16 rue de la Grange aux Belles, F-75010, Paris, France

    M. E. Pueyo &  G. Velho

  3. INSERM U-30, HÔpital Necker-Enfants Malades, Paris, France

    B. Rakotoambinina & J. -J. Robert

  4. INSERM U-290, HÔpital Saint Lazare, Paris, France

    F. Thuillier

  5. Service d'Endocrinologie et Diabétologie, HÔpital Saint Louis, Paris, France

    Ph. Passa

Authors
  1. K. Clément
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  2. M. E. Pueyo
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  3. M. Vaxillaire
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  4. B. Rakotoambinina
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  5. F. Thuillier
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  6. Ph. Passa
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  7. Ph. Froguel
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  8. J. -J. Robert
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  9. G. Velho
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Clément, K., Pueyo, M.E., Vaxillaire, M. et al. Assessment of insulin sensitivity in glucokinase-deficient subjects. Diabetologia 39, 82–90 (1996). https://doi.org/10.1007/BF00400417

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  • DOI: https://doi.org/10.1007/BF00400417

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