Published online April 14, 2008
Diabetes Care
31:1321-1323,
2008
DOI: 10.2337/dc07-2017
© 2008 by the American Diabetes Association
Clinical Care/Education/Nutrition/Psychosocial Research
Original Research |
Long-Term Follow-Up of Oral Glucose Tolerance Test–Derived Glucose Tolerance and Insulin Secretion and Insulin Sensitivity Indexes in Subjects With Glucokinase Mutations (MODY2)
Delphine Martin, MD1,
Christine Bellanné-Chantelot, PHD2,
Inge Deschamps, MD1,
Philippe Froguel, MD, PHD3,
Jean-Jacques Robert, MD, PHD1 and
Gilberto Velho, MD, PHD4
1 Department of Pediatric Diabetology, AP-HP Hôpital Necker-Enfants Malades, Paris, France
2 Department of Genetics, AP-HP Groupe Hospitalier Pitié-Salpétrière, Paris, France
3 CNRS, UMR 8090, Institute of Biology, Pasteur Institute, Lille, France
4 INSERM, Unité 695, Paris, France
Corresponding author: Dr. Gilberto Velho, velho{at}bichat.inserm.fr
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ABSTRACT
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OBJECTIVE—We investigated the natural history of glucokinase (GCK)-related maturity-onset diabetes of the young type 2 (MODY2), notably the factors associated with deterioration of hyperglycemia over time.
RESEARCH DESIGN AND METHODS—We report an 11-year follow-up of glucose tolerance and indexes of insulin secretion and insulin sensitivity derived from oral glucose tolerance tests in 33 MODY2 subjects.
RESULTS—The variation between tests of glucose tolerance (expressed as the area under the glucose curve) was 6.9 ± 3.2% (mean ± SEM), but individual results ranged from –20 to 61%. Deterioration of glucose tolerance between tests was associated with decreased insulin sensitivity, while insulin secretion remained stable.
CONCLUSIONS—Glucose tolerance can remain stable over many years in subjects with MODY2 due to the relative stability of the GCK-related β-cell defect. However, the development of insulin resistance may have an important role in the deterioration of the glucose tolerance and in the long-term evolution of the disorder.
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INTRODUCTION
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Maturity-onset diabetes of the young type 2 (MODY2) is a familial form of hyperglycemia caused by heterozygous mutations in the gene encoding glucokinase (GCK) (1). Hyperglycemia related to GCK mutations results from defects in glucose-stimulated insulin secretion (2) and hepatic synthesis of glycogen from glucose (3). The hyperglycemia of MODY2 is often mild. Most patients have impaired fasting glucose or impaired glucose tolerance, and <50% of affected individuals have overt diabetes (1). To investigate the natural history of MODY2, and notably the factors associated with deterioration of hyperglycemia, we retrospectively analyzed hospital records of 33 MODY2 subjects. We report an 11-year follow-up of glucose tolerance and of indexes of insulin secretion and insulin sensitivity derived from oral glucose tolerance tests (OGTTs).
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RESEARCH DESIGN AND METHODS—
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We studied 17 women and 16 men from 14 MODY2 kindred of French ancestry who had undergone two OGTTs with insulin measurement, spaced by at least 4 years. GCK mutations were confirmed by direct sequencing (online appendix Table 1 [available at http://dx.doi.org/10.2337/dc07-2017]). The area under the curve (AUC) relating glucose or insulin levels and the time during the OGTT was calculated by the trapezoidal rule. Glucose tolerance was expressed as AUCglucose. Variation of AUCglucose between tests ( AUCglucose) was computed as the difference between values at the second and first OGTTs, expressed as a percent of the value at the first OGTT. Variations of other clinical and biological parameters between tests were calculated similarly. Indexes of β-cell function were computed as the ratios of AUCinsulin to AUCglucose and insulin30–0min to glucose30min (4). Insulin sensitivity was assessed by Matzuda's composite insulin sensitivity index (5). Homeostasis model assessment (HOMA) indexes of β-cell function (%B) and insulin sensitivity (%S) were also computed. Results are expressed as means ± SEM.
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RESULTS—
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The average follow-up period, defined as the interval between OGTTs, was 11.0 ± 1.1 years (range 4.3–25.1). Clinical and OGTT data are shown in Table 1 and in online appendix Fig. 1. Both fasting and 2-h glucose levels were slightly but significantly increased in the second compared with the first OGTT. Indexes of insulin secretion were similar at the first and second OGTTs. Insulin sensitivity was significantly decreased at the second OGTT. All quantitative clinical or biological parameters were significantly correlated at the first and second OGTTs (Table 1).
Although the average AUCglucose was only mildly increased between tests (variation 6.9 ± 3.2%), individual results of AUCglucose were heterogeneous, ranging –20 to 61% (online appendix Fig. 2). To investigate parameters associated with AUCglucose heterogeneity, we compared subjects whose glucose tolerance remained stable or had improved during follow-up with subjects whose glucose tolerance had deteriorated (online appendix Table 2). Groups were defined by a AUCglucose below or above the median of the distribution (4.69%), respectively. Subjects whose glucose tolerance deteriorated were older at the second OGTT (38 ± 4 vs. 27 ± 4 years, P = 0.02) and had a longer follow-up (14 ± 2 vs. 8 ± 1 years, P = 0.007). AUCglucose correlated both with age at the second OGTT (R2 = 0.17; P = 0.01) and with the duration of follow-up (R2 = 0.16; P = 0.01). Subjects whose glucose tolerance deteriorated had a higher BMI increase during follow-up, but the differences were not statistically significant. However, insulin sensitivity was correlated with BMI at the second OGTT (r2 = 0.19; P = 0.01).
Subjects whose glucose tolerance deteriorated showed significantly decreased HOMA%S during follow-up compared with subjects whose glucose tolerance remained stable (–27 ± 12% vs. 18 ± 15%, P = 0.04). They also showed a trend toward higher AUCinsulin. These observations are best explained by a deterioration of insulin sensitivity between tests in the former group. The variation of HOMA%B index of insulin secretion between tests was not significantly different in the two groups of subjects (16 ± 10% vs. 6 ± 10%, P = 0.49).
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CONCLUSIONS—
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This is the first systematic follow-up study of the natural history of MODY2. Our results suggest that glucose tolerance can remain stable over the course of many years in subjects with this form of diabetes. This may be related to the relative stability of the glucokinase-related β-cell defect, as insulin secretion in MODY2 subjects does not seem to aggravate substantially over time. However, if or when insulin resistance develops, the β-cell defect may prevent an adequate compensatory increase in insulin secretion, resulting in a deterioration of the glucose tolerance. We have previously documented that insulin resistance is frequent in subjects with MODY2 (6). Our present results suggest that it may have an important role in the deterioration of the glucose tolerance and in the long-term evolution of the disorder. These results contrast with those observed in MODY1 (HNF4A) and MODY3 (HNF1A), associated with a progressive decrease of insulin secretion and severe deterioration of hyperglycemia (7,8).
Insulin sensitivity is influenced by polygenic determinants interacting with multiple environmental factors. Putative unfavorable alleles are probably frequent in the general population, given the increasing worldwide prevalence of type 2 diabetes associated with changes in lifestyle. These unfavorable alleles could affect the clinical phenotype of MODY2 subjects. Their identification may provide a better understanding of the role of modifier genes in the clinical progression of monogenic types of diabetes. Regarding treatment, in most MODY2 cases, diet therapy satisfactorily controls blood glucose levels and no hypoglycemic medication is required (1). However, as for all patients with diabetes, subjects with MODY2 should be instructed not to gain excessive weight and to have a regular physical activity to avoid the development or aggravation of insulin resistance.
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Footnotes
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Published ahead of print at http://care.diabetesjournals.org on 14 April 2008.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C Section 1734 solely to indicate this fact.
Received for publication October 18, 2007.
Accepted for publication April 4, 2008.
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References
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- Velho G, Froguel P, Gloyn A, Hattersley AT: Maturity onset diabetes of the young type 2. In Glucokinase and Glycemic Diseases: From the Basics to Novel Therapeutics. Magnuson M, Matschinsky F, Eds. Basel, Karger, 2004, p. 42–64
- Byrne MM, Sturis J, Clément K, Vionnet N, Pueyo ME, Stoffel M, Takeda J, Passa P, Cohen D, Bell G, Velho G, Froguel P, Polonsky KS: Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations. J Clin Invest 93:1120–1130, 1994[Medline]
- Velho G, Petersen KF, Perseghin G, Hwang J-H, Rothman DL, Pueyo ME, Cline GW, Froguel P, Shulman GI: Impaired hepatic glycogen synthesis in glucokinase-deficient (MODY-2) subjects. J Clin Invest 98:1755–1761, 1996[Medline]
- Stumvoll M, Mitrakou A, Pimenta W, Jenssen T, Yki-Jarvinen H, Van Haeften T, Renn W, Gerich J: Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity. Diabetes Care 23:295–301, 2000[Abstract]
- Matsuda M, DeFronzo RA: Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 22:1462–1470, 1999[Abstract/Free Full Text]
- Clément K, Pueyo ME, Vaxillaire M, Rakotoambinina B, Thuillier F, Passa P, Froguel P, Robert JJ, Velho G: Assessment of insulin sensitivity in glucokinase-deficient subjects. Diabetologia 39:82–90, 1996[Medline]
- Pearson ER, Velho G, Clark P, Stride A, Shepherd M, Frayling TM, Bulman MP, Ellard S, Froguel P, Hattersley AT: B-cell genes and diabetes: quantitative and qualitative differences in the pathophysiology of hepatic nuclear factor 1-alpha and glucokinase mutations. Diabetes 50(Suppl. 1):S101–S107, 2001
- Fajans SS, Bell GI, Polonsky KS: Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med 345:971–980, 2001[Free Full Text]
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