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© 2004 by the American Diabetes Association, Inc.
Letters: Observations |
Normal Insulin Sensitivity During the Late Preclinical Stage of Type 1 Diabetes
1 Service d’endocrinologie-diabétologie, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, Paris, France
2 Unité Diabète de l’Enfant et de l’Adolescent, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
3 Service d’immunologie clinique, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
Address correspondence to Dr. Etienne Larger, Service d’endocrinologie-diabétologie, Hôpital Bichat, 46 rue H. Huchard, 75877 Paris cedex 18, France. E-mail: etienne.larger{at}bch.ap-hop-paris.fr
In most cases, type 1 diabetes is the late consequence of a ß-cell autoimmune destruction leading to absolute insulin deficiency (1). At onset of clinical diabetes, ß-cell mass is thought to be reduced by 80–90% (2), and 73% of adult patients have ketosis or ketoacidosis at diagnosis (3). Patients with type 1 diabetes have major defects in insulin sensitivity at diagnosis of overt diabetes (4–8). However, the fact that pre-diabetic patients can maintain normal blood glucose levels in spite of dramatically low insulin secretory capacities suggests that their insulin sensitivity is normal.
Here we report that insulin sensitivity, measured by the glucose clamp method in nine patients, remains normal even during the very late preclinical stage of type 1 diabetes. None of these patients had clinical symptoms of overt diabetes, spontaneous weight loss, or ketosis before or at the time of the study. Mean age at entry in the study was 27 years (range 20–41). The mean BMI was 20.9 kg/m2 (range 16.3–23.2). All patients were islet cell antibody positive, and seven of eight tested had at least one susceptibility HLA haplotype. Mean fasting glucose level was 7.2 ± 1.3 mmol/l (range 5–9.6). Of the eight patients who met the criteria for diabetes, four had fasting blood glucose level <7 mmol/l; in the ninth patient, oral glucose tolerance test disclosed impaired glucose tolerance. The mean HbA1c level was 6.4 ± 0.8% (range 5.3–7.8; normal values 5.0 ± 0.5%). The sum of 1- and 3- min plasma insulin levels after the intravenous glucose tolerance test was 15.3 ± 5.8 mU/l (range 11–25).
Four patients were treated with insulin immediately after the metabolic explorations reported here. Four others have initiated permanent insulin therapy within 24 months of follow-up. The last patient was still non-insulin dependent when last seen 1 year after the study.
During clamp studies, the insulin dose-response curve of preclinical type 1 diabetic subjects was superimposable to that of 20 healthy control subjects. Maximal glucose infusion rate, at a plasma insulin level of 1,400 ± 120 mU/l, was 17.2 ± 1.6 mg · kg–1 · min–1 (Fig. 1). It was 16.4 ± 0.6 mg · kg–1 · min–1 in 20 control subjects at a similar plasma insulin level: 1,500 ± 100 mU/l. By contrast, the maximal glucose infusion rate was significantly lower in 15 patients with symptomatic diabetes of recent onset (11 ± 1.4 mg · kg–1 · min–1, P = 0.003 by Mann-Whitney U test). These results confirm, at an even later stage of the natural history of the disease, those observed in a substudy of the Diabetes Prevention Trial-1 (9). Thus, the onset of overt clinical diabetes may be triggered by the addition of insulin resistance to insulin deficiency; the triggers may be external or internal factors. In this respect, the seasonal peaks of the incidence of diabetes (10) suggest that viral infections may play a role in the very final act of the preclinical phase by triggering insulin resistance and metabolic storm. The respective parts of insulin deficiency and insulin resistance may be determinants for the onset and duration of the honeymoon period.
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). For the purpose of comparison, results obtained in control subjects (
) and in patients with symptomatic diabetes studied within 1–3 week after diagnosis (
) are shown. The latter two are from ref. Footnotes
M.E. is currently affiliated with the UFR de Physiologie, Faculté des sciences, nutrition et endocrinologie, Errachidia, Morocco; J.T. and C.B. are currently affiliated with the Service d’immunologie-diabétologie, hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Paris, France; R.B. is currently affiliated with UMR 5018 CHU Rangueil, Toulouse, France.
Deceased in August 2003. 
References
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- Burcelin R, Eddouks M, Beylot M, Normand S, Boitard C, Feutren G, Landais P, Riou JP, Girard JR, Bach JF, Assan RI: Hypersensitivity to insulin during remissions in cyclosporin-treated IDDM patients. Diabetes Care 16:880–895, 1993
- DeFronzo RA, Matsuda M, Barrett E: Diabetic ketoacidosis: a combined metabolic-nephrologic approach. Diabetes Rev 2:209–238, 1994
- Greenbaum CJ, Prigeon RL, D’Alessio DA: Impaired ß-cell function, incretin effect, and glucagon suppression in patients with type 1 diabetes who have normal fasting glucose. Diabetes 51:951–957, 2002
[Abstract/Free Full Text]
- Lévy-Marchal C, Patterson C, Green A: Variation by age group and seasonality at diagnosis of chilhood IDDM in Europe. Diabetologia 38:823–830, 1995[Medline]
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