The Loss of Postprandial Glycemic Control Precedes Stepwise Deterioration of Fasting With Worsening Diabetes LOUIS MONNIER, MD 1 CLAUDE COLETTE, PHD 2 GARETH J. DUNSEATH, MPHIL 3 DAVID R. OWENS, MD 3 OBJECTIVE — The aim of the study was to determine whether the loss of fasting and post- prandial glycemic control occurs in parallel or sequentially in the evolution of type 2 diabetes. RESEARCH DESIGN AND METHODS — In 130 type 2 diabetic patients, 24-h glucose profiles were obtained using a continuous glucose monitoring system. The individuals with type 2 diabetes were divided into five groups according to A1C levels: 1 (6.5%, n = 30), 2 (6.5– 6.9%, n = 17), 3 (7–7.9%, n = 32), 4 (8 – 8.9%, n = 25), and 5 (9%, n = 26). The glucose profiles between the groups were compared. The overall glucose concentrations for the diurnal, nocturnal, and morning periods, which represent the postprandial, fasting, and the dawn phe- nomenon states, respectively, were also compared. RESULTS — Glucose concentrations increased steadily from group 1 to 5 in a stepwise man- ner. The initial differences in mean glucose concentrations reaching statistical significance oc- curred 1) between groups 1 and 2 (6.4 vs. 7.7 mmol/l, P = 0.0004) for daytime postprandial periods, followed by differences; 2) between groups 2 and 3 (7.5 vs. 9.3 mmol/l, P = 0.0003) for the morning periods (dawn phenomenon); and finally 3) between groups 3 and 4 (6.3 vs. 8.4 mmol/l, P  0.0001) for nocturnal fasting periods. CONCLUSIONS — The deterioration of glucose homeostasis in individuals with type 2 diabetes progressed from postprandial to fasting hyperglycemia following a three-step process. The first step related to the three diurnal postmeal periods considered as a whole, the second step occurred during the morning period, and the third and final step corresponded to sustained hyperglycemia over the nocturnal fasting periods. Such a description of the key stages in the evolution of type 2 diabetes may be of interest for implementing antidiabetes treatment. Diabetes Care 30:263–269, 2007 T he steady decline in the quality of glucose homeostasis (1) as observed in type 2 diabetes results from an increasing defect (2) in both insulin sen- sitivity and secretion (3). The data from the UK Prospective Diabetes Study indi- cate that the gradual increase in both A1C levels and fasting glucose concentrations is mainly due to a relentless linear deteri- oration in -cell function from the time of diagnosis. In contrast, the years that pre- cede the development of type 2 diabetes are characterized by a progressive decline in both insulin action and defects in the early phase of the insulin secretion (4,5). Such abnormalities lead to a progressive transition from normal glucose tolerance to impaired glucose tolerance and finally to frank type 2 diabetes. As impaired glu- cose tolerance is acknowledged as a pre- diabetic stage, it has been postulated that losses of postprandial glucose control oc- cur before deterioration in fasting glucose concentration (4,6,7). In a previous study (8), we have demonstrated that postpran- dial glucose increments are predominant contributors to the overall hyperglycemia in patients with an A1C 7.3%, while fasting increments represent the major contributor to worsening diabetic con- trol. These results, along with the findings of others (9), indicate that postprandial glucose deteriorates before fasting glu- cose. However, the exact sequence of events in the deterioration of glycemic status is not completely understood. It re- mains unclear whether the loss in glucose control during fasting or postprandial pe- riods occurs in parallel or sequentially. Furthermore, it is known that postmeal glucose excursions after breakfast, lunch, and dinner are not equally affected and may deteriorate at different rates over the time course of the disease, which may also differ across different population groups. To gain further insight into these ques- tions, which are of practical importance for tailoring the introduction of available antidiabetes treatments, we used the CGMS data (10) in 130 patients with type 2 diabetes. The glucose profiles obtained during this investigation were further an- alyzed after the patients had been strati- fied into 5 groups according to A1C levels. RESEARCH DESIGN AND METHODS — A total of 130 individ- uals with type 2 diabetes (100 men and 30 women) were entered consecutively into the study with an A1C ranging from 5.2 to 12.5%. Diabetes duration from diagnosis ranged from newly diagnosed to 36 years (means  SE duration, 7.0  0.8 years). None were on insulin therapy, with treat- ment consisting of diet alone or diet plus different individual or combinations of oral antidiabetes drugs (Table 1). Exclu- sion criteria included patients who had experienced an acute intercurrent illness or who had been treated with steroids during the preceeding 3-month period. Also, all individuals treated with -gluco- sidase inhibitors or glinides were ex- cluded to avoid any bias in the interpretation of postprandial glucose ex- cursions. The study was conducted only after the patients had given their oral in- formed consent in accordance with the ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● From the 1 Department of Metabolic Diseases, Lapeyronie Hospital, Montpellier, France; the 2 Laboratory of Human Nutrition and Atherogenesis, University Institute of Clinical Research, Montpellier, France; and the 3 Diabetes Research Unit, Academic Centre, Llandough Hospital, Penarth, Cardiff, U.K. Address correspondence and reprint requests to Professor Louis Monnier, Department of Metabolic Diseases, Lapeyronie Hospital, 34295 Montpellier Cedex 5, France. E-mail: l-monnier@chu-montpellier.fr. Received for publication 31 July 2006 and accepted in revised form 30 October 2006. Abbreviations: CGMS, continuous glucose monitoring system; FPG, fasting plasma glucose. A table elsewhere in this issue shows conventional and Syste `me International (SI) units and conversion factors for many substances. DOI: 10.2337/dc06-1612 © 2007 by the American Diabetes Association. 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. Pathophysiology/Complications O R I G I N A L A R T I C L E DIABETES CARE, VOLUME 30, NUMBER 2, FEBRUARY 2007 263