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Received: 2008.03.04 Accepted: 2008.05.05 Published: 2008.11.01

Glycemic variability and its responses to intensive insulin treatment in newly diagnosed type 2 diabetes
Jian ZhouACDEF, Weiping JiaADEFG, Yuqian BaoAD, Xiaojing MaBC, Wei LuB, Huating LiE, Cheng HuEF, Kunsan XiangADE

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Summary
http://www.medscimonit.com/fulltxt.php?ICID=869442 2593 2 2 40

Authors Contribution: A Study Design B Data Collection C Statistical Analysis D Data Interpretation E Manuscript Preparation F Literature Search G Funds Collection

Shanghai Clinical Center for Diabetes, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Afliated Sixth Peoples Hospital, Shanghai Diabetes Institute Source of support: Shanghai United Developing Technology Project of Municipal Hospitals (SHDC12006101)

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Recent data show that blood glucose (BG) variability is an HbA1c-independent risk factor for diabetic complications. This study investigated the characteristics of BG variability in type 2 diabetic patients and the effect of intensive treatment. Forty-eight subjects with normal glucose regulation and 69 patients with newly diagnosed type 2 diabetes were monitored using the continuous glucose monitoring system. A subset of the type 2 diabetic patients (n=23) whose HbA1c was >8.5% was monitored a second time following 2 to 3 weeks of treatment with multiple daily injections. The mean amplitude of glycemic excursions (MAGE), mean of daily differences (MODD), and the incremental areas above preprandial glucose values (AUCpp) were used for assessing intra-day, inter-day, and postprandial BG variability.

In type 2 diabetic patients, the MAGE, MODD, and AUCpp levels were all higher than those of subjects with normal glucose regulation (P<0.001). Multivariant regression analysis indicated that AUCpp was the main independent factor inuencing MAGE (Adjusted R2=0.56), while postprandial hyperglycemia was most prominent following breakfast and less evident during lunch and dinner. After intensive treatment, signicant decreases in MAGE, MODD, and AUCpp were observed (41%, 29%, and 49%, respectively, P<0.001). AUCpp after breakfast was higher than after lunch and dinner (P<0.05). In 65.2% of the subjects, peak intra-day values occurred 10330 minutes after breakfast. Minimizing glycemic variability in type 2 diabetic patients, especially postprandial glucose excursions following breakfast, may be an important aspect of glucose management.

continuous glucose monitoring type 2 diabetes glycemic variability HbA1c hypoglycemia

Weiping Jia, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Afliated Sixth Peoples Hospital, 600 Yishan Road, Shanghai 200233, China, e-mail: wpjia@yahoo.com

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Zhou J et al Glycemic variability in type 2 diabetes

BACKGROUND
Current therapeutic strategies in diabetes are aimed at controlling blood glucose (BG) levels close to the standard target in order to prevent the development of diabetes-related complications, with HbA1c being the gold standard for the evaluation of glycemic control [13]. Recent epidemiological and interventional studies have shown that the occurrence and development of chronic complications in patients with diabetes is not only closely related to HbA1c levels, but also to BG variability. In designing strategies to reduce diabetic complications, both HbA1c and glycemic variability should be taken into account [4,5]. Therefore it is interesting to investigate the characteristics of glycemic variability in subjects with type 2 diabetic as well as changes following different hypoglycemic treatments. Efforts to quantify glycemic variability have relied on intermittent BG determinations. The continuous glucose monitoring (CGM) system measures interstitial subcutaneous tissue glucose levels continuously, recording values on average every 5 minutes and providing information about the style, direction, magnitude, duration, and frequency of BG variability [69]. Recent studies with continuous glucose sensors have found that continuous subcutaneous insulin infusion and multiple daily injection (MDI) display similar patterns of glycemic excursions, implying that factors inuencing glycemic instability in type 1 diabetes mellitus appear to be independent of treatment modality [10,11]. In overweight or obese patients with type 2 diabetes, post-breakfast hyperglycemia appears to be the postprandial glucose excursion that remains the most resistant to calorie restriction [12].

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MATERIAL AND METHODS

Subjects

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To date, the characteristics of BG variability have not been investigated in newly diagnosed patients with type 2 diabetes. The aim of this study was to investigate the characteristics of BG variability in subjects with normal glucose regulation (NGR) or newly diagnosed type 2 diabetes by conducting CGM over three consecutive days. Additionally, changes in glycemic variability were determined in the newly diagnosed type 2 diabetic patients after intensive treatment with MDI for 2 to 3 weeks.

A total of 132 Chinese (76 with newly diagnosed type 2 diabetes, 56 with NGR) were recruited in Shanghai to participate in this clinical trial from October 2005 to December 2006. The study was approved by the institutional review board of Shanghai Jiaotong University Afliated Sixth Peoples Hospital, with written informed consent being obtained from all participants. No acute complications, such as diabetic ketoacidosis, hyperglycemic hyperosmolar nonketotic syndrome, or other disorders affecting glucose metabolism, were reported in any of the newly diagnosed type 2 diabetic patients. No patients had received diabetes treatment interventions (diet, exercise, or drugs) prior to or during CGM. After the initial CGM, the newly diagnosed type 2 diabetic patients whose HbA1c levels were >8.5% underwent intensive treatment with exible MDIs based on the CGM results. The selection of subjects

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Study design

The healthy controls had normal glucose tolerance, as determined by the 75-g oral glucose tolerance test [15]. Additionally, no liver, kidney, coronary artery, lipid metabolism, or blood pressure abnormalities were detected in the healthy controls and none reported a family history of diabetes.

The CGM system sensor (Medtronic MiniMed) was inserted in all subjects by the same specialized nurse on day 0 and removed midmorning on day 3. Data were downloaded and glucose proles were evaluated based on the data collected on days 1 and 2. The patients were instructed to input at least four calibration readings per day and the times of key events (meals, exercise, insulin doses). The following cutoff criteria for optimal accuracy were adhered to: 1) when the difference in the BG values of the meter reading was 5.6 mmol/l, mean absolute deviation 28%, and correlation coefcient 0.79 and 2) when the difference in the BG values of meter reading was <5.6 mmol/l and the mean absolute differences were 18% [16]. Data not meeting the criteria were excluded. Additionally, analyses were performed of the frequency of hypoglycemic episodes, dened as a period with a CGM reading <3.9 mmol/l for at least 15 minutes with an antecedent non-hypoglycemic episode of at least 30 min [17-18]. Readings between 6:00 a.m. and 10:00 p.m. were considered daytime values and those between 10:00 p.m. and 6:00 a.m. were considered nighttime values. Assessment of intra-day glycemic variability The mean amplitude of glycemic excursions (MAGE), described by Service et al. [19,20] and designed to quantify major swings of glycemia and to exclude minor ones, was used for assessing intra-day BG variability in this study. Only increases of more than one standard deviation of the mean glycemic values were taken into account. MAGE calculations were obtained by measuring the arithmetic mean of the differences between consecutive peaks and nadirs; measurements in the peak-to-nadir or nadir-to-peak direction were determined by the rst qualifying excursion. Assessment of inter-day glycemic variability The mean of the daily differences (MODD), described by Molnar et al. [21,22], was used to assess day-to-day glycemic variability. MODD was calculated from the absolute difference between paired continuous glucose monitoring values during two successive 24 hour periods (days 1 and 2).

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with HbA1c concentrations >8.5% was based on the HbA1c threshold value recommended by the American Diabetes Association and the European Association for the Study of Diabetes [13]. The MDI regimen consisted of regular insulin injections before breakfast, lunch, and dinner and an NPH insulin injection before bedtime. The target BG levels were set in accordance with the American Diabetes Association at 5.07.2 mmol/l before meals and <10.0 mmol/l 12 hours after the beginning of a meal [14]. A second round of CGM over three consecutive days was then performed in 23 subjects with newly diagnosed type 2 diabetes following 2 to 3 weeks of treatment with MDI.

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Table 1. Clinical characteristics and glycemic parameters from continuous glucose monitoring (CGM) of all subjects included in the study. Subjects with normal glucose regulation N Sex (M/F) Age (years) Body mass index (kg/m2) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Total cholesterol (mmol/l) Triglycerides (mmol/l) HDL-C (mmol/l) LDL-C (mmol/l) 48 24/24 4111 22.72.6 11910 786 4.460.80 1.150.70 Subjects with newly diagnosed type 2 diabetes 69 42/27 5413 25.52.9 13317 8411 0.261 <0.001 <0.001 <0.001 0.008 P value

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5.021.12 2.572.02

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1.820.61 2.430.78 1.420.83 2.591.12 4.650.48 9.101.43 5.101.06 15.61.81 5.540.46 5.40.5 8.021.46 10.92.9 0.80.3 2.30.6 2.00.7 5.71.6 0.80.3 1.80.6

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Fasting plasma glucose (mmol/l)

2-h postprandial plasma glucose (mmol/l) HbA1c (%) AUC24h (mmold/l) SDBG (mmol/l) MAGE (mmol/l) MODD (mmol/l)

HDL-C high-density lipoprotein cholesterol; LDL-C low-density lipoprotein cholesterol; HbA1c glycated hemoglobin; AUC24h area under the curve obtained during 24 hour continuous glucose monitoring; SDBG standard deviation of the mean blood glucose values; MAGE mean amplitude of glycemic excursions; MODD mean of daily differences.
Assessment of postprandial glucose variability variables were compared using a two-sided t test or paired t test for changes within each subject. Relationships between variables were assessed using a Pearsons correlation test. Multiple regression models were used to explore the inuence of different variables on MAGE and to adjust for covariates. P<0.05 was considered to be statistically significant. Data analyses were performed using the SPSS11.0 software package.

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The area under the curve obtained during a 24-hour period (AUC24h) is an indicator of the overall BG level. Division of this 24-hour period into preprandial and postprandial periods enabled the evaluation of postprandial glucose variability, with AUCpp calculated during the 4-hour period following the beginning of each meal. Analysis of the postprandial peak value and time to peak was also performed in order to evaluate the characteristics of postprandial glucose excursion. All parameters above were based on the mean values taken on days 1 and 2. Laboratory examination

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RESULTS
Subject characteristics (Table 1) All subjects tolerated the CGM for at least 3 days. Of the 132 subjects, 117 (69 with newly diagnosed type 2 diabetes, 48 with NGR) were available for analysis. In the remaining 15 subjects the sensor was either disconnected or did not meet the criteria for optimal accuracy. Body mass index, blood pressure, triglyceride, fasting plasma glucose, twohour postprandial plasma glucose, and HbA1c of the subjects with newly diagnosed type 2 diabetes were all greater than those of the subjects with NGR, whereas high-density lipoprotein cholesterol values in the subjects with newly diagnosed type 2 diabetes were clearly lower than those observed in the NGR group.

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HbA1c was measured by high-performance liquid chromatography (Arkary, Japan), which has a nondiabetic normal range of 4.95.8%. Plasma glucose concentrations were determined by the glucose oxidase method (Automatic Biochemistry Analyzer, Beckman). Capillary glucose concentrations were measured by a Roche glucotrend 2 BG meter. Statistical methods Descriptive data were expressed as means standard deviation (95%CI) unless otherwise indicated. Continuous

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<0.001 0.021

0.038 0.516 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001

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Zhou J et al Glycemic variability in type 2 diabetes

Table 2. Comparison of incremental areas above preprandial glucose values (AUCpp), postprandial glucose peak, and time to postprandial glucose peak from continuous glucose monitoring (CGM) between subjects with normal glucose regulation (n=48) and newly diagnosed type 2 diabetic patients (n=69). Breakfast AUCpp (mmold/l) Postprandial glucose peak (mmol/l) Time to postprandial glucose peak (min) NGR* Type 2 diabetes** NGR* Type 2 diabetes** NGR* Type 2 diabetes** 0.110.04 0.600.20 6.91.1 17.53.2 4019 9037 Lunch 0.120.04 0.440.19 6.70.8 14.43.6 4219 10141 Dinner 0.120.04 0.590.21 6.91.1 14.82.5 4520 10535

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20 Glucose concentration (mmol/L) 16 12 8 4 0 0:00

3:00

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Blood glucose variability of newly diagnosed type 2 diabetes (Table 2) After adjustment for age and gender, the MAGE, MODD, and AUC24h values of the subjects with newly diagnosed type 2 diabetes were signicantly higher than those of the subjects with NGR (P<0.001), with 1.9-, 1.2-, and 1.0-fold increases observed in MAGE, MODD, and AUC24h, respectively. A signicant positive correlation between HbA1c and AUC24h was identied (r=0.83, P<0.01). However, no correlation was detected between HbA1c and MAGE, MODD, or AUCpp (r=0.067, 0.151, and 0.254, respectively, P>0.05). Using MAGE as a dependent variable and HbA1c, AUC24h, fasting plasma glucose, two-hour postprandial plasma glucose, postprandial glucose peak, and AUCpp as independent variables, multivariant regression analyses indicated that AUCpp inuences MAGE (adjusted R2=0.56). Further, analyses concerning characteristics of postprandial glucose variability indicated no signicant differences of AUCpp, postprandial peak value, or time to peak among three meals in NGR subjects (P>0.05). The AUCpp of breakfast in the patients with type 2 diabetes was signicantly higher

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6:00 9:00 12:00 Time (hour) 16:00 19:00 22:00

* No significant differences of AUCpp, postprandial glucose peak and time to postprandial glucose peak among three meals in NGR subjects (P>0.05); ** AUCpp, postprandial glucose peak, and time to postprandial glucose peak of breakfast in patients with type 2 diabetes were significantly different from those after lunch and dinner (P<0.01). Figure 1. Mean blood glucose profiles from continuous glucose monitoring in 48 subjects with normal glucose regulation and in 23 subjects with newly diagnosed type 2 diabetes before and after 2 to 3 weeks of intensive insulin treatment. , subjects with newly diagnosed type 2 diabetes before intensive treatment; , subjects with newly diagnosed type 2 diabetes after intensive treatment; , subjects with normal glucose regulation.

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than that of lunch (P<0.01), but similar to that of dinner (P>0.05). The time to peak BG after breakfast was shorter and its peak value higher than those after lunch and dinner (P<0.05). Comparison between pre-treatment and post-treatment of subjects with newly diagnosed type 2 diabetes Among the 23 newly diagnosed type 2 diabetic patients who repeated CGM 23 weeks after starting insulin treatment, MAGE, MODD, and AUC24h values were all signicantly lower after therapy. However, the values remained signicantly higher in the 23 newly diagnosed type 2 diabetic patients after 23 weeks of insulin treatment than in the subjects with NGR (P<0.01, Figure 1). MAGE levels decreased 41%, dropping from 6.421.50 to 3.801.20 mmol/l (P<0.001), MODD levels decreased 29%, dropping from 1.890.52 to 1.340.43 mmol/l (P<0.001), and AUC24h levels decreased 42%, dropping from 12.372.65 to 7.160.80 mmold/l (P<0.001). The breakfast, lunch, and dinner AUCpp decreased 46%, 43%, and 55%, respectively, after MDI treatment. Furthermore, the after-breakfast AUCpp was higher than that after lunch and dinner (P<0.05, Figure 2). In 65.2% of the subjects

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0.11 Breakfast

0.12 Lunch

0.12 Dinner

(n=15), the peak intra-day values (11.20.7 mmol/l) occurred 10330 minutes after breakfast.

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Among the 23 subjects who had not experienced hypoglycemic episodes prior to treatment, 54.5% (n=12) had a total of 19 hypoglycemic episodes that lasted, on average, 50 minutes (range: 30100 minutes) after treatment. Five of the 19 episodes occurred at night, with 5 episodes 2.8 mmol/l. The MAGE values in subjects experiencing hypoglycemic episodes after treatment were higher compared with those of the subjects without hypoglycemic episodes (4.341.25 vs. 3.200.95 mmol/l, P<0.05). No statistical difference in AUC24h was observed between those experiencing and those not experiencing hypoglycemic episodes after treatment (6.990.57 vs. 7.341.00 mmold/l, P>0.05). A positive correlation between MAGE values and the number of hypoglycemic episodes was observed (r=0.21, P<0.05).

DISCUSSION

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Hyperglycemia is a hallmark of diabetes, and both the chronic and sustained deleterious effects of hyperglycemia are reected by HbA1c levels and glycemic variability [23]. Some prospective clinical studies, such as the Diabetes Control and Complications Trial (DCCT) and the Verona Diabetes study, have shown that HbA1c-unrelated BG proles, such as glycemic variability, may have an effect on the occurrence and development of chronic complications in diabetes [24,25]. CGM can detect glucose variability in more detail than conventional self-monitoring methods of BG monitoring [2628]. MAGE, MODD, and AUCpp values derived from CGM can be used to characterize intra-day, inter-day, and postprandial glucose variability in type 2 diabetic patients. In this study, in addition to an overall elevation in BG levels using the CGM system, subjects with newly diagnosed type 2 diabetes presented with greater glycemic variability. Correlation analyses demonstrated that HbA1c represents the overall BG level, but did not reect glycemic variability; hence type 2 diabetic patients with similar HbA1c values may differ in terms of glucose variability. The present study suggests that minimizing glycemic variability may be an important aspect of glucose management. Different therapeutic strategies should be evaluated for their potential to minimize glycemic variability as well as for their ability to reduce HbA1c. Our study demonstrates that intensive

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treatment with MDI for 2 to 3 weeks could signicantly decrease the amplitude of glycemic excursions when overall BG levels are decreased in type 2 diabetic patients with severe hyperglycemia. Additionally, our study demonstrates that intra-day glycemic variability can be largely attributed to post-meal glucose excursion in patients with type 2 diabetes. Compared with healthy controls, patients with type 2 diabetes had higher values and longer duration of postprandial glucose, which attributed to their postprandial glucose variability. Meanwhile, the peak BG values after breakfast were higher and the time to peak shorter than those after lunch and dinner, explaining the increased frequency of acute postprandial hyperglycemia observed after breakfast compared with lunch and dinner. Current data have shown that an acute increase in glycemia, as observed in the postprandial state, can exert deleterious effects on the arterial wall through mechanisms including oxidative stress, endothelial dysfunction, and activation of the coagulation cascade [2932]. The study by Ceriello and colleagues [33] demonstrated that pramlintide reduced markers of oxidative stress in the postprandial period in patients with type 2 diabetes. Therefore, controlling glucose variability after breakfast should be the focal point of glucose monitoring and intervention in patients with type 2 diabetes. Furthermore, after intensive treatment with MDI, the AUCpp of breakfast was highest and the peak intra-day values occurred after breakfast in 65.2% of the subjects. In accordance with previous observations [34], the present study shows that postprandial hyperglycemia was most prominent following breakfast and less evident during lunch and dinner. Whether medicines, such as a-glucosidase inhibitors, rapid-acting insulin secretagogues, or short-acting insulin analogs, which aim to control postprandial glucose could lead to the same result or not remains unclear and requires further research. Meanwhile, we also found that glucose peaks after meals were at around 100 min in type 2 diabetic patients. Colette et al. [12] assessed the nycthemeral peaks of glucose using CGMS in type 2 diabetic patients. The results showed that the peaks of glucose were observed 12024 min after breakfast. The study by Wentholt [35] demonstrated that the mean peak width for the postprandial glucose curves was 100.825.0 min and for the CGMS sensor curves 110.020.5

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1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

AUCpp (mmold/L)

0.69 0.49 0.37

NGR Pre-treatment Post-treatment 0.65

Figure 2. The incremental areas above preprandial glucose values (AUCpp) from continuous glucose monitoring in 48 subjects with normal glucose regulation and in 23 subjects with newly diagnosed type 2 diabetes before and after 2 to 3 weeks of treatment with multiple daily injection (all P<0.001, ANOVA among the groups). 0.29

0.28

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Zhou J et al Glycemic variability in type 2 diabetes

9. Klonoff DC: Continuous glucose monitoring: roadmap for 21st century diabetes therapy, Diabetes care, 2005; 28: 123139 10. Bode BW, Steed RD, Schleusener DS, Strange P: Switch to multiple daily injections with insulin glargine and insulin lispro from continuous subcutaneous insulin infusion with insulin lispro: a randomized, open-label study using a continuous glucose monitoring system. Endocr Pract, 2005; 11: 15764 11. Alemzadeh R, Palma-Sisto P, Parton EA, Holzum MK: Continuous subcutaneous insulin infusion and multiple dose of insulin regimen display similar patterns of blood glucose excursions in pediatric type 1 diabetes. Diabetes Technol Ther, 2005; 7: 58796 12. Colette C, Ginet C, Boegner C et al: Dichotomous responses of inter and postprandial hyperglycaemia to short-term calorie restriction in patients with type 2 diabetes. Eur J Clin Invest, 2005; 35: 25964 13. Nathan DM, Buse JB, Davidson MB et al: Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia, 2006; 49: 171121 14. American Diabetes Association: Standards of medical care in diabetes. Diabetes care, 2005; 28: S436 15. The expert committee on the diagnosis and classication of diabetes mellitus: Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care, 2003; 26: 316067 16. Mastrototaro J: The MiniMed continuous glucose monitoring system (CGMS). J Pediatr Endocrinol Metab, 1999; 12: 75178

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CONCLUSIONS

This study showed that type 2 diabetic patients presented greater glycemic variability, independent of HbA1c. Intensive insulin treatment could signicantly decrease the amplitude of glycemic excursions which increase the risk of the hypoglycemia. Intra-day glycemic variability can be largely attributed to postprandial glucose excursions, while postprandial hyperglycemia was most prominent following breakfast and less evident after lunch and dinner. Our ndings suggest that minimizing glycemic variability in type 2 diabetic patients, especially postprandial glucose excursions following breakfast, may be an important aspect of glucose management.

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We are grateful to all colleagues at the Shanghai Clinical Center for Diabetes for their assistance in recruiting patients.

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Acknowledgments

REFERENCES:

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Iatrogenic hypoglycemia has been the main hindrance in the management of patients with type 2 diabetes [39,40]. The time distribution and type and cause of hypoglycemia could be analyzed well by CGM. Through the use of CGM, we found in this study that intensive glucose control would increase the risk of hypoglycemia, with larger glycemic excursions occurring within the day potentially representative of a predictor for increased risk of hypoglycemia after intensive treatment. Further studies are required to determine the best pharmacologic strategies for minimizing glycemic variability and lowering the incidence of hypoglycemia when BG levels are controlled.

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25. Muggeo M, Zoppini G, Bonora E et al: Fasting plasma glucose variability predicts 10-year survival of type 2 diabetic patients: the Verona Diabetes Study. Diabetes Care, 2000; 23: 4550 26. Zhou J, Jia WP, Yu M et al: The reference values of glycemic parameters for continuous glucose monitoring and its clinical application. Zhonghua Nei Ke Za Zhi, 2007; 46: 18992 27. Monnier L, Colette C, Dunseath GJ, Owens DR: The loss of postprandial glycemic control precedes stepwise deterioration of fasting with worsening diabetes. Diabetes Care, 2007; 30: 26369 28. Maia FF, Araujo LR: Efcacy of continuous glucose monitoring system (CGMS) to detect postprandial hyperglycemia and unrecognized hypoglycemia in type 1 diabetic patients. Diabetes Res Clin Pract, 2007; 75: 3034 29. Rubio-Guerra AF, Vargas-Robles H, Ayala GV, Escalante-Acosta BA: Correlation between circulating adhesion molecule levels and albuminuria in type 2 diabetic normotensive patients. Med Sci Monit. 2007; 13(8): CR34952 30. Bonora E: Postprandial peaks as a risk factor for cardiovascular disease: epidemiological perspectives. Int J Clin Pract Suppl, 2002; (129): 511 31. Milagros Rocha M, Victor VM: Targeting antioxidants to mitochondria and cardiovascular diseases: the effects of mitoquinone. Med Sci Monit, 2007;13(7): RA13245

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min in type 1 diabetic patients. However, a recent study using CGMS found either type 1 or type 2 diabetes reached a peak 72 minutes after eating with a variation of 23 minutes [36]. Current data using CGMS showed that the time of the postprandial glucose peak after a meal varies greatly among individuals [37]. Various factors contribute to the magnitude and time of the peak BG concentration, including the timing, composition, and quantity of the meal [38]. Therefore, the time to measure postprandial glycemia is not codied. Further studies are required to determine the optimal time to measure postprandial glucose.

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36. Daenen S, Sola A, Larger E et al: Use of the CGMS to assess the optimal time to measurepostprandial glucose [abstract]. Diabetes, 2006; 55: A17 37. Ben-Haroush A, Yogev Y, Chen R et al: The postprandial glucose prole in the diabetic pregnancy. Am J Obstet Gynecol, 2004; 191: 57681 38. American Diabetes Association: Postprandial blood glucose. Diabetes Care, 2001; 24: 77578 39. Cryer PE, Davis SN, Shamoon H: Hypoglycemia in diabetes. Diabetes Care, 2003; 26: 190212 40. UK Prospective Diabetes Study Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet, 1998; 352: 83753

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