DRUG DEVELOPMENT RESEARCH 67:582–586 (2006)

Clinical Commentary

Postprandial Hyperglycemia: Why Do We Care About It?What Should We Do?

Marc S. Rendell�

The Creighton Diabetes Center and the Rose Salter Medical Research Foundation,Omaha, Nebraska

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ABSTRACT There is increasing evidence that elevated postprandial plasma glucose (PPG) exertsa more deleterious effect on the vascular system than elevation of fasting plasma glucose (FPG). Inparticular, individuals with normal FPG but impaired glucose tolerance (IGT) have significantly increasedrisk of cardiovascular events. With the recognition of the importance of PPG and the availability of newpharmacologic options, management of diabetes will shift to greater attention to PPG levels. There aremany approaches to reduction of PPG; dietary management and promotion of exercise are very effective.Sulfonylureas, meglitinides, metformin, thiazolidinediones, and disaccharidase inhibitors all counteractPPG elevation. The development of glucagon-like peptide-1 (GLP-1) agonists such as exendin anddipeptidyl peptidase IV inhibitors offers a new approach to suppression of PPG elevation. Newsemisynthetic insulin analogues permit a more aggressive response to post-prandial glucose elevation,with lower risk of hypoglycemia, than with regular insulin. The advent of accurate continuousglucose monitoring will facilitate the treatment of post-prandial hyperglycemia. Drug Dev. Res.67:582–586, 2006. �c 2006 Wiley-Liss, Inc.

Key words: post-prandial hyperglycemia; incretins; GLP-1; continuous glucose monitoring

INTRODUCTION

Diabetes is characterized by abnormally highplasma glucose levels. A fasting plasma glucose of126 mg/dL (7 mMol/L) or greater is considered diag-nostic of diabetes. However, it is after a meal thatglucose levels are highest. In healthy individuals, bloodglucose levels peak approximately 1 h after the startof a meal. Postprandial plasma glucose (PPG) levels atone hour normally range from 70 to 100 mg/dl (3.9 to5.5 mMol/L), rarely exceeding140 mg/dL (7.8 mMol/L).

Impaired glucose tolerance (IGT) is character-ized by normal FPG levels but a 2-h value on theoral glucose tolerance test between 140 and 199 mg/dl.Impaired glucose tolerance tends to progress todiabetes [Edelstein et al., 1997] as a result of gradualloss of beta cell function [Bagust and Beale, 2003;Maedler and Donath, 2004].

Hemoglobin A1C has become the standardmeasure for assessing and monitoring long-termglycemic control, reflecting both basal and post-prandial glucose levels. There is a well-establishedrelationship between high HbA1c levels and micro-vascular disease in diabetes [DCCT Group, 1995;Zhang et al., 2001]. Despite the strength of the riskreduction of microvascular disease, the relationshipbetween the lowering of HbA1c and prevention ofcardiovascular disease in diabetes is less clear-cut.

DDR

Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ddr.20127

Grant sponsor: Rose Salter Medical Research Foundation.

�Correspondence to: Marc Rendell, MD, CreightonDiabetes Center, 601 North 30th Street, Omaha, NE 68131.E-mail: Rendell@asndi.com

�c 2006 Wiley-Liss, Inc.

In three separate studies, the DCCT in type I diabetesand the UKPDS and the Veterans Affairs CooperativeStudy on Glycemic Control and Complication in TypeII diabetes, the reduction in myocardial infarctions andstrokes with improved HbA1c was far less impressivethan the impact on microvascular outcomes [WritingTeam DCCT, 2002; Stratton et al., 2000; Abraira et al.,1997]. In contrast, levels of PPG appear to be a muchstronger predictor of cardiovascular disease thanelevated fasting plasma glucose [Eastman et al., 1997;Ceriello, 2003]. In the Diabetes Intervention Study,post-challenge hyperglycemia and elevated PPG levelsin type 2 diabetes directly correlated with the risk ofcardiovascular disease, independent of FPG [Hanefeldet al., 1996, 1997]. The Diabetes EpidemiologyCollaborative Analysis of Diagnostic Criteria in Europestudy (DECODE) indicated that elevated 2-h post-loadplasma glucose is associated with an increased mortal-ity risk independent of FPG [DECODE Study Group,2001]. Increased mortality in IGT patients is not dueto the progression to diabetes; in a 10-year study ofover 2,500 individuals, subjects with IGT who did notproceed to a diagnosis of diabetes had a multivariateadjusted hazard ratio of 1.49 (0.95–2.34) for CHDincidence, 2.34 (1.42–3.85) for CVD mortality, and 1.65(1.13–2.40) for all-cause mortality [Qiao et al., 2003].

In the STOP NIDDM trial, acarbose, whichreduces PPG by decreasing absorption of diasacchar-ides, was used to treat individuals with IGT. There wasnot only a 36% reduction in the risk of progressionto diabetes but also a 34% decrease in the developmentof new cases of hypertension and a 49% reduction incardiovascular events [Chiasson et al., 2002, 2003].

POSTPRANDIAL GLUCOSE: WHAT WE CAN DO

Diet and Physical Activity

Dietary regulation and active exercise are keyto the control of postprandial hyperglycemia. In aFinnish study of IGT subjects, intensive individualizeddietary instruction and guidance on increasing physicalactivity resulted in a 58% relative reduction in theincidence of diabetes after a 3-year followup [Tuomi-lehto et al., 2001]. These results were duplicated in theUnited States in the Diabetes Prevention Program(DPP). After about 3 years, a 58% relative reduction inthe progression to diabetes was observed in the lifestylemodification group (absolute incidence 4.8%), com-pared to only 31% in a contrast group treated withmetformin [Diabetes Prevention Research Group,2002]. Similar results were observed in the Da QingIGT and Diabetes Study conducted in mainland China[Pan et al., 1997].

Reducing carbohydrate intake is a key elementin dietary therapy [Nuttall and Gannon, 1991; Kelley,2003]. Even a diet high in fat reduces postprandialglucose levels as compared to a diet high in carbohy-drate [Allick et al., 2004]. It is also important to selectcarbohydrates with a low glycemic index [Wolever andBolognesi, 1996; Brand-Miller et al., 2003]. There is adefinite advantage in eating carbohydrates with a highfiber content [Guevin et al., 1996, Tappy et al., 1996].

Pharmacoglogical Treatment

All oral hypoglycemics lower postprandial hyper-glycemia [Rendell and Kirchain, 2000]. Sulfonylureasreduce post-prandial glucose through stimulation ofinsulin secretion and perhaps additional extrapancrea-tic effects [Rendell, 2004]. The meglitinides lowerpostprandial glucose by a mechanism similar to thesulfonylureas [Carroll et al., 2003]. Metformin reduceshepatic gluconeogenesis after a meal [Wu et al., 1990;Fery et al., 1997]. The thiazolidinediones improve post-prandial peripheral glucose utilization [Antonucciet al., 1997; St. John Sutton et al., 2002]. Disacchar-idase inhibitors like acarbose and miglitol effectivelycompensate for defective early phase insulin release byinhibiting post-prandial absorption of monosaccharides[Lembcke et al., 1990]. The overall glucose-loweringeffect of these agents is somewhat inferior to that of thesulfonylureas [Segal et al., 1997], but the effect on post-prandial hyperglycemia is much greater than on fastingglucose levels [Johnston et al., 1988].

Exenatide is a reptilian peptide with affinity forthe mammalian GLP-1 receptor and relative resistanceto degradation. Treatment with exenatide significantlylowers post-prandial hyperglycemia in type II diabetes[Fineman et al., 2003; see also Holcombe et al., 2006,Mack et al., 2006]. There is also a reduction in Type Idiabetes, confirming that the mechanism of action doesnot rely solely on insulin secretion [Dupre et al., 2004].Pramlintide is a synthetic analogue of the beta cellhormone amylin. Like GLP-1, it inhibits glucagonsecretion, delays gastric emptying, and acts as a satietyagent. Pramlintide is effective in lowering postprandialglucose in patients with type I and type II diabetes[Weyer et al., 2003; Maggs et al., 2004]. An alternativeto supplementation of GLP-1 is to inhibit the rapiddegradation of this hormone by dipeptidyl peptidase IV(DPP-4) [Mest and Mentlein, 2005]. Several DPP-IVinhibitors are proceeding to market [Ahren et al., 2005;Herman et al., 2005].

Insulin

Basal insulin treatment has very little effect onpostprandial glucose levels, and therefore the use ofshort-acting insulins at mealtime is indicated to directly

583POSTPRANDIAL HYPERGLYCEMIA

Drug Dev. Res. DOI 10.1002/ddr

target postprandial hyperglycemia in both Type I andType II diabetes. Several semisynthetic insulin analo-gues now exist with more rapid absorption anddisappearance kinetics than regular human insulin.These include lispro insulin, aspart insulin, andglulisine insulin [Howey et al., 1995; Becker et al.,2005]. As a result, these rapid-acting insulin analoguescan be used aggressively at the time of a meal topromote disposal of post-prandial glucose. In patientswith type I and type II diabetes, these insulins reducepostprandial hyperglycemia faster and more effectivelythan regular human insulin with less risk of hypogly-cemia [Chase et al., 2001; Holleman et al., 1997; Helleret al., 1999; Raskin et al., 2000; Danne et al., 2005].

MEASURING POSTPRANDIAL GLUCOSE

Despite the increasing recognition that elevationof postprandial glucose levels is unfavorable for thevascular system, current day practice patterns do notfocus on reduction of post-meal values. The goal ofcurrent diabetes treatment is to lower HbA1c to non-diabetic levels. Self–blood glucose monitoring is usedas a tool to guide therapy to lower HbA1c. Typicallypatients are advised to measure their fasting glucosevalues and then test prior to lunch, supper, andbedtime. The measurement of post-prandial glucoseis much more dynamic since values change rapidlyafter a meal. In order to focus on post-prandial glucoseas a treatment target, it is essential to have frequentmeasurements after a meal. It is not feasible to do thiswith present day techniques of finger stick followedby placing a drop of blood on a glucose oxidase stripto be measured by a meter.

The advent of accurate continuous glucoseoxidase monitoring techniques will make it possible toassess glucose levels following a meal and will beextremely useful for assessing therapeutic response andadjusting dose schedules. Continuous monitoring canaccurately detect high post-prandial glucose levels andnocturnal hypoglycemic events that may be unrecog-nized by intermittent blood glucose monitoring [Garget al., 2004; Clarke et al., 2005; Wilhelm et al., 2005;Yates et al., 2006].

CONCLUSIONS

There is good evidence that the transient rise inblood glucose that occurs after a meal may have veryspecific deleterious effects on blood vessels. There isa marked increase in cardiovascular risk in individualswith post-prandial hyperglycemia. There needs to be anew focus on suppression of postprandial hyperglyce-mia in treatment not only of diabetic patients but alsoindividuals with impaired glucose tolerance. Modifica-tion of dietary intake and promotion of exercise activity

has proven to be very effective in preventing theprogression of impaired glucose tolerance to diabetes.Pharmacologic agents including sulfonylureas, metfor-min, disccharidase inhibitors, and thiazolidinedionesare all effective in treating postprandial hyperglycemia.Agents that mimic the action of glucagons like peptide1 or inhibit its degradation are now available tospecifically target postprandial hyperglycemia. Gluca-gon like peptide 1 has a number of potential mech-anisms affecting postprandial glucose elevation. Newsynthetic insulin analogues, which have rapid absorp-tion and disappearance times, permit more aggressivemanagement of mealtime hyperglycemia. We expectthat treatment approaches will shift to post-prandialhyperglycemia as a primary goal. Continuous glucosemonitoring will facilitate the application of these newapproaches.

REFERENCES

Abraira C, Colwell J, Nuttall F, Sawin CT, Henderson W, ComstockJP, Emanuele NV, Levin SR, Pacold I, Lee HS. 1997.Cardiovascular events and correlates in the Veterans AffairsDiabetes Feasibility Trial. Veterans Affairs Cooperative Study onGlycemic Control and Complications in Type II Diabetes ArchIntern Med 157:181–188.

Ahren B, Pacini G, Foley JE, Schweizer A. 2005. Improved meal-related beta-cell function and insulin sensitivity by the dipeptidylpeptidase-IV inhibitor vildagliptin in metformin-treated patientswith type 2 diabetes over 1 year. Diabetes Care 28:1936–1940.

Allick G, Bisschop PH, Ackermans MT, Endert E, Meijer AJ,Kuipers F, Sauerwein HP, Romijn JA. 2004. A low carbohydrate/high fat diet improves glucoregulation in type 2 diabetes mellitusby reducing postabsorptive glycogenolysis. J Clin EndocrinolMetab 89:6193–6197.

Antonucci T, Whitcomb R, McLain R, Lockwood D, Norris RM.1997. Impaired glucose tolerance is normalized by treatment withthe thiazolidinedione troglitazone. Diabetes Care 20:188–193.

Bagust A, Beale S. 2003. Deteriorating beta-cell function in type 2diabetes: a long-term model. Q J Med 96:281–288.

Becker RH, Frick AD, Burger F, Potgieter JH, Scholtz H. 2005.Insulin glulisine, a new rapid-acting insulin analogue, displays arapid time-action profile in obese non-diabetic subjects. Exp ClinEndocrinol Diabetes 113:435–443.

Brand Miller J, Hayne S, Petocz P, Colagiuri S. 2003. Low glycemicindex diets in the management of diabetes: a meta analysis ofrandomized controlled trials. Diabetes Care 26:2261–2267.

Carroll MF, Gutierrez A, Castro M, Tsewang D, Schade DS. 2003.Targeting postprandial hyperglycemia: a comparative study ofinsulinotropic agents in type 2 diabetes. J Clin Endocrinol Metab88:5248–5254.

Ceriello A. 2003. The possible role of postprandial hyperglycaemiain the pathogenesis of diabetic complications. Diabetologia46(Suppl 1):M9–M16.

Chase HP, Lockspeiser T, Peery B, Shepherd M, MacKenzie T,Anderson J, Garg SK. 2001. The impact of the diabetes controland complications trial and humalog insulin on glycohemoglobinlevels and severe hypoglycemia in type 1 diabetes. Diabetes Care24:430–434.

584 RENDELL

Drug Dev. Res. DOI 10.1002/ddr

Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M,the STOP NIDDM Trail Research Group. 2002. Acarbose forprevention of type 2 diabetes mellitus: the STOP NIDDMrandomised trial. Lancet 359:2072–2077.

Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M,the STOP NIDDM Trial Research Group. 2003. Acarbosetreatment and the risk of cardiovascular disease and hypertensionin patients with impaired glucose tolerance: the STOP NIDDMtrial. JAMA 290:486–494.

Clarke WL, Anderson S, Farhy L, Breton M, Gonder-Frederick L,Cox D, Kovatchev B. 2005. Evaluating the clinical accuracy of twocontinuous glucose sensors using continuous glucose-error gridanalysis. Diabetes Care 28:2412–2417.

Danne T, Becker RH, Heise T, Bittner C, Frick AD, Rave K. 2005.Pharmacokinetics, prandial glucose control, and safety of insulinglulisine in children and adolescents with type 1 diabetes.Diabetes Care 28:2100–2105.

DCCT Research Group. 1995. Effect of intensive therapy on thedevelopment and progression of diabetic nephropathy in theDiabetes Control and Complications Trial. The Diabetes Controland Complications (DCCT) Research Group Kidney Int 47:1703–1720.

The DECODE Study Group. 2001. Glucose tolerance andcardiovascular mortality: comparison of fasting and 2-hourdiagnostic criteria. Arch Intern Med 161:397–405.

Diabetes Prevention Research Group. 2002. Reduction in theevidence of type 2 diabetes with life-style intervention ormetformin. N Engl J Med 346:393–403.

Dupre J, Behme MT, McDonald TJ. 2004. Exendin-4 normalizedpostcibal glycemic excursions in type 1 diabetes.: J ClinEndocrinol Metab 89:3469–3473.

Eastman RC, Cowie CC, Harris MI. 1997. Undiagnosed diabetes orimpaired glucose tolerance and cardiovascular risk. Diabetes Care20:127–128.

Edelstein SL, Knowler WC, Bain RP, Andres R, Barrett-ConnorEL, Dowse GK, Haffner SM, Pettit DJ, Sorkin JD, Muller DC,Collins VR, Hamman RF. 1997. Predictors of progression fromimpaired glucose tolerance to NIDDM: an analysis of sixprospective studies. Diabetes 46:701–710.

Fery F, Plat L, Balasse EO. 1997. Effects of metformin on thepathways of glucose utilization after oral glucose in non-insulin-dependent diabetes mellitus patients. Metabolism 46:227–233.

Fineman MS, Bicsak TA, Shen LZ, Taylor K, Gaines E, Varns A,Kim D, Baron AD. 2003. Effect on glycemic control of exenatide(synthetic exendin-4) additive to existing metformin and/orsulfonylurea treatment in patients with type 2 diabetes. DiabetesCare 26:2370–2377.

Garg SK, Schwartz S, Edelman SV. 2004. Improved glucoseexcursions using an implantable real-time continuous glucosesensor in adults with type 1 diabetes. Diabetes Care 27:734–738.

Guevin N, Jacques H, Nadeau A, Galibois I. 1996. Postprandialglucose, insulin, and lipid responses to four meals containingunpurified dietary fiber in non-insulin-dependent diabetesmellitus (NIDDM), hypertriglyceridemic subjects. J Am CollNutr 15:389–396.

Hanefeld M, Fischer S, Julius U, Schulze J, Schwanebeck U,Schmechel H, Ziegelasch HJ, Lindner J. 1996. Risk factors formyocardial infarction and death in newly detected NIDDM: theDiabetes Intervention Study, 11-year follow-up. Diabetologia39:1577–1583.

Hanefeld M, Schmechel H, Schwanebeck U, Lindner J. 1997.Predictors of coronary heart disease and death in NIDDM:the Diabetes Intervention Study experience. Diabetologia40(Suppl 2):S123–S124.

Heller SR, Amiel SA, Mansell P. 1999. Effect of the fast-actinginsulin analog lispro on the risk of nocturnal hypoglycemia duringintensified insulin therapy. U.K. Lispro Study Group. DiabetesCare 22:1607–1611.

Herman GA, Stevens C, Van Dyck K, Bergman A, Yi B,De Smet M, Snyder K, Hilliard D, Tanen M, Tanaka W, WangAQ, Zeng W, Musson D, Winchell G, Davies MJ, Ramael S,Gottesdiener KM, Wagner JA. 2005. Pharmacokinetics andpharmacodynamics of sitagliptin, an inhibitor of dipeptidylpeptidase IV, in healthy subjects: results from two randomized,double-blind, placebo-controlled studies with single oral doses.Clin Pharmacol Ther 78:675–688.

Holcombe JH, Kim DD, Stonehouse AH, Kendall DM. 2006.Management of Type 2 Diabetes: The Role of Incretin Mimetics.Drug Dev Res 67:545–552 (this issue).

Holleman F, Schmitt H, Rottiers R, Rees A, Symanowski S,Anderson JH. 1997. Reduced frequency of severe hypoglycemiaand coma in well-controlled IDDM patients treated with insulinlispro. The Benelux-UK Insulin Lispro Study Group. DiabetesCare 20:1827–1832.

Howey DC, Bowsher RR, Brunelle RL, Rowe HM, Santa PF,Downing-Shelton J, Woodworth JR. 1995. [Lys(B28), Pro(B29)]-human insulin: effect of injection time on postprandial glycemia.Clin Pharmacol Ther 58:459–469.

Johnston PS, Lebovitz HE, Coniff RF, Simonson DC, Raskin P,Munera CL. 1988. Advantages of alpha-glucosidase inhibition asmonotherapy in elderly type 2 diabetic patients. J Clin EndocrinolMetab 83:1515–1522.

Kelley DE. 2003. Sugars and starch in the nutritional managementof diabetes mellitus. Am J Clin Nutr 78:858S–864S.

Lembcke B, Diederich M, Folsch UR, Creutzfeldt W. 1990.Postprandial glycemic control, hormonal effects and carbohydratemalabsorption during long term administration of the alphaglucosidase inhibitor miglitol. Digestion 47:47–55.

Mack C, Laugero K, Liu Q, Jodka C, Young A, Parkes D. 2006.Therapeutic applications of incretin mimetics for metabolicdiseases: preclinical studies. Drug Dev Res 67:553–558 (thisissue).

Maedler K, Donath MY. 2004. Beta-cells in type 2 diabetes: a loss offunction and mass. Horm Res 62(Suppl 3):67–73.

Maggs DG, Fineman M, Kornstein J, Burrell T, Schwartz S, Wang Y,Ruggles JA, Kolterman OG, Weyer C. 2004. Pramlintide reducespostprandial glucose excursions when added to insulin lispro insubjects with type 2 diabetes: a dose-timing study. DiabetesMetab Res Rev 20:55–60.

Mest HJ, Mentlein R. 2005. Dipeptidyl peptidase inhibitors as newdrugs for the treatment of type 2 diabetes. Diabetologia 48:616-620.

Nuttall FQ, Gannon MC. 1991. Plasma glucose and insulin responseto macronutrients in nondiabetic and NIDDM subjects. DiabetesCare 14:824–838.

Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, Hu ZX, Lin J,Xiao JZ, Cao HB, Liu PA, Jiang XG, Jiang YY, Wang JP, Zheng H,Zhang H, Bennett PH, Howard BV. 1997. Effects of diet andexercise in preventing NIDDM in people with impaired glucosetolerance: the Da Qing IGT and Diabetes Study. Diabetes Care20:537–544.

585POSTPRANDIAL HYPERGLYCEMIA

Drug Dev. Res. DOI 10.1002/ddr

Qiao Q, Jousilahti P, Eriksson J, Tuomilehto J. 2003. Predictiveproperties of impaired glucose tolerance for cardiovascular riskare not explained by the development of overt diabetes duringfollow-up. Diabetes Care 26:2910–2914.

Raskin P, Guthrie RA, Leiter L, Riis A, Jovanovic L. 2000. Use ofinsulin aspart, a fast-acting insulin analog, as the mealtime insulinin the management of patients with type 1 diabetes. DiabetesCare 23:583–588.

Rendell M. 2004. The role of sulphonylureas in the management oftype 2 diabetes mellitus. Drugs 64:1339–1358.

Rendell MS, Kirchain WR. 2000. Drug treatments in type 2 diabetesmellitus. Annals of Pharmacotherapy 34:878–895.

Segal P, Feig PU, Schernthaner G, Ratzmann KP, Rybka J,Petzinna D, Berlin C. 1997. The efficacy and safety ofmiglitol therapy compared with glibenclamide in patients withNIDDM inadequately controlled by diet alone. Diabetes Care20:687–691.

St John Sutton M, Rendell M, Dandona P, Dole JF, Murphy K,Patwardhan R, Patel J, Freed M. 2002. A comparison of theeffects of rosiglitazone and glyburide on cardiovascular functionand glycemic control in patients with type 2 diabetes. DiabetesCare 25:2058–2064.

Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, CullCA, Hadden D, Turner RC, Holman RR. 2000. Association ofglycaemia with macrovascular and microvascular complications oftype 2 diabetes (UKPDS 35): prospective observational study.BMJ 321:405–412.

Tappy L, Gugolz E, Wursch P. 1996. Effects of breakfast cerealscontaining various amounts of beta-glucan fibers on plasmaglucose and insulin responses in NIDDM subjects. Diabetes Care19:831–834.

Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H,Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta

A, Rastas M, Salminen V, Uusitupa M. 2001. Prevention oftype 2 diabetes mellitus by changes in lifestyle among subjectswith impaired glucose tolerance. N Engl J Med 344:1343–1350.

Weyer C, Gottlieb A, Kim DD, Lutz K, Schwartz S, Gutierrez M,Wang Y, Ruggles JA, Kolterman OG, Maggs DG. 2003.Pramlintide reduces postprandial glucose excursions when addedto regular insulin or insulin lispro in subjects with type 1 diabetes:a dose-timing study. Diabetes Care 26:3074–3079.

Wilhelm B, Forst S, Weber MM, Larbig M, Pfutzner A, Forst T.2006. Evaluation of CGMS during rapid blood glucose changesin patients with type 1 diabetes. Diabetes Technol Ther 8:146–155.

Wolever TM, Bolognesi C. 1996. Source and amount of carbo-hydrate affect postprandial glucose and insulin in normal subjects.J Nutr 126:2798–2806.

Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and ComplicationsResearch Group. 2002. Effect of intensive therapy on themicrovascular complications of type 1 diabetes mellitus. JAMA287:2563–2569.

Wu MS, Johnston P, Sheu WH, Hollenbeck CB, Jeng CY, GoldfineID, Chen YD, Reaven GM. 1990. Effect of metformin oncarbohydrate and lipoprotein metabolism in NIDDM patients.Diabetes Care 13:1–8.

Yates K, Hasnat Milton A, Dear K, Ambler G. 2006. Continuousglucose monitoring-guided insulin adjustment in children andadolescents on near-physiological insulin regimens: a randomizedcontrolled trial. Diabetes Care 29:1512–1517.

Zhang L, Krzentowski G, Albert A, Lefebvre PJ. 2001. Risk ofdeveloping retinopathy in Diabetes Control and ComplicationsTrial type 1 diabetic patients with good or poor metabolic control.Diabetes Care 24:1275–1279.

586 RENDELL

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