Importance of Postprandial Glucose Control.

ABSTRACT: Although a traditional goal of glycemic control in the treatment of diabetes mellitus is to normalize fasting plasma glucose, emerging data indicate that modulation of postprandial plasma glucose levels plays an important role in overall glycemic control. This article reviews the evidence linking postprandial glucose levels with long-term indices of diabetes control, such as glycosylated hemoglobin, lipid abnormalities, and the risk of microvascular and macrovascular complications. Early in the development of type 2 diabetes, the initial burst of insulin release in response to food intake is compromised, allowing postprandial hyperglycemia to develop. Meal-associated hyperglycemia further contributes to increase insulin resistance and decrease insulin production. Evidence of a strong correlation between high postprandial glycemic levels and the development of vascular complications underscores the significance of treating mealtime glycemia. Emerging drugs that reduce postprandial hyperglycemia inclu de the D-phenylalanine derivative nateglinide, amylin derivative pramlintide, and glucagon-like insulinotropic peptide.

THE GOAL in the management of patients with type 2 diabetes is to control fasting plasma glucose and glycosylated hemoglobin ([HbA.sub.1c]) levels. In patients with well-controlled diabetes ([HbA.sub.1c] [less than]7%, or within 1% of normal) or glucose intolerance (fasting plasma glucose level [less than]126 mg/dL, and a 2-hour plasma glucose of 140 to 200 mg/dL after 75 g of oral glucose), postprandial hyperglycemia has a greater effect on [HbA.sub.1c] than fasting glucose levels. Jovanovic [1] recently reported that the postprandial glucose level at 1 hour is the best predictor of [HbA.sub.1c] in patients with well-controlled type 2 diabetes mellitus. In addition, a French study of patients with type 2 diabetes showed that glucose concentrations at 2 and 5 hours after a meal were better predictors of the [HbA.sub.1c] than prebreakfast or prelunch values. [2] Therefore, in patients with elevated [HbA.sub.1c], the postprandial plasma glucose levels may play a disproportionate role in the genesis of both micr ovascular and macrovascular complications of diabetes.

The recent change in plasma glucose threshold for the diagnosis of diabetes was based on evidence such as that from the United Kingdom Prospective Diabetes Study, which showed that 50% of patients with type 2 diabetes already had one or more chronic complications by the time it was diagnosed. [3] The standard for diagnosis is still a plasma glucose level [greater than]200 mg/dL at 2 hours after a 75-g glucose load. Postprandial levels [greater than]200 mg/dL are seen in 97% of patients with a fasting plasma glucose value of 126 mg/dL In addition, 52% of patients with fasting plasma glucose [less than]126 mg/dL still have postprandial levels [greater than]200 mg/dL. Therefore, patients with fasting glucose levels between 110 and 126 mg/dL should undergo a 2-hour, 75-g glucose challenge to assess their postprandial glucose levels, since early detection and treatment can delay or prevent the onset of complications. [3]

WHY IS GLUCOSE CONTROL SO IMPORTANT?

In the fasting state, the suppression of insulin production and stimulation of glucagon production control the concentration of blood glucose. These processes allow the liver to mobilize glucose from its glycogen stores and synthesize glucose from amino acids and pyruvate (gluco-neogenesis). In addition, when insulin levels are low, the uptake of glucose by muscle is minimized, and adipocytes release free fatty acids. This homeostatic mechanism effects a stable plasma glucose level in the fasting state so that the brain, which has no energy stores, has a sufficient supply of nutrients for normal activity.

In the fed state, insulin is released in two phases. The first phase, a short, small burst released on food intake or an increase in plasma glucose concentration, preempts and decreases the postprandial glucose elevation. Later, a more sustained, second-phase insulin release directly proportional to the plasma glucose elevation occurs. In response to this biphasic release of insulin, the liver takes up glucose, converting it to glycogen (animal starch). The muscle and adipose tissues also take up glucose, storing it as glycogen and triglycerides, respectively. Furthermore, the production of free fatty acids in adipocytes is suppressed. The loss of first-phase insulin release has adverse metabolic and physiologic consequences, even if the second-phase release is adequate or even excessive.

FIRST-PHASE INSULIN RELEASE

One of the earliest changes in the development of type 2 diabetes is the loss of first-phase insulin release, which occurs with fasting glucose levels of about 110 mg/dL. The loss can be documented by measuring plasma insulin concentrations over the 10 minutes immediately after an intravenous glucose load, calculated on the basis of the patient's weight. Lack of first-phase insulin release, an excellent predictor of both types of diabetes, is thought to be the earliest sign of the adverse effects of hyperglycemia on insulin-producing [beta]-cells and insulin-sensitive tissues (glucotoxicity). [4] When the first-phase insulin response fails, plasma glucose levels rise sharply after a meal. Initially, this precipitates an increased stimulation of second-phase insulin release that, in the early stages of glucose intolerance, may lead to postprandial hypoglycemia resulting from elevated plasma insulin remaining after the nutrients have disappeared. [5] High insulin levels also cause down-regulation of the insulin postreceptor pathways on the muscle and fat cells, thus increasing insulin resistance. [6]

The higher glucose level in islet cells prompts a decrease in glucose-transporter activity, resulting in a reduction of insulin release, [7] which is reversed by a decrease in plasma glucose level. If there is no decrease, the prolonged hyperglycemia will eventually cause an accelerated loss of insulin-producing [beta]-cells in both type 1 and type 2 diabetes. [4] Thus, metabolic loss of first-phase insulin release results in postprandial hyperglycemia, an increase in insulin resistance, and a further decrease in insulin production.

EFFECT OF POSTPRANDIAL GLUCOSE LEVELS ON MICROVASCULAR COMPLICATIONS

The effects of postprandial hyperglycemia on the development of microvascular complications of diabetes have been well documented. There is evidence that uncontrolled glycemic peaks activate protein kinase C, the enzyme that may link hyperglycemia to microvascular complications. [8] Elevated glucose levels lead to increased intracellular synthesis of diacylgycerol, which, in conjunction with elevated intracellular calcium, activates protein kinase C. [8] The activity of protein kinase C impairs contraction of smooth muscle cells or pericytes, increases production of basement membrane materials, and enhances cell proliferation and capillary permeability. Thus, activation of protein kinase C by postprandial hyperglycemia could be responsible for microvascular complications that may be developing even in the early stages of diabetes. [8]

Data from the National Health and Nutrition Examination Survey showed that patients who had 2-hour postprandial glucose levels of 194 mg/dL had a threefold increase in the incidence of retinopathy, despite normal fasting glucose levels. [3] Studies of Pima Indian and Egyptian populations revealed a similar increase in the incidence of retinopathy in subjects with normal fasting glucose levels but 2-hour postprandial glucose values of [greater than]200 mg/dL. [3]

The development of microvascular complications in patients with type 2 diabetes has been documented in a number of clinical trials. In a long-term study of complications in patients who had type 2 diabetes for more than 25 years, Mohan et al [9] reported that postprandial glucose levels were associated with diabetic nephropathy. In a recent study of Pima Indian subjects, hyperfiltration, a precursor of diabetic nephropathy, in subjects with impaired glucose tolerance was found to increase with the onset of type 2 diabetes. [10] In a population study, Beghi et al [11] showed that elevated fasting and postprandial glucose levels, as well as prolonged disease duration, were associated with an increased incidence of diabetic neuropathy.

POSTPRANDIAL GLUCOSE LEVELS AND MACROVASCULAR COMPLICATIONS

The glycemic threshold for the development of macrovascular complications is lower than that for microvascular complications, so there is more evidence for an association with postprandial glycemia. Postprandial glucose elevations are associated with postprandial hyperinsulinemia and higher plasma levels of triglycerides, chylomicrons, chylomicron remnants, and free fatty acids. High concentrations of free fatty acids have been associated with endothelial dysfunction, [12] and high triglyceride levels have been linked to low levels of high-density lipoprotein (HDL) cholesterol and a preponderance of small, dense, low-density lipoprotein (LDL) particles. Although only the relationship between fasting-state hypertriglyceridemia and coronary artery disease (CAD) has been established, postprandial high triglyceride levels most likely have the same effect. [13] In addition, high postprandial glucose levels result in protein and cellular glycosylation. Glycosylated LDL particles are more easily oxidized and taken u p by macrophages through the scavenger receptor. This, in turn, leads to higher foam cell production, and, ultimately, atherosclerotic plaque. In addition, glycosylated LDL also stimulates platelet aggregation. Glycosylated HDL is less efficient than nonglycosylated in transporting cholesterol back to the liver for metabolism. Additionally, the formation of advanced glycosylated end products in the collagen of the vessel wall itself may directly stimulate or accelerate the atherosclerotic process. [14]

Acute increases in plasma glucose also stimulate the production of free radicals, another factor involved in the atherosclerotic process. [15] Excessive postprandial plasma glucose levels have also been associated with transient hypercoagulability resulting from increased thrombin production and decreased fibrinogen breakdown. These, in turn, result from the overproduction of plasminogen activator inhibitor, which directly inhibits tissue plasminogen activator activity. Control of postprandial hyperglycemia reverses this hypercoagulable state. [16]

Endothelial dysfunction is another consequence of postprandial hyperglycemia. Activation of protein kinase C in the endothelium increases adhesion molecules [17] that facilitate leukocyte uptake into the blood vessel wall; increases production of the vasodilators nitric oxide and prostaglandin; increases expression of the vasoconstrictor endothelin; and induces platelet aggregation. [8]

The Honolulu Heart Study found that the risk of CAD correlated with plasma glucose levels measured 1 hour after a 50-g oral glucose load. The incidence of CAD was twice as high n patients with postprandial plasma glucose levels between 157 and 189 mg/dL as in those with levels [less than]144 mg/dL, [18] and the incidence of sudden death was doubled with postprandial plasma glucose levels [greater than]151 mg/dL. [19] The Whitehall Study of British male civil servants showed that plasma glucose levels [greater than]96 mg/dL 2 hours after a meal were associated with a twofold increase in mortality from CAD. [20] Another British study, the Islington Diabetes Survey, reported that the incidence of major CAD (defined as major electrocardiographic changes or myocardial infarction) was 17% in subjects with a 2-hour postprandial glucose level between 120 and 180 mg/dL, compared with 9% in subjects with levels [less than]120 mg/dL. [21] The Bedford Survey showed that protection from CAD was lost in patients with eleva ted postprandial glucose. [22] By studying the progression of CAD in young men with previous myocardial infarction, Bavenholm et a1 [23] found that fasting and postprandial plasma glucose levels were independently related to disease progression. The Oslo Study indicated that the nonfasting plasma glucose level was a predictor of fatal stroke in diabetic patients, with the risk increasing by 13% for each 18-mg/dL elevation in postprandial glucose. [24] The Diabetes Intervention Study also showed that postprandial, not fasting, hyperglycemia was an independent risk factor for myocardial infarction and cardiac death. [25]

The Hoorn Study documented an increased risk of peripheral vascular disease in elderly patients with diabetes and in subjects with impaired glucose tolerance. [26] Ankle to brachial pressure indices [less than]0.9 were found in 7% of nondiabetic subjects, 9.5% of subjects with impaired glucose tolerance, 15.1% of patients with newly diagnosed diabetes, and 20.9% of patients with established type 2 diabetes. After logistical regression analysis and correction for other cardiovascular risk factors, the 2-hour postprandial plasma glucose value remained an independent risk factor for peripheral vascular disease, whereas plasma insulin did not. [26]

Overexposure to insulin in response to postprandial hyperglycemia has been shown to be a risk factor for cardiovascular events. The Paris Prospective Study found that postprandial hyperinsulinemia was a better predictor for fatal CAD than either hyperglycemia or diabetes. [27] Similarly, the Helsinki Policemen Study revealed an independent association between fatal and nonfatal CAD events and 1- and 2-hour postprandial insulin levels that was stronger than that with fasting plasma insulin levels. [28] Finally, a recent report suggested an association between postprandial levels and intellectual function in elderly Alzheimer's patients who were not ApoE4 positive. [29]

Another factor associated with postprandial hyperglycemia is postprandial hyperlipidemia. Elevated triglyceride levels after a meal predict the development of CAD and are associated with carotid artery atherosclerosis in nonobese white subjects. [30] Therefore, a reduction of postprandial glucose levels, which also reduces plasma insulin and lipids after a meal, could reduce the incidence of CAD.

POSTPRANDIAL GLUCOSE LEVELS AND PREGNANCY OUTCOMES

In women who have gestational diabetes and require insulin, controlling postprandial plasma glucose levels has consistently been shown to result in better outcomes than controlling fasting plasma glucose. In a study that compared preprandial and postprandial monitoring of glycemic control in women with gestational diabetes, 33 women in the postprandial glucose control group had lower [HbA.sub.1c] levels. Their babies had lower birth weights, lower risk of neonatal hypoglycemia, and were less likely to be born by cesarean section than those of the 33 women randomly assigned to fasting glucose control. [31] The Diabetes in Early Pregnancy Study showed that high birth weight correlated closely with the mothers' third trimester nonfasting glucose levels. [32]

Similarly, Combs et al [33] reported that there was a strong correlation between macrosomia and high postprandial glucose levels occurring during the 29th to 32nd week of pregnancy. Demarini et al [34] studied two groups of pregnant women with different target levels of postprandial glucose, [less than]120 and [greater than]140 mg/dL, respectively. Neonatal hypoglycemia occurred at a higher frequency in babies born to women in the [less than]140 mg/dL group. Because of these studies, the American Diabetes Association now recommends monitoring both fasting and 1-hour plasma serum glucose levels during pregnancy. [35]

METHODS OF CONTROLLING POSTPRANDIAL HYPERGLYCEMIA

Postprandial glycemic control is important in avoiding microvascular and macrovascular complications, lowering insulin resistance, restoring normal insulin secretion, and avoiding complications in the offspring of women with diabetes. It is recommended that the treatment of diabetes include methods that lower both fasting and postprandial glucose levels.

In type I diabetes, postprandial glucose levels can be controlled only with very fast-acting insulin, such as insulin lispro. [36] Lispro differs structurally from regular insulin in the reversal of the two amino acids at positions 28 and 29 on the B chain (proline-lysine to lysine-proline). [36] Subcutaneous regular insulin, especially in large doses, forms a hexamer that has to be broken down to a dimer or a monomer before it can be absorbed into the blood stream to lower plasma glucose. Thus, after a meal, glucose levels rise before subcutaneous regular insulin can be absorbed. In addition, the longer action of regular insulin leads to unphysiologically elevated plasma insulin. Since this state often results in late hypoglycemia, between-meal snacks are needed. Snacking can increase total calorie intake, causing an undesired weight gain. Lispro insulin does not form hexamers, is quickly absorbed into the blood stream, covers the meal appropriately, and does not linger long enough to cause postprandial hypo glycemia or the need for a snack. For similar reasons, a fast-acting lisprolike insulin is needed in patients with type 2 diabetes who take insulin, even if they have some endogenous production, because they lack first-phase insulin release.

New antidiabetic drugs in development, such as the injectable amylin analog pramlintide and glucagon-like insulinotropic polypeptide (GLIP), target the suppression of postprandial hyperglycemia. [37,38] These drugs slow gastric emptying and suppress glucagon production. Pramlintide also replenishes hepatic glycogen stores, and GLIP increases insulin production in response to a meal. Although both agents suppress postprandial hyperglycemia, as yet, neither can be taken orally and therefore must be injected subcutaneously.

In patients with type 2 diabetes who require none or just one evening or nighttime injection of intermediate-acting insulin to control the fasting glucose level, an oral agent capable of stimulating an insulin release sufficient to cover the meal or delay the absorption of glucose from the intestine (bolus agents) should be used. Drugs with these properties should be used in combination with oral agents that lower insulin resistance, decrease hepatic glucose production, or stimulate insulin production (basal agents). This therapy can be described as oral basal-bolus therapy for type 2 diabetes, in contrast to injection-based basal-bolus therapy using insulin for type 1.

Bolus drugs include acarbose, miglitol, [37] repaglinide, and possibly glimepiride. Examples of basal drugs are troglitazone, pioglitazone, rosiglitazone, metformin, long-acting sulfony-lureas, and intermediate and long-acting insulins. [39] It is easier to achieve the long-term [HbA.sub.1c] goal [less than or equal to]7% using basal-bolus therapy, because at this level of control, the biggest contributor to [HbA.sub.1c] values is the postprandial glucose level. [1]

Several drugs that stimulate a short-lived insulin release are in development. Nateglinide, a D-phenylalanine derivative representing a new class of oral antidiabetic agents, stimulates early insulin release in response to elevated glucose levels in the blood by inhibiting the energy-sensitive potassium channels in pancreatic [beta]-cells. This agent enhances, rather than suppresses, insulin release in the presence of high glucose levels. This rapid and short-lived increase in insulin secretion prevents the effects frequently associated with hyperinsulinemia such as postprandial hypoglycemia and weight gain. Nateglinide has a much higher affinity for [beta]-cell potassium channels than for those on smooth muscle cells, [39] which may provide enhanced safety, since potassium channel closure in the myocardium and coronary arteries can result in an increased incidence of cardiac events. [40]

Regardless of the drugs available, for optimal postprandial glycemic control, patients must monitor their glucose levels after eating a meal. When diabetes is poorly controlled, only preprandial glucose readings are necessary. However, once control is achieved, it is important to monitor glucose levels both before and after meals. This allows for appropriate adjustments of bolus drug administration to reach postprandial glycemic goals and to maximize the patient's protection from diabetic complications.

CONCLUSION

In the prevention of diabetic complications, controlling postprandial plasma glucose in patients with well-controlled type 2 diabetes is at least as important as controlling fasting glucose levels. Therefore, the ideal treatment for patients with type 2 diabetes should include a combination of agents that lower basal plasma glucose and agents that control meal-related glucose excursions.

From the Department of Medicine, University of Alabama at Birmingham School of Medicine.

Reprint requests to David S. Bell, MB, University of Alabama at Birmingham, Department of Medicine, 1808 7th Ave 5, Room 813, Birmingham, AL 35294.

References

(1.) Jovanovic L: Rationale for prevention and treatment of postprandial glucose-mediated toxicity. Endocrinologist 1999; 9:87-92

(2.) Avignon A, Radauceanu A, Monnier L: Nonfasting plasma glucose is a better marker of diabetic control than fasting plasma glucose in type 2 diabetes. Diabetes Care 1997; 20:1822-1826

(3.) Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1998; 22(suppl 1):S5-S19

(4.) Poitout V, Robertson RP: An integrated view of [beta]-cell dysfunction in type-II diabetes. Annu Rev Med 1996; 47:69-83

(5.) Mitrakou A, Kelley D, Mokan M, et al: Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance, N Engl J Med 1992; 326:22-29

(6.) Mandarino L, Baker B, Rizza R, et al: Infusion of insulin impairs human adipocyte glucose metabolism in vitro without decreasing adipocyte insulin receptor binding. Diabetologia 1984; 27:358-363

(7.) Rossetti L, Giaccari A, DeFronzo RA: Glucose toxicity. Diabetes Care 1990; 13:610-630

(8.) Koya D, King GL: Protein kinase C activation and the development of diabetic complications. Diabetes 1998; 47:859-866

(9.) Mohan V, Vijayaprabha R, Rema M: Vascular complications in long-term South Indian NIDDM of over 25 years' duration. Diabetes Res Clin Pract 1996; 31:133-140

(10.) Nelson RG, Tan M, Beck GJ, et al: Changing glomerular filtration with progression from impaired glucose tolerance to type II diabetes mellitus. Diabetologia 1999; 42:90-93

(11.) Beghi E, Monticelli ML, and the Italian General Practitioner Study Group (IGPSG): Diabetic polyneuropathy in the elderly, prevalence and risk factors in two geographic areas of Italy. Acta Neurol Scan 1997; 96:223-228

(12.) Groot PHE, van Stiphout WAHJ, Krauss XH, et al: Postprandial lipoprotein metabolism in normolipidemic men with and without coronary artery disease. Arterioscier Thromb 1991; 11:653-662

(13.) Patsch JR, Miesenbock G, Hopferwieser T, et al: Relation of triglyceride metabolism and coronary artery disease, studies in the postprandial state. Arterioscler Thromb 1992; 12:1336-1345

(14.) Bucala R, Cerami A, Viassara H: Advanced glycosylation end products in diabetic complications, biochemical basis and prospects for therapeutic intervention. Diabetes Rev 1995; 3:258-268

(15.) Habib MP, Dickerson FD, Mooradian AD: Effect of diabetes, insulin, and glucose load on lipid peroxidation in the rat. Metabolism 1994; 43:1442-1445

(16.) Ceriello A, Quatraro A, Marchi E, et al: Impaired fibrinolytic response to increased thrombin activation in type 1 diabetes mellitus: effects of the glycosaminoglycan sulodexide. Diabetes Metab 1993; 19:225-229

(17.) Ceriello A, Falleti E, Bortolotti N, et al: Increased circulating intercellular adhesion molecule-1 levels in type II diabetic patients: the possible role of metabolic control and oxidative stress. Metabolism 1996; 45:498-501

(18.) Donahue RP, Abbott RD, Reed DM, et al: Postchallenge glucose concentration anti coronary heart disease in men of Japanese ancestry. Honolulu Heart Program. Diabetes 1987; 36:689-692

(19.) Curb JD, Rodriguez BL, Burchfiel CM, et al: Sudden death, impaired glucose tolerance, and diabetes in Japanese American men. Circulation 1995; 91:2591-2595

(20.) Fuller JH, Shipley MJ, Rose G, et al: Coronary-heart-disease risk and impaired glucose tolerance, the Whitehall Study. Lancet 1980; 1:1373-1376

(21.) Jackson CA, Yudkin JS, Forrest RD: A comparison of the relationships of the glucose tolerance test and the glycated haemoglobin assay with diabetic vascular disease in the community. the Islington Diabetes Survey. Diabetes Res Clin Pract 1992; 17:111-123

(22.) Jarrett RJ, McCartney P, Keen. H: The Bedford Survey: ten-year mortality rates in newly diagnosed diabetics, borderline diabetics and normoglycaemic controls and risk indices for coronary heart disease in borderline diabetics. Diabetologia 1982; 22:79-84

(23.) Bitvenholm P, de Faire U, Landou C, et al: Progression of coronary artery disease in young male post-infraction patients is linked to disturbances of carbohydrate and lipoprotein metabolism anti to impaired fibrinolytic function. Eur Heart J 1998; 19:402-410

(24.) Haheim LL, Holme I, Hjermann I, et al: Nonfasting serum glucose and the risk of fatal stroke in diabetic and nondiabetic subjects. 18-year follow-up of the Oslo Study. Stroke 1995; 26:774-777

(25.) Hanefeld M, Temelkova-Kurktschiev T: The postprandial state and the risk of atherosclerosis. Diabetic Med 1997; 4(suppl 3):S6-S11

(26.) Beks PJ, Mackaay AJC, de Neeling JND, et al: Peripheral arterial disease in relation to glycaemic level in an elderly caucasian population: the Hoorn Study. Diabetologia 1995; 38:86-96

(27.) Fontbonne AM, Eschwege EM: Insulin and cardiovasculardisease. Paris Prospective Study. Diabetes Care 1991; 14:461-469

(28.) Pyorala K, Savolainen E, Kaukola S, et al: Plasma insulin as coronary heart disease risk factor: relationship to other risk factors and predictive value during 91/2-year follow-up of the Helsinki Policemen Study population. Acta Med Scand 1985; 701 (suppl):38-52

(29.) Stolk RP, Breteler MMB, Ott A, et al: Insulin and cognitive function in an elderly population. the Rotterdam Study. Diabetes Care 1997; 20:792-795

(30.) Sharrett AR, Chambless LE, Heiss G, et al, for the ARIC Investigators: Association of postprandial triglyceride and retinyl palmitate responses with asymptomatic carotid artery atherosclerosis in middle-aged men and women. the Atherosclerosis Risk in Communities (ARIC) Study. Arterioscler Thromb Vasc Biol 1995; 15:2122-2129

(31.) de Veciana M, Major CA, Morgan MA, et al: Postprandial versus preprandial blood glucose monitoring in women with gestational diabetes mellitus requiring insulin therapy. N Engl J Med 1995; 333:1237-1241

(32.) Jovanovic-Peterson L, Peterson CM, Reed GF, et al: Maternal postprandial glucose levels and infant birth weight: the Diabetes in Early Pregnancy Study Am J Obstet Gynecol 1991; 164:103-111

(33.) Combs CA, Gunderson E, Kitzmiller JL, et al: Relationship of fetal macrosomia to maternal postprandial glucose control during pregnancy. Diabetes Care 1992; 15:1251-1257

(3l.) Demarini S, Mimouni F, Tsang RC, et al: Impact of metabolic control of diabetes during pregnancy on neonatal hypocalcemia: a randomized study. Obstet Gynecol 1994; 83:918-922

(35.) American Diabetes Association: Monitoring. Medical Management of Pregnancy Complicated by Diabetes. Jovanovic L (ed). Alexandria, Va, American Diabetes Association, 2nd Ed, 1995, pp 29-38

(36.) Holleman F, Hoekstra JBL: Insulin lispro. N Engl J Med 1997; 337:176-183

(37.) Joubert PH, Venter HL, Foukaridis GN: The effect of miglitol and acarbose after an oral glucose load: a novel hypoglycaemic mechanism? Br J Clin Pharmacol 1990; 30:391-396

(38.) Schmitz O, Nyholm B, Orskov L, et al: Effects of amylin and the amylin agonist pramlintide on glucose metabolism. Diabetes Med 1997; 14(suppl 2):S19-S23

(39.) Wolffenbuttel BHR, Nijst L, Sels JPJE, et al: Effects of a new oral hypoglycaemic agent, repaglinide, on metabolic control in sulphonylurea-treated patients with NIDDM. Eur J Clin Pharmacol 1993; 45:113-116

(40.) Bell DSH: University group diabetes program--deja vu all over again"? Endocr Pract 1998; 4:64-65

KEY POINTS

* Modulation of postprandial plasma glucose plays an important role in overall glycemic control.

* There is a strong correlation between high postprandial glucose level and the development of vascular complications.

* First phase insulin release is lost early in the development of type 2 diabetes, leading to postprandial hyperglycemia, increased insulin resistance, and decreased insulin production.

* With loss of the first phase insulin release, an exaggerated second phase insulin release in response to the postprandial hyperglycemia can cause postprandial hypoglycemia.

* Emerging drugs that reduce postprandial hyperglycemia include nateglinide, pramlitide, and glucagon-like insulinotropic peptide.