To this end, they posed the following questions. (1) How frequently do diabetic patients experience broad glucose excursions after meals? (2) To what extent does fasting plasma glucose influence subsequent glucose levels during the day? (3) How strongly are plasma glucose levels at different times of the day interrelated? (4) Is HbA1c influenced more strongly by fasting or non-fasting plasma glucose?
HbA1c levels and plasma glucose profiles (samples taken before and 2–3 h after meals) were measured in three groups of patients: 371 outpatients measured once daily at the diabetes clinic; 30 patients self-measured at home five times per day over the course of 1 month; and 455 inpatients measured on the day of admission to hospital.
After meals many subjects had glucose levels >8.9 mmol/l (160 mg/dl) and/or glucose excursions >2.2 mmol/l (40 mg/dl) even when their HbA1c levels were satisfactory (<7%). In the outpatients who attended the clinic on a daily basis, 67.4% showed exaggerated increases in postmeal plasma glucose levels (>2.2 mmol/l), whereas in those who performed home glucose monitoring, 79.0% had exaggerated increases in postmeal plasma glucose; among inpatients this figure was 64.6%.
Glucose levels at different times of the day in every group showed significant correlations, but most were not particularly strong.
Coefficients of correlation ranged from 0.52 to 0.88. Multiple regression analysis revealed that premeal but not postmeal plasma/blood glucose levels were independent predictors of HbA1c. The results of this study suggest that:
— the majority of non-insulin-treated type 2 diabetic patients have large postprandial glucose concentrations and meal-induced glucose excursions;
— glucose levels throughout the day are not as strongly interrelated as might be expected;
— HbA1c is more dependent on preprandial than on postprandial glucose levels.
These results also clearly show that a considerable proportion of type 2 diabetic patients with satisfactory HbA1c levels had inadequate postprandial glucose control and that the drugs at present most frequently used for treating type 2 diabetes are not able in most cases to prevent exaggerated postmeal glucose excursions.

Comment
Several recent studies have suggested that hyperglycemia is a major modifiable risk factor to reduce diabetic complications. Fasting glucose levels, postchallenge hyperglycemia and even isolated postprandial hyperglycemia are important factors in the development of atherosclerosis and fatal coronary heart disease [1, 2]; further, 2-h postprandial glucose levels are better predictors of mortality from cardiovascular disease than are fasting blood glucose levels [2]. Some reports have suggested that raised glucose levels are also accompanied by increased postprandial hyperlipidemia, which is a well-known risk factor for cardiovascular disease [3, 4].
The loss of early or first-phase insulin release, which is responsible for the suppression of endogenous postmeal hepatic glucose production (HGP), plays a major role in postprandial hyperglycemia [4]. In non-diabetic subjects early insulin release suppresses HGP by 50% within 30 min of a meal, but in type 2 diabetic patients no suppression occurs until 2 h after a meal and, moreover, HGP is 50% higher at baseline. The suppression of HGP by insulin in non-diabetic subjects predominantly results from insulin’s inhibition of lipolysis in adipose tissue, by which the decreased delivery of free fatty acids from the fat cells signals to the liver to suppress HGP [5]. The increased baseline HGP in diabetics is partly the consequence of adipose tissue insulin resistance and is fuelled by excess non-esterified fatty acid release from the fat cells. The chronic increase in circulating free fatty acids also has a detrimental effect on the islet cells: triglyceride (and long-chain acyl coenzyme A) concentrations increase within the cells and this ‘lipotoxicity’ induces progressive impairment in insulin secretion [4].
If the loss of early insulin secretion plays a major role in the pathogenesis of postprandial hyperglycemia, strategies to augment early insulin secretion would represent novel therapeutic interventions to improve glycemic control and to prevent the chronic complications of diabetes. To achieve this goal we need to answer some basic questions. (1) Is the restoration of early insulin release able to prevent exaggerated postmeal glucose excursions? (2) Does the restoration of insulin secretion have a long-term effect on the progression of diabetes or on the development of complications? (3) What are the levels of postprandial hyperglycemia in treated type 2 diabetic patients? (4) Are traditional hypoglycemic drugs able to improve early insulin secretion?
Several studies (reviewed in [4]) have proved that replacement of the first-phase insulin peak with an exogenous insulin infusion can suppress HGP to levels similar to those observed in non-diabetic subjects. Genetic predisposition limits the ability of the b-cells to compensate for insulin resistance and is behind several environmental effects such as those of weight gain, physical inactivity and a high-fat diet. There have been no prospective clinical studies to establish how long b-cell function could be preserved with the new types of interventions. We know that by the time type 2 diabetes becomes manifest b-cell function is already reduced by about 50%, and the subsequent deterioration of further insulin secretion is not associated with a change in insulin sensitivity. Interventions should thus focus on preserving islet function.
From the present and from previous studies [6] it is clear that conventional parameters such as HbA1c and premeal plasma/blood glucose levels are inadequate determinants of postchallenge hyperglycemia and the excess morbidity and mortality that accompany it. As most guidelines recommend monitoring of HbA1c and premeal glucose levels, evaluation of glucose control based on measuring postprandial glucose values represents an attractive target in primary care.
Conventional sulfonylureas augment insulin secretion, but this effect is not specific to first-phase insulin secretion, since basal and second-phase insulin secretion are also increased. The new non-sulfonylurea insulin secretagogues, repaglinide and nateglinide, increase early insulin secretion but not basal and second-phase insulin secretion, and thereby lower postprandial glucose levels without exhausting b-cell insulin production.
The pulmonary administration of regular insulin and the new rapid-acting insulin analogues with their more rapid pharmacodynamic profile are another means of improving glycemic control by a faster and more complete suppression of endogenous glucose production.
Glucagon-like peptide-1 (GLP-1) provides another means of augmenting early insulin secretion and controlling postprandial glycemia. In clinical studies, GLP-1 increased insulin secretion in a glucose-dependent manner [4].
Last, but not least, diet, physical exercise and weight loss are the most physiological interventions for improving glycemic control. Weight gain following exposure to a high-fat diet (50% of calories from fat) causes a decline in acute insulin secretory response which can largely be reversed with weight loss. All these effects may be mediated in part through the effect of increased/decreased non-esterified fatty acids [4].
In conclusion, everyday diabetes care should focus on better glycemic measures based on postprandial glucose values, as there is strong evidence that postmeal glucose values predict cardiovascular disease even in the absence of fasting hyperglycemia. Recent developments in diabetic pharmacotherapy have produced effective interventions to preferentially modify postprandial glucose levels.

References
1. Henefeld M, Koehler C, Schaper F et al. Postprandial plasma glucose is an independent risk factor for increased carotid intima-media thickness in non-diabetic individuals. Atherosclerosis 1999; 144: 229–35.
2. Kuizon D, Gordon SM, Dolmatch BL et al. Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria. Arch Intern Med 2001; 161: 397–405.
3. Agboola-Abu CF, Ohwovoriole AE, Akinlade KS et al. The effect of glycaemic control on the prevalence and pattern of dyslipidaemia in Nigerian patients with newly diagnosed non-insulin dependent diabetes mellitus. West Afr J Med 2000; 19: 27–33.
4. Pratley RE, Weyer C. The role of impaired early insulin secretion in the pathogenesis of type II diabetes mellitus. Diabetologia 2001; 44: 929–45.
5. Luzi L, deFronzo RA. Effect of loss of first-phase insulin secretion on hepatic glucose production and tissue glucose disposal in humans. Am J Physiol 1989; 257: E704–11.
6. Erlinger TP, Brancati FL. Postchallenge hyperglycemia in a national sample of U.S. adults with type 2 diabetes. Diabetes 2001; 24: 1734–8.

Summary and Comment:
László Korányi, Balatonfüred, Hungary