Conclusions
This study presents novel data on several aspects related to the shape of the glucose response curve during an OGTT. First, it is the first large study of its kind in people with type 2 diabetes, all on metformin only, that includes both men and women over a broad range of ethnicities and BMI. Second, the analysis highlights novel associations in the prevalence of glucose response curve patterns by sex, race, age, and BMI. Third, it investigates a new continuous rise glucose pattern, which has only previously been evaluated in youth in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study,10 and more recently in youth and adults with impaired glucose tolerance or newly diagnosed type 2 diabetes in the Restoring Insulin Secretion (RISE) study.16 Fourth, the study highlights the differences in β-cell function linked with each glucose response curve pattern, with a biphasic shape, although uncommon, demonstrating better β-cell function and the continuous rise subgroup showing reduced measures of late β-cell function relative to those with a monophasic shape.
Differences by sex in the prevalence of the monophasic and continuous rise subgroups were present that were independent of race and BMI using both a least squares and classification approach. Previous studies found that the biphasic or multiphasic pattern was more common in women (3-hour OGTT analysis in a large Chinese adult population with and without diabetes5 and a European population without diabetes3) or did not differ by sex.2 4 However, none of these studies included an analysis of a continuously rising glucose pattern. In GRADE, we found that more women exhibited a continuous rise shape, which has lower β-cell function, findings that are opposite to that in populations without diabetes, where the biphasic or multiphasic shape, associated with better β-cell function, was more common in women. The reason for a sex difference in the prevalence of the monophasic and continuous rise glucose curve shapes among GRADE participants is not clear but warrants further investigation.
Race also impacted the prevalence of the glucose curve subgroups but was in part due to differences in BMI. When BMI category was added to the classification analysis, race dropped out, but race remained independently associated with glucose response curve shape when adjusting for BMI in the least squares analysis. The most significant finding was a higher prevalence of the continuous rise shape in African American/black. Racial differences in curve shape distribution have not been reported for adults with type 2 diabetes and there were no differences in glucose response curve shape by race in youth with type 2 diabetes in the TODAY study.10 If the continuous rise pattern in adults follows the more aggressive course observed in youth in the TODAY study,10 the greater prevalence of this pattern in African American/black could portend a higher risk of progression to glycemic failure. African American/black individuals are disproportionally affected by type 2 diabetes, with a prevalence in the USA of 16.4% compared with 11.9% in non-Hispanic white.17 They also are at higher risk of developing type 2 diabetes, with the Coronary Artery Risk Development in Young Adults study finding a more than twofold higher risk of developing type 2 diabetes, although the disparity was no longer significant after adjusting for known modifiable risk factors, with biological factors having the greatest impact.18
Differences in both age and diabetes duration were also noted in the prevalence of the monophasic and continuous rise subgroups, with the monophasic subgroup being older and having a longer duration of diabetes. This is perhaps not surprising. A systematic review of the literature indicates that β-cell function declines with aging, consistent with the increase in incidence of type 2 diabetes in the aging population.19
The continuous rise curve shape has not yet been described in a large cohort of adults with type 2 diabetes. The two large studies that evaluated glucose response curve shape in adults with type 2 diabetes5 6 based classification on a 3-hour OGTT rather than the standard 2-hour test. Delays or deficiencies in insulin secretion and response that result in a continuous rise shape on a 2-hour test need a longer sampling time frame to capture the eventual fall in glucose. In essence, the classification of monophasic versus continuous rise glucose curve shapes reflects differences in timing. Thus, classification by curve shape alone during a 3-hour test is likely to miss important differences in timing between monophasic and continuous rise subgroups identified on a 2-hour test.
In GRADE, the early insulin and C peptide responses to glucose did not differ between the continuous rise and monophasic subgroups, but the continuous rise subgroup was characterized by lower late insulin and total insulin and C peptide responses, suggesting greater loss of insulin secretory ability. Peak glucose also differed between these two subgroups, being higher in the monophasic subgroup. Glucose acts not only to stimulate insulin secretion directly but can prime the β-cell to enhance subsequent insulin secretion.20 21 The higher responses in the monophasic subgroup may reflect an effect of higher peak glucose concentrations to potentiate late-phase insulin secretion or β-cells that are more responsive to the effects of potentiation. Consistent with our results, the TODAY study in youth with type 2 diabetes10 and the RISE study comparing youth and adults with impaired glucose tolerance (n=249 adults) or newly diagnosed type 2 diabetes (n=104 adults)16 both found that the continuous rise pattern was associated with the lowest β-cell function.
The continuous rise subgroup appears to have unique characteristics. The profiles for insulin and C peptide depicted in figure 1 suggest a ‘sluggish’ glucose response in those with a continuously rising glucose response curve. The rise in the glucose concentration, which acts as the stimulus for insulin secretion, also appears to be somewhat delayed, and the insulin and C peptide curves mimic the glucose response curve. While not tested in GRADE, one possible explanation for this delay could be that gastric emptying or glucose absorption is delayed. This hypothesis would need to be tested with studies designed to directly measure rates of glucose absorption.
The continuous rise glucose curve shape may identify a subgroup of individuals at higher risk of progression or who may respond differentially to specific treatment approaches. In youth with type 2 diabetes in the TODAY study, a pattern of a continuously rising glucose was associated with a higher HbA1c and lower late insulin and total insulin and C peptide responses, and presaged increased glycemic failure rates and accelerated deterioration of β-cell function.10 In RISE, progression from impaired glucose tolerance to diabetes or change in glycemic outcomes at 12 months did not differ by baseline glucose response curve categorization but may have been limited by the short follow-up time.16 Interestingly, progression from a biphasic to a monophasic and then ultimately to a continuous rise pattern along with corresponding decreasing β-cell function was also recently reported to occur during progression to type 1 diabetes in the TrialNet Pathway to Prevention study.22 Once GRADE is completed, we will be able to test a similar hypothesis in adults to determine if the continuous rise pattern identifies those at highest risk of progression and whether the biphasic pattern identifies those with more stable disease.
The biphasic glucose response pattern was uncommon, being present in only 5.5% of participants. These data are consistent with findings from a large population study in China in which only 3% of those with a diagnosis of type 2 diabetes had a multiphasic pattern based on a 3-hour OGTT.5 In populations without diabetes, biphasic or multiphasic curve shapes correlate with lower glucose values, higher insulin sensitivity and β-cell function,2–4 7 9 and lower risk of progression to diabetes23 and are present in a higher percentage of the population (20%–30% in adults). In GRADE, HbA1c and fasting glucose values were similar with the monophasic and continuous rise subgroups, but estimates of β-cell function were higher. The presence of the biphasic pattern within a small proportion of the diabetes population suggests that this may identify a subgroup that may differ in terms of pathophysiology and/or indicate a lower risk of progression.
The strengths of this study include the large multiethnic cohort of men and women with relatively early type 2 diabetes (<10 years) and use of OGTT to assess β-cell function. As all participants were treated with metformin alone for their diabetes, there was no confounding by use of other glucose-lowering medications. The study is generalizable to a large portion of the US population that has type 2 diabetes treated with metformin alone. Limitations include the cross-sectional analysis and the lack of more precise measures of insulin sensitivity and β-cell function.
In conclusion, this is the first large multiethnic cohort of adults with early type 2 diabetes to identify differences in OGTT glucose curve shape distribution by sex, race, and BMI and metabolic differences between the two most common curve shapes, monophasic and continuous rise. The continuous rise curve shape exhibited more advanced β-cell dysfunction and higher HbA1c compared with the monophasic subgroup and may serve as a biomarker for more advanced disease. Further mechanistic studies are needed to evaluate the metabolic processes underlying these differences. In the future, once GRADE is completed, analysis of GRADE outcome data will allow us to determine if these patterns predict differential progression and/or response to the four glucose-lowering therapies being studied.