Physiological factors contributing to HbA1c in the normal and pre-diabetic range: a cross-sectional analysis.

Abstract

Little is known about the underlying physiology that contributes to Haemoglobin A1c (HbA1c) in the normal and pre-diabetic range. We determined the contribution of fasting plasma glucose (FPG), 2-h plasma glucose (2hPG), insulin secretion, insulin sensitivity and endogenous glucose production to HbA1c levels in the normal and pre-diabetic range. A total of 62 Danish men and women with normal or impaired glucose regulation were studied. HbA1c levels were measured and participants underwent an oral glucose tolerance test with measurements of FPG and 2hPG, an intravenous glucose tolerance test for determination of first-phase insulin release, and a hyperinsulinaemic euglycaemic clamp for estimation of peripheral and hepatic insulin sensitivity. Associations of HbA1c with the different measures of glucose metabolism were analysed by linear regression analysis. HbA1c levels ranged from 28 to 45 mmol/mol (4.7-6.3%) in the study population. 1 SD higher (log) FPG concentration (~1 mmol/L) was associated with 2 mmol/mol higher HbA1c concentration (P < 0.001). In comparison, 1 SD higher levels of (log) first-phase insulin secretion or (log) disposition index were associated with 1.5 mmol/mol lower HbA1c levels (P < 0.05). HbA1c was not associated with peripheral or hepatic insulin sensitivity, endogenous glucose production or 2hPG levels. HbA1c levels within the normal and pre-diabetic range seem to reflect decreased insulin secretion to a higher extent than insulin resistance. Therefore, early prevention strategies for high-risk individuals identified by HbA1c are not straightforward. More research on how to improve the health of beta cells either directly or indirectly in high-risk individuals is needed.