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

Purpose: Little is known about the underlying physiology that contributes to Haemoglobin A1c (HbA _1c) 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 HbA _1c levels in the normal and pre-diabetic range. Methods: A total of 62 Danish men and women with normal or impaired glucose regulation were studied. HbA _1c 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 HbA _1c with the different measures of glucose metabolism were analysed by linear regression analysis. Results: HbA _1c 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 HbA _1c 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 HbA _1c levels (P < 0.05). HbA _1c was not associated with peripheral or hepatic insulin sensitivity, endogenous glucose production or 2hPG levels. Conclusion: HbA _1c 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 HbA _1c are not straightforward. More research on how to improve the health of beta cells either directly or indirectly in high-risk individuals is needed.