Association of glycemia with insulin sensitivity and β-cell function in adults with early type 2 diabetes on metformin alone

Abstract

Aims: Evaluate the relationship between measures of glycemia with β-cell function and insulin sensitivity in adults with early type 2 diabetes mellitus (T2DM).

Methods: This cross-sectional analysis evaluated baseline data from 3108 adults with T2DM <10 years treated with metformin alone enrolled in the Glycemia Reduction Approaches in Diabetes. A Comparative Effectiveness (GRADE) Study. Insulin and C-peptide responses and insulin sensitivity were calculated from 2-h oral glucose tolerance tests. Regression models evaluated the relationships between glycemic measures (HbA1c, fasting and 2-h glucose), measures of β-cell function and insulin sensitivity.

Results: Insulin and C-peptide responses were inversely associated with insulin sensitivity. Glycemic measures were inversely associated with insulin and C-peptide responses adjusted for insulin sensitivity. HbA1c demonstrated modest associations with β-cell function (range: r - 0.22 to -0.35). Fasting and 2-h glucose were associated with early insulin and C-peptide responses (range: r - 0.37 to -0.40) as well as late insulin and total insulin and C-peptide responses (range: r - 0.50 to -0.60).

Conclusion: Glycemia is strongly associated with β-cell dysfunction in adults with early T2DM treated with metformin alone. Efforts to improve glycemia should focus on interventions aimed at improving β-cell function. This Trial is registered in Clinicaltrials.gov as NCT01794143.

Keywords: Beta-cell function; Glucose tolerance; Glycemic control; Insulin sensitivity; Type 2 diabetes.

Conflict of interest statement

Declaration of competing interest The writing group reports the following as relevant conflicts of interest: KMU reports support from Medtronics, personal fees from Novo Nordisk, outside the submitted work; NR reports grants and other support from Novo Nordisk, outside the submitted work; RMC reports grants from National Institutes of Health during the conduct of the study; other support from Bristol Myers Squibb and Pfizer, outside the submitted work; DJW reports grants from an NIDDK funded trial during the conduct of the study; and other support from Novo Nordisk, outside the submitted work. SEK reports grants from NIH during the conduct of the study; personal fees from Boehringer Ingelheim, Eli Lilly, Intarcia, Janssen, Merck, Novo Nordisk, and Pfizer, outside the submitted work. KJM reports grants from National Institutes of Health during the conduct of the study; and at the time of publication. KJM is an employee of Eli Lilly and Company. Data collection, analysis, and preparation of the manuscript occurred prior to this employment and were independent of Eli Lilly and Company. NY, JB, MAB, EVG, FIB, JML, and PR have nothing to disclose. KMU and SEK are supported by funding from the United States Department of Veterans Affairs.

Published by Elsevier Inc.

Figures

Figure 1:

Scatterplots of HOMA2-S and Matsuda index against the insulinogenic index, the late insulin response, the C-peptide index, and the ratios of incremental areas under the insulin and C-peptide curves to the incremental area under the glucose curve. The smooth curves are from lowess smoothers. For each plot, the Spearman correlation and its asymptotic p-value are reported.

Figure 2.

Unadjusted associations between glycemic variables (rows across) and insulin sensitivity and insulin (ins) and C-peptide (CP) responses (columns down) are depicted. HbA1c and fasting and 2-hour plasma glucose concentrations were inversely associated with insulin sensitivity and insulin and C-peptide responses. The associations were steeper for insulin and C-peptide responses than for insulin sensitivity. Only Spearman correlations significant at the p

Figure 3.

Relationships between multiple measures of glycemia and insulin (ins) and C-peptide (CP) responses. All partial correlation models were adjusted for sex, age, race, BMI, eGFR, metformin dose, diabetes duration and HOMA2-S. The solid circles represent correlations that met both absolute r values >0.1 and p