Diabetogenesis in Rheumatoid Arthritis: Do Inflammation and Glucocorticoid-induced Incretin Overproduction Cause β-Cell Overcompensation and Consequent Premature Decompensation?

Metabolic abnormalities occur frequently in rheumatoid arthritis (RA)¹. In this regard, metaanalyses documented an enhanced diabetes prevalence (OR 1.74, 95% CI 1.22–2.50) in RA². Diabetes increases the risk of combined cardiovascular (CV) morbidity including myocardial infarction, angina, heart failure, stroke, and peripheral artery disease (RR 1.94, 95% CI 1.58–2.30) in RA³. Poor RA activity control strongly predicts incident-impaired fasting glucose and type 2 diabetes⁴. Diabetes is likely to account for a substantial proportion of the enhanced CV disease burden in RA.

In healthy persons, glucose homeostasis is maintained by optimal (1) insulin sensitivity; (2) hepatic insulin extraction; (3) pancreatic β-cell insulin secretion; and (4) interactions of all three⁵. Type 2 diabetes development typically comprises the sequential stages of long-lasting adverse lifestyle factor (excess adiposity and physical inactivity)–induced insulin resistance and reduced hepatic insulin extraction that exacerbates reduced insulin sensitivity, compensatory increased β-cell insulin secretion, and β-cell decompensation with reduced insulin secretion that results in prediabetes [impaired fasting glucose (5.6–6.9 mmol/l), impaired glucose tolerance (7.8–11.0 mmol/l), and/or raised hemoglobin A1c concentrations (6.0–6.4%/42–46 mmol/l)] and ultimately diabetes (Figure 1).

Insulin resistance is a pathological state in which the ability of insulin to transport glucose into the cells is impaired. It associates with other metabolic abnormalities and increases CV risk, but in itself does not cause diabetes^6,7,8. By contrast, impaired β-cell function is essential in diabetes development and is genetically mediated^7,8. Whereas genetic factors are also implicated in impaired hepatic insulin extraction, its main determinant is pulsatile pancreatic insulin secretion extent (insulin release pulse mass) into the portal vein …

Address correspondence to Dr. P.H. Dessein, Cardiovascular Pathophysiology and Genomics Research Unit, School of Physiology, University of the Witwatersrand Medical School, 7 York Road, Parktown, 2193, Johannesburg, South Africa. E-mail: patrick.dessein22{at}gmail.com