Dementia Risk According to Indices of Insulin Sensitivity and Beta-Cell Function in Individuals With Newly Diagnosed Type 2 Diabetes: A Cohort Study

Background: Insulin resistance and impaired insulin secretion are hallmarks of type 2 diabetes (T2D) and may influence risks of complications including dementia. We investigated dementia risk across T2D subgroups defined by beta-cell function and insulin sensitivity. Methods: We used Homeostasis Model Assessment-2 indices of beta-cell function (HOMA2-B) and insulin sensitivity (HOMA2-S) to classify 7221 individuals with recently diagnosed T2D into insulinopenic (low HOMA2-B, high HOMA2-S), classical (low HOMA2-B, low HOMA2-S), and hyperinsulinemic (high HOMA2-B, low HOMA2-S) subgroups. Incident dementia was ascertained by validated hospital diagnosis codes and dementia-specific medication over 13 years. Absolute risks were estimated using the Aalen-Johansen estimator and adjusted hazard ratios (aHRs) using Cox regression. Results: Over a median follow-up of 9 years, 179 (2.5%) developed dementia. The 10-year risk (95% CI) was 3.8% (2.4%–5.8%) in the insulinopenic subgroup versus 2.8% in both classical (2.3%–3.5%) and hyperinsulinemic (2.0%–3.8%) subgroups. Compared with classical T2D, aHRs (95% CI) were 1.31 (0.83–2.09) for insulinopenic and 1.10 (0.78–1.54) for hyperinsulinemic T2D. No robust associations with dementia were observed with insulin resistance (HOMA-IR) or C-peptide levels, although compared to the lowest C-peptide levels (quartile 1), aHRs (95% CI) were decreased at 0.67 (0.45–1.01) in quartile 2, 0.73 (0.48–1.09) in quartile 3, and 0.89 (0.59–1.33) in quartile 4. Conclusions: We found no clear associations between T2D subgroup, insulin resistance, or C-peptide level at T2D diagnosis and dementia risk. The numerically higher risk in those with lower insulin secretion was statistically imprecise and warrants further study.