Is T1D protective against Parkinson’s disease?

Researchers from Singapore found an association between type 1 diabetes (T1D) and Parkinson’s disease (PD) in a Mendelian randomization (MR) study.

“To study their association, we performed a two-sample MR using four statistical methods: inverse variance weighting (IVW), MR-Egger, weight median, and weighted mode … [U]sing large independent GWAS* datasets, our MR study demonstrated an association between T1D and PD risk,” said the researchers.

All MR methods found a significantly lower risk of PD in T1D (odds ratio [OR], 0.93; p=3.12×10⁻⁵ [IVW], OR, 0.93; p=1.45×10⁻² [MR-Egger], OR, 0.93; p=2.76×10⁻³ [weighted median], and OR, 0.94; p=1.58×10⁻² [weighted mode]). [J Clin Med 2024;doi:10.3390/jcm13020561]

These results were replicated using another independent GWAS dataset on T1D (OR, 0.97; p=3.10×10⁻³, OR, 0.96; p=1.08×10⁻², OR, 0.97; p=1.88×10⁻², and OR, 0.97; p=1.43×10⁻², respectively) and on sensitivity analysis using the stricter FinnGen T1D dataset (OR, 0.94; p=3.68×10⁻⁵, OR, 0.92; p=3.10×10⁻², OR, 0.94; p=4.16×10⁻⁴, and OR, 0.94; p=1.57×10⁻²).

“In summary, various statistical methods have demonstrated a significant protective effect of T1D against PD, and our findings were replicated with a separate and independent GWAS dataset on T1D,” said the researchers.

T1D affects brain development

There is evidence linking type 2 diabetes (T2D; and even prediabetes) to an increased PD risk but there is insufficient data on the relationship between T1D and PD. [Front Neurosci 2021;doi:10.3389/fnins.2020.604150; Transl Neurodegener 2022;doi:10.1186/s40035-022-00288-z; Mov Disord 2021;36:1420-1429]

“T1D is an entirely different disorder hallmarked by autoimmune destruction of insulin-secreting pancreatic islet beta cells. Whilst generally considered to be pathophysiologically and genetically distinct, T1D and T2D have been shown to share certain genetic features and key pathophysiologic steps, such as the apoptosis of pancreatic islet beta cells,” the researchers explained.

“T1D has a profound impact on the developing brain, most likely secondary to chronic hyperglycaemia and episodes of diabetic ketoacidosis. Prior research has demonstrated that the dysglycaemia found in T1D is injurious to the brain and its development,” they added. [Lancet Child Adolesc Health 2019;3:427-436; Diabetes Care 2021;44:983-992] Nonetheless, the neurological impact of T1D remains unclear.

The researchers thus conducted this MR study to address this knowledge gap. The analysis comprised 5,928 cases and 183,185 controls. For PD, a meta-analysed dataset from the IPDGC** was employed (n=33,674 cases and 449,056 controls). The independent dataset did not involve FinnGen participants (n=9,266 and 15,574, respectively).

Of note, all datasets involved participants of European descent, thus limiting the study’s generalizability to other ethnicities and racial backgrounds.

Implications

“Our study provides evidence that T1D may have a protective effect on PD risk,” said the researchers. “Clinicians should therefore maintain a high index of suspicion for PD when T1D patients report or exhibit tremor or other signs of rigidity and bradykinesia.”

“Further functional studies may unravel common pathophysiologic clues and further our understanding of the underlying mechanisms, potentially identifying novel biomarkers and therapeutic targets,” the researchers added.

Future trials should look into the potential effect of T1D treatment on PD risk and should have large and more geographically diverse sample sizes.

“[Moreover, the] integration of longitudinal clinical data with genomic and other multi-omic data would be helpful in studying the evolution of a disease over time, deriving biomarkers, and identifying different subgroups,” they said.