T2D Ethnic Differences in Incretin Secretion and Action

The incretin hormones — glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) — enhance insulin secretion glucose-dependently and are responsible for 50–70% of post-challenge insulin secretion in Caucasians. ¹

Key Findings

Incretin Secretion Is Not Impaired in East Asian T2D

• Studies in Japanese (Yabe et al. 2010, Kozawa et al. 2010, Lee et al. 2010) and Korean (Oh et al. 2014) populations found no difference in GLP-1 or GIP secretion between NGT (Normal Glucose Tolerance) and T2D subjects, similar to the current consensus in Caucasians. ¹
• This argues against incretin secretion deficiency as a primary cause of T2D in either population. ¹

Lower GLP-1 Secretion in Japanese vs. Caucasians

• When measured by the same assay system, meal-induced GLP-1 secretion is negligible in Japanese and significantly lower than in Caucasians. ¹
• Whether this difference in GLP-1 secretion contributes to the reduced β-cell function in East Asians remains unknown. ¹

β-Cell Responsiveness to Incretins (Incretin Effect) Differs by Ancestry

The incretin effect is the amplification of insulin secretion by GIP and GLP-1 — distinct from the amount of incretin secreted.

• Caucasian T2D: Incretin effect is impaired — GIP-induced (but not GLP-1-induced) insulin secretion is attenuated. ¹
• East Asian T2D: Incretin effect is not impaired in Japanese and Korean subjects (Hamasaki et al. 2011, Oh et al. 2014). ¹
• Yabe et al. found that a novel mechanism (glutamate-mediated incretin/cAMP signaling amplification) is impaired in obese model rats but preserved in non-obese diabetic model rats, consistent with preserved incretin action in less-obese East Asians. ¹

Greater Therapeutic Efficacy in East Asians

• Meta-analyses confirm that dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have greater HbA1c-lowering efficacy in Asians than non-Asians (Kim et al. 2013, Kim et al. 2014). ¹
• This is consistent with β-cell dysfunction being the primary driver of hyperglycemia in East Asians — incretin-based therapies target β-cell function directly.
• If the therapeutic logic is mechanism-based (β-cell dysfunction → incretin efficacy), then any population with β-cell-dominant T2D — including Yakuts from our same-cohort prior work (Markelova et al. 2025) — may also show greater incretin efficacy. This is an untested inference, not a finding from Yabe et al.
• DPP-4i efficacy in Japanese patients is enhanced by fish intake (eicosapentaenoic and docosahexaenoic acids), which promote GLP-1 secretion. ¹
• Eating fish before rice enhances GLP-1 secretion, increases insulin secretion, and delays gastric emptying compared to the reverse order. ¹

Safety Considerations

• Severe hypoglycemia with DPP-4i + sulfonylurea (SU) was initially 6.4-fold more common in Japan than the USA, attributed to widespread SU use. ¹

Relevance to PBMC Ancestry Project

While incretin biology is pancreatic/gut-centric, the differential efficacy of incretin-based therapies by ancestry has implications for PBMC immune profiling:

• If East Asian patients are more likely to receive DPP-4i and sulfonylureas (SUs) (as was standard in Japan), while European patients receive metformin, medication regimens differ systematically by ancestry and may confound PBMC immune comparisons unless controlled.
• DPP-4i have immune-modulating effects beyond glucose control (T-cell regulation, inflammation), so medication-driven immune differences could masquerade as ancestry-driven ones.

Sources

• Yabe et al. 2015

Footnotes

1. extracted from Yabe et al. 2015 ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹ ↩¹⁰ ↩¹¹ ↩¹²