Yabe et al. 2015 β Cell Dysfunction Versus Insulin Resistance in East Asians

Yabe et al. 2015 — β Cell Dysfunction Versus Insulin Resistance in the Pathogenesis of Type 2 Diabetes in East Asians

Authors: Daisuke Yabe, Yutaka Seino, Mitsuo Fukushima, Susumu Seino
Journal: Current Diabetes Reports, 15:36 (2015)
DOI: 10.1007/s11892-015-0602-9
Source: _raw/Yabe2015_betacell.pdf

Key Claim

T2D in East Asians is characterized primarily by β-cell dysfunction evident immediately after glucose or meal ingestion, with less obesity and insulin resistance compared to Caucasians. These pathophysiological differences have important implications for prevention and therapeutic strategy.

Supporting Evidence

Insulin Secretion

• East Asians (Japanese, Korean, Chinese) show lower insulin secretory capacity, especially early-phase, across NGT, IGT, and T2D, measured by insulinogenic index (IGI), HOMA-β, and acute insulin response during IVGTT.
• The reduced IGI in Japanese is evident throughout all stages of glucose tolerance compared to Caucasian reference populations (Botnia Study). ¹
• Systematic review and meta-analysis by Kodama et al. 2013 confirmed reduced insulin secretory capacity in East Asians vs. Caucasians and Africans. ¹

Insulin Resistance

• HOMA-IR is lower in Japanese throughout NGT, IGT, and T2D compared to Caucasians.
• Japanese accumulate visceral fat more readily than Caucasians at the same BMI, so subtle increases in insulin resistance from visceral fat can disturb the balance with low insulin secretory capacity and trigger T2D.

Genetic Variants (East Asian GWAS)

Gene/Locus	Population	Notes
KCNQ1	Japanese	Potassium voltage-gated channel; expressed in insulin-secreting cells; blocker inhibits insulin secretion
UBE2E2	Japanese	Ubiquitin-conjugating enzyme; expressed in pancreas and insulin-secreting cells; implicated in insulin biosynthesis
C2CD4A/B	Japanese	Expression similar to UBE2E2; function largely unknown
PTPRD	Taiwanese (Han Chinese)	Protein tyrosine phosphatase receptor; function in T2D obscure
SRR	Taiwanese (Han Chinese)	Serine racemase; D-serine dysregulation may affect insulin secretion
SPRY2, CDC123	Taiwanese (Han Chinese)	Sprouty family and CaMK1 subfamily; roles in T2D unknown

• Most T2D-susceptibility genes identified in East Asians are also replicated in non-East Asians, so individual variants cannot explain the characteristic reduced β-cell function of East Asians. ¹

Thrifty Gene Hypothesis

The thrifty gene hypothesis (Neel 1962) proposes that genetic variants promoting efficient energy storage were evolutionarily selected for during periods of feast-famine cycling, but become detrimental in modern sedentary, calorie-rich environments — predisposing to obesity and T2D. Yabe et al. tested it against known T2D loci and found no consistent selection signal, so the hypothesis lacks direct genetic support in East Asians.

• Tested for 17 confirmed T2D-susceptibility loci and 15 East Asian-specific loci; no consistent selection patterns detected. ¹
• Gene-environment interactions, gene-gene interactions, and epigenetic modifications are required to clarify East Asian diabetes pathophysiology. ¹

Incretin Biology

• Incretin secretion (GLP-1, GIP) per se is not impaired in East Asian T2D, similar to Caucasians. ¹
• However, GLP-1 secretion is lower in Japanese compared to Caucasians when measured by the same assay system. ¹
• The incretin effect (GIP-induced insulin secretion) is not impaired in Japanese and Korean T2D subjects, unlike the impaired incretin effect in Caucasian T2D. ¹

Therapeutic Implications

• Incretin-based therapies (DPP-4 inhibitors, GLP-1 receptor agonists) show greater HbA1c-lowering efficacy in Asians than non-Asians, consistent with β-cell dysfunction being the primary driver of hyperglycemia. ¹
• Dipeptidyl peptidase-4 inhibitor (DPP-4i) efficacy is enhanced by fish intake (eicosapentaenoic and docosahexaenoic acids) in Japanese patients. ¹
• Severe hypoglycemia with DPP-4i + sulfonylurea (SU) combination was initially more common in Japan (16.3 per million patients, ~6.4-fold higher than USA), attributed to widespread SU use for β-cell dysfunction. ¹

Dietary Pattern Changes

• East Asian countries (Japan, China, Korea) show a marked shift: reduced carbohydrate intake, increased fat intake from 1950–2010, correlating with rising T2D prevalence. ¹
• Japanese Americans who adopted Western dietary habits (higher animal fat) show higher diabetes rates than native Japanese. ¹

Significance for the PBMC Ancestry Project

This paper provides the pathophysiological framework for why ancestry matters in T2D: the predominant disease mechanism (β-cell dysfunction vs. insulin resistance) varies systematically between East Asian and European populations. This directly supports the project’s motivation:

1. Within-cohort relevance: Our prior work (Markelova et al. 2025) found that Yakut populations (genetically close to East Asians) show β-cell-dominant T2D genetic mechanisms, while Chechens and Tatars show insulin-resistance/obesity patterns — exactly the pattern Yabe et al. describe at the continental level.
2. The Yabe framework provides literature backing for the claim that T2D pathophysiology differs by ancestry, which motivates looking for ancestry-specific PBMC immune correlates of these different T2D mechanisms.
3. If β-cell dysfunction vs. insulin resistance dominance shapes systemic metabolic and inflammatory states differently, PBMC immune profiles may differ correspondingly across ancestry groups within the same cohort.

Limitations

• Review article, not a primary data study — synthesizes existing evidence.
• Primarily cites Japanese data; generalizes to “East Asian” but acknowledges heterogeneity among Japanese, Korean, and Chinese populations.
• Does not address PBMC or immune system directly — provides metabolic context for immune interpretation.
• No ancestry-stratified analysis of immune biomarkers.

Key Sources Cited

• Kodama et al. 2013 — systematic review and meta-analysis of ethnic differences in insulin sensitivity and response. Diabetes Care 36:1789–96.
• Moller et al. 2014a — direct comparison of insulin secretion/resistance in Japanese vs. Caucasians during IVGTT. J Clin Endocrinol Metab 99:4273–80.
• Moller et al. 2014b — body composition as the main determinant for T2D pathophysiology differences between Japanese and Caucasians. Diabetes Care 37:796–804.
• Kim et al. 2013 — meta-analysis of DPP-4i efficacy in Asians vs. non-Asians. Diabetologia 56:696–708.
• Yasuda et al. 2008 — KCNQ1 variants associated with T2D in Japanese. Nat Genet 40:1092–7.
• Yamauchi et al. 2010 — GWAS identifies UBE2E2 and C2CD4A/B in Japanese. Nat Genet 42:864–8.
• Tsai et al. 2010 — GWAS identifies PTPRD and SRR in Han Chinese. PLoS Genet 6:e1000847.

Footnotes

1. extracted from Yabe et al. 2015 ↩ ↩² ↩³ ↩⁴ ↩⁵ ↩⁶ ↩⁷ ↩⁸ ↩⁹ ↩¹⁰ ↩¹¹ ↩¹² ↩¹³