Scholarlink

Aims/hypothesis <p>Genetic association studies have demonstrated that partial loss of <i>SLC30A8</i> Function protects against type 2 diabetes in humans. We investigated the impact of complete loss of <i>SLC30A8</i> Function on type 2 diabetes risk and related phenotypes in humans.</p> Methods <p>The Pakistan Genome Resource (PGR), a biobank comprising whole-exome and whole-genome sequences of 145,037 participants, was analysed for phenotypic associations with <i>SLC30A8</i> loss-of-function (LoF) variants. To follow up on the observations in the PGR, we conducted recall-by-genotype analyses of <i>SLC30A8</i> LoF heterozygotes and homozygotes, as well as their participating family members, using OGTTs.</p> Results <p>We identified 18 <i>SLC30A8</i> knockouts, including homozygotes for a variant enriched in South Asians (Gln174Ter), and 1024 heterozygotes for LoF variants. Type 2 diabetes risk was lower in <i>SLC30A8</i> LoF heterozygotes and homozygotes relative to non-carriers, and the protective effect strengthens in a gene dose-dependent manner (OR<sub>additive</sub>=0.62; 95% CI 0.53, 0.72; <i>p</i>=1.1×10<sup>–9</sup>; OR<sub>recessive</sub>=0.34; 95% CI 0.12, 0.93; <i>p</i>=0.04). OGTTs in recall-by-genotype studies showed a gene dose-dependent reduction in glucose levels, coupled with elevated insulin.</p> Conclusions/interpretation <p>The corrected insulin response, disposition index and insulin sensitivity index in LoF heterozygotes and homozygotes indicated higher glucose-stimulated insulin secretion with preserved beta cell function that was independent of BMI. These data suggest that therapeutic inhibition of <i>SLC30A8</i>, up to and including complete knockout, may treat type 2 diabetes safely and effectively.</p> Graphical Abstract <p></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Complete loss of SLC30A8 in humans improves glucose metabolism and beta cell function

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年9月29日

查看全文
  • Lindsey B. Lamarche,
  • Christopher Koch,
  • Shareef Khalid,
  • Maleeha Zaman Khan,
  • Richard Zessis,
  • Matthew E. Clement,
  • Daniel P. Denning,
  • Allison B. Goldfine,
  • Igor Splawski,
  • Ali Abbasi,
  • Jennifer L. Harrow,
  • Christina Underwood,
  • Kazuhisa Tsunoyama,
  • Makoto Asaumi,
  • Ikuyo Kou,
  • Juan L. Rodriguez-Flores,
  • Alan R. Shuldiner,
  • Asif Rasheed,
  • Muhammad Jahanzaib,
  • Muhammad Rehan Mian,
  • Muhammad Bilal Liaqat,
  • Usman Abdulsalam,
  • Riffat Sultana,
  • Anjum Jalal,
  • Muhammad Hamid Saeed,
  • Shahid Abbas,
  • Fazal Rehman Memon,
  • Mohammad Ishaq,
  • Allan M. Gurtan,
  • John E. Dominy,
  • Danish Saleheen

摘要

Aims/hypothesis

Genetic association studies have demonstrated that partial loss of SLC30A8 Function protects against type 2 diabetes in humans. We investigated the impact of complete loss of SLC30A8 Function on type 2 diabetes risk and related phenotypes in humans.

Methods

The Pakistan Genome Resource (PGR), a biobank comprising whole-exome and whole-genome sequences of 145,037 participants, was analysed for phenotypic associations with SLC30A8 loss-of-function (LoF) variants. To follow up on the observations in the PGR, we conducted recall-by-genotype analyses of SLC30A8 LoF heterozygotes and homozygotes, as well as their participating family members, using OGTTs.

Results

We identified 18 SLC30A8 knockouts, including homozygotes for a variant enriched in South Asians (Gln174Ter), and 1024 heterozygotes for LoF variants. Type 2 diabetes risk was lower in SLC30A8 LoF heterozygotes and homozygotes relative to non-carriers, and the protective effect strengthens in a gene dose-dependent manner (ORadditive=0.62; 95% CI 0.53, 0.72; p=1.1×10–9; ORrecessive=0.34; 95% CI 0.12, 0.93; p=0.04). OGTTs in recall-by-genotype studies showed a gene dose-dependent reduction in glucose levels, coupled with elevated insulin.

Conclusions/interpretation

The corrected insulin response, disposition index and insulin sensitivity index in LoF heterozygotes and homozygotes indicated higher glucose-stimulated insulin secretion with preserved beta cell function that was independent of BMI. These data suggest that therapeutic inhibition of SLC30A8, up to and including complete knockout, may treat type 2 diabetes safely and effectively.

Graphical Abstract