How genetic traits contribute to earlier diabetes onset and metabolic challenges in South Asians

by · News-Medical

Study highlights genetic factors driving earlier diabetes onset, reduced insulin production, and obesity patterns in South Asians.

Study: Genetic basis of early onset and progression of type 2 diabetes in South Asians. Image Credit: Olezzo/Shutterstock.com

The genetic predisposition of British Pakistani and British Bangladeshi linked to lipodystrophy and insulin deficiency has not only been associated with earlier onset of type 2 diabetes (T2D) but faster progression to complications, poorer response to medication, and insulin dependence.

A recent Nature Medicine study investigated why South Asians are more vulnerable to the early development and progression of type 2 diabetes.

T2D prevalence in South Asian individuals

In comparison to Europeans, South Asians are diagnosed with T2D at younger ages and with lower body mass index (BMI). For example, Asian Indians are four times more likely to develop diabetes at an age of less than forty years than Europeans. A recent study revealed that 12.7% of South Asians develop T2D.

Previous research conducted in India used phenotypic genotyping strategies and detected a higher prevalence of severe insulin-deficient diabetes (SIDD) in South Asians. Studies that included individuals of European ancestry have shown the prevalence of insulin resistance. However, not many genetic studies have included South Asian individuals to understand the genetic basis for their early T2D onset and progression.

Compared to polygenic risk scores (PRSs), partitioned polygenic scores (pPSs) were found to be more efficient in identifying associations with diabetes-related complications.

Multiple studies have indicated differences in genetic architecture and clinical phenotype of T2D between South Asians and Europeans. It is important to understand whether a pPS strategy could elucidate the genetic basis of this difference.

About the study

The current study used the pPS strategy to understand the etiological factors behind the early onset of T2D among British Pakistani and British Bangladeshi individuals. All relevant data was collected from Genes & Health. This long-term, community-based study included British Bangladeshi and British Pakistani individuals aged 16 years and above living in the UK.

At baseline, all recruited participants provided saliva samples for genotyping and completed a short questionnaire for demographic information. Both primary care and secondary care data were obtained from UK NHS electronic health records (EHR).

pPSs for 12 diabetes-associated genetically determined endotypes were determined using PLINK. These include three endotypes linked with insulin secretion (beta cell 2), glucose sensing (beta cell 1), and insulin production (proinsulin); three clusters associated with insulin resistance and abnormal adiposity; and six clusters were linked with effects on insulin resistance and deficiency.

Study findings

The current study included 9,771 British Bangladeshi and British Pakistani individuals diagnosed with T2D and 34,073 individuals without diabetes (control). Bangladeshi individuals were found to be diagnosed with T2D at a younger age and lower BMI compared to Pakistani individuals. Bangladeshi women also exhibited a higher rate of gestational diabetes mellitus (GDM) than Pakistani women.

After five years of T2D diagnosis, Pakistani individuals exhibited a higher glycated hemoglobin (HbA1c) and BMI than Bangladeshi individuals. It was observed that Pakistanis were more likely to receive insulin prescriptions and develop nephropathy than Bangladeshis.

The current study observed higher unmodified pPSs in Bangladeshi individuals, particularly for beta cell 2, obesity, and lipodystrophy 1, than in Pakistanis. The distributions of pPSs were compared between T2D-diagnosed individuals of European and South Asian ancestry, which indicated a higher score among South Asians for several pPSs, particularly beta cell 2 and lipodystrophy 1. However, obesity pPS was found to be higher in individuals of European ancestry.

In comparison to the control group, the scores for all pPSs, except bilirubin, were higher among GDM cases, T2D cases, and incident T2D after GDM. After adjustment for sex and ancestry, an association between pPS and T2D risk was observed. This association also existed between pPS and GDM and incident T2D after GDM. In both cases, the strongest association was observed for beta cell 1 and beta cell 2.

All pPSs (except bilirubin) were associated with an earlier age of T2D onset. However, the strongest association was linked with beta cell 2, obesity, and lipodystrophy 1. The current study established an association between pPS and response to oral anti-diabetic medications through HbA1c measurements.

For example, a higher beta cell 2 pPS score was linked with elevated HbA1c after initiation of thiazolidinediones. Interestingly, beta cell 2 and lipodystrophy 1 pPSs were associated with progression to insulin treatment. Previous studies highlighted that faster progression to insulin treatment indicates poor T2D management.

Conclusions

The current study observed that beta cell 2 and lipodystrophy 1 are strongly associated with T2D and GDM and are younger than T2D diagnosed. This study concludes that South Asians with increased genetic risk of insulin deficiency (beta cell 2) and lipodystrophy are at a higher risk of T2D, insulin dependence, and poorer response to medication.

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