Impaired beta-cell function, with lack of compensation for declining insulin sensitivity, appears to be the primary mechanism leading to type 2 diabetes and prediabetes in people from East Asia, a new study suggests.
The findings, from the prospective, community-based Korean Genome and Epidemiology Study, were published online November 11 in Lancet Diabetes & Endocrinology by Jung Hun Ohn, MD, of Seoul National University College of Medicine, South Korea, and colleagues.
Using oral glucose-tolerance tests, Dr Ohn and team assessed both pancreatic beta-cell function and insulin sensitivity in more than 4000 South Korean adults with normal glucose tolerance at baseline.
Over a 10-year follow-up, those progressing to abnormal glucose tolerance had lower beta-cell function at baseline than did those who did not progress, and their beta-cell function did not compensate sufficiently for declines in insulin sensitivity over time.
The underlying reason for the decrease in beta-cell function may ultimately involve genetic, epigenetic, environmental, and lifestyle factors, study coauthor Kyong Soo Park, MD, PhD, professor, department of internal medicine, College of Medicine, and department of molecular medicine and biopharmaceutical sciences, Seoul National University, told Medscape Medical News.
Therapeutically, Dr Park said, "it is important to preserve and enhance beta-cell function in Asian patients with type 2 diabetes. Studies are warranted that investigate the role of pharmacologic and lifestyle interventions in enhancing beta-cell function in Asians."
An accompanying editorial notes that the new findings support prior research showing that insulin response to glucose ingestion is lower in Japanese people than in their white counterparts (Curr Diab Rep. 2015;15:36).
"[Dr] Ohn and colleagues have now solidified the notion that the pathophysiology of type 2 diabetes in east Asians is unique," write Daisuke Yabe, MD, PhD, and Yutaka Seino, MD, of the Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, in Kobe, Japan, and the Center for Diabetes, Endocrinology and Metabolism at the Kansai Electric Power Hospital, in Osaka, Japan.
"Lifestyle and pharmacological interventions should be rigorously investigated in the future to improve prevention and management of type 2 diabetes in East Asian people, and such evidence should be used to establish dedicated recommendations for this ethnic group," they add.
Reduced Beta-Cell Function in the Face of Declining Insulin Sensitivity
The study population comprised 4106 participants aged 40 to 69 years who had normal glucose tolerance at baseline and were followed every 2 years for up to 10 years (mean follow-up, 9.3 years). During that time, 1093 people (27%) progressed to prediabetes and 498 (12%) to type 2 diabetes.
Pancreatic beta-cell function was estimated by the 60-minute insulinogenic index (IGI60) calculated with plasma insulin and glucose levels at 0 and 60 minutes of an oral glucose-tolerance test and the homoeostasis model assessment of beta-cell function (HOMA-β).
Insulin sensitivity was measured by composite (Matsuda) insulin sensitivity index (ISI) and the homoeostasis model assessment of insulin resistance index (HOMA-IR).
After adjustment for baseline age, sex, fasting glucose, and HbA1c, the subjects who progressed to prediabetes or diabetes had higher body mass indexes (BMIs), waist circumferences, blood pressure, and triglycerides than did those who didn't progress (P < .0001). Those who progressed also had higher baseline fasting glucose, 2-hour glucose, and HbA1c than those who did not (P < .0001).
Progressors had 35.4% lower unadjusted baseline pancreatic beta-cell function, as assessed by IGI60, than did nonprogressors (P < .0001) and 18.0% lower unadjusted ISI (P < .0001) than did nonprogressors, "suggesting that insulin secretory defects might at least coexist with decreased insulin sensitivity during the course of diabetes development," Dr Ohn and colleagues write.
The subjects were categorized into four groups: high IGI60/high ISI, high IGI60/low ISI, low IGI60/high ISI, and low IGI60/low ISI.
Compared with the reference high-IGI60/high-ISI group that had the least risk for progression, the hazard ratios for incident diabetes was highest, 6.08 (P < .0001), for those with both reduced beta-cell function and insulin sensitivity (low IGI60/low ISI).
Of the two intermediary groups, the hazard ratio was 2.62 (P < .0001) for subjects who only had decreased insulin sensitivity (high IGI60/low ISI), vs 3.35 (P < .0001) for those with only decreased beta-cell function (low IGI60/high ISI).
Insulin sensitivity by composite ISI decreased significantly (P < .0001) from baseline to year 10 in all three groups, by 26.7% in nonprogressors, by 44.9% in those who progressed to prediabetes, and by 64.3% in progressors to diabetes.
At the same time, IGI60 increased significantly compared with baseline only among the nonprogressors (69.6%, P < .0001) and progressors to prediabetes (51.7%, P < .0001), but there was no significant change in IGI60 among those who progressed to diabetes (P = .95).
Managing Patients With East Asian Backgrounds
Dr Park discussed potential treatment strategies in Asian patients, pointing to a recent meta-analysis finding that use of dipeptidyl peptidase-IV (DPP-4) inhibitors in Asians was more effective in lowering HbA1c compared with white people (J Diabetes. 2014;7:347-359).
"As DPP-4 inhibitors are suggested to work by improving beta-cell function through the incretin system, [this drug class] may have a beneficial role in glycemic control of Asian patients," he told Medscape Medical News.
He also said that cross-sectional and longitudinal studies in Koreans, Japanese, and Chinese have all pointed to similar conclusions regarding the major role of reduced insulin secretory function in prediabetes and diabetes, and thus, "we think our study result may apply in the three ethnic groups."
However, studies are lacking that investigate the pathogenesis of diabetes in other East Asian groups, such as Vietnamese or Indians, and no study has directly investigated the ethnic differences among Asians in the development of type 2 diabetes.
"We think that future sufficiently powered multiethnic studies among Asians are necessary to address the question," he observed.
For clinicians who care for patients of the relevant Asian ethnic groups outside of their countries of origin, he cautioned that the social environment and dietary habits may differ among Asians residing in United States, Europe, or elsewhere.
Diets in the United States or Europe may contain more fat than Korean or Japanese foods, and therefore Asians in the United States or Europe may be more likely to have declines in insulin sensitivity, he noted.
"According to our study, Asians have limited beta-cell reserve ethnically and cannot compensate for minor decline in insulin sensitivity.
"Therefore, we suggest that doctors in US and Europe discuss the point with their Asian patients and emphasize they should make more efforts to maintain insulin sensitivity and preserve beta-cell function compared with white people," he concluded.
The study authors have no relevant financial relationships. Dr Yabe has received personal fees from Eli Lilly, Intarcia Therapeutics, Merck Sharp Dohme, Sanofi, Novo Nordisk, Boehringer Ingelheim, Takeda, and Taisho Toyama and research grants from Boehringer Ingelheim, Eli Lilly, and Merck Sharp Dohme. Dr Seino has received personal fees from Arkray, Eli Lilly, Intarcia Therapeutics, Sanofi, Novo Nordisk, Taisho, Astellas Pharma, BD, Boehringer Ingelheim, and Takeda and research grants from Merck Sharp Dohme, Boehringer Ingelheim, and Eli Lilly.
Lancet Diabetes Endocrinol. Published online November 11, 2015. Abstract, Editorial
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Cite this: Beta-Cell Defect Underlies Diabetes Risk in East Asians - Medscape - Nov 24, 2015.
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