In This Issue of Diabetes

Intermittent fasting in the form of eating every other day might have metabolic benefits that extend beyond those of simple calorie restriction, according to Zheng et al. (p. 864). Specifically, this dietary approach resulted in significant metabolic improvements in mice with diabetes that included better glucose tolerance, reduced hyperglycemia, and lower liver glucose output. The findings come from a series of studies with diabetic and lean mice that were variously exposed to an ad libitum diet, calorie-restricted feeding given twice per day, or the equivalent calories given once every other day. Mice with diabetes that ate every other day had greater improvement in glucose homeostasis than mice that ate twice per day, both in terms of reduced fasting glucose levels and enhanced glucose tolerance. Eating every other day also resulted in about one-third less food being consumed compared with ad libitum eating. Hyperglycemia and insulin resistance were also improved on this diet. Notably, however, none of the effects were evident in wild-type lean mice. Further experiments confirmed that eating every other day resulted in benefits beyond those achievable with calorie reduction. Mechanistic studies also revealed a role for liver-specific glucocorticoid receptors and Kruppel-like factor 9 that ultimately led to suppression of liver gluconeogenesis. The authors note several limitations in translating these findings to humans (particularly the length of the fasting period) and that further research will be needed to determine mechanisms and any potential side effects of using the approach in humans. “For patients with diabetes, intermittent fasting every other day may be an effective dietary management strategy for improving glucose metabolism,” said author Wei Wang. “However, it needs to be adapted to individual needs (such as weight loss or reducing blood glucose levels), and long-term implementation of this strategy may require closer medical monitoring.”

The relationship between β-cells and adipose tissue in the context of obesity in youth is explored by Trico et al. (p. 941). They identify an association between primary insulin hypersecretion and a range of obesogenic features and progression to dysglycemia. In youth with obesity but not diabetes, insulin hypersecretion appears to be associated with higher levels of free fatty acids and leptin, faster lipid turnover, ectopic fat accumulation, and adipose hypertrophy. Notably, the authors also identify evidence of altered adipocyte size and phenotype in those with insulin hypersecretion that in turn appears to affect β-cell function over time. They propose that the overall phenotype covers most of the early alterations that come prior to obesity-related type 2 diabetes, meaning that individuals who are at highest risk may now be targeted with appropriate interventions. The findings come from a multiethnic cohort of adolescents with obesity but no diabetes who underwent a series of tests and examinations to characterize the metabolic phenotype of insulin hypersecretion compared with that of individuals with normal insulin secretion. The authors also repeated tests in a subset of individuals over time to understand trajectories and the influence of β-cell function and adipose tissue. They also note a considerable number of metabolic differences between individuals with insulin hypersecretion and those with normal secretion, giving an overall impression of a complex relationship between β-cells and adipose tissue. The authors also note some limitations of the study, including a relatively small sample size and no comparison with youth with normal body weight, suggesting that further research is warranted on the subject. “We are excited to share these pathogenetic insights that shed light on the intricate and often underrecognized cross talk between β-cells and adipocytes,” said author Domenico Trico. “These early alterations, which are promoted by an obesogenic environment, can influence the trajectory of glucose tolerance in individuals at risk.”

A new polygenic risk score for type 2 diabetes in African Americans is reported by Irvin et al. (p. 993), with them showing results comparable with previously published scores based mainly on data from people with European ancestry. However, the score did not outperform risk scores based on multiancestry data. African American populations as well as African populations have historically been underrepresented in genomic databases that polygenic risk scores are based on, with European populations typically being overrepresented. This raises the prospect that any health benefits coming from clinical translational work might not be transferable to individuals of African ancestry. The findings are based on an integration of genome-wide data from multiple observational studies that focused on type 2 diabetes. Based on data from just over 100,000 African American individuals in the studies, the authors developed a polygenic risk score via a Bayesian polygenic modeling method that was focused on individuals of African American heritage. They also validated the score against three independent studies. They found that an increase of 1 SD in the score was associated with a 40–60% increase in odds for type 2 diabetes, with positive predictive values between 14% and 35%, depending on the study comparison. However, the authors note that evaluation of the score for the purposes of identifying incident cases in a prospective manner was beyond the scope of the study. As such, they suggest further work is needed to expand the genetic resources for the African American ancestry and to collect genetic data that are linked to incident type 2 diabetes. This would help determine whether scores that are based on specific ancestries can be used to predict future cases of diabetes and whether they help reduce disease burden in African Americans.

Distinct types of adiposity may exist that have differing risks for type 2 diabetes, according to Abraham et al. (p. 1012). Their investigation reveals that unique groups of independent genetic variants are linked to percent body fat and BMI, leading to diverse risks for type 2 diabetes. Indeed, five clusters appear to be associated with increased risks for type 2 diabetes, but three were associated with reduced risks. The findings come from further analyses of a series of large genome-wide association studies and is based on genetic variants previously identified as being associated with the two measures of adiposity. The authors then applied a type of Mendelian randomization to identify the clusters and assessed a whole series of biomarkers and other measures to characterize the traits associated with each cluster. They found two primary mechanisms linking higher adiposity with lower risk for type 2 diabetes: 1) higher adiposity but lower liver fat, improved insulin sensitivity, and reduced risks for cardiometabolic and other complications of diabetes and 2) larger body size and higher muscle quality. In contrast, higher adiposity was associated with increased risk for type 2 diabetes through mechanisms that included cholesterol and inflammation pathways. The authors also performed a detailed analysis of the data, finding an overall impression of distinct but multiple causal mechanisms that link higher adiposity with varying levels of type 2 diabetes risks. “Our findings provide further evidence that obesity is a multifaceted and intricate condition, shedding light on why individuals with similar levels of adiposity exhibit varying susceptibilities to cardiometabolic disease,” said author Hanieh Yaghootkar. “These insights regarding the existence of distinct mechanisms and subtypes of adiposity can play a pivotal role in shaping improved strategies for precision medicine in managing type 2 diabetes and a host of related conditions through targeted adiposity management, ultimately advancing patient care.”