A high-risk phenotype associates with reduced improvement in glycaemia during a lifestyle intervention in prediabetes

Abstract

Aims/hypothesis Lack of reversal of prediabetes (impaired glucose tolerance and/or impaired fasting glucose) to normal glucose regulation (NGR) during a lifestyle intervention is strongly associated with a higher incidence of diabetes later in life. In the Tübingen Lifestyle Intervention Program (TULIP) we hypothesised that an at-risk phenotype may exist at baseline that associates with this nonresponse to the intervention. Methods A total of 120 participants of TULIP with prediabetes at baseline were studied. Participants underwent 9 months of lifestyle intervention and had measurements of insulin secretion and insulin sensitivity during a 75 g OGTT, and measurements of liver fat content by proton magnetic resonance spectroscopy. Results During the lifestyle intervention, 55% of the participants did not revert to NGR. Even among participants with the largest body fat loss (upper quartile: −6.9±3.3%, mean±SD), 40% did not revert to NGR. In this regard, we identified at baseline a high-risk phenotype (n=72) consisting of low disposition index or low insulin sensitivity+nonalcoholic fatty liver disease (NAFLD) and a low-risk phenotype (n=48, all other traits). While the adjusted decrease in body fat was almost identical between these phenotypes (−5.7±15.3% vs −7.7±15.2%, p=0.49), the high-risk phenotype had a smaller decrease in adjusted 2 h blood glucose levels (−3.7±20.3% vs −18.5±20.0%, p=0.0009). In addition, only 31% of the participants with the high-risk phenotype, but 67% with the lowrisk phenotype, reverted to NGR (p<0.0001). The odds ratio for reaching the status NGR was 4.54 (95% CI 2.08, 9.94) for participants having the low-risk phenotype. Conclusions/interpretation Stratification of individuals with prediabetes at baseline into a high-risk and a low-risk phenotype, based on corrected insulin secretion and insulin-resistant NAFLD, may help to determine the effectiveness of a lifestyle intervention to revert individuals to NGR.

Non-alcoholic fatty liver disease and impaired proinsulin conversion as newly identified predictors of the long-term non-response to a lifestyle intervention for diabetes prevention: results from the TULIP study

“…For the design, development and practice of improved and more successful lifestyle intervention programmes, it is important to reveal risk factors for short-and long-term success of a lifestyle intervention. Regarding short-term success, we previously found that the phenotype encompassing participants with a low disposition index or insulin-resistant NAFLD have a high risk for acute glycaemic non-response to lifestyle intervention [15]. The present study now demonstrates that such a phenotype is also associated with long-term non-response and extends the phenotype to impaired proinsulin conversion.…”

“…One factor might be the decrease in insulin sensitivity that is correlated with the amount of weight loss [19]. However, the correlation of weight loss and glycaemia is not very strong [15]. Paradoxically, in the US DPPOS a stronger weight loss even adversely affected diabetes risk, independent of the previous intervention [20].…”

“…Impaired insulin secretion as well as insulin resistance are wellestablished pathophysiological mechanisms in the development of type 2 diabetes [11][12][13][14]. Recently, we found that, besides baseline impaired insulin secretion, the presence of an insulinresistant fatty liver is an important predictor of the short-term response to a standard lifestyle intervention [15]. Sufficient data are still lacking to elucidate the contribution of fatty liver to the long-term effects of a lifestyle intervention [11].…”

Relationship of Serum Trimethylamine N-Oxide (TMAO) Levels with early Atherosclerosis in Humans

“…Caucasians from the southern part of Germany participated in the Tübingen Lifestyle Intervention Program (TULIP)1617. Individuals were included into the study when they fulfilled at least one of the following criteria: a family history of type 2 diabetes, a BMI >27 kg/m 2 , previous diagnosis of impaired glucose tolerance or gestational diabetes.…”

The Metabolic Phenotype in Obesity: Fat Mass, Body Fat Distribution, and Adipose Tissue Function

“…This is exemplified by a recent analysis of data from the TULIP study, demonstrating that stratification of subjects with prediabetes by phenotype (including impaired insulin secretion, insulin resistance, and non-alcoholic fatty liver) at baseline predicts the effectiveness of a lifestyle intervention to achieve normal glucose homeostasis. More specific, the latter study demonstrated that a high-risk phenotype at baseline was associated with reduced improvement in glycemia following lifestyle intervention [60]. …”