In This Issue of Diabetes Care

A neuroimaging study by Hunt et al. (p. 1787) reveals the brain responses to food ingestion in patients following Roux-en-Y gastric bypass (RYGB) surgery with the suggestion that the surgical procedure results in weight loss via significantly altered brain responses in comparison to those seen in subjects with obesity or normal weight. The study used [¹⁸F]-fluorodeoxyglucose positron emission tomography to investigate brain responses following fasting and again after consumption of a standardized meal. Fullness, sickness, postscan meal consumption, and the neuroimaging data were also assessed. In addition, the RYGB patients also repeated the studies with somatostatin infusion and basal insulin replacement to understand the effects of gut peptide inhibition. As expected, the RYGB patients experienced greater fullness and postprandial sickness, reduced food consumption, and exaggerated gut peptide release in comparison to the control obese and the normal weight groups. According to the authors, various brain responses to food ingestion in the RYGB patients suggested food ingestion became a greater physiological stimulus and was likely associated with unpleasant—rather than pleasant—sensations after eating. Differences in responses in inhibitory control regions were consistent with loss of normal inhibitory responses in obesity and restoration of normal responses after RYGB. Exaggerated deactivation in other regions suggested food ingestion might also be considered a greater task in the RYGB group. Meanwhile, the results of the somatostatin infusion suggested that exaggerated gut peptide responses in the RYGB group may mediate some but not all of the brain responses observed. Commenting more widely on the significance of the study, author Katharine F. Hunt told Diabetes Care: “In this study we were able to look for the first time at the impact of RYGB on brain responses to ingestion of a mixed meal per se. We believe this increases understanding of mechanisms reducing meal size after RYGB, one of the contributors to weight loss, and will inform ongoing development of novel treatments for obesity.”

Hunt et al. Differences in regional brain responses to food ingestion after Roux-en-Y gastric bypass and the role of gut peptides: a neuroimaging study. Diabetes Care 2016;39:1787–1795

The strength of association between a specific variant in the glucokinase regulatory protein (GKRP) gene and plasma lipid levels is reportedly affected by glucose metabolism status. According to the study by Simons et al. (p. 1811), this could have major implications for a new approach that targets the GKRP-glucokinase complex to stimulate hepatic glucose disposal. The study focused on rs1260326, a common functional gene variant in the gene that encodes GKRP. Following genotyping in two cohorts of subjects with normal or impaired glucose metabolism or type 2 diabetes, the study then examined the strength of association between a range of relevant phenotypic traits and the genetic variant. According to the authors, the strength of association between the minor T allele variant of rs1260326 and plasma triglycerides increased with impaired glucose metabolism and type 2 diabetes. A reverse effect on HDL cholesterol was also noted where it was most reduced in type 2 diabetes. At issue is that the effect sizes uncovered in terms of triglycerides present in type 2 diabetes when either the C or T alleles are present are large. This means that the notion of using small molecules that are designed to disrupt the GKRP-glucokinase complex and thus increase glucokinase to stimulate glucose disposal (the issue that is central to type 2 diabetes) may also result in considerable dyslipidemia, particularly when glucose control is poor. If this is the case, this would render the potential drug treatment largely nonapplicable for type 2 diabetes treatment. According to study author Martijn C.G.J. Brouwers: “Previous genetic association studies have shown that they can be instrumental in forecasting the beneficial and disadvantageous effects of potential new drugs long before they have been introduced to phase III clinical trials. Our study clearly demonstrates that the implementation of these association studies in the specific disease state of interest—in this case type 2 diabetes—matters as the effect size may differ.”

Simons et al. A common gene variant in glucokinase regulatory protein interacts with glucose metabolism on diabetic dyslipidemia: the combined CODAM and Hoorn studies. Diabetes Care 2016;39:1811–1817

A phase II clinical trial comparing monthly and weekly dosing of exenatide given in injectable microspheres has concluded that they are equally effective at improving glycemic control in patients with type 2 diabetes. According to the article by Wysham et al. (p. 1768) on the trial, the success of the monthly dosing when compared with the weekly dosing might result in better adherence to the treatment regime and therefore better clinical outcomes. The original randomized, controlled, single-blind study investigated the effects of a weekly dose of self-administered exenatide versus three different monthly doses of exenatide in 121 patients with type 2 diabetes over 20 weeks. Outcome measures included changes in HbA_1c, fasting plasma glucose levels, body weight, blood pressure, and treatment satisfaction. The secondary analysis of Wysham et al. revealed that after 20 weeks of intervention all dose regimes resulted in reductions in HbA_1c and in many cases to levels below 7%, a level considered to be approaching glycemic control. Fasting plasma glucose levels and weight also fell in all groups tested. Treatment satisfaction also reportedly increased over the 20 weeks. According to the authors, the safety evaluation indicated that the most common adverse events were nausea and headache but that in general the different dosing approaches were well tolerated. They suggest that the natural titration that occurs through the slow release of exenatide from the microspheres used to encapsulate the drug may be important in reducing more serious gastrointestinal complaints usually associated with daily exenatide dosing. Author Carol H. Wysham said: "Although the study drug was given in the clinic, the formulation could be administered at home. Knowing that adherence is a major barrier to efficacy of any treatment for diabetes, this would allow patients and clinicians to choose what would be the best option for the patient—much like we do for patients on testosterone replacement therapy."

Wysham et al. Efficacy and safety of multiple doses of exenatide once-monthly suspension in patients with type 2 diabetes: a phase II randomized clinical trial. Diabetes Care 2016;39:1768–1776

Recent results from the Insulin Resistance Intervention after Stroke (IRIS) trial suggest that pioglitazone reduces the risk of developing diabetes in nondiabetic stroke patients who have insulin resistance. In a follow-up secondary analysis, Inzucchi et al. (p. 1684) explored the metabolic effects of the drug and its effects on diabetes in much greater detail. The original IRIS trial compared pioglitazone intervention with placebo in ∼3,800 patients who had suffered a recent stroke and had insulin resistance but no history of diabetes. Five years of surveillance for the onset of diabetes was then carried out via periodic interviews and annual testing of fasting plasma glucose. Diabetes developed in 3.8% of the participants in the pioglitazone group and 7.7% in the placebo group. According to the authors, this translated to a reduced risk of diabetes of 52% in the pioglitazone group compared with the placebo group. They speculate that the drug’s insulin-sensitizing effects may be important for both the effects on diabetes risk and the observed cardiovascular effects. Reductions in blood pressure and C-reactive protein and increases in HDL cholesterol may have also contributed to improved cardiovascular health. Significantly, the authors note that the majority of effects on diabetes risk appear to have been driven by patients who were at the highest baseline risk for diabetes. However, they remain cautious about potential mechanisms. Commenting more widely on the analysis, author Silvio E. Inzucchi stated: “We feel that IRIS is an important trial, not only because it finally confirms the cardiovascular protective effects of pioglitazone in patients with established cerebrovascular disease, but also extends this observation to patients who do not even have diabetes. So, pioglitazone, a very cost-effective generic drug, should be considered as a novel secondary prevention strategy in these high-risk individuals. It is also interesting to reflect that pioglitazone is now the only oral glucose-lowering drug with demonstrated antiatherosclerotic effects. Our data should compel the scientific community to explore these effects further, perhaps in patients with coronary artery disease. Of course, there are adverse effects from pioglitazone that need to be considered, but the benefits are now quite clear.”

Inzucchi et al. Pioglitazone prevents diabetes in patients with insulin resistance and cerebrovascular disease. Diabetes Care 2016;39:1684–1692