By Max Bingham, PhD

Exercise may not be linked to improvements in cardiorespiratory fitness in a significant proportion of patients with type 2 diabetes. However, exercise is associated with significant metabolic effects such as improvements in glycemic control (HbA1c) and measures of adiposity. These are the conclusions of a secondary analysis of the HART-D trial that are published in this issue of Diabetes Care (p. 1494). Using a measure of cardiorespiratory fitness response (ΔVO2peak), the study looked at the effects of different training regimes versus control over a 9-month period in around 200 patients with type 2 diabetes. Patients were then classified as fitness “responders” if ΔVO2peak was >5%. Conversely, they were classified as “nonresponders” if fitness response was below this level or missing completely. Outcome assessments also included changes in HbA1c, weight, waist circumference, and body composition parameters and any changes in medication type and dosage. These were compared between baseline and follow-up at 9 months. Only 36.6% of patients could be classified as having a clinically meaningful cardiorespiratory response to exercise, with the balance having no or low response (43% had no response at all). However, both groups did show significant improvements in both glycemic control and metabolic outcomes. The authors’ conclusions are clear: “[Exercise training] is associated with significant improvements in metabolic parameters irrespective of improvement in cardiorespiratory fitness.” Commenting more widely on the study, Dr. Berry said: “We were interested in the relationship between the change in cardiorespiratory fitness, or exercise capacity, and change in metabolic parameters. What we see here is that exercise improves diabetes control regardless of improvement in exercise capacity. This would suggest that our definition of ‘nonresponders’ is too narrow. We need to broaden our understanding of what it means to respond to exercise training.” He added that exercise is important for all, but especially so for people with type 2 diabetes.

Pandey et al. Metabolic effects of exercise training among fitness-nonresponsive patients with type 2 diabetes: the HART-D study. Diabetes Care 2015;38:1494–1501

Early detection and treatment of glycemia and cardiovascular risk factors in type 2 diabetes are likely to result in major benefits to patients, according to new modeling data reported in this issue of Diabetes Care (p. 1449). Using the Michigan Model for type 2 diabetes and data from the ADDITION-Europe study, Herman et al. show that early detection and treatment of type 2 diabetes should result in substantial absolute and relative risk reductions in cardiovascular morbidity and mortality. Notably, the intensity of treatment following diagnosis appeared to be less important than when treatment was initiated, suggesting that there is value in screening for type 2 diabetes. Although the conclusions of the study are based on simulations and modeling (with all their inherent limitations), the authors stress that when the model was programmed with the baseline and clinical characteristics of the ADDITION-Europe population, it did accurately predict the outcomes of that study. Given that the health benefits of screening and early intervention in type 2 diabetes are difficult to test in clinical studies due to ethical issues, computer simulation and modeling remains a valuable approach. They conclude that “efforts to reduce the delay between the time at which diabetes is first detectable and the time at which it is actually detected and treated are warranted.” Commenting more widely on the implications of the study, Dr. Herman stated: “Besides having elevated blood glucose levels, people with undiagnosed diabetes often have suboptimally controlled hypertension and dyslipidemia. When a person is diagnosed with diabetes, providers immediately address the A, B, C’s of diabetes care (A1c [blood glucose] control, blood pressure control, and cholesterol management) and revisit lifestyle issues including diet, physical activity, weight management, and smoking cessation. Primary care–based screening for type 2 diabetes and early diagnosis initiate this cascade of events and appear to offer real long-term health benefits.”

Herman et al. Early detection and treatment of type 2 diabetes reduce cardiovascular morbidity and mortality: a simulation of the results of the Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen-Detected Diabetes in Primary Care (ADDITION-Europe). Diabetes Care 2015;38:1449–1455

A bone-derived amino acid glycoprotein called sclerostin is likely increased in individuals with prediabetes and correlates with insulin resistance. That is according to the conclusion of a cross-sectional study published in this issue of Diabetes Care (p. 1509). The study by Daniele et al. compared individuals with normal glucose tolerance with those with impaired glucose regulation (i.e., prediabetes) who underwent an oral glucose tolerance test and DXA whole-body scans to determine fat and lean body mass. Measurements of sclerostin plus a range of other biochemical/hormone analyses were also conducted. Sclerostin levels were higher in prediabetes in comparison with control, positively correlated with HOMA-insulin resistance, and negatively correlated with insulin-mediated glucose disposal. A range of other correlations were also observed. Dr. Folli explained more about the mechanisms involved and background of the study: “Sclerostin inhibits Wnt signaling through binding to LRP5-6 coreceptor, a pathway that has been linked to insulin resistance and so suggests a role in the progression from normal glucose control toward diabetes. It has been previously shown by the groups of Dr. Arya Mani and Dr. Richard Lifton that in rare young healthy nondiabetic subjects, a mutation in LRP6 is linked to impaired skeletal muscle insulin signaling, early onset atherosclerosis, and metabolic syndrome.” While the study is suggestive of potential mechanisms, the authors do urge that further work is needed to clarify these and particularly the role of sclerostin in progression from prediabetes to full type 2 diabetes. Commenting more widely on the study, Dr. Folli said: “Sclerostin, a bone-derived hormone, makes its premier appearance as a potential actor in the regulation of insulin action and glucose metabolism in normal and prediabetic human subjects. Future studies should evaluate the role of cross talk between sclerostin and other bone-derived hormones and insulin in glucose metabolism alterations present in type 2 diabetes.”

Daniele et al. Sclerostin and insulin resistance in prediabetes: evidence of a cross talk between bone and glucose metabolism. Diabetes Care 2015;38:1509–1517