Highlights From the Latest in Diabetes Research

There is no doubt that a Western lifestyle, including excess caloric intake and limited physical activity, increases the risk of type 2 diabetes. Understanding the risks associated with specific aspects of unfavorable lifestyle choices may facilitate the development of prevention efforts that are tailored to the needs of specific patients. One feature of the Western diet is a relatively high consumption of animal protein. Recently, pooled data from several observational studies suggested that red meat intake was associated with increased risk of diabetes. The investigators in that study report that a one-serving increase in total red meat consumption was associated with a 14% increase in diabetes risk. However, this research focused on the association between red meat intake at a single point in time and related this exposure to diabetes risk without considering the potential impact that changes in meat consumption may have on this risk. The new research by Pan et al. extends previous findings by looking at the dynamic relationship between meat intake over time and the risk of diabetes in nearly 150,000 individuals. The investigators relied on 20 years of follow-up (1986–2006) from the Health Professionals Follow-up Study, 20 years of follow-up (1986–2006) from the Nurses’ Health Study, and 16 years of follow-up (1991–2007) from the Nurses’ Health Study II. The exposure of central interest was the change in red meat intake in each 4-year period of follow-up, and the main outcome was the incidence of type 2 diabetes in the subsequent 4 years. Pooled analyses indicated that relative to people who did not change their red meat consumption, the risk of diabetes increased 30% (hazard ratio 1.30, 95% CI 1.21–1.41) over the next 4 years among those who increased their consumption by one-half serving per day. These results add strength to the body of evidence suggesting an unfavorable impact of red meat consumption on diabetes risk. — Helaine E. Resnick, PhD, MPH

Pan el al. Changes in red meat consumption and subsequent risk of type 2 diabetes mellitus: three cohorts of US men and women. JAMA Intern Med 2013;173:1328–1335

Promotion of weight loss is a fundamental aspect of both prevention and treatment of type 2 diabetes. Although there is clear evidence that weight loss—whether induced by surgical means or lifestyle modification—results in short-term improvements in glycemic control and cardiovascular disease (CVD) risk factors in people with diabetes, there is limited evidence regarding the long-term benefit of weight loss in preventing CVD morbidity and mortality in diabetic individuals. The Look AHEAD study randomized 5,145 obese individuals to receive either an intensive lifestyle intervention or diabetes support and education. The intervention group aimed at a 7% weight loss through decreased caloric intake and increased physical activity. The intention was to follow participants for a maximum of 13.5 years and examine a composite end point consisting of CVD death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization from angina. The trial was halted at 9.6 years of follow-up because a futility analysis indicated that there was only a 1% likelihood of observing the prespecified differences between study arms. Despite greater weight loss, larger reductions in A1C, and early improvements in a number of CVD risk factors, rates of the primary end point were similar across study arms. The investigators proposed a number of potential explanations that could help explain the negative findings: Insufficient statistical power, the need for greater sustained weight loss in the intervention group, increased use of statins in the control group, and better overall medical management of diabetes in both groups were among the potential reasons for the rather disappointing findings. However, the investigators point out that in addition to reduced A1C in the early part of the trial, participants in the intervention group had reduced urinary incontinence, sleep apnea, and depression, along with improved quality of life and physical function. — Helaine E. Resnick, PhD, MPH

Look AHEAD Research Group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013;369:145–154

A common therapeutic strategy for type 1 and type 2 diabetes is to identify and eventually restore factors that are critical for protecting pancreatic β-cell function even when challenged by metabolic and immune stressors. GLIS3 stands out as the only diabetes susceptibility locus with polymorphisms associated with both type 1 and type 2 diabetes. GLIS3 is a Kruppel-like zinc finger transcription factor that promotes β-cell development. Although loss of function mutations of GLIS3 in humans and mice impair the development of β-cells and cause severe neonatal diabetes, the mechanism underpinning how GLIS3 promotes the development of sufficient β-cell numbers remains unclear. A recent article by Nogueira et al. revealed that GLIS3 expression is not only important for maintaining expression of β-cell markers, but it also ensures β-cell survival, especially when these cells are challenged by pro-apoptotic inflammatory cytokines or free fatty acids. The investigators found that even a slight knock down of GLIS3 expression in cultured β-cells or primary islets reduced the expression of β-cell markers and also induced β-cell apoptosis. Conversely, overexpression of GLIS3 enhanced expression of the β-cell maturation transcription factor MafA and partially protected these cells from interleukin-1β– and INF-γ–induced apoptosis. By evaluating various pro-apoptotic pathways, the authors found that GLIS3 deficiency induced the intrinsic mitochondrial apoptotic pathway. Collectively, their data support a novel model in which GLIS3 deficiency activates the intrinsic apoptotic pathway by elevating expression of Bim while simultaneously promoting splicing to its most active form by reducing the expression of SRp55. This model may explain the development of diabetes and the loss of β-cell mass associated with GLIS3 deficiency. In the future, elucidating the mechanism by which GLIS3 regulates Bim and SRp55 expression and confirming that this mechanism occurs in vivo will be critical for establishing these factors as potential therapeutic targets for both type 1 and type 2 diabetes. — Anthony Romer, PhD

Nogueira et al. GLIS3, a susceptibility gene for type 1 and type 2 diabetes, modulates pancreatic β-cell apoptosis via regulation of a splice variant of the BH3-only protein Bim. PLoS Genet 2013;9:e1003532

Dipeptidyl peptidase-4 (DPP-4) inhibitors are used to treat type 2 diabetes because of their ability to control hyperglycemia by upregulating incretins such as glucagon-like peptide 1 (GLP-1). These agents are also important because they appear to have the previously unrecognized potential to treat the high blood pressure and cardiac dysfunction that often occurs prior to the development of overt diabetes. In a recently published article by Aroor et al., the vascular benefits of linagliptin—a potent DPP-4 inhibitor—were investigated. Using insulin-resistant male Zucker obese rats, which were shown to have 3.3-fold higher circulating DPP-4 levels compared with controls, the investigators found that pharmacological inhibition of DPP-4 greatly improved vascular endothelial function and blood pressure. These improvements were attributed to improved stiffness in the left ventrical, altered calcium signaling resulting from increased sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) protein levels, repair of damaged mitochondria ultra-structure, and improved insulin signaling in the heart myocardium. The new findings highlight the clinical potential for treating obesity-related cardiac dysfunction with DPP-4 inhibitors. Of particular interest is the idea that DPP-4 inhibitors could be applied to the treatment of early stages of cardiac diastolic dysfunction associated with adolescent obesity. However, a potential limitation of this line of thinking is that cardiac dysfunction in the animal model that was the focus of this study is tightly associated with its unique physiological condition, which is characterized by a combination of obesity and insulin resistance. In turn, this profile is associated with increased DPP-4 levels and may not reflect environments in which insulin resistance is not associated with increased DPP-4 levels. Nonetheless, these new results support the idea that DPP-4 inhibitors may help offset the deleterious effects of obesity-related diastolic dysfunction prior to the appearance of frank diabetes. — Shouhong Xuan, PhD

Aroor et al. Dipeptidylpeptidase inhibition is associated with improvement in blood pressure and diastolic function in insulin-resistant male Zucker obese rats. Endocrinology 2013;154:2501–2513