Edited by Helaine E. Resnick, PhD, MPH

Diabetes is a recognized risk factor for impaired cutaneous wound healing, but less is known about its impact on mucosal wound repair. Data in this issue of Diabetes by Xu et al. (p. 243) suggest a complex role for Forkhead box 1 (Foxo1) in the link between diabetes and mucosal wound healing. Keratinocytes are epidermal cells whose motility and proliferation facilitate re-epithelialization, the process by which an intact epidermal barrier is re-established after injury. Regulatory cytokines associated with inflammation play an important role in this process because they affect the migration of keratinocytes to the site of a wound. In the newly published work, Foxo1 was removed from keratinocytes of Cre transgenic mice to determine the impact of this deletion on wound healing. Mice in four treatment groups—normoglycemic Foxo1-control (NG control), normoglycemic Foxo1-knockdown (NG knockdown), diabetic Foxo1-control (diabetic control), and diabetic Foxo1-knockdown (diabetic knockdown)—received small wounds to the tongue. On days 1 and 2 after wounding, tissue was harvested, wound size was quantified, and migration and proliferation of mucosal epithelial cells were estimated. The results showed that diabetic controls were slower to heal than normoglycemic controls: On day 1 of healing, wounds in the diabetic control mice were about 70% larger than their normoglycemic counterparts. Compared with normoglycemic mice, diabetic controls also exhibited significantly reduced epithelial cell proliferation and an 83% decrease in epithelial cell migration. Deletion of Foxo1 partly negated the unfavorable impact of diabetes, with diabetic knockdown mice showing a 98% improvement in cell proliferation and a 63% improvement in overall wound healing compared with diabetic controls. Surprisingly, after 1 day, wound healing was impeded in NG knockdown mice, whose wounds were 37% larger than matched controls. To understand the divergent impact of Foxo1 deletion, human mucosal epithelial cells were cultured under high-glucose or standard conditions. These experiments focused on measures of CCL20 and IL-36γ, proinflammatory cytokines that are associated with the inhibition of epithelial cell migration. Under high-glucose conditions, Foxo1 promoted CCL20 and IL-36γ expression, while Foxo1 deletion prevented increases in both cytokines. By contrast, under normoglycemic conditions, Foxo1 stimulated transforming growth factor-β1 (TGF-β1), a growth factor that aids in the healing process. Taken together, these results contribute substantially to improved understanding of the mechanisms that underpin the role of Foxo1 in mucosal wound healing. — Wendy Chou, PhD

Xu et al. Foxo1 inhibits diabetic mucosal wound healing but enhances healing of normoglycemic wounds. Diabetes 2015;64:243–256

Photomicrographs of mucosal wounds. Keratinocyte-specific Foxo1 deletion impairs mucosal healing in normoglycemic mice, whereas it accelerates healing in diabetic mice.

Photomicrographs of mucosal wounds. Keratinocyte-specific Foxo1 deletion impairs mucosal healing in normoglycemic mice, whereas it accelerates healing in diabetic mice.

Although current evidence suggests a link between diabetes and impaired cognitive function, the mechanisms supporting this association are not well understood. New research by Korol et al. (p. 79) in this issue of Diabetes supports the hypothesis that incretins may be involved in this link. Incretins are gastrointestinal hormones that reduce blood glucose levels. This process not only regulates metabolic homeostasis, but it also affects higher brain functions including cognition. The new research describes contrasting effects of two incretins—glucagon-like peptide 1 (GLP-1) and exendin-4, a mimetic—on pyramidal neurons in the hippocampus, a center for memory formation. To understand the potential role of incretins on hippocampal function, the investigators focused on the activity of GABA (γ-aminobutyric acid), a major inhibitory neurotransmitter in the central nervous system. GABA-activated whole-cell currents were recorded for pyramidal neurons in hippocampal slices from young rats. Both synaptic currents (characterized by spontaneous, or phasic, activation) and tonic currents (characterized by persistent activation) were evaluated. Low concentrations of GLP-1 (0.01–1 nmol) produced a dose-dependent, transient increase in both synaptic and tonic currents with the greatest increase in amplitude and frequency of the synaptic currents occurring at 0.01 nmol GLP-1. The coupling of GLP-1 treatment with tetrodotoxin, a voltage-gated sodium channel blocker, enhanced tonic, but not synaptic, currents, suggesting that GABA activation by GLP-1 is a spatially distinct process for the two currents. Exendin-4, a GLP-1 agonist, has attracted attention as a potential neuroprotective agent in models of Alzheimer, Parkinson, and Huntington diseases. In the newly published work, exendin-4 at concentrations of 10, 50, and 100 nmol produced results very similar to those observed with GLP-1, including transient increases in average synaptic current frequency. These intriguing findings suggest that further study of the relationship between metabolic hormones and hippocampal function may elucidate whether treatment with GLP-1 or a mimetic might help alleviate cognitive dysfunction. — Wendy Chou, PhD

Korol et al. GLP-1 and exendin-4 transiently enhance GABAA receptor–mediated synaptic and tonic currents in rat hippocampal CA3 pyramidal neurons. Diabetes 2015;64:79–89

A cartoon illustrating GABA signaling in hippocampal neurons.

A cartoon illustrating GABA signaling in hippocampal neurons.

Data from skin biopsy samples collected during the Diabetes Control and Complications Trial (DCCT) indicate an important role for several advanced glycation end products (AGEs) in predicting the progression of microvascular complications. An intriguing aspect of the new report from Genuth et al. (p. 266) is that it examines the role of four AGEs that were not available in 1993 when the samples were originally frozen, and shows that the new AGEs strengthened associations between previously identified AGEs and diabetes complications. In some cases, the combination of the new and historical AGE data eliminated the significance of A1C on the risk of the progression of these complications. The new work builds on a body of research from this group that showed associations between a panel of four AGEs and two solubility abnormalities that were available at the time of the DCCT and the prevalence of nephropathy, retinopathy, and neuropathy. The earlier work also showed that two of these abnormalities were associated with the progression of retinopathy and nephropathy during follow-up in the Epidemiology of Diabetes Interventions and Complications (EDIC) study. At the time that the skin biopsies were stored in 1993, AGEs such as glucosepane (GSPNE) and hydroimidazolones of methylglyoxal (MG-H1) had not yet been identified. The new work examined these and two other AGEs and found that the new AGEs strengthened the association between the original AGEs and the risk of retinopathy progression. Importantly, the analyses showed no impact of A1C on the risk of retinopathy progression when the whole (old and new) AGE panel was considered. Parallel results were observed for neuropathy. Although AGEs predicted the progression of nephropathy, the new AGEs did not strengthen the association between the original AGE panel and the progression of this complication. The data presented in the new report cement the importance of skin AGEs in predicting the progression of microvascular complications, and highlight the value of tight glycemic control in preventing the onset and progression of these unfavorable outcomes. — Helaine E. Resnick, PhD, MPH

Genuth et al. Skin advanced glycation end products glucosepane and methylglyoxal hydroimidazolone are independently associated with long-term microvascular complication progression of type 1 diabetes. Diabetes 2015;64:266–278

Findings by Garg et al. (p. 236) in this issue of Diabetes suggest that among people with type 2 diabetes who are on ACE inhibition, blocking the mineralocorticoid receptor (MR) by adding spironolactone therapy improves coronary flow reserve (CFR) and may represent a new strategy to reduce cardiovascular mortality in these patients. The new data are based on a 6-month study of 64 men and women aged 18–70 years with well-controlled diabetes who were randomized to one of three groups: add-on treatment with either spironolactone or hydrochlorothiazide (HCTZ) or placebo. The primary hypothesis underpinning the new report was that the addition of spironolactone to existing angiotensin-converting enzyme (ACE) therapy would improve CFR as measured by positron emission tomography (PET) scan. CFR measures were collected at baseline and at study end, along with a variety of other clinical measurements. Results showed that compared with HCTZ alone or to HCTZ and placebo, spironolactone treatment was associated with significant improvements in CFR. These improvements persisted despite adjustments for race, use of statins, baseline CFR, and change in BMI, and they are highly consistent with the known consequences of MR activation. These consequences include vascular damage and inflammation, as well as increased expression of PAI-1 and ICAM, all factors that promote dysfunction of the coronary microvasculature. The newly published findings suggest that MR blockade may be a promising strategy to reduce coronary morbidity and mortality in diabetes patients who are on ACE inhibition. — Helaine E. Resnick, PhD, MPH

Garg et al. Mineralocorticoid receptor blockade improves coronary microvascular function in individuals with type 2 diabetes. Diabetes 2015;64:236–242