Highlights From the Latest in Diabetes Research

Although the clinical risk factors for cardiovascular disease and diabetes have been studied extensively, the biochemical pathways that enhance risk for the underlying metabolic abnormalities that characterize these conditions remain elusive. In a new report published in Circulation, Cheng et al. hypothesized that circulating substrates or metabolites of primary metabolism may be involved in the development of cardiometabolic disease. The authors utilized metabolomics to study the individual metabolic profiles of participants from two longitudinal, community-based cohort studies, the Framingham Heart Study (FHS) Offspring cohort and the Malmö Diet and Cancer (MDC) study. Their analyses indicated higher circulating concentrations of glutamate, branched-chain amino acids, and other amino acid derivatives, as well as lower concentrations of glutamine, among individuals with common metabolic risk factors such as central adiposity, glucose intolerance, dyslipidemia, and hypertension. A notable observation from both cohorts was the consistent, inverse association between both glutamine and the glutamine-to-glutamate ratio and a number of key metabolic risk factors. The authors supplemented cross-sectional analyses with prospective studies of incident diabetes in the two cohorts and found that glutamine was associated with reduced diabetes risk in both groups. In the FHS, the glutamine-to-glutamate ratio also reduced risk, whereas glutamate was associated with increased risk. The authors performed companion studies in C57/BL6 mice whose diet was supplemented with either glutamine or glutamate. After a glucose load, only the glutamine-fed mice exhibited improved glucose tolerance. Further, intraperitoneal administration of glutamine decreased blood pressure in these mice, but glutamate showed no differences relative to controls. The authors suggest that the glutamine-to-glutamate ratio may play a pivotal role in regulating cardiometabolic risk and decreased glutamine may be both a biomarker of and a risk factor for cardiometabolic disease. — Eileen M. Resnick, PhD

Cheng et al. Metabolite profiling identifies pathways associated with metabolic risk in humans. Circulation 2012;125:2222–2231

Although large numbers of patients with type 2 diabetes eventually require insulin, it is common for these patients to experience declining glycemic control over time despite their high doses of insulin. Treatment of these patients is challenging because increasing the insulin dose can result in unfavorable outcomes including weight gain, hypoglycemia, and fluid retention. Acting independently of insulin, dapagliflozin reduces renal glucose reabsorption and increases glucose excretion. Short-term studies of this drug have suggested improvements in glucose control and body weight when it is given as monotherapy and when it is added to metformin and glimepiride. A recent report by Wilding et al. examined the effects of dapagliflozin (2.5, 5, and 10 mg once daily for 48 weeks) on glycemic control among inadequately controlled type 2 diabetic patients receiving at least 30 units of insulin daily. In the first 24 weeks of follow-up, HbA_1c (mean difference −0.40 to −0.57%), body weight (mean difference −1.3 to −2.04 kg), and daily insulin dose (mean difference −6.28 to −7.60 units) decreased in a generally dose-dependent manner relative to placebo, and these changes were sustained at 48 weeks. However, relative to placebo, the pooled dapagliflozin groups had more hypoglycemic events (56.6 vs. 51.8%) as well as genital (9.0 vs. 2.5%) and urinary tract infections (9.7 vs. 5.1%). Fifty-six weeks of additional follow-up are currently underway in this cohort. Although this report was not intended to assess long-term safety, these preliminary results may be a source of cautious optimism among clinicians who are eager to identify effective treatment strategies for poorly controlled patients on high doses of insulin. — Helaine E. Resnick, PhD, MPH

Wilding et al. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern Med 2012;156:405–415

Abnormalities of carbohydrate metabolism are a hallmark of diabetes, and numerous therapies target mechanisms that regulate both the fasted and fed states. In mammals, the liver ensures availability of carbohydrates during fasting and the interplay of numerous signals coordinates the feeding response. It has long been held that Foxo1 regulates the liver during fasting and that it is inactivated by Akt after a meal, thereby suppressing hepatic glucose release. Akt-associated inactivation of Foxo1 is thought to occur as part of one of several insulin signaling pathways. A paradigm shift may be in order as a result of new data from Lu et al. suggesting a less critical role for Akt in hepatic glucose suppression. In a series of experiments using genetically altered mice, the authors explored Akt and Foxo1 function in the liver and showed that mice with deletions in both Akt and Foxo1 adapted to both the fasting and fed states and that feeding and insulin appropriately inhibited hepatic glucose output. These findings indicate that hepatic glucose suppression can occur in vivo in the absence of insulin signaling to Akt when Foxo1 is absent, thereby suggesting alternative pathways by which the liver is able to respond to feeding and insulin. Indeed, the authors describe the role of Akt as “dispensable” in these circumstances. In the future, the additional pathways by which insulin signaling regulated hepatic glucose output in these experiments may lead to new therapies aimed at normalizing carbohydrate metabolism in diabetes. — H.E.R.

Lu et al. Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1. Nat Med 2012;18:388–395

Diabetes-associated damage to small vessels results in considerable morbidity, and these complications also substantially increase mortality risk among affected individuals. Although the underlying signaling cascades that lead to microvascular damage in diabetes are poorly understood, it has been suggested that mitochondrial dysfunction is a key feature of these pathways. Rho-associated coiled coil-containing protein kinase 1 (ROCK1) is thought to play a role in diabetic nephropathy (DN) by mediating the impact of RhoA on cellular apoptosis and ROS production, two features of microvascular tissue damage. Building on a series of experiments showing that inhibition of ROCK improved albuminuria and DN progression, Wang et al. used two mouse models with ROCK1 deletions to explore the molecular mechanisms that may connect ROCK1 and DN. These experiments suggest that the impact of ROCK1 on DN occurs via a signaling cascade that ultimately results in mitochondrial fission. In the hyperglycemic state, mitochondrial fission has been shown to mediate ROS production, thereby potentially closing the ROCK1–mitochondiral fission–DN loop. The contribution of this recently published work is that it sheds new light on a potentially important upstream role for ROCK1 in inducing mitochondrial fission and associated small vessel damage. This improved understanding may offer opportunities to explore targeted therapies aimed at inhibiting ROCK1. — H.E.R.

Wang et al. Mitochondrial fission triggered by hyperglycemia is mediated by ROCK1 activation in podocytes and endothelial cells. Cell Metab 2012;15:186–200