Type 2 Diabetes is a Delayed Late Effect of Whole-Body Irradiation in Nonhuman Primates

Abstract

One newly recognized consequence of radiation exposure may be the delayed development of diabetes and metabolic disease. We document the development of type 2 diabetes in a unique nonhuman primate cohort of monkeys that were whole-body irradiated with high doses (6.5–8.4 Gy) 5–9 years earlier. We report here a higher prevalence of type 2 diabetes in irradiated monkeys compared to age-matched nonirradiated monkeys. These irradiated diabetic primates demonstrate insulin resistance and hypertriglyceridemia, however, they lack the typical obese presentation of primate midlife diabetogenesis. Surprisingly, body composition analyses by computed tomography indicated that prior irradiation led to a specific loss of visceral fat mass. Prior irradiation led to reductions in insulin signaling effectiveness in skeletal muscle and higher monocyte chemoattractant protein 1 levels, indicative of increased inflammation. However, there was an absence of large defects in pancreatic function with radiation exposure, which has been documented previously in animal and human studies. Monkeys that remained healthy and did not become diabetic in the years after irradiation were significantly leaner and smaller, and were generally smaller and younger at the time of exposure. Irradiation also resulted in smaller stature in both diabetic and nondiabetic monkeys, compared to nonirradiated age-matched controls. Our study demonstrates that diabetogenesis postirradiation is not a consequence of disrupted adipose accumulation (generalized or in ectopic depots), nor generalized pancreatic failure, but suggests that peripheral tissues such as the musculature are impaired in their response to insulin exposure. Ongoing inflammation in these animals appears to be a consequence of radiation exposure and can interfere with insulin signaling. The reasons that some animals remain protected from diabetes as a late effect of irradiation are not clear, but may be related to body size. The translational relevance for these results suggest that muscle may be an important and underappreciated target organ for the delayed late effect of whole-body irradiation, leading to increased risk of insulin resistance and diabetes development.

Late Effects of Total-Body Gamma Irradiation on Cardiac Structure and Function in Male Rhesus Macaques

“…The current finding that MCP-1 and LBP were elevated several years postirradiation (5–8 years) is suggestive of a persistent pro-inflammatory state, which may have a long-lasting impact on many tissues, including the heart. Increased incidence of T2DM and higher circulating MCP-1 levels were also observed in a subset of the animals in the current study, although these phenotypes did not appear to be correlated with one another or causally linked ( 40 ).…”

“…TBI animals with diabetes exhibited higher TG than controls ( P < 0.005) and TBI nondiabetic monkeys ( P = 0.003), and had lower HDLc compared to control ( P < 0.03) and nondiabetic irradiated monkeys ( P < 0.002). Further details on the pathophysiology of T2DM in irradiated macaques have been previously published elsewhere ( 40 ).…”

Diabetes and Metabolic Syndrome in Survivors of Childhood Cancer

“…Importantly, growth hormone deficiency is associated with reduced lean body mass and increased visceral adiposity in both healthy individuals and childhood cancer survivors [38, 42], and may also contribute to metabolic dysregulation in this cohort. The loss of muscle mass in this cohort may also contribute to diabetes development after TBI; one study of non-human primates exposed to whole-body irradiation suggests that reduced insulin signaling by skeletal muscle plays a central role in the pathophysiology of diabetes after radiation therapy [43]. Further work is needed to clarify the mechanisms leading to diabetes after TBI.…”

White Matter is the Predilection Site of Late-Delayed Radiation-Induced Brain Injury in Non-Human Primates

“…Nevertheless, to our knowledge, this is the first published work reporting on cerebral transcriptomic data from NHP years after single-fraction high-dose TBI. In the event of a large-scale nuclear accident or malicious exposure, anatomic sites of radiation exposure and extent of shielding within the exposed population will be heterogeneous, often with multiple organ systems affected, as has been demonstrated by published studies of the Hiroshima and Chernobyl survivors, and the NHP RSC (4,114). Therefore, radiation-associated comorbidities are anticipated in survivor populations, and related alterations in cerebral gene expression are relevant to considerations for long-term survivors of radiation exposure.…”