Overnutrition and sedentary activity reinforce the growing trend of worldwide obesity, insulin resistance, and type 2 diabetes. However, we have limited insight into how food intake generates sophisticated metabolic perturbations associated with obesity. Accumulation of mitochondrial oxidative stress contributes to the metabolic changes in obesity, but the mechanisms and significance are unclear. In white adipose tissue (WAT), mitochondrial oxidative stress, and the generation of reactive oxygen species (ROS) impact the endocrine and metabolic function of fat cells. The central role of mitochondria in nutrient handling suggests pharmacological targeting of pathological oxidative stress likely improves the metabolic profile of obesity. This review will summarize the critical pathogenic mechanisms of obesity-driven oxidative stress in WAT.

Longstanding β-cell function in patients with T1D appears to be largely a result of β cells that persist, without any evidence of attempted β-cell regeneration, small islet/ductal neogenesis, or transdifferentiation from other islet endocrine cell types.

The pathophysiology of canine diabetes remains poorly understood, in part due to enigmatic clinical features and the lack of detailed histopathology studies. Canine diabetes, similar to human type 1 diabetes, is frequently associated with diabetic ketoacidosis at onset or after insulin omission. However, notable differences exist. Whereas human type 1 diabetes often occurs in children, canine diabetes is typically described in middle age to elderly dogs. Many competing theories have been proposed regarding the underlying cause of canine diabetes, from pancreatic atrophy to chronic pancreatitis to autoimmune mediated β-cell destruction. It remains unclear to what extent β-cell loss contributes to canine diabetes, as precise quantifications of islet morphometry have not been performed. We used high-throughput microscopy and automated image processing to characterize islet histology in a large collection of pancreata of diabetic dogs. Diabetic pancreata displayed a profound reduction in β-cells and islet endocrine cells. Unlike humans, canine non-diabetic islets are largely comprised of β-cells. Very few β-cells remained in islets of diabetic dogs, even in pancreata from new onset cases. Similarly, total islet endocrine cell number was sharply reduced in diabetic dogs. No compensatory proliferation or lymphocyte infiltration was detected. The majority of pancreata had no evidence of pancreatitis. Thus, canine diabetes is associated with extreme β-cell deficiency in both new and longstanding disease. The β-cell predominant composition of canine islets and the near-total absence of β-cells in new onset elderly diabetic dogs strongly implies that similar to human type 1 diabetes, β-cell loss underlies the pathophysiology of canine diabetes.

Beta cells are partially replaced in neonatal rodents after deletion with streptozotocin (STZ). Exposure of pregnant rats to a low protein (LP) diet impairs endocrine pancreas development in the offspring, leading to glucose intolerance in adulthood. Our objective was to determine whether protein restriction has a similar effect on the offspring in mice, and if this alters the capacity for beta cell regeneration after STZ. Pregnant Balb/c mice were fed a control (C) (20% protein) or an isocaloric LP (8% protein) diet during gestation. Pups were given 35 mg/kg STZ (or vehicle) from d 1 to 5 for each dietary treatment. Histologic analysis showed that C-fed offspring had largely replaced beta cell mass (BCM) after STZ by d 30, but this was not sustained over time. Female LP-fed offspring showed an initial increase in BCM by d 14 but developed glucose intolerance by d 130. In contrast, male LP offspring showed no changes in BCM or glucose tolerance. However, LP exposure limited the capacity for recovery of BCM in both genders after STZ treatment. (Pediatr Res 68: 16-22, 2010) P oor fetal growth and low birth weight are associated with increased risk of impaired glucose tolerance (1), type 2 diabetes (2), the metabolic syndrome (3), and cardiovascular disease (4) in adult life. Animal models that have been developed to understand the role of the intrauterine environment in susceptibility to postnatal disease have included maternal dietary calorie restriction (5), nutritional imbalance (6), and pharmacological (7) or surgical intervention (8). Administration of a low protein (LP) diet to rats during pregnancy results in reduced birth weight (6), impaired islet cell development, deficient insulin release (9), an increased islet apoptotic rate (10,11), and decreased beta cell mass (BCM) in the offspring (9 -11). Offspring of LP-fed dams were glucose intolerant at 130 d of age (12). Our first objective was to characterize an LP model in mice, to facilitate future exploration into the mechanisms, whereby nutritional insult can predispose to adult disease by using genetic manipulation.Pancreatic beta cells have a significant capacity to regenerate after injury in early life. Subtotal deletion of beta cells with streptozotocin (STZ) is followed by their partial regeneration and remission of hyperglycemia in young rodents (13,14). However, this regenerative ability decreases with age (15).New beta cells have been postulated to be generated through three possible mechanisms: 1) beta cell replication (16), 2) pancreatic duct progenitor cell differentiation (17), and 3) acinar cell transdifferentiation (18). It remains to be determined, which mechanism is most important for beta cell regeneration and could be exploited for beta cell therapy. It is not known if administration of an LP diet to the pregnant rodent will alter beta cell renewal, or by which mechanism, in the offspring after an STZ insult, which constitutes our second objective in this study. Understanding how the intrauterine environment alters plasticity ...