Embolic stroke is thought to cause irreparable damage in the brain immediately adjacent to the region of reduced blood perfusion. Therefore, much of the current research focuses on treatments such as ...anti-inflammatory, neuroprotective, and cell replacement strategies to minimize behavioral and physiological consequences. In the present study, intravenous delivery of human umbilical cord blood cells (HUCBC) 48 h after a middle cerebral artery occlusion (MCAo) in a rat resulted in both behavioral and physiological recovery. Nissl and TUNEL staining demonstrated that many of the neurons in the core were rescued, indicating that while both necrotic and apoptotic cell death occur in ischemia, it is clear that apoptosis plays a larger role than first anticipated. Further, immunohistochemical and histochemical analysis showed a diminished and/or lack of granulocyte and monocyte infiltration and astrocytic and microglial activation in the parenchyma in animals treated with HUCBC 48 h poststroke. Successful treatment at this time point should offer encouragement to clinicians that a therapy with a broader window of efficacy may soon be available to treat stroke.
Objectives
To understand the development of iron deficiency in obesity and its long‐term impact on the profile of anemia in spontaneously obese nonhuman primates.
Methods
The study included 69 adult ...male nonhuman primates, (NHPs, Macaca mulatta, rhesus monkeys), ranging from normal to obese, and type 2 diabetes (T2D) as defined for humans.
Results
Iron deficiency was present in 31.9% and mild anemia in 13% of the rhesus monkey in the colony. Serum iron levels were significantly lower in obese (p < .01) and T2D (p < .01)) compared with normal NHP. Obese NHPs also had significantly higher hemoglobin (p < .05), and red blood cell count (p < .05) than normal weight NHPs, thus not related to anemia.
Conclusions
Iron deficiency with increased hemoglobin and red blood cells was significantly associated with increased adiposity, insulin resistance, and diabetes. Iron deficiency does not cause and is not related to anemia in obese and T2D NHPs.
Academic medicine professionals spend their careers striving for promotion and standing in their respective institutions and the global scientific community. Publishing in high-impact journals aids ...in that pursuit; yet, formal coursework and training rarely emphasize scientific writing, making it difficult to gain the skills necessary to succeed. The authors implemented an intramural peer-review service in the medical school of a preeminent university to offer guidance, resources, and hands-on writing assistance at no cost. This program model bridges a gap in scientific writing instruction, boosts academic productivity, and increases opportunities to publish in higher impact journals.
Objective
The aim of this study was to test the obesity–type 2 diabetes mellitus (T2DM) link in the context of longitudinal changes in body weight during the progression to diabetes in mature adult ...nonhuman primates (NHP).
Design and Methods
A colony of 245 adult rhesus monkeys aged 8‐41 years with 179 males were used to define overweight in males as a body weight: ≥13.5 kg or body fat (BF) ≥18% and obesity as ≥16.5 kg or BF ≥27%, and overweight in nonpregnant females was identified as a body weight >8.5 kg or BF >21% and obesity as ≥10.5 kg or BF ≥30%. A subgroup of 48 males (24 T2DM and 24 age‐matched non‐T2DM) males were studied before and following the onset of overt T2DM for the effects of changes in body weight and obesity in inducing this conversion to overt T2DM.
Results
Three years before overt T2DM, mean body weight was 18.4 ± 3.3 kg. The DM‐destined group body weight was 3.2 ± 1.1 kg greater and had a longer duration and greater severity of obesity, with peak body weight reached at 3.2 ± 1.8 years before overt T2DM. At DM onset the two groups did not differ significantly in body weight or adiposity.
Conclusions
The natural progression from pre‐DM to overt T2DM is caused neither by the amount of excess body weight at DM onset nor by the proximate increases in body weight/adiposity during the pre‐DM period of impaired glucose tolerance. Obesity was, however, essential preceding all NHP cases that developed T2DM.
Umbilical cord blood (UCB) banking has become a new obstetrical trend. It offers expectant parents a biological insurance policy that can be used in the event of a child or family member's ...life-threatening illness and puts patients in a position of control over their own treatment options. However, its graduation to conventional therapy in the clinical realm relies on breakthrough research that will prove its efficacy for a range of ailments. Expanding the multipotent cells found within the mononuclear fraction of UCB so that adequate dosing can be achieved, effectively expanding desired cells ex vivo, establishing its safety and limitations in HLA-mismatched recipients, defining its mechanisms of action, and proving its utility in a wide variety of both rare and common illnesses and diseases are a few of the challenges left to tackle. Nevertheless, the field is moving fast and new UCB-based therapies are on the horizon.
Low muscle mass has been associated with insulin resistance and the development of type 2 diabetes (T2DM). Serum creatinine is a metabolite of creatine present in the skeletal muscle. The creatinine ...concentration is stable and directly proportional to skeletal muscle mass. Low levels of creatinine have been shown to be associated with the development of T2DM. The underlying mechanism of low creatinine and its risk for the development of diabetes is not known. Nonhuman primates (NHPs), maintained on a healthy diet, frequently develop spontaneous middle-aged obesity, metabolic syndrome (MetSyn), and T2DM similar to humans. In the present study, longitudinal evaluation of the associations between creatinine and the development of obesity, MetSyn, and T2DM in 125 male rhesus monkeys were studied. In addition, 7 male monkeys with long term calorie-restriction (CR) to maintain a healthy lean mass were used as a comparison group. Creatinine decreased as age (r=-0.39, p\0.001), body fat percent (r=-0.27, p\0.001), HbA1c% (r=-32, p\0.001) increased. Decrease in insulin sensitivity was significantly (r=0.07, p\0.001) associated with a decrease in percent fat free mass. Creatinine also declined with decreasing insulin sensitivity (r=0.23, p\0.05) and fat free mass (FFM) (r=0.26, p\001) indicating that monkeys with higher lean muscle mass exhibited better insulin sensitivity. Creatinine was significantly decreased in monkeys with T2DM compared to both MetSyn and metabolically normal monkeys (p\0.001). Longitudinal data analysis showed progressive decline of creatinine with MetSyn and the development of T2DM. CR monkeys showed no significant change in creatinine throughout the lifelong duration of calorie restriction. Also unchanged during CR were fasting plasma glucose, body fat, FFM, or body weight. This is the first longitudinal study showing the association of creatinine with the development of T2DM. Serum creatinine levels declined with decrease in fat free mass and insulin sensitivity.
Disclosure
U.K. Chaudhari: None. J.D. Newcomb: None. B.C. Hansen: None.
Decreased levels of amylase have been reported in type 2 diabetes (T2DM), however, longitudinal within subject study ranging from healthy normal levels to preT2DM and overt DM has not previously been ...conducted in humans or in nonhuman primates. Rhesus monkeys provide the ideal subjects for this study as they are maintained under constant dietary and environmental conditions, and have, to date, been shown to have the same gastrointestinal/pancreas physiology and pathophysiology as humans. They frequently develop T2DM spontaneously and naturally, with no experimental intervention, and with life time rates of T2DM estimated to be 20 to 30 %. Adult rhesus monkeys were studied for a minimum of 3 years and a maximum of 20 years, with a minimum of 2 metabolic parameter measurements per year. These parameters included fasting plasma glucose (FPG), fasting plasma insulin (FPI), complete blood chemistry, and lipid profiles. Body fat was determined by the tritiated water dilution method or by the dual energy xray absorptiometry (DEXA). Insulin sensitivity was quantified by the euglycemic hyperinsulinemic clamp method. These parameters were used to identify the phases in the progression of monkeys from normal to overt diabetes as follows: normal = phases 1–3; metabolic syndrome = phases 4–6, impaired glucose tolerance= phase 7, and overt type 2 diabetes = phase 8. Diabetic monkeys requiring insulin treatment were excluded from this study. Human criteria were used to define MetSyn, IGT and T2DM. Normal healthy serum amylase levels were determined for the first time and shown to be 253 ±5.1 U/L for adults 7 to 11 yrs old (“human years” about 21 to 35 yrs), with normal lipase levels of 29.7± 1.6 U/L. Serum amylase levels declined with age by about 25%, with no change in serum lipase levels with age. In those that progressed through phases 4 to 8 reaching overt type 2 diabetes, serum amylase showed significantly greater declines from ages 13 to 20 yrs with progressive and parallel declines in metabolic parameters, including insulin sensitivity, and HDL cholesterol levels and increases in serum triglycerides and subsequently increases in fasting plasma glucose. The significant rise in serum triglycerides and the decline in amylase together serve as excellent early predictors of the progression to overt T2DM. These risk factors were highly predictive of both early and late onset diabetes. The lower amylase levels observed previously in people with diabetes were clearly not a consequence of diabetes, but were in fact markers of impending diabetes. Such biomarkers are likely to be useful in predicting the development of T2DM in patients years before the disease becomes overt.
This study was carried out in accord with the FASEB principles for the use of animals in research.
Support or Funding Information
The work was supported by NIA N01AG31012 and NIA HHSN2532008002C to BCH, and the Department of Health Research, Government of India Human Resources Development Fellowship to UKC.
This is from the Experimental Biology 2018 Meeting. There is no full text article associated with this published in The FASEB Journal.
Abstract only
Severe hypertriglyceridemia is a condition where serum triglyceride levels increase above 500 mg/dl. Severe hypertriglyceridemia may result from primary (genetic defects in triglyceride ...metabolism) or may occur secondary to a high fat diet, excess alcohol consumption, obesity or type 2 diabetes. Severe hypertriglyceridemia has serious consequences for the development of coronary artery disease, pancreatitis and glomerulonephritis. In mice, diet‐induced hypertriglyceridemia and transgenic models of hyperlipidemia have been used to investigate the pathophysiology and associated co‐morbidities induced by hypertriglyceridemia. None of these models has, however, reproduced either severe hypertriglyceridemia (triglyceride levels above 1000mg/dl) or the co‐morbidities associated with the human condition. In the present study of 173 adult genetically unrelated nonhuman primates, ingesting only a low fat diet, we have characterized the progression of hypertriglyceridemia using the ATP National Cholesterol Education Program classifications: normal <150 mg/dl; borderline‐high 150–199; high 200–499; very high >500 mg/dl. This progression of hypertriglyceridemia was found to increase in parallel to the progression of metabolic syndrome to prediabetes and overt, then severe diabetes in the nonhuman primates. Ninety‐nine monkeys were normal, and the elevated triglyceride groups had respective means of 176.9 ± 23.6 mg/dl (N=15); 275.4±40.5 mg/dl (N=34); and 643.5 ± 43.4 (N=25). In addition, 8 monkeys had naturally occurring very severe hypertriglyceridemia (1000–4000 mg/dl). Hypertriglyceridemia was significantly correlated with HbA1c% (r
2
=0.2564). Further analysis of serum lipase and amylase levels showed increased levels of lipase in overt diabetes (57.7 ± 3.5 U/L). This is the first report showing the development of spontaneous severe hypertriglyceridemia in prediabetic and diabetic rhesus macaques and associated increased serum lipase levels. Characterization of this nonhuman primate model of naturally‐occurring severe hypertriglyceridemia provides a spontaneously occurring and ideal animal model for understanding the pathophysiology of severe hypertriglyceridemia and for evaluating therapeutic interventions.
Over the past 30 years, in prospective longitudinal studies of the development of T2DM and its risk factors, within-subject individual variable trajectories (as characterized in nonhuman primates ...(NHPs) have shown very different individual profiles compared to data synchronized retrospectively on the time point of DM diagnosis (DM DX) (e.g., Whitehall II or ARIC studies). About 30% of unrelated NHPs naturally and spontaneously develop T2DM at an average age of 19.2 ± 5.4 years (equivalent to ∼60 years in humans). New trajectory analyses of the standardized fasting glucose (FPG), fasting insulin (FPI) and β- cell function of those monkeys that became DM while under longitudinal study indicate that the functional β-cell changes in the pre-DM period, applying the usual epidemiological analytical approach used in humans, is likely to be highly misleading. The NHP DM progression data of 24 adult monkeys studied for an average of 8 years, with pre-DM data obtained up to 18 years pre-DM DX show that these trajectories must be analyzed individually and then standardized for rate of progression, timing of progression and amplitude of changes in order to establish the valid naturally-occurring patterns of the pre-DM progression seen below.
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