Xenia T. Tigno

Differential hypertrophy and atrophy among all types of cutaneous innervation in the glabrous skin of the monkey hand during aging and naturally occurring type 2 diabetes

Diabetic neuropathy (DN) is a common severe complication of type 2 diabetes. The symptoms of chronic pain, tingling, and numbness are generally attributed to small fiber dysfunction. However, little is known about the pathology among innervation to distal extremities, where symptoms start earliest and are most severe, and where the innervation density is the highest and includes a wide variety of large fiber sensory endings. Our study assessed the immunochemistry, morphology, and density of the nonvascular innervation in glabrous skin from the hands of aged nondiabetic rhesus monkeys and from age‐matched monkeys that had different durations of spontaneously occurring type 2 diabetes. Age‐related reductions occurred among all types of innervation, with epidermal C‐fiber endings preferentially diminishing earlier than presumptive Aδ‐fiber endings. In diabetic monkeys epidermal innervation density diminished faster, became more unevenly distributed, and lost immunodetectable expression of calcitonin gene‐related peptide and capsaicin receptors, TrpV1. Pacinian corpuscles also deteriorated. However, during the first few years of hyperglycemia, a surprising hypertrophy occurred among terminal arbors of remaining epidermal endings. Hypertrophy also occurred among Meissner corpuscles and Merkel endings supplied by Aβ fibers. After longer‐term hyperglycemia, Meissner corpuscle hypertrophy declined but the number of corpuscles remained higher than in age‐matched nondiabetics. However, the diabetic Meissner corpuscles had an abnormal structure and immunochemistry. In contrast, the expanded Merkel innervation was reduced to age‐matched nondiabetic levels. These results indicate that transient phases of substantial innervation remodeling occur during the progression of diabetes, with differential increases and decreases occurring among the varieties of innervation. J. Comp. Neurol. 501:543–567, 2007.

Metabolomics Reveals Attenuation of the SLC6A20 Kidney Transporter in Nonhuman Primate and Mouse Models of Type 2 Diabetes Mellitus

To enhance understanding of the metabolic indicators of type 2 diabetes mellitus (T2DM) disease pathogenesis and progression, the urinary metabolomes of well characterized rhesus macaques (normal or spontaneously and naturally diabetic) were examined. High-resolution ultra-performance liquid chromatography coupled with the accurate mass determination of time-of-flight mass spectrometry was used to analyze spot urine samples from normal (n = 10) and T2DM (n = 11) male monkeys. The machine-learning algorithm random forests classified urine samples as either from normal or T2DM monkeys. The metabolites important for developing the classifier were further examined for their biological significance. Random forests models had a misclassification error of less than 5%. Metabolites were identified based on accurate masses (<10 ppm) and confirmed by tandem mass spectrometry of authentic compounds. Urinary compounds significantly increased (p < 0.05) in the T2DM when compared with the normal group included glycine betaine (9-fold), citric acid (2.8-fold), kynurenic acid (1.8-fold), glucose (68-fold), and pipecolic acid (6.5-fold). When compared with the conventional definition of T2DM, the metabolites were also useful in defining the T2DM condition, and the urinary elevations in glycine betaine and pipecolic acid (as well as proline) indicated defective re-absorption in the kidney proximal tubules by SLC6A20, a Na+-dependent transporter. The mRNA levels of SLC6A20 were significantly reduced in the kidneys of monkeys with T2DM. These observations were validated in the db/db mouse model of T2DM. This study provides convincing evidence of the power of metabolomics for identifying functional changes at many levels in the omics pipeline.

Effects of aleglitazar, a balanced dual peroxisome proliferator-activated receptor α/γ agonist on glycemic and lipid parameters in a primate model of the metabolic syndrome

BackgroundGlycemic control and management of dyslipidemia to reduce cardiovascular risk are major therapeutic goals in individuals with type 2 diabetes mellitus (T2DM). This study was performed to evaluate the effects of aleglitazar, a balanced dual peroxisome proliferator-activated receptor α/γ (PPARα/γ) agonist, on both lipid and glycemic parameters in obese, hypertriglyceridemic, insulin-resistant rhesus monkeys.MethodsA 135-day efficacy study was performed in six rhesus monkeys. After a 28-day baseline assessment (vehicle only), monkeys received oral aleglitazar 0.03 mg/kg per day for 42 days, followed by a 63-day washout period. Plasma levels of markers of glycemic and lipid regulation were measured at baseline, at the end of the dosing period, and at the end of the washout period.ResultsCompared with baseline values, aleglitazar 0.03 mg/kg per day reduced triglyceride levels by an average of 89% (328 to 36 mg/dL; P = 0.0035 when normalized for baseline levels) and increased high-density lipoprotein cholesterol levels by 125% (46 to 102 mg/dL; P = 0.0007). Furthermore, aleglitazar reduced low-density lipoprotein cholesterol levels (41%) and increased levels of apolipoprotein A-I (17%) and A-II (17%). Aleglitazar also improved insulin sensitivity by 60% (P = 0.001). Mean body weight was reduced by 5.9% from baseline values with aleglitazar at this dose (P = 0.043).ConclusionsAleglitazar, a dual PPARα/γ agonist, has beneficial effects on both lipid and glucose parameters and may have a therapeutic role in modifying cardiovascular risk factors and improving glycemic control in patients with T2DM.

Endogenous and diet-induced hypercholesterolemia in nonhuman primates: effects of age, adiposity, and diabetes on lipoprotein profiles.

Nonhuman primates (NHPs) share with humans many features of lipid metabolism and often develop all features of the metabolic syndrome, including hypertriglyceridemia and low high-density lipoprotein cholesterol, and have been used in many studies of potential therapeutics during the preclinical phase. Here we identify for the first time in middle-aged and older rhesus the natural occurrence of hypercholesterolemia, and this hypercholesterolemia develops despite maintenance on a low-cholesterol diet. The aims of this study were to (a) define normal and hypercholesterolemia in rhesus monkeys, (b) determine the factors associated with the development of hypercholesterolemia, (c) compare the lipoprotein profiles in adult rhesus monkeys fed a low-fat/low-cholesterol diet (LFLC) with the profiles of human subjects, and (d) determine the effect of a 16-week high-fat/high-cholesterol (HFHC) diet feeding on total cholesterol and lipoprotein profiles in middle-aged and older monkeys. In our colony, maintained on a constant diet with negligible cholesterol, the mean total cholesterol level in healthy nondiabetic monkeys was 3.7 ± 0.02 mmol/L, with hypercholesterolemia identified as the 95th percentile of the normal cholesterol distribution (≥5.2 mmol/L). Severe hypercholesterolemia developed in the HFHC-fed group; however, despite the high-fat diet composition, unexpectedly, no weight gain occurred in these NHPs. The diet-induced hypercholesterolemia differed significantly in lipoprotein pattern from that of the spontaneous hypercholesterolemia. In summary, despite ingesting only a LFLC, NHPs frequently develop hypercholesterolemia, reflecting lipoprotein patterns similar to human subjects; and this lipid profile of spontaneous hypercholesterolemia differs significantly from the hypercholesterolemia induced by an HFHC diet.

Vasomotion becomes less random as diabetes progresses in monkeys

Please cite this paper as: Tigno, Hansen, Nawang, Shamekh, and Albano (2011). Vasomotion Becomes Less Random as Diabetes Progresses in Monkeys. Microcirculation 18(6), 429–439.

VASOMOTION SPECTRA AND PRINCIPAL COMPONENTS OF POOLED MEASURES PREDICT DIABETES IN MONKEYS

Diabetic neuropathy may be a result of disturbed vasomotion, the spontaneous rhythmic oscillations of vessel diameter, flow, or pressure in the microcirculation. To examine the differences in vasomotion prior to overt diabetes and with diagnosed diabetes, metabolic and blood flow measurements were obtained from three metabolically distinct groups of nonhuman primates: normoglycemic, metabolic syndrome/prediabetic, and overtly diabetic. Three of these indices characterize spectral properties of microcirculatory vasomotion: (1) the fraction of spectral power in a band around 2.0 Hz, (2) the ratio of spectral power in a band around 1.0 Hz to that around 2.0 Hz, (3) the Hurst exponent. The rest were more traditional measures including (4) fasting plasma Glucose (FPG), (5) glycosylated hemoglobin level (HbA1c), (6) fasting insulin levels (IRI), (7) average systolic blood pressure, and (8) average diastolic blood pressure. We found that the mean fraction of the spectral power of the vasomotion in the 2 Hz band ...

The Undergraduate Interdisciplinary Research Experience on Women's Health: Promoting "Learning that Lasts a Lifetime"

The University of South Florida piloted an undergraduate initiative on Womens Health consisting of a 6-week intensive mentored research and two parallel formal courses. Faculty included those from the Colleges of Medicine, Public Health, Nursing, Womens Studies and Honors. The results encourage us to continue and expand the project.