Search tips
Search criteria

Results 1-7 (7)

Clipboard (0)

Select a Filter Below

Year of Publication
Document Types
1.  Successful β cells islet regeneration in streptozotocin-induced diabetic baboons using ultrasound-targeted microbubble gene therapy with cyclinD2/CDK4/GLP1 
Cell Cycle  2014;13(7):1145-1151.
Both major forms of diabetes mellitus (DM) involve β-cell destruction and dysfunction. New treatment strategies have focused on replenishing the deficiency of β-cell mass common to both major forms of diabetes by islet transplantation or β-cell regeneration. The pancreas, not the liver, is the ideal organ for islet regeneration, because it is the natural milieu for islets. Since islet mass is known to increase during obesity and pregnancy, the concept of stimulating pancreatic islet regeneration in vivo is both rational and physiologic. This paper proposes a novel approach in which non-viral gene therapy is targeted to pancreatic islets using ultrasound targeted microbubble destruction (UTMD) in a non-human primate model (NHP), the baboon. Treated baboons received a gene cocktail comprised of cyclinD2, CDK, and GLP1, which in rats results in robust and durable islet regeneration with normalization of blood glucose, insulin, and C-peptide levels. We were able to generate important preliminary data indicating that gene therapy by UTMD can achieve in vivo normalization of the intravenous (IV) glucose tolerance test (IVGTT) curves in STZ hyperglycemic-induced conscious tethered baboons. Immunohistochemistry clearly demonstrated evidence of islet regeneration and restoration of β-cell mass.
PMCID: PMC4013164  PMID: 24553120
cell cycle regulation; GLP-1; CyclinD2; CDK4; gene therapy; insulin gene promoter; proliferation; differentiation; islets regeneration; diabetes; baboons; nonhuman primates
2.  Body composition and cardiometabolic disease risk factors in captive baboons (Papio hamadryas Sp.): sexual dimorphism 
Baboons (Papio hamadryas Sp.) exhibit significant sexual dimorphism in body size. Sexual dimorphism is also exhibited in a number of circulating factors associated with risk of cardiometabolic disease. We investigated whether sexual dimorphism in body size and composition underlie these differences. We examined data from 28 male and 24 female outdoor group-housed young adult baboons enrolled in a longitudinal observational study of cardiometabolic disease risk factors. Animals were sedated with ketamine HCl (10mg/Kg) before undergoing venous blood draws, basic body measurements, and dual-energy X-ray absorptiometry (DXA) body composition scans. Percentage glycated hemoglobin (%HbA1C) was measured in whole blood. Serum samples were analyzed for glucose, insulin, C-peptide, HDL-, and triglyceride concentrations. Males were heavier and had greater body length and lean tissue mass than females. Females had a greater body fat percentage relative to males (10.8 ±6.4 vs. 6.9 ±4.0, P=0.01). Although C-peptide, fasting glucose, and %HbA1C did not differ between the sexes, females had greater fasting insulin and triglyceride compared to their male counterparts. Insulin and percentage body fat were significantly correlated in males (r=0.61, P=0.001) and to a lesser extent in females (r=0.43, P=0.04). Overall, relations between adiposity and fasting insulin and fasting triglyceride were stronger in males. After accounting for differences in percentage body fat, fasting insulin and triglyceride were no longer statistically different between males and females. Despite stronger correlations between relative adiposity and insulin and triglyceride in males, the higher fasting insulin and triglyceride of female baboons may be underlain by their greater relative body fat masses.
PMCID: PMC4025923  PMID: 24318937
sex differences; baboon; body fat; triglyceride; insulin
3.  Hyperglycemic Challenge and Distribution of Adipose Tissue in Obese Baboons 
Blood glucose levels regulate the rate of insulin secretion, which is the body’s mechanism for preventing excessive elevation in blood glucose. Impaired glucose metabolism and insulin resistance have been linked to excess body fat composition. Here, we quantify abdominal muscle and abdominal adipose tissue compartments in a large nonhuman primate, the baboon, and investigate their relationship with serum glucose response to a hyperglycemic challenge.
Five female baboons were fasted for 16 hours prior to 90 minute body imaging experiment that consisted of a 20-min baseline, followed by a bolus infusion of glucose (500mg/kg). The blood glucose was sampled at regular intervals. The total volumes of the muscle, visceral and subcutaneous adipose tissue were measured.
Results and discussion
We found that adipose tissue composition predicted fluctuations in glucose responses to a hyperglycemic challenge of a non-human primate. Animals with higher visceral adiposity showed significantly reduced glucose elimination. The glucose responses were positively correlated with body weight, visceral and muscle fat (p < 0.005). Polynomial regression analysis showed that body weight, visceral and muscle were significant
These results reveal the similarity between humans and baboons with respect to glucose metabolism and strengthen the utility of baboon for biomedical research.
PMCID: PMC4241571  PMID: 25429366
Hyperglycemic Challenge; Perfusion Imaging; Body Fat Composition
4.  Replication of obesity and diabetes-related SNP associations in individuals from Yucatán, México 
Frontiers in Genetics  2014;5:380.
The prevalence of type 2 diabetes (T2D) is rising rapidly and in Mexicans is ~19%. T2D is affected by both environmental and genetic factors. Although specific genes have been implicated in T2D risk few of these findings are confirmed in studies of Mexican subjects. Our aim was to replicate associations of 39 single nucleotide polymorphisms (SNPs) from 10 genes with T2D-related phenotypes in a community-based Mexican cohort. Unrelated individuals (n = 259) living in southeastern Mexico were enrolled in the study based at the University of Yucatan School of Medicine in Merida. Phenotypes measured included anthropometric measurements, circulating levels of adipose tissue endocrine factors (leptin, adiponectin, pro-inflammatory cytokines), and insulin, glucose, and blood pressure. Association analyses were conducted by measured genotype analysis implemented in SOLAR, adapted for unrelated individuals. SNP Minor allele frequencies ranged from 2.2 to 48.6%. Nominal associations were found for CNR1, SLC30A8, GCK, and PCSK1 SNPs with systolic blood pressure, insulin and glucose, and for CNR1, SLC30A8, KCNJ11, and PCSK1 SNPs with adiponectin and leptin (p < 0.05). P-values greater than 0.0014 were considered significant. Association of SNPs rs10485170 of CNR1 and rs5215 of KCNJ11 with adiponectin and leptin, respectively, reached near significance (p = 0.002). Significant association (p = 0.001) was observed between plasma leptin and rs5219 of KCNJ11.
PMCID: PMC4235406  PMID: 25477898
Single Nucleotide Polymorphisms (SNP); association analysis; minor allele frequency; type 2 diabetes; obesity
5.  Coordinated Defects in Hepatic Long Chain Fatty Acid Metabolism and Triglyceride Accumulation Contribute to Insulin Resistance in Non-Human Primates 
PLoS ONE  2011;6(11):e27617.
Non-Alcoholic fatty liver disease (NAFLD) is characterized by accumulation of triglycerides (TG) in hepatocytes, which may also trigger cirrhosis. The mechanisms of NAFLD are not fully understood, but insulin resistance has been proposed as a key determinant.
To determine the TG content and long chain fatty acyl CoA composition profile in liver from obese non-diabetic insulin resistant (IR) and lean insulin sensitive (IS) baboons in relation with hepatic and peripheral insulin sensitivity.
Twenty baboons with varying grades of adiposity were studied. Hepatic (liver) and peripheral (mainly muscle) insulin sensitivity was measured with a euglycemic clamp and QUICKI. Liver biopsies were performed at baseline for TG content and LCFA profile by mass spectrometry, and histological analysis. Findings were correlated with clinical and biochemical markers of adiposity and insulin resistance.
Obese IR baboons had elevated liver TG content compared to IS. Furthermore, the concentration of unsaturated (LC-UFA) was greater than saturated (LC-SFA) fatty acyl CoA in the liver. Interestingly, LC-FA UFA and SFA correlated with waist, BMI, insulin, NEFA, TG, QUICKI, but not M/I. Histological findings of NAFLD ranging from focal to diffuse hepatic steatosis were found in obese IR baboons.
Liver TG content is closely related with both hepatic and peripheral IR, whereas liver LC-UFA and LC-SFA are closely related only with hepatic IR in non-human primates. Mechanisms leading to the accumulation of TG, LC-UFA and an altered UFA: LC-SFA ratio may play an important role in the pathophysiology of fatty liver disease in humans.
PMCID: PMC3220682  PMID: 22125617
6.  Eight week exposure to a high sugar high fat diet results in adiposity gain and alterations in metabolic biomarkers in baboons (Papio hamadryas sp.) 
Baboons (Papio hamadryas Sp.) develop features of the cardiometabolic syndrome and represent a clinically-relevant animal model in which to study the aetiology of the disorder. To further evaluate the baboon as a model for the study of the cardiometabolic syndrome, we developed a high sugar high fat diet and hypothesized that it could be used to induce adiposity gain and affect associated circulating biomarkers.
We developed a diet enriched with monosaccharides and saturated fatty acids that was composed of solid and liquid energy sources. We provided a group of baboons (n = 9) ad libitum access to this diet for 8 weeks. Concurrently, a control group (n = 6) was maintained with ad libitum access to a low sugar low fat baseline diet and normal water for 8 weeks. Body composition was determined by dual-energy X-ray absorptiometry and circulating metabolic biomarkers were measured using standard methodology before and after the 8 week study period.
Neither body composition nor circulating biomarkers changed in the control group. Following the 8 weeks, the intervention group had a significant increase in fat mass (1.71 ± 0.98 vs. 3.23 ± 1.70 kg, p = 0.004), triglyceride (55 ± 13 vs. 109 ± 67 mg/dL, p = 0.006,), and leptin (1.19 ± 1.40 vs. 3.29 ± 2.32 ng/mL, p = 0.001) and a decline in adiponectin concentrations (33530 ± 9744 vs. 23330 ± 7863 ng/mL, p = 0.002). Percentage haemoglobin A1C (4.0 ± 0.3 vs. 6.0 ± 1.4, p = 0.002) also increased in the intervention group.
Our findings indicate that when exposed to a high sugar high fat diet, young adult male baboons develop increased body fat and triglyceride concentrations, altered adipokine concentrations, and evidence of altered glucose metabolism. Our findings are in keeping with observations in humans and further demonstrate the potential utility of this highly clinically-relevant animal model for studying diet-induced metabolic dysregulation.
PMCID: PMC2988722  PMID: 21034486
7.  Appetite Enhancement and Weight Gain by Peripheral Administration of TrkB Agonists in Non-Human Primates 
PLoS ONE  2008;3(4):e1900.
Loss of function mutations in the receptor tyrosine kinase TrkB pathway resulted in hyperphagia and morbid obesity in human and rodents. Conversely, peripheral or central stimulation of TrkB by its natural ligands BDNF or NT4 reduced body weight and food intake in mice, supporting the idea that TrkB is a key anorexigenic signal downstream of the melanocortin-4 receptor (Mc4r) system. Here we show that in non-human primates TrkB agonists were anorexigenic when applied centrally, but surprisingly orexigenic, leading to gain in appetite, body weight, fat deposits and serum leptin levels, when given peripherally. The orexigenic and pro-obesity effects of peripherally administered TrkB agonists appear to be dose dependent, not associated with fluid retention nor with evidence of receptor down regulation. Our findings revealed that TrkB signaling exerts dual control on energy homeostasis in the primates that could be targeted for the treatment of either wasting disorders or obesity.
PMCID: PMC2270901  PMID: 18382675

Results 1-7 (7)