Physiological and Molecular Determinants of Insulin Action in the Baboon

Abstract

OBJECTIVE-To quantitate insulin sensitivity in lean and obese nondiabetic baboons and examine the underlying cellular/ molecular mechanisms responsible for impaired insulin action to characterize a baboon model of insulin resistance.RESEARCH DESIGN AND METHODS-Twenty baboons received a hyperinsulinemic-euglycemic clamp with skeletal muscle and visceral adipose tissue biopsies at baseline and at 30 and 120 min after insulin. Genes and protein expression of key molecules involved in the insulin signaling cascade (insulin receptor, insulin receptor substrate-1, p85, phosphatidylinositol 3-kinase, Akt, and AS160) were sequenced, and insulin-mediated changes were analyzed.RESULTS-Overall, baboons show a wide range of insulin sensitivity (6.2 Ϯ 4.8 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ), and there is a strong inverse correlation between indexes of adiposity and insulin sensitivity (r ϭ Ϫ0.946, P Ͻ 0.001 for % body fat; r ϭ Ϫ0.72, P Ͻ 0.001 for waist circumference). The genes and protein sequences analyzed were found to have ϳ98% identity to those of man. Insulin-mediated changes in key signaling molecules were impaired both in muscle and adipose tissue in obese insulinresistant compared with lean insulin-sensitive baboons. CONCLUSIONS-The obese baboon is a pertinent nonhuman primate model to examine the underlying cellular/molecular mechanisms responsible for insulin resistance and eventual development of type 2 diabetes. Diabetes 57:899-908, 2008 I nsulin resistance is characterized by impaired response of target organs (e.g., skeletal muscle, liver, adipose tissue, and heart) to the physiological effects of insulin and results in impaired glucose metabolism. Insulin resistance is a characteristic feature of many common metabolic disorders, including obesity, type 2 diabetes, hypertension, and dyslipidemia, and of the normal aging process, which collectively constitute risk factors for the development of atherosclerotic cardiovascular disease (1-3).Nonhuman primates occupy a unique place in biomedical and evolutionary research by virtue of their close genetic and physiological similarity to humans and represent a valuable model that has great relevance to the study of human disease. Old World monkeys, which recently (ϳ25 millions years ago in evolutionary terms) diverged from the Hominoidea, have been most extensively studied (4,5). This taxonomic group includes vervet monkeys (Chlorocebus aethiops), rhesus macaques (Macaca mulatta), cynomolgus monkeys (Macaca fascicularis), and baboons (Papio hamadryas) (6). Despite the relevance of primate study to human disease research, there has been a shortage of primates available for biomedical research (7). Baboons and humans share great genetic similarity, with ϳ96% homology evident at the DNA level (8). The sequences of specific genes and the arrangements of genetic loci on chromosomes reflect the close evolutionary relationship between these two species (9). Not surprisingly, nonhuman primates develop many diseases similar to those in man, and they have been used as a model for osteoporos...

Cross-species replication of a resistin mRNA QTL, but not QTLs for circulating levels of resistin, in human and baboon

“…In both humans and baboons the metabolic response to an increase in body weight is characterized by augmentation of body fat percentage, circulating levels of insulin, insulin resistance, glucose, lipids and lower levels of adiponectin (Banks et al, 2003;Comuzzie et al, 2003;Tejero et al, 2004;Chavez et al, 2008). The baboon resistin (RETN) cDNA sequence is very similar to the reported human sequence (96% identical) (Tejero et al, 2005).…”

“…The genetic and physiologic similarity between baboons and humans has been demonstrated in various studies (Rogers et al, 2000;Banks et al, 2003;Tejero et al, 2004, Chavez et al, 2008. The similarity in the genomes between these two species permits replication of results (Rogers et al, 2000).…”

“…The baboon has been used as a model for the study of obesity and insulin resistance due to its genetic and physiologic similarity to humans (Rogers et al, 2000;Banks et al, 2003;Chavez et al, 2008). In both humans and baboons the metabolic response to an increase in body weight is characterized by augmentation of body fat percentage, circulating levels of insulin, insulin resistance, glucose, lipids and lower levels of adiponectin (Banks et al, 2003;Comuzzie et al, 2003;Tejero et al, 2004;Chavez et al, 2008).…”

Successful β cells islet regeneration in streptozotocin-induced diabetic baboons using ultrasound-targeted microbubble gene therapy with cyclinD2/CDK4/GLP1

“…16 Baboon genomic DNA was extracted from Papio hamadryas peripheral blood with a QIAamp Blood kit (Qiagen Inc). Baboon insulin gene promoter primers forward: 5-AGCGCTTAAT GTGGAAAGTG GGCC-3, reversed: 5-CTCGAGGGCA GAAGGACAGT GACC-3.…”

Increased levels of the Akt-specific phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP)-1 in obese participants are associated with insulin resistance

“…Insulin resistance is a key feature of both conditions [1] and is characterised by a reduced ability of target insulin tissues to take up and metabolise glucose in response to insulin. Although some defects in the early steps of the insulin signalling pathway have been reported in insulin target tissues from mouse models, non-human primates and humans [2][3][4][5][6][7][8][9][10][11][12][13][14], the underlying molecular mechanisms responsible for impaired insulin signalling have not been completely elucidated and are being intensely investigated. Insulin initiates its action by binding to the insulin receptor and activating its intrinsic tyrosine kinase.…”