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Objectiveβ-Cell turnover and its potential to permit β-cell regeneration in adult primates are unknown. Our aims were 1) to measure β-cell turnover in adult nonhuman primates; 2) to establish the relative contribution of β-cell replication and formation of new β-cells from other precursors (defined thus as β-cell neogenesis); and 3) to establish whether there is an adaptive increase in β-cell formation (attempted regeneration) in streptozotocin (STZ)-induced diabetes in adult nonhuman primates.Research design and methodsAdult (aged 7 years) vervet monkeys were administered STZ (45-55 mg/kg, n = 7) or saline (n = 9). Pancreas was obtained from each animal twice, first by open surgical biopsy and then by euthanasia. β-Cell turnover was evaluated by applying a mathematic model to measured replication and apoptosis rates.Resultsβ-Cell turnover is present in adult nonhuman primates (3.3 ± 0.9 mg/month), mostly (~80%) derived from β-cell neogenesis. β-Cell formation was minimal in STZ-induced diabetes. Despite marked hyperglycemia, β-cell apoptosis was not increased in monkeys administered STZ.ConclusionsThere is ongoing β-cell turnover in adult nonhuman primates that cannot be accounted for by β-cell replication. There is no evidence of β-cell regeneration in monkeys administered STZ. Hyperglycemia does not induce β-cell apoptosis in nonhuman primates in vivo.

Objectiveβ-Cell turnover and its potential to permit β-cell regeneration in adult primates are unknown. Our aims were 1) to measure β-cell turnover in adult nonhuman primates; 2) to establish the relative contribution of β-cell replication and formation of new β-cells from other precursors (defined thus as β-cell neogenesis); and 3) to establish whether there is an adaptive increase in β-cell formation (attempted regeneration) in streptozotocin (STZ)-induced diabetes in adult nonhuman primates.Research design and methodsAdult (aged 7 years) vervet monkeys were administered STZ (45-55 mg/kg, n = 7) or saline (n = 9). Pancreas was obtained from each animal twice, first by open surgical biopsy and then by euthanasia. β-Cell turnover was evaluated by applying a mathematic model to measured replication and apoptosis rates.Resultsβ-Cell turnover is present in adult nonhuman primates (3.3 ± 0.9 mg/month), mostly (~80%) derived from β-cell neogenesis. β-Cell formation was minimal in STZ-induced diabetes. Despite marked hyperglycemia, β-cell apoptosis was not increased in monkeys administered STZ.ConclusionsThere is ongoing β-cell turnover in adult nonhuman primates that cannot be accounted for by β-cell replication. There is no evidence of β-cell regeneration in monkeys administered STZ. Hyperglycemia does not induce β-cell apoptosis in nonhuman primates in vivo.

Caloric restriction (CR) retards aging processes, extends maximal life span, and consistently improves insulin resistance in lower species. Insulin resistance is associated with cardiovascular disease, but data is lacking demonstrating that increased insulin sensitivity reduces atherosclerosis progression. We initiated a study in 32 adult cynomolgus monkeys to evaluate increased insulin sensitivity secondary to CR on atherosclerosis extent. Following pretrial determinations, animals were randomized to a moderately atherogenic (0.25 mg cholesterol/Cal containing 30% of calories from fat)-fed control group or CR group (30% reduction) with equivalent dietary cholesterol intake. CR significantly improved insulin sensitivity and reduced intraabdominal fat over the 4-year intervention, while no significant differences were seen for the lipid profile between groups. Despite improved insulin sensitivity with CR, atherosclerosis extent did not differ between the ad libitum-fed or CR groups. These studies demonstrate that CR significantly improves insulin sensitivity, but when elevated plasma cholesterol concentrations were held similar, there was no effect on atherosclerosis extent. However, the composition of these lesions and changes in endothelial function may have been improved but were not evaluated in this study. Thus, further studies are needed to determine if improved insulin sensitivity might decrease arterial inflammation and improve endothelial function, despite no changes in atherosclerosis extent.

The dietary consumption of soy protein has been linked to a reduction in coronary heart disease and improvements in a number of related risk factors. Recent investigations have focused on isoflavone components of soy protein. The purpose of this study was to examine plasma lipids and lipoproteins, particularly LDL, with the intake of intact soy protein or casein-lactalbumin diets with and without a semipurified extract of soy, rich in isoflavones. Sixty ovariectomized cynomolgus monkeys were assigned to one of three groups fed diets containing the following: 1) casein-lactalbumin as the protein source (CAS; n = 20); 2) CAS plus a semipurified extract of soy, rich in isoflavones (ISO; n = 20); or 3) intact soy protein (SOY; n = 20) for 12 wk. Lipoproteins were fractionated by combined ultracentrifugation and HPLC. Isolated LDL particles were further subfractionated by dividing the LDL peak into three fractions for compositional analyses. The SOY group had significantly lower plasma total cholesterol, VLDL plus IDL cholesterol and LDL cholesterol, and significantly less HDL cholesterol than the CAS group. LDL particles from the SOY group had a significantly less cholesteryl ester than the CAS group. The semipurified extract of soy, rich in isoflavones, added to casein-lactalbumin protein did not have the same effects as intact soy protein on plasma lipids and lipoproteins. Other components of soy protein, either alone or in combination with isoflavones, may be involved in the effects seen in this study. KEY WORDS: cynomolgus monkeys; isoflavones; lipoproteins; menopause; soy protein

Caloric restriction has been demonstrated to retard aging processes and extend maximal life span in rodents, and is currently being evaluated in several nonhuman primate trials. We initiated a study in 32 adult cynomolgus monkeys to evaluate the effect of caloric restriction on parameters contributing to atherosclerosis extent. Following pretrial determinations, at which time a baseline measure of ad libitum (ad lib) dietary intake was assessed, animals were randomized to an ad lib fed group (control) or a caloric restriction group (30% reduction from baseline intake). The animals are being evaluated for glycated proteins, insulin, glucose, insulin sensitivity measures, and specific measures of body fat composition by CT scans (e.g., intra-abdominal fat) over specified intervals. The results from the first year of observation demonstrate a significant diet effect on body weight, and specifically intra-abdominal fat. Further, insulin sensitivity has been significantly increased after 1 year of caloric restriction compared to the ad lib fed group. These studies indicate that caloric restriction has a marked effect on a pathologic fat depot, and this change is associated significantly with an improvement in peripheral tissue insulin sensitivity.

Abstract Background Arterial proteoglycans are implicated in the pathogenesis of atherosclerosis by their ability to trap plasma lipoproteins in the arterial wall and by their influence on cellular migration, adhesion and proliferation. In addition, data have suggested an anti-atherogenic role for heparan sulfate proteoglycans and a pro-atherogenic role for dermatan sulfate proteoglycans. Using a non-human primate model for human diabetes, studies examined diabetes-induced changes in arterial proteoglycans that may increase susceptibility to atherosclerosis. Methods Control (n = 7) and streptozotocin-induced diabetic (n = 8) cynomolgous monkeys were assessed for hyperglycemia by measurement of plasma glycated hemoglobin (GHb). Thoracic aortas obtained at necropsy, were extracted with 4 M guanidine HCL and proteoglycans were measured as hexuronic acid. Atherosclerosis was measured by enzymatic analysis of extracted tissue cholesterol. Glycosaminoglycan chains of arterial proteoglycans were released with papain, separated by agarose electrophoresis and analysed by scanning densitometry. Results Tissue cholesterol was positively associated with hexuronic acid content in diabetic arteries (r = .82, p < .025) but not in control arteries. Glycosaminoglycan chain analysis demonstrated that dermatan sulfate was associated with increased tissue cholesterol in both control (r = .8, p < 0.05) and diabetic (r = .8, p < .025) arteries, whereas a negative relationship was observed between heparan sulfate and tissue cholesterol in diabetic arteries only (r = -.7, p < .05). GHb, which was significantly higher in diabetic animals (8.2 ± 0.9 vs 3.8 ± 0.2%, p < .0005) was negatively associated with heparan sulfate in diabetic arteries (r = -.7, p < .05). Conclusions These data implicate hyperglycemia induced modifications in arterial proteoglycans that may promote atherosclerosis.

We previously reported that one mechanism for the hypocholesterolemic effects of soy may be a reduction in cholesterol absorption. In this abstract, we report that reductions in cholesterol absorption may be attenuated by high amounts of cholesterol in the diet. Results from two studies examining 20 wk of soy protein consumption in ovariectomized cynomolgus monkeys are reported. All monkeys were fed either caseinlactalbumin (CAS) or isolated soy protein (SOY) as a protein source. In the first study, monkeys were fed diets containing 0.28 mg cholesterol/kcal. In the second study, monkeys were fed diets containing 0.36 mg cholesterol/kcal. Cholesterol absorption was determined by using the fecal isotope ratio method. Data are presented as means [+ or -] SEM. A significant reduction in cholesterol absorption was found in monkeys consuming isolated soy protein with 0.28 mg cholesterol/kcal compared with monkeys consuming casein-lactalbumin protein (SOY 66 [+ or -] 3% vs. CAS 74 [+ or -] 2%). However, there was no significant difference between the SOY and CAS groups consuming 0.36 mg cholesterol/kcal (SOY 63 [+ or -] 2% vs. CAS 66 [+ or -] 3%). Additionally, non-HDL cholesterol concentrations were significantly lowered in the SOY group compared with CAS group consuming 0.28 mg cholesterol/kcal (SOY 118 [+ or -] 14% vs. CAS 326 [+ or -] 37%). This was not the case in the monkeys consuming 0.36 mg cholesterol/kcal (SOY 324 [+ or -] 51% vs. CAS 403 [+ or -] 51%). Although many studies in humans suggest that soy protein is more beneficial in hypercholesterolemic individuals, most of these studies have included a low cholesterol diet in their design. The results from this study suggest that a threshold of dietary cholesterol consumption may exist above which soy protein may not be effective in lowering plasma cholesterol.

We previously showed that soy protein consumption improves lipoprotein concentrations and reduces progression of atherosclerosis in cynomolgus monkeys. The mechanism for these beneficial effects is unclear. The purpose of this study was to determine potential mechanisms for the atheroprotective effects and to determine whether these effects extend to diabetic monkeys. As such, we designed an experiment with a 2 x 2 factorial design in which adult male monkeys (n = 23) were fed an atherogenic diet; the protein source was soy isolate (n = 11) or casein lactalbumin (n = 12), and monkeys were either control (n = 12) or streptozotocin-induced diabetic (n = 11). Diabetics had significantly increased fasting glucose and glycated hemoglobin levels; this relationship was not affected by protein consumption. Soy consumption significantly reduced total cholesterol and increased HDL cholesterol concentrations in both control and diabetic monkeys. To determine plasma and arterial LDL metabolism, radiolabeled LDL was injected before necropsy, 125I-LDL was injected 48 h and 131I-tyramine cellobiose-LDL was injected 1 h before necropsy to determine arterial LDL concentration and permeability, respectively. An increase in whole-body plasma LDL fractional catabolic rate was found with soy consumption. Soy reduced arterial LDL concentration across all arterial sites and LDL permeability in the carotid bifurcation and internal carotid arteries. Arterial delivery of LDL was calculated as LDL permeability X plasma LDL concentration and was also reduced across all arterial sites. There was no additional effect of diabetes. In conclusion, these beneficial effects of soy on both plasma and arterial LDL metabolism would be expected to reduce atherosclerosis progression and were found in both control and diabetic monkeys.