Scott T. Baum

Pioglitazone Increases Insulin Sensitivity, Reduces Blood Glucose, Insulin, and Lipid Levels, and Lowers Blood Pressure, in Obese, Insulin-Resistant Rhesus Monkeys

The antidiabetic effects of pioglitazone hydrochloride were evaluated in 6 spontaneously obese, insulin-resistant rhesus monkeys. The animals were studied during six successive 2-wk treatment phases separated by 2-wk rest periods: two placebo phases; 0.3, 1.0, and 3.0 mg · kg−1 · day−1 pioglitazone hydrochloride phases; and a final placebo phase. During the second week of each treatment phase, serum insulin (immunoreactive insulin [IRI]), plasma glucose, and serum triglyceride (TG) levels were measured after an overnight fast and after a standardized meal. Blood pressure was measured and glucose tolerance tests (modified minimal model protocol) were performed a few days after the meal tests. Pioglitazone hydrochloride significantly improved fasting and postprandial levels of IRI, plasma glucose, and TG in a dose-related manner (P < 0.05). Fasting values during treatment with 3.0 mg · kg−1 · day−1 were reduced by 64% for IRI, 19% for plasma glucose, and 44% for TG compared with the placebo phase before treatment. Efficacy of pioglitazone hydrochloride was more marked for those animals with fasting hyperglycemia. Insulin sensitivity was increased by pioglitazone hydrochloride (P = 0.05), whereas glucose effectiveness and glucose disappearance rate were not detectably affected. Systolic and mean arterial blood pressures were significantly decreased by pioglitazone hydrochloride (P < 0.05). No toxic side effects of pioglitazone hydrochloride treatment were noted.

Long-term calorie restriction decreases metabolic cost of movement and prevents decrease of physical activity during aging in rhesus monkeys.

BACKGROUND Short-term (<1 year) calorie restriction (CR) has been reported to decrease physical activity and metabolic rate in humans and non-human primate models; however, studies examining the very long-term (>10 year) effect of CR on these parameters are lacking. OBJECTIVE The objective of this study was to examine metabolic and behavioral adaptations to long-term CR longitudinally in rhesus macaques. DESIGN Eighteen (10 male, 8 female) control (C) and 24 (14 male, 10 female) age matched CR rhesus monkeys between 19.6 and 31.9 years old were examined after 13 and 18 years of moderate adult-onset CR. Energy expenditure (EE) was examined by doubly labeled water (DLW; TEE) and respiratory chamber (24 h EE). Physical activity was assessed both by metabolic equivalent (MET) in a respiratory chamber and by an accelerometer. Metabolic cost of movements during 24 h was also calculated. Age and fat-free mass were included as covariates. RESULTS Adjusted total and 24 h EE were not different between C and CR. Sleeping metabolic rate was significantly lower, and physical activity level was higher in CR than in C independent from the CR-induced changes in body composition. The duration of physical activity above 1.6 METs was significantly higher in CR than in C, and CR had significantly higher accelerometer activity counts than C. Metabolic cost of movements during 24 h was significantly lower in CR than in C. The accelerometer activity counts were significantly decreased after seven years in C animals, but not in CR animals. CONCLUSIONS The results suggest that long-term CR decreases basal metabolic rate, but maintains higher physical activity with lower metabolic cost of movements compared with C.

Age and sex differences in body size and composition during Rhesus monkey adulthood

Body size and composition were measured in forty-one adult Rhesus monkeys (Macaca mulatta) in order to characterize changes that occur during later life for both genders. Data were obtained by traditional somatometric techniques and by dual-energy X-ray absorptiometry. Representative monkeys were chosen within six categories defined by age (Young Adult, 6–9 yearold; Middle Aged, 15–19 year-old; Older Adult, 26–30 year-old), and sex. Body weight and most external measures of body size were greater during middle age and later life than in young adulthood, as were body fat content and lean body mass. Females tended to have a higher percentage body fat than males in all age categories. Lean tissue mass was markedly greater in the two younger groups for both sexes, compared to older adults. Bone mineral content and density were higher in the males than the females, but differences in bone mineralization among age groups did not achieve statistical significance. Such data derived from adult nonhuman primates are useful for defining fundamental biological changes with age in these species, and have value as a comparative model for studies of human aging and age-related morbidity.

Prenatal androgen excess negatively impacts body fat distribution in a nonhuman primate model of polycystic ovary syndrome

Introduction:Prenatally androgenized (PA) female rhesus monkeys share metabolic abnormalities in common with polycystic ovary syndrome (PCOS) women. Early gestation exposure (E) results in insulin resistance, impaired pancreatic β-cell function and type 2 diabetes, while late gestation exposure (L) results in supranormal insulin sensitivity that declines with increasing body mass index (BMI).Objective:To determine whether PA females have altered body fat distribution.Design:Five early-treated PA (EPA), five late-treated PA (LPA) and five control adult female monkeys underwent somatometrics, dual-X-ray absorptiometry (DXA) and abdominal computed tomography (CT). Five control and five EPA females underwent an intravenous glucose tolerance test to assess the relationship between body composition and glucoregulation.Results:There were no differences in age, weight, BMI or somatometrics. LPA females had ∼20% greater DXA-determined total fat and percent body fat, as well as total and percent abdominal fat than EPA or control females (P⩽0.05). LPA females also had ∼40% more CT-determined non-visceral abdominal fat than EPA or control females (P⩽0.05). The volume of visceral fat was similar among the three groups. EPA (R 2=0.94, P⩽0.01) and LPA (R 2=0.53, P=0.16) females had a positive relationship between visceral fat and BMI, although not significant for LPA females. Conversely, control females had a positive relationship between non-visceral fat and BMI (R 2=0.98, P⩽0.001). There was a positive relationship between basal insulin and total body (R 2=0.95, P⩽0.007), total abdominal (R 2=0.81, P⩽0.04) and visceral (R 2=0.82, P⩽0.03) fat quantities in EPA, but not control females.Conclusions:Prenatal androgenization in female rhesus monkeys induces adiposity-dependent visceral fat accumulation, and late gestation androgenization causes increased total body and non-visceral fat mass. Early gestation androgenization induces visceral fat-dependent hyperinsulinemia. The relationship between the timing of prenatal androgen exposure and body composition phenotypes in this nonhuman primate model for PCOS may provide insight into the heterogeneity of metabolic defects found in PCOS women.

Assessment of nutritional status in rhesus monkeys: comparison of dual-energy X-ray absorptiometry and stable isotope dilution.

Abstract:  Body composition estimates from dual‐energy X‐ray absorptiometry and stable isotope dilution (2H and 18O) were compared in 61 rhesus monkeys (Macaca mulatta) from the ongoing long‐term energy restriction study at the University of Wisconsin. Their average age was 18.9 ± 2.5 y/o. Of the animals, 51% were in the energy restricted group and 38% were females. Although the correlation between methods was highly significant for fat mass (R2 = 0.97, SEE = 0.25 kg or 7.5%, P < 0.0001) and fat‐free mass (R2 = 0.98, SEE = 0.29 kg or 3.6%, P < 0.0001), we observed that dual‐energy X‐ray absorptiometry underestimated fat mass by 0.67 ± 0.26 kg (7.5%, P < 0.0001) and overestimated fat‐free mass by 0.57 ± 0.29 kg (20%, P < 0.0001) when compared with isotope dilution. Taken together with data from the literature, the present results emphasize the usefulness of dual‐energy X‐ray absorptiometry to derive body composition and thus nutritional status in monkeys, but demonstrate the importance of validation experiments for a given DXA model and software.

Glucose regulation in captivePongo pygmaeus abeli, P. p. pygmaeus,andP. p. abeli x P. p. pygmaeusorangutans

Intravenous glucose tolerance tests (IVGTT) were performed on 30 anesthetized, captive Sumatran (Pongo pygmaeus abeli), Bornean (P. p. pygmaeus), and hybrid (P. p. ablie x P. p. pygmaeus) orangutans, and fasted blood samples were taken from two additional juvenile orangutans in 11 U.S. zoos from 1989 to 1997. The age range of animals was 3.5 to 40.5 years. Plasma and serum samples were assayed for glucose and insulin concentrations. Glucose disappearance rate (KG), an index of glucose tolerance, was calculated, as were the early (acute) and second phase insulin responses to administered glucose. The mean ± SE (and median) fasting glucose and insulin concentrations were 113 ± 16 mg/dL (90 mg/dL) and 45 ± 7 μU/mL (27 μU/mL), respectively. Two animals previously suspected to be diabetic were easily identified by their markedly elevated fasting glucose concentrations (380 and 562 mg/dL) and relatively low fasted insulin concentrations (21 and 14 μU/mL); their insulin responses during the IVGTTs were also low or non-detectable. Without these diabetics, the mean ± SE (median) fasting glucose concentration was 92 ± 18 mg/dL (89 mg/dL). Two animals, ages 18 and 40, were identified as potentially pre-diabetic based on age, adiposity, elevated fasted glucose (116 and 137 mg/dL, respectively), and elevated fasted insulin concentrations (114 and 217 μU/mL, respectively). In addition, nearly half of the animals of varying ages, all sub-species and both sexes exhibited delayed or attenuated acute insulin responses during the IVGTTs, resulting in lower KG (P < 0.04) and suggesting propensity for glucose intolerance in captive orangutans. Glucose and insulin concentrations and insulin responses to glucose did not differ between females on hormonal contraception regimes and those not receiving treatment. Zoo Biol 19:193–208, 2000.

Metabolizable energy intake during long-term calorie restriction in rhesus monkeys.

Calorie restriction (CR) is a dietary intervention shown to increase maximum life-span. The aim of this study was to compare the metabolizable energy of the pelleted semi-purified diet with estimated energy intake from food weight. Energy density of diet, urine and feces were measured by bomb calorimetry in rhesus monkeys (23-29 years old) on CR (CR, n=11) and control (C, n=9). Food moisture was measured to be 2-fold higher (9+/-1%) than indicated on the label (approximately 5%). The measured gross energy of diet was 4.4 kcal/g dry weight of CR and 4.5 kcal/g dry weight of C diets. In a two-day trial, food intake (mean+/-SD) was 112+/-20 g and 136+/-26 g of dry mass/d in the CR and C monkeys, respectively (p=0.003). The fraction of the diet absorbed (CR=0.91; C=0.95) was different (p<0.001) between CR and C monkeys. Using these coefficients, the metabolizable energy intake averaged over 6 months was 450+/-53 and 534+/-97 kcal/d in CR and C monkeys, respectively (Diff=16%; p=0.03). These values were compared with energy expenditure (EE), as measured annually by indirect calorimetry (490+/-61 kcal/d in CR and 532+/-62 kcal/d in C monkeys). Adjusted for changes in body composition (2+/-10 kcal/d in CR and -7+/-12 kcal/d in C), energy balance was not different from zero in CR (-42+/-42 kcal/d) and C (9+/-61 kcal/d) monkeys. Use of diet weight is a reasonable estimate of the level of CR when food waste is assessed.