Female African Green Monkeys Exhibit Protection Against Glucose Loading Indicative of Type 2 Diabetes Mellitus

다국어 초록 (Multilingual Abstract)

Over 30 million Americans have diabetes, roughly 90% of which exhibit the type 2 form. Overall, males have a higher prevalence of Type 2 Diabetes Mellitus (T2DM) and glucose intolerance than females. A co‐morbidity of T2DM and the resultant elevated blood glucose is decreased kidney function and elevated plasma creatinine. African Green Monkeys (AGM; Chlorocebus aethiops sabaeus) are known to express glucose intolerance similar to T2DM and renal pathologies making them an optimal nonhuman primate experimental model. Given the AGM genetic homology to humans, we hypothesized that female AGM would have protection against T2DM compared to males. A total of 9 healthy, age matched AGM were utilized in the study (male: 4.96±0.47 kg, n=4; female: 3.10±0.34 kg, n=5). Systolic blood pressure (SBP) measurements were taken by forearm plethysmography. Glucose handling was measured via a standard oral glucose tolerance test protocol. Fasted (12 hours) AGM were anesthetized (ketamine, 15mg/kg, i.m.) and baseline glucose was obtained via finger prick. AGM were gavaged with a 5% glucose load (15ml/kg) in water. Plasma glucose measurements were taken at 15, 30, 60, 90, and 120 minutes after gavage. Venous blood samples were obtained at baseline, 30, 60, and 120 minutes after glucose administration. Females had lower SBP and were normotensive, while males were borderline hypertensive (99±4.8 mmHg; 132±8.6 mmHg, respectively; p≤0.05). Females had higher baseline plasma glucose levels than males (female: 95±6.5 mg/dl; male: 84±9.8 mg/dl), but a lower peak at 30 minutes post glucose load (female: 108±33.2 mg/dl; male: 145±86.4 mg/dl; p≤0.05). Females also had a lower area under the curve (AUC) than males measured over the 120 minutes post‐glucose administration (female: 11,670±722.9 min*mg/dl; male: 14,411±1,143.2 min*mg/dl; p≤0.05). Plasma osmolality was not different between male and female AGMs prior to glucose administration (females: 297 ±9.2 mosm/kg; males: 314±7.6 mosm/kg; p≥0.05). Fasting female AGM had lower plasma creatinine levels than males (female: 1.28±0.23 mg/dl; males: 2.16±0.23 mg/dl; p≤0.05). These data demonstrate that peak plasma glucose at 30 minutes following an oral glucose load in females was decreased compared with age matched males. This reduced female response occurred despite female AGM fasting glucose being greater than that of male AGM. Furthermore, female AUC was reduced compared with male AUC over two hours following the oral glucose load. Females also had lower plasma creatinine levels than males. The higher creatinine levels indicate decreased kidney function in the males. These data coupled with the borderline hypertension demonstrate both cardiovascular and renal dysfunction in these male AGMs. Together, these data suggest increased efficiency of glucose handling by female AGM, retention of normal kidney function, and maintenance of normotension compared to age matched males. Overall, the data suggest that female AGM are doubly protected from T2DM and cardiovascular disease. Future studies will include conscious glucose and insulin measurements of AGM, and insulin/glucose clamp studies to understand the metabolomic differences between male and female AGM.