Long-term blood glucose monitoring with implanted telemetry device in conscious and stress-free cynomolgus monkeys

Abstract

Aims: Continuous blood glucose monitoring, especially long-term and remote, in diabetic patients or research is very challenging. Nonhuman primate (NHP) is an excellent model for metabolic research, because NHPs can naturally develop Type 2 diabetes mellitus (T2DM) similarly to humans. This study was to investigate blood glucose changes in conscious, moving-free cynomolgus monkeys (Macaca fascicularis) during circadian, meal, stress and drug exposure.

Materials and methods: Blood glucose, body temperature and physical activities were continuously and simultaneously recorded by implanted HD-XG telemetry device for up to 10 weeks.

Results and discussion: Blood glucose circadian changes in normoglycemic monkeys significantly differed from that in diabetic animals. Postprandial glucose increase was more obvious after afternoon feeding. Moving a monkey from its housing cage to monkey chair increased blood glucose by 30% in both normoglycemic and diabetic monkeys. Such increase in blood glucose declined to the pre-procedure level in 30 min in normoglycemic animals and >2 h in diabetic monkeys. Oral gavage procedure alone caused hyperglycemia in both normoglycemic and diabetic monkeys. Intravenous injection with the stress hormones, angiotensin II (2 μg/kg) or norepinephrine (0.4 μg/kg), also increased blood glucose level by 30%. The glucose levels measured by the telemetry system correlated significantly well with glucometer readings during glucose tolerance tests (ivGTT or oGTT), insulin tolerance test (ITT), graded glucose infusion (GGI) and clamp.

Conclusion: Our data demonstrate that the real-time telemetry method is reliable for monitoring blood glucose remotely and continuously in conscious, stress-free, and moving-free NHPs with the advantages highly valuable to diabetes research and drug discovery.

Keywords: Continuous glucose monitoring; Diabetes; Glucose circadian; Implantable telemetry device; Nonhuman primate.

Fig. 1

a Implantable HD-XG telemetry device for continuous monitoring of glucose, temperature, and locomotor activity. b Experimental monkey with an implantable device and wearing a monkey jacket in which a small transmitter was placed and used for signal collection from outside cage. c Signals of blood glucose, body temperature, and locomotor activity from a conscious, moving-free monkey were recorded continuously from its outside cage. d Significant correlation between the blood glucose levels measured by the telemetry method and glucometer test

Fig. 2

Representative traces collected continuously from a conscious monkey implanted with a HD-XG device. From top to bottom, body temperature (1st trace) with the maker on top to indicate day (open bar) and night (black bar) time, physical activity (2nd trace), blood glucose electrical signal (3rd trace), blood glucose level (4th trace) after calculation from the corresponding glucose electrical signal

Fig. 3

Daily blood glucose fluctuations averaged from 7-day consecutive recordings of each monkey in normal (n = 3, upper panel) and diabetic (n = 2, low panel) NHPs. The solid line in each panel represented the median level of instant blood glucose concentration from the seven consecutive days of each monkey for normoglycemia (n = 3) and diabetes (n = 2) ones, and the shadowed areas above or below the line were the deviations of high and low levels of blood glucose

Fig. 4

a Typical effects of feeding on blood glucose were shown from one conscious normoglycemia monkey. The solid line was the median level of instant blood glucose averaged from the seven consecutive days, and shadowed areas above or below the line were the deviations of high and low levels of blood glucose. b Representative stress responses to the operation procedures in one conscious normoglycemia monkey implanted with the telemetry device. Procedure from cage to chair, the monkey was removed from its cage and placed into a monkey chair. Gavage procedure, the monkey was chaired and encountered an oral gavage operation without any solution or drug delivery

Fig. 5

Effects of operation procedures on blood glucose in normoglycemia (n = 3) and diabetes (n = 2) monkeys with implanted telemetry device. Procedure from cage to chair (a), the monkeys were removed from their cages and placed into their monkey chairs. Gavage procedure (b), the monkeys were chaired and encountered oral gavage operation without delivery of any drug or solution. Compared with normoglycemic monkeys, the stress responses to the operation procedures were markedly prolonged in diabetes animals

Fig. 6

Effects of norepinephrine and angiotensin II on blood glucose in normoglycemic and diabetic monkeys implanted with the telemetry device. Left panel norepinephrine at 0.4 µg/kg/min was intravenously infused for 40 min in anesthetized (10 mg/kg ketamine, intramuscularly) normoglycemic (L02) and diabetic (J04) monkeys. The blue bar represents the time period with norepinephrine infusion. Right panel angiotensin II at 2 µg/kg was intravenously injected in conscious normoglycemic (L02) and diabetic (J04) monkeys. The arrows indicated the time point for angiotensin II bolus injection. L02 and J04 were the identification codes of the normoglycemic and diabetic monkeys used in both left and right panels

Fig. 7

Representative data to make comparison of the outcomes measured by glucometer and telemetry. Blood glucose levels responded to single ivGTT in one normoglycemic animal (upper left) and dual ivGTTs in one normoglycemic (Blue) and one diabetes (Green) monkeys (upper right) measured with both telemetry (solid line) or glucometer (scatted squares or circles). Blood glucose levels responded to single oGTT (low left) and ITT (low right) in one normoglycemic monkey were measured with both the telemetry (solid line) or glucometer (scatted squares) methods

Fig. 8

Comparison of the outcomes measured by glucometer and telemetry. Graded glucose infusion in anesthetized normoglycemic (blue line, n = 1) and diabetic (green and red lines, one animal per line) monkeys with similar glucose levels measured by telemetry (solid line) and glucometer (solid dotted circles). Each animal was anesthetized with ketamine at 10 mg/kg (i.m.) plus additional dose 5 mg/kg each time during procedure if needed. The upper panel shows the glucose levels and low panel shows the graded glucose infusion rates

Fig. 9

Comparison of the blood glucose levels measured by glucometer (scatted dots) and telemetry (solid lines) during glucose clamp. Hyperinsulinemic-euglycemic clamps were conducted in normoglycemic (n = 3) and diabetic (n = 2) monkeys. Blood glucose was measured by both telemetry (solid line) and glucometer (solid scatted circles) methods. The animals were anesthetized with ketamine at 10 mg/kg (i.m.) initially and then 5 mg/kg each time during clamp procedure if needed