Decrease in β-Cell Mass Leads to Impaired Pulsatile Insulin Secretion, Reduced Postprandial Hepatic Insulin Clearance, and Relative Hyperglucagonemia in the Minipig
Article Figures & Tables
Figures
- FIG. 1.
A: The plasma insulin concentrations in minipigs at the portal and arterial sampling site after a bolus of insulin (80 mU) was injected into the splenic vein at t = 0 min during a somatostatin infusion to inhibit endogenous insulin secretion. The decay curve of the log insulin concentration was monoexponential at the arterial and biexponential at the portal sampling site. B: Simultaneous plasma insulin concentrations in the portal vein and the arterial sampling sites in the fasting state (−40 to 0 min) and during a hyperglycemic clamp (30–70 min) in a representative pig. The presence of a detected pulse is shown by a star. There is a close relationship between the pulses detected in the portal and arterial sampling sites.
- FIG. 2.
The relationship between the β-cell mass and the fasting plasma glucose concentrations (A) and the plasma glucose/insulin concentration ratio ([mmol/l × 10]/pmol/l) 30 min after the meal (B) in pigs that had been treated with alloxan (n = 8) and pigs that had not received alloxan (n = 4 in A; n = 3 in B).
- FIG. 3.
The mean plasma glucose (top), insulin (middle), and glucagon (bottom) concentrations before (−40 to 0 min) and after (0–210 min) ingestion of a mixed meal.
- FIG. 4.
The insulin concentration profile (measured each minute) from the arterial sampling site in the fasting state (−40 to 0 min) and after ingestion of a mixed meal given at t = 0 min in two representative pigs (left, before alloxan administration; right, after alloxan administration). Note the expanded vertical scale after alloxan administration so that pulses can still be seen. The insulin concentration profiles from −40 to 0 min and from 15 to 75 min were deconvolved to determine the pulsatile insulin secretion rate under fasting conditions versus fed conditions, respectively (Fig. 5).
- FIG. 5.
The insulin secretion rates in two representative pigs (left, pig 1; right, pig 2) in the fasting state (basal) and after meal ingestion before (top) and after (bottom) alloxan administration. Note that the vertical scales are adapted to accommodate the differing data range in each pig and are expanded after alloxan administration so that pulses can be seen.
- FIG. 6.
Mixed meal. The mean insulin secretion rate (left), insulin pulse mass (middle), and interpulse interval (right) are shown for each pig before and after alloxan administration after meal ingestion. The decreased insulin secretion rate after alloxan administration (P < 0.03) is due to a decrease in insulin pulse mass (P < 0.05) and not any change in pulse frequency (P = NS).
- FIG. 7.
The clearance rate of endogenously secreted insulin before and after alloxan intervention in the basal state and after a meal or during a clamp. The reduction in β-cell mass induced by alloxan resulted in decreased insulin clearance.
- FIG. 8.
The relationship between the clearance rate of endogenously secreted insulin and the mean insulin pulse amplitude in each pig before and after meal ingestion and alloxan administration.
- FIG. 9.
There was a positive relationship between β-cell mass and both insulin secretion (A) and insulin pulse mass (B) after meal ingestion in pigs that received alloxan (n = 7).
- FIG. 10.
Mean plasma glucose and arterial insulin concentrations in the fasting state (−40 to 0 min) and during a hyperglycemic clamp (0–70 min) before and after alloxan administration. At t = 0 min, the glucose infusion was initiated to achieve a steady-state hyperglycemic clamp at t = 30 min. Sampling for measurement of insulin concentrations was performed every minute from −40 to 0 for the basal period and from 30 to 70 min for the clamp period. At t = 70 min, an intravenous glucose bolus was given to elicit first-phase insulin secretion (at comparable glucose concentrations in the studies before and after alloxan administration).
- FIG. 11.
Individual insulin concentration profiles in representative pigs before and after alloxan administration in the basal fasting state (−40 to 0 min) and during the hyperglycemic clamp (0–70 min). Note the expanded vertical scales after alloxan administration. Insulin concentrations were obtained every minute from –40 to 0 min and from 30 to 70 min for deconvolution of insulin secretion rates (see Fig. 11). Insulin was measured at 5-min intervals from 0 to 30 min during the period when the glucose infusion rate was initiated and increased rapidly to achieve steady-state hyperglycemia by t = 30–70 min.
- FIG. 12.
Secretion profiles in two individual pigs (pig 2, left; pig 4, right) before and after alloxan administration in the fasting (basal) state (−40 to 0 min) and during the clamp (30–70 min). Vertical scales expanded to individual secretion profiles.
- FIG. 13.
Clamp. The mean insulin secretion rate (left), pulse mass (middle), and pulse interval (right) for each pig are shown before and after alloxan administration. The decreased insulin secretion rate during the clamp (P < 0.01) after alloxan treatment was due to decreased insulin pulse mass (P < 0.01) with no change in pulse frequency.
Tables
- TABLE 1
Demographic data
Before alloxan After alloxan Age (months) 20.8 ± 4.2 Sex (M/F) 5/2 Weight (kg) 25.2 ± 1.9 24.5 ± 1.8 Glucose (mmol/l) 4.4 ± 0.1 7.4 ± 1.1* Insulin (pmol/l) 86.0 ± 17.3 55 ± 7.5* Glucagon (pg/ml) 110 ± 16 105 ± 4.1 Data are means ± SD or n. The age, sex, weight, and fasting plasma glucose, insulin, and glucagon concentrations in pigs included in protocol 2 (n = 7) before and after alloxan administration (
- *
* P < 0.05). Five of these pigs were used in protocol 3.
- TABLE 2
Pulsatile insulin secretion
Pulse interval (min/pulse) Pulse amplitude (pmol/min) Pulse mass (pmol · kg−1 · pulse) Pulsatile secretion (pmol · kg−1 · min) Total insulin secretion (pmol · kg−1 · min) % Pulsatile insulin secretion Insulin clearance (l/min) Meal (n = 7) Pre-alloxan Fasting 6.5 ± 0.5 10.8 ± 3.4* 24.0 ± 7.1* 4.1 ± 1.5 5.9 ± 2.0 65.1 ± 5.1 0.85 ± 0.1* Fed 5.8 ± 0.4 77.0 ± 28.2* 203.8 ± 81.7* 35.8 ± 13.5* 42.4 ± 14.1* 80.3 ± 3.7** 1.08 ± 0.14** Post-alloxan Fasting 5.8 ± 0.6 4.5 ± 1.4 12.6 ± 5.4 1.9 ± 0.6 3.2 ± 0.9 54.2 ± 4.0 0.67 ± 0.06 Fed 7.1 ± 0.8 19.7 ± 8.3 75.8 ± 36.0 12.7 ± 6.0 21.3 ± 8.4 54.1 ± 3.2 0.69 ± 0.14 Clamp (n = 5) Pre-alloxan Fasting 7.3 ± 0.5* 7.7 ± 0.7* 22.4 ± 04.3** 3.1 ± 0.5 4.8 ± 0.6 65.0 ± 6.9 0.89 ± 0.14 Clamp 5.5 ± 0.7 42.6 ± 17.7* 80.9 ± 19.0** 16.0 ± 5.5** 31.1 ± 6.1** 47.1 ± 7.8 0.64 ± 0.17 Post-alloxan Fasting 4.7 ± 0.3 4.2 ± 1.4 14.1 ± 6.4 3.1 ± 1.4 4.3 ± 1.4 65.2 ± 6.2 0.62 ± 0.04 Clamp 5.7 ± 0.5 3.4 ± 1.5 8.5 ± 4.3 1.5 ± 0.6 2.8 ± 0.6 45.0 ± 10.6 0.42 ± 0.08 Data are means ± SE. The calculated insulin secretion rate and parameters for pulsatile insulin secretion before and after alloxan administration after glucose injection and during the hyperglycemic clamp.
- *
* P < 0.05;
- **
** P < 0.01 before versus after alloxan administration.
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