Impaired insulin secretion and enhanced insulin sensitivity in cholecystokinin-deficient mice

Abstract

Objective: Cholecystokinin (CCK) is released in response to lipid intake and stimulates insulin secretion. We hypothesized that CCK deficiency would alter the regulation of insulin secretion and glucose homeostasis.

Research design and methods: We used quantitative magnetic resonance imaging to determine body composition and studied plasma glucose and insulin secretion of CCK gene knockout (CCK-KO) mice and their wild-type controls using intraperitoneal glucose and arginine infusions. The area of anti-insulin staining in pancreatic islets was measured by immunohistochemistry. Insulin sensitivity was assessed with euglycemic-hyperinsulemic clamps.

Results: CCK-KO mice fed a low-fat diet had a reduced acute insulin response to glucose but a normal response to arginine and normal glucose tolerance, associated with a trend toward greater insulin sensitivity. However, when fed a high-fat diet (HFD) for 10 weeks, CCK-KO mice developed glucose intolerance despite increased insulin sensitivity that was associated with low insulin secretion in response to both glucose and arginine. The deficiency of insulin secretion in CCK-KO mice was not associated with changes in β-cell or islet size.

Conclusions: CCK is involved in regulating insulin secretion and glucose tolerance in mice eating an HFD. The impaired insulin response to intraperitoneal stimuli that do not typically elicit CCK release suggests that this hormone has chronic effects on β-cell adaptation to diet in addition to acute incretin actions.

FIG. 1.

IPGTT and arginine stimulation test (AST) in mice fed the LFD. IPGTT (2 mg/g body wt) in 5-h–fasted wild-type and CCK-KO mice maintained on an LFD. A: Plasma glucose. B: Means of glucose AUC. C: Plasma insulin over 120 min. Arginine stimulation test (4.8 mmol/kg body wt i.p.) in 5-h–fasted mice maintained on an LFD. D: Plasma glucose. E: Plasma insulin. F: Mean insulin AUC over 60 min. Data are expressed as means ± SEM. *Significant differences relative to the wild-type groups at the same time point (P < 0.05).

FIG. 2.

Euglycemic-hyperinsulinemic clamps in mice fed an LFD. A: Blood glucose levels. B: GIR. C: Means of GIR at 90–120 min during the euglycemic clamp. D: Rg into selected tissues. Data are expressed as means ± SEM for six animals per group. *Significant differences relative to the wild-type mice (P < 0.05).

FIG. 3.

IPGTT and arginine stimulation (AST) tests in mice fed the HFD. IPGTT (2 mg/g body wt) in 5-h–fasted wild-type and CCK-KO mice maintained on an HFD. A: Plasma glucose. B: Means of glucose AUC. C: Plasma insulin over 120 min. Arginine stimulation test (4.8 mmol/kg body wt i.p.) in 5-h–fasted mice maintained on an HFD. D: Plasma glucose. E: Plasma insulin. F: Insulin AUC over 60 min. Data are expressed as means ± SEM. *Significant differences relative to the wild-type groups at the same time point (P < 0.05).

FIG. 4.

Euglycemic-hyperinsulinemic clamps in mice fed an HFD. A: Blood glucose levels. B: GIR. C: Means of GIR at 90–120 min during the euglycemic clamp. D: Rg into selected tissues. Data are expressed as means ± SEM for six animals per group. *Significant differences relative to the wild-type mice (P < 0.05).

FIG. 5.

Pancreatic morphology in fasted mice on an HFD. A: Anti-insulin islet area. B: Pancreatic islet mass stained with anti-insulin. Data are expressed as means ± SEM for four animals per group. (A high-quality digital representation of this figure is available in the online issue.)