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

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.Obesity and type 2 diabetes are epidemic in both developing and developed countries, and consumption of high-fat diets (HFDs) is thought to be a contributing factor. In particular, consumption of an HFD promotes excess energy intake and contributes to the development of obesity and insulin resistance (1) and to abnormalities of fat metabolism (2). An HFD also stimulates the release of gastrointestinal hormones including cholecystokinin (CCK), glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) (3–5), all of which are secreted from the intestine as ingested food is being processed for absorption. Each of these gut hormones enhances insulin secretion and facilitates glucose tolerance (6).CCK is secreted by intestinal I cells in response to consumption of lipid and is involved in modulating intestinal motility, stimulating pancreatic enzyme secretion, enhancing gall bladder contraction, and regulating meal size (2,7,8). Pure preparations of natural porcine CCK, the synthetic octapeptide of CCK (CCK-8), or synthetic caerulein, which contains a COOH-terminal pentapeptide identical to CCK, have all been found to stimulate insulin secretion in vivo and in vitro (9,10). CCK-8 and CCK-33 are potent stimuli for insulin release, an effect mediated by the CCK1-receptor (CCK1R) both in vitro and in animal models (11–13). Although the role of CCK action on insulin secretion is controversial in healthy humans (14,15), there is evidence that CCK decreases postprandial glucose levels and potentiates increased insulin levels in humans with type 2 diabetes (15,16). CCK also potentiates arginine- and amino acid–induced insulin in normal human subjects (17). To clarify the role of CCK in insulin and glucose homeostasis, we used mice with a targeted global deletion of the CCK gene (CCK knockout [CCK-KO]) mice and their wild-type controls.