Evidence of a Role for Insulin-Like Growth Factor Binding Protein (IGFBP)-3 in Metabolic Regulation

Abstract

IGF-binding protein (IGFBP)-3 is a metabolic regulator that has been shown to inhibit insulin-stimulated glucose uptake in murine models. This finding contrasts with epidemiological evidence of decreased serum IGFBP-3 in patients with type 2 diabetes. The purpose of this study was to clarify the role of IGFBP-3 in metabolism. Four-week-old male IGFBP-3(-/-) and control mice were subjected to a high-fat diet (HFD) for 12 wk. IGFBP-3(-/-) mice were heavier before the initiation of HFD and at the end of the study period. Resting metabolic rate was significantly decreased in knockout mice; however, respiratory exchange ratio was not significantly different. Fasting blood glucose and insulin levels were significantly elevated in IGFBP-3(-/-) mice. However, IGFBP-3(-/-) mice had relatively normal glucose tolerance because the relative glucose excursion over time was not different between the groups. During hyperinsulinemic clamps, IGFBP-3(-/-) mice had increased basal hepatic glucose production, but after insulin stimulation, no differences in hepatic glucose production were observed. A second cohort of older IGFBP-3(-/-) mice on HFD displayed unexpected evidence of hepatic steatosis. In summary, glucose tolerance and clamp testing indicate that IGFBP-3(-/-) mice preserve insulin sensitivity despite evidence of increased basal glucose turnover and hepatic steatosis. We provide evidence that genetic deletion of IGFBP-3 modulates hepatic carbohydrate and lipid metabolism.

Glucose Intolerance in Aging Male IGFBP-3 Transgenic Mice: Differential Effects of Human IGFBP-3 and Its Mutant IGFBP-3 Devoid of IGF Binding Ability

“…In contrast, hIGFBP-3 enhanced adipocyte differentiation and stimulated the lipogenic enzyme glycerol-3-phosphate dehydrogenase in visceral and sc preadipocytes (44). This observation is in line with the increase in serum glycerol in the Tg mice and with a recent report that IGFBP-3-null mice had reduced adipose tissue mass and circulating triglycerides (10). It has also been suggested that ternary complex formation between IGF-1, IGFBP-3, and ALS is important for adipogenesis.…”

“…However, mice overexpressing hIGFBP-3 [phosphoglycerate kinase (PG-K)BP3] or its Gly56/Gly80/Gly81-mutant (PGKmutBP3) under the PGK promoter are not insulin-resistant (8,9), but they are glucose intolerant and have impaired ␤-cell function (9). Also, a recent report indicates that IGFBP-3-null mice have fasting hyperglycemia with normal insulin sensitivity (10). IGFBP-3 levels increase in mice to peak around age 4 weeks and then decline (11).…”

Role of insulin-like growth factor binding protein-3 in glucose and lipid metabolism

“…Moreover, each experiment was done in different conditions, such as diet (fasting, fed with normal chow, or fed high-fat diet), and age at the time of experiment. Nevertheless, it is of note that IGFBP-3 KO mice with a high-fat diet had heavier weight compared with WT and showed fasting hyperglycemia and hyperinsulinemia, indicating insulin resistance, even not in glucose tolerance test18).…”

“…In contrast, IGFBP-3 KO mice exhibited normal insulin level and glucose response after glucose challenge. More recent study in IGFBP-3 KO mice with a high-fat diet demonstrated that IGFBP-3 KO mice exhibited heavier weight, decreased resting metabolic rate, and elevated fasting glucose and insulin levels18). However, IGFBP-3 KO mice had relatively normal glucose response after glucose challenge, and increased basal hepatic glucose production, but after insulin stimulation during hyperinsulinemic clamps, indicating that IGFBP-3 KO mice preserve insulin sensitivity despite evidence of increased basal glucose turnover.…”

Posttranslational modifications of the insulin-like growth factor-binding protein 3 in patients with type 2 diabetes mellitus assessed by affinity chromatography

“…Yamada et al [22] have reported decreased serum IGFBP-3 in patients with type 2 diabetes and studies on patients with type 1 diabetes also found the concentration of IGFBP-3 to be lower [23,24]. According to Cortizo et al, levels of IGF-I and IGFBP-3 were comparable in the type 2 diabetic patients and controls for the population ranging from 35 to 70 years [9].…”