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Departments of Internal Medicine and Physiology University of Manitoba Winnipeg, Manitoba, Canada R3E 3P4
Address all correspondence and requests for reprints to: Liam J. Murphy, Departments of Internal Medicine and Physiology, Room 843 John Buhler Research Centre, University of Manitoba, 715 McDermot Avenue, Winnipeg, Manitoba, Canada R3E 3P4. E-mail: ljmurph{at}cc.umanitoba.ca.
Despite more than half a century of modern diabetes research, much of which has been devoted to understanding type 2 diabetes mellitus (DM2), obtaining good glycemic control in individuals with this condition remains a challenge. In part this is due to our incomplete understanding of the pathogenesis and natural history of DM2. The debate about the importance of insulin resistance vs. pancreatic failure in the pathogenesis of DM2 that has raged back and forth over the last three decades has now largely been settled. Clearly both are important. In an era of recombinant insulin, it ought to be possible to provide sufficient insulin or, insulin analog, to meet the demands of even the most insulin-resistant individual. However, in clinical practice this is not the case, and disappointingly, insulin treatment of individuals with DM2 does not fully correct glycemic control in many, if not the majority, of these individuals. Once established, the disturbances in glucose homeostasis that represent the continuum from impaired fasting glucose, impaired glucose tolerance, and frank diabetes is difficult to reverse. In addition to innate insulin resistance, which is genetically determined in some individuals and racial groups, hyperglycemia itself (glucotoxicity), and probably other disturbances, such as elevated free fatty acids (lipotoxicity), can enhance insulin resistance and thus perpetuate the disturbances in glucose and fuel homeostasis in individuals with DM2.
Given the increasing number of individuals with DM2 worldwide, the reluctance to accept insulin treatment for this condition and its failure to normalize glucose homeostasis, there has been intense interest in developing newer agents to enhance insulin sensitivity and preserve ß-cell function. IGF-I and -II, which are structurally and functionally related to insulin, initially were hotly pursued in this regard and indeed showed considerable promise in vitro and in vivo in both respects. However, worrying toxicology data, largely related to increased tumor incidence in rodent studies, dampened this initial enthusiasm. Although these concerns remain, they may have been overstated and certainly have not limited the licensing of IGF-I for the treatment of other conditions. Furthermore, it is not clear whether this increased tumorigenesis reflects increase growth, anabolism, and hypernutrition, which may also be seen with high-dose insulin treatment in rodents (1).
In addition to their positive effects on ß-cell growth, survival, and insulin secretion (2, 3), the IGFs have insulin-like effects in adipose tissue and skeletal muscle resulting in increased glucose transport, increased lipogenesis and glycogenesis and decreased lipolysis (4). In whole animal experiments, IGF-I decreases blood glucose and free fatty acids similarly to insulin (4).
IGF-I levels are reduced in insulin-resistant states such as the metabolic syndrome with or without DM2 (5) and studies with recombinant IGF-I in human subjects with DM2 and with syndromes of severe insulin resistance have demonstrated that IGF-I can enhance insulin sensitivity, reduce insulin requirements, and improve glycemic control (6, 7, 8). These effects are not due simply to the interaction of IGF-I with the insulin receptor but rather involve more complex mechanisms. For example, when IGF-I is administrated to human subjects to achieve comparable glucose disappearance rates to insulin, IGF-I preferentially enhances peripheral glucose uptake and augments the decrease in whole body protein breakdown compared with insulin but has a less marked effect on suppression of hepatic glucose output (9). This may reflect the known differences in tissue distribution of insulin and IGF-I receptors but also may reflect differences in postreceptor signaling pathways.
Like the respective ligands, the IGF-I and the insulin receptor are structurally similar and their signal transduction pathways overlap. IGF-I receptors are abundant in skeletal muscle, whereas adipose and hepatic tissues have fewer IGF-I receptors and are therefore less responsive to IGF-I than muscle. In addition, there is also a variable abundance of hybrid insulin/IGF-I receptors in different tissues. These hybrid receptors are particularly abundant in skeletal muscle (10, 11, 12). Despite being functionally similar to insulin receptors and coupled to signal transduction pathways involved in metabolic processes rather than mitogenic processes, these receptors preferentially bind IGF-I compared with insulin (13). These hybrid receptors are more abundant when insulin receptors are down-regulated in response to the hyperinsulinemia as seen in insulin-resistant patients with DM2 and patients with insulinomas (11, 12). These observations using muscle biopsies from human subjects support the hypothesis that increased hybrid receptor abundance may be contribute to muscle insulin resistance in DM2. In this issue of Endocrinology, Pennisi et al. (14) have explored further the effects of IGF-I on insulin sensitivity and glucose metabolism using the MKR mouse. These MKR mice demonstrate inhibition of both IGF-I and insulin-stimulated glucose uptake in muscle as a result of the formation of hybrid receptors derived from dimerization of the defective IGF-I receptor and endogenous IGF-I receptors and insulin receptors (15). Severe insulin resistance, hyperinsulinemia, hepatic insulin resistance, and frank diabetes develop with age in these mice. The progression of the disturbances in glucose homeostasis that occurs in MKR mice is similar to that seen in DM2 in human subjects. In contrast, MIRKO mice, in which there is a muscle-specific deletion of the insulin receptor (16), and a transgenic mouse that overexpressed a dominant-negative insulin receptor specifically in muscle (17), exhibit only mild insulin resistance and do not develop diabetes. These observations underline the importance of functional muscle IGF-I receptors in glucose homeostasis and add support to the notion that IGF-I may be useful therapeutically in the treatment of DM-2.
Pennisi et al. (14) now have examined the effects of recombinant IGF-I treatment on glucose homeostasis in the MKR mouse model of DM2. They report that 3 wk of treatment of MKR mice with IGF-I at a dose that had no significant effects on serum glucose, whole body insulin sensitivity or endogenous glucose production in wild-type mice, significantly reduced serum glucose without affecting insulin levels in MKR mice. Not unexpectedly, MKR mice treated with IGF-I showed no improvement in whole body insulin sensitivity measured in the hyperinsulinemic-euglycemic clamp. Whole body insulin sensitivity measured in this fashion largely reflects muscle glucose uptake, which is severely attenuated in the MKR mice because of the abundance of nonfunctional hybrid receptors due to overexpression of the dominant-negative IGF-I receptor. Rather surprisingly, the effect of recombinant IGF-I treatment was on gluconeogenesis, measured as a reduction in basal endogenous glucose production, a finding that was confirmed by improvement in pyruvate and glutamine tolerance tests after 3 wk of treatment with recombinant IGF-I. Although the basal glucose production rate was significantly reduced in IGF-I-treated MKR mice compared with saline-treated mice, it was not particularly suppressed by insulin during the glucose clamp compared with wild-type mice, indicating that gluconeogenesis in the MKR mice was not very insulin sensitive. The major sources of glucose production are the liver, kidney, and small intestine. The liver, an organ with relatively few IGF-I receptors and not considered to be particularly IGF-I sensitive, contributes the major share, although probably not as much as previously thought. Previous studies in DM2 subjects treated with recombinant IGF-I had demonstrated decreased fasting glucose levels and suppression of basal endogenous glucose production in the euglycemic clamp, but the investigators emphasized enhanced whole body insulin sensitivity as the major mechanism of IGF-I improvement in glycemia (18). Importantly, Pennisi et al. (14) demonstrate significant effects of IGF-I treatment on gluconeogenesis. Furthermore, the lack of changes in trigycerides and free fatty acids suggests that this effect on gluconeogenesis was not due to reversal of lipotoxicity. Reversal of glucotoxicity also seems unlikely because, when MKR mice were treated with phloridzin, an agent that lowers serum glucose by inhibiting intestinal glucose uptake and renal glucose reabsorption, no significant effect on endogenous glucose output was observed (19). Thus, the effects of IGF-I treatment on basal gluconeogenesis in this mouse model are likely to be direct effects of IGF-I on gluconeogenic tissues, although the exact mechanism remains unclear.
Fasting hyperglycemia as a result of enhanced overnight gluconeogenesis is a common problem in DM2 that is often unresponsive to bedtime insulin, even with the availability of longer acting insulin analogs. The report by Pennisi et al. (14) suggests that recombinant IGF-I may have some therapeutic potential in this regard. In addition to this effect of IGF-I treatment on gluconeogenesis eloquently demonstrated in the MKR mouse model, in DM2 subjects where muscle insulin resistance is not necessarily as severe, additional benefits of IGF-I treatment in enhancing insulin sensitivity and possibly enhancing pancreatic ß-cell survival and mass may be realized.
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Received March 15, 2006.
Accepted for publication March 24, 2006.
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