Therapeutic Aspects Of Gip And

A. Type 2 Diabetes Mellitus

The potent insulinotropic actions of GIP and GLP 1 and their strict glucose dependency, thereby avoiding hypoglycemia, make these hormones potentially important agents in the treatment of type 2 diabetes. GLP 1's other antihyperglycemic actions (inhibition of glucagon secretion, gastric emptying, food intake, etc.) additionally make it particularly suited to an antidiabetic role. However, there are two major difficulties associated with using these hormones as therapeutic agents, 1) their extremely rapid degradation in circulation (particularly GLP 1), and 2) the diminished responsiveness of diabetic individuals to the insulinotropic action of GIP. This latter difficulty has resulted in most work on the therapeutic potential of the incretins in type 2 diabetes, focusing on the possible use of GLP 1 or its analogues.

Continuous IV infusion of GLP 1 can effectively normalize glucose concentrations in type 2 diabetes [61], but simple subcutaneous injections are ineffective, as > 90 percent of the peptide is rapidly degraded under these circumstances [62]. However, recent studies using minipumps to deliver subcutaneous GLP 1 continuously have demonstrated a clinically significant improvement in plasma glucose and HbA1C, together with modest weight loss, over a six-week period [63] (Figure 2.3). This mode of delivery is not, however, ideal for everyday treatment.

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FIGURE 2.3 Plasma glucose profiles and weight losses in type 2 diabetics before and following a six-week course of GLP 1 infusions. From Zander, M, et al., Effect of a 6-week course of glucagon-like peptide-1 on glycemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study, Lancet, 359, 824, 2002.

The observation that GLP 1 secretion is diminished in diabetics has prompted the investigation of dietary strategies to increase endogenous GLP 1 secretion. Increasing large-bowel fermentation by means of lactulose (as a model of resistant starch carbohydrate) or with viscous fiber (psyllium) is ineffective in raising GLP 1 levels [64, 65], as is the manipulation of the mono-unsaturated acid/polyunsatu-rated fatty acid (MUFA/PUFA) content of the diet [66]. However, the alpha-glycosi-dase inhibitor acarbose, used in the treatment of both type 1 and type 2 diabetes, which delays the upper-intestinal absorption of sucrose, diminishes GIP, but markedly potentiates GLP 1 secretion [67] (Figure 2.4). The therapeutic efficacy of acarbose in diabetes could be partly due to this ability to augment GLP 1 secretion.

More recent strategies to enhance the action of GLP 1 in diabetes have centered around extending its biologically active half-life in the plasma by circumventing the inactivation of GLP 1 (and GIP) by DPP-IV. This has been tackled by a two-pronged approach: 1) the use of DPP-IV inhibitors, and 2) the development of degradation-resistant GLP 1 and GIP analogues. Treatment with DPP-IV inhibitors promote marked improvements in glycemic control in both animal models of diabetes and in human diabetic studies [68]. A major advantage to this approach lies in the ability to administer DPP-IV inhibitors orally; however, there is also an intrinsic disadvantage due to a lack of specificity of the DPP-IV enzyme. DPP-IV exerts physiological actions on a wide range of regulatory peptides in addition to GLP 1 and GIP. Its pharmacological inactivation may therefore have other clinical consequences beyond

Time following sucrose administration (minutes)

FIGURE 2.4 Plasma GIP and GLP 1 in healthy subjects following a 100 g oral sucrose load, with (o) or without (■) the addition of the alpha-glycosidase inhibitor acarbose. (From Ranganath, LR, et al., Diabetic Med., 15, 120, 1998. With permission.)

Time following sucrose administration (minutes)

FIGURE 2.4 Plasma GIP and GLP 1 in healthy subjects following a 100 g oral sucrose load, with (o) or without (■) the addition of the alpha-glycosidase inhibitor acarbose. (From Ranganath, LR, et al., Diabetic Med., 15, 120, 1998. With permission.)

its antidiabetic action, and these will need to be carefully evaluated before the clinical efficacy of DPP-IV inhibitors can be confirmed.

The other approach, namely the development of specific DPP-IV-resistant GLP 1 analogues modified at the N-terminus around the enzyme cleavage site, has proved to be more promising. A number of analogues are effective in improving glucose tolerance and insulin secretion in animal models of diabetes [69]. Studies are currently in progress to extend the half-lives of these analogues still further by the attachment of acyl side-chains to selected residues; these bind to albumin and thus delay renal clearance of the analogues. More convenient forms of delivery of the peptides are also being explored, such as nasal sprays and transdermal patches, to avoid the need for frequent injections or continuous infusion of the analogues.

A final approach has been the utilization of DPP-IV-resistant receptor agonists. One such, exendin-IV, a naturally occurring agonist found in the saliva of the Gila monster lizard, is an effective antidiabetic agent in a wide range of animal studies, and is currently undergoing clinical trials in type 2 diabetes [70].

While most interest in the therapeutic potential of incretins in diabetes has centered around DPP-IV-resistant GLP 1, some studies have been carried out on DPP-IV-resistant GIP analogues. GIP analogues have some potential advantages over GLP 1 in that enhanced activity is generally easier to achieve with GIP than with GLP 1 analogues, and the lack of any significant effects of GIP on gastric emptying can be advantageous when treating diabetics with neurological complications. A number of N-terminally modified GIP analogues have been developed and characterized that have a greater potency than GIP in stimulating insulin secretion and improving glucose tolerance in diabetic animal models [9], but their therapeutic potential in human type 2 diabetes, which is characterized by GIP insensitivity, remains to be proven.

B. Obesity

The evidence that GIP might have a role in the etiology of obesity has supported the concept of using GIP-receptor antagonists to treat obesity. Receptor antagonists based on fragments of the full-length hormone have been developed [7, 9], together with antisera that bind either to GIP itself or to the GIP receptor. These are all very effective in blocking the insulinotropic action of GIP, but the effects of chronic administration on body weight have yet to be reported [71]. The concept of GIP antagonists as antiobesity agents is an attractive one, but the antagonistic effects of such compounds on the other actions of GIP also need to be considered. Thus, chronic treatment with a GIP-receptor antagonist might worsen glucose tolerance, and interfere with postprandial triglyceride disposal, leading to increased circulating triglyceride levels and hence increased cardiovascular-disease risk. The beneficial effects of fat loss may outweigh such deleterious effects, but a note of caution should be sounded regarding the potential loss of GIP's other beneficial actions. It remains to be seen whether GIP antagonists with spectra of biological activities that specifically target adipose tissue can be developed, thus maximizing antiobesity activity while minimizing unwanted side effects.

The effect of GLP 1 in increasing satiety, hence diminishing food intake, has hitherto received very little attention in terms of its potential use as an antiobesity agent. The vast, built-in redundancy of hypothalamic satiety mechanisms, together with the observation that GLP 1-receptor knock-out mice do not become obese, indicates that GLP 1 might not be indispensable for normal appetite regulation. However, the finding that chronic GLP 1 administration in type 2 diabetes not only improves glucose tolerance but also has modest but significant beneficial effects in terms of weight loss [63] (Figure 2.3) is clearly of great interest, as the majority of type 2 diabetic individuals are overweight. Improvement of insulin sensitivity resulting from weight loss would confer an additional therapeutic advantage in these patients.

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