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Gut-Derived Incretin Hormones and New Therapeutic Approaches

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Gut-Derived Incretin Hormones and New Therapeutic Approaches Reviews/Commentaries/ADA Statements PERSPECTIVES ON THE NEWS Gut-Derived Incretin Hormones and New Therapeutic Approaches ZACHARY T. BLOOMGARDEN, MD showing in somatostatin-, insulin-, and glucagon-infused dogs (thus not allowing GLP-1 to change insulin or glucagon lev- els) that peripherally administering the his is the first of a series of articles on from nil to 100%. Conversely, when glu- peptide increased hepatic glucose uptake presentations at the American Dia- cose was infused peripherally versus in 60%, while administration either via the Ϫ Ϫ T betes Association Annual Meeting, the portal vein at 2.5 mg ⅐ kg 1 ⅐ min 1, portal vein or hepatic artery let to a 150% Orlando, Florida, 4–8 June 2004, ad- arterial glucose levels were identical but increase in hepatic glucose uptake, sug- dressing an important theme of the meet- there was a rapid drop from hepatic glu- gesting the effect to be in the liver rather ing: new therapeutic approaches based on cose output to uptake with portal deliv- than specifically requiring GLP-1 levels to gut-derived incretin hormones. ery, whereas a much slower fall was seen increase in the portal venous system. Io- in hepatic glucose output occurring with nut et al. (abstract 1412) similarly showed peripheral delivery, with consequent lack a glucose-lowering effect of portal vein Physiology of glucagon-like peptide of increased peripheral glucose uptake GLP-1 infusion. 1 action following intraportal administration. Pe- Cherrington concluded that the por- Alan Cherrington (Nashville, TN) de- ripheral glucose administration led to tal vein and liver may contain nutrient- scribed a series of studies of peripheral most glucose uptake being peripheral. and hormone-sensing mechanisms that help coordinate the disposition of in- and hepatic arterial and portal vein flow Thus, whole-body glucose clearance did gested nutrients. Portal vein glucose de- measurement and sampling that allowed not change with the method of glucose livery generates a signal that augments the for the assessment of hepatic glucose bal- administration, but the portal signal ap- role of the liver and limits muscle glucose ance and effects of glucagon-like peptide peared to instruct the liver to take up disposition, with portal vein GLP-1 infu- (GLP)-1. In a study comparing peripheral more, and muscle to take up less, glucose. sion studies suggesting an important di- with portal venous glucose delivery dur- This is not due to lower peripheral insulin ing hyperglycemia (glucose increased rect hepatic effect of the hormone, which levels, as these tended to be somewhat mediates at least part of this process. In from 75 to 150 mg/dl), with somatostatin higher after portal glucose administra- to suppress endogenous insulin and glu- response to questions, he suggested that tion, suggesting alternative mechanisms, cagon and administration of glucagon to the molecular mechanism of glucose potentially including the incretin effect replace basal levels and insulin to levels sensing may involve glucokinase and and neurally mediated metabolic signals. approximately four times greater than GLUT2, noted that the effect of hepatic Addressing the incretin effect, GLP-1 basal, there was a similar increase in the ϳ denervation includes decreased response hepatic glucose load, from ϳ25 to 50 mg levels increased from basal levels of 15 to portal and increased response to pe- Ϫ Ϫ ⅐ kg 1 ⅐ min 1, but portal glucose delivery pmol/l to arterial levels of 30 pmol/l and ripheral glucose delivery, and suggested doubled hepatic glucose uptake. Net he- to 60 pmol/l in the portal vein, leading that GLP-1 produces similar augmenta- Cherrington to note that levels above tion of hepatic response with and without patic glucose uptake remained consider- ϳ ably greater with intraportal glucose 100 pmol/l should be considered non- somatostatin, suggesting that this experi- physiological. In a study administering delivery when the hepatic glucose load Ϫ Ϫ mental method did not artifactually alter Ϫ ⅐ 1 ⅐ 1 was varied from 50 to 75 to 100 mg ⅐ kg 1 glucose at a rate of 4 mg kg min via the results of his studies. Ϫ ⅐ min 1. Thus, Cherrington suggested, the portal vein, as well as peripheral glu- In a fascinating study related to this hepatic glucose entry depends on insulin cose to increase plasma glucose levels to topic presented at the meeting, Li and and glucose levels and a “portal signal.” 160 mg/dl, intraportal GLP-1 increased Drucker (abstract 1) studied mice not ex- ϳ Portal glucose delivery, then, can be said arterial and portal GLP-1 to 40 and 85 pressing the GLP-1 receptor, showing to “activate the liver,” which may be in pmol/l and tripled hepatic glucose up- that superimposing transgenic expression part the mechanism of increased hepatic take, in part because of greater increase in of the receptor restricted to pancreatic ␤- glucose uptake following oral glucose de- insulin and suppression of glucagon, but and ductal cells via the PDX-1 gene al- livery. When measuring hepatic sinusoi- peripheral GLP-1 in a similar study had a lowed restoration of normal fasting glu- dal insulin, as levels increase, the net lesser effect in increasing hepatic glucose cose and response to intraperitoneal hepatic glucose uptake increases but uptake, suggesting this to be an important glucose with and without administration there is further uptake with activation of direct influence “without the mediation of of exendin-4, a natural peptide with the portal glucose signal. In further stud- a change in [insulin and glucagon] secre- Ͼ50% sequence homology to GLP-1, but ies varying peripheral and portal vein glu- tion.” In a presentation at the American with greater potency and longer duration cose delivery and maintaining Diabetes Association Annual Meeting on of action, produced in the saliva of the hyperinsulinemia, a fivefold increase in this topic by Cherrington’s group, Dard- Gila monster. This study suggests that al- hepatic glucose uptake was demon- evet et al. (abstract 1410) assessed the po- though the stomach, nervous system, and strated, as portal glucose delivery ranged tential direct effects of GLP-1 on the liver, liver also express the GLP-1 receptor, ac- 2554 DIABETES CARE, VOLUME 27, NUMBER 10, OCTOBER 2004 Bloomgarden tion at these sites may not be required for duction in body weight, and decelerating mediated insulin secretion, improves the peptide’s systemic glycemic effect. gastric emptying. Although Nauck stated insulin sensitivity, and slows gastric emp- that there is no evidence of effect on insu- tying, either via a central nervous system Potential effects of GLP-1 in type 2 lin sensitivity, the studies discussed by (CNS) effect or by activation of vagal af- diabetes Cherrington suggest the possibility that ferent fibers. An important question, she Michael A. Nauck (bad Laukenberg em the peptide changes hepatic versus pe- noted, is whether albumin-bound GLP-1 Nacht, Germany) discussed GLP-1 and ripheral partitioning of glucose metabo- will be able to access CNS sites. GLP-1 glucose-dependent insulinotropic pep- lism. Initial studies of persons with type 2 also increases ␤-cell mass via stimulation tide (GIP) in type 2 diabetes. GLP-1 is diabetes showed that subcutaneous of neogenesis and inhibition of apoptosis, produced by L-cells in the distal small GLP-1 injection stimulated insulin and again leading to the question of whether bowel, while GIP comes from K-cells in inhibited glucagon secretion, decreased larger albumin-bound complexes will be proximal small intestine. Classically, the gastric emptying, and, with repeated in- able to access ␤-cells to produce trophic incretin effect has been demonstrated by jections, normalized plasma glucose (6). effects. comparing effects of intravenous versus Nauck described a study of 34 persons GLP-1 action controls fasting and oral glucose administered to produce with type 2 diabetes who received a postprandial insulin release in a glucose- similar plasma glucose curves and hence 6-week intravenous infusion of GLP-1 or dependent manner. GLP-1 is rapidly in- “glycemic stimulus.” Under such condi- saline and had baseline HbA1c of 9.4%. activated by dipeptidyl peptidase (DPP)- tions, oral glucose produces a threefold Glucagon levels were suppressed, insulin IV, limiting its therapeutic potential, higher insulin and C-peptide response. In and C-peptide levels were increased, fast- although as discussed above therapeutic persons with type 2 diabetes, however, ing and mean glucose levels were de- effects can be shown when the peptide is the incretin effect is attenuated or even creased by 77 and 99 mg/dl, respectively, administered by continuous infusion. completely lost. One explanation would HbA1c was reduced by 1.3%, and there The development of long-acting safe and be that the relative secretion of hormones was a weight loss of 4 lb (7). Below a efficacious GLP-1 receptor agonists, such mediating the incretin effect is decreased. blood glucose of 120 mg/dl, the insulin as exenatide, allows consideration of Indeed, comparing persons with and secretory and glucagon suppressive ef- practical therapeutic trials. In phase 3 without type 2 diabetes, differences in fects lessened, with levels of both hor- studies completed by Amylin and Lilly, GLP-1 appear ϳ1 h after oral glucose (1), mones returning to the basal range. In a two injections daily are required for ef- while GIP may either be hypo- or hyper- study from Nauck’s group, Fehse et al. fect, with a 1-year open-label study show- secreted (2) and therefore was not felt to (abstract 351) compared 13 persons with ing a 1.2% decrease in HbA1c,an8-lb explain the lack of incretin effect in type 2 type 2 diabetes, using insulin infusion to weight loss, mild to moderate nausea, and diabetes. Studies comparing the effects of attain euglycemia with and without a 5-h hypoglycemia in patients also receiving GIP and GLP-1 in diabetic and nondia- exenatide infusion, and 12 healthy con- sulfonylureas.
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