While the incretin response (IR) after whole-pancreas transplantation (systemic drainage) is normalized (1), little is known of the incretin effect after allogeneic intraportal islet transplantation. The incretin effect (regulated by neurogenic mechanisms or gastrointestinal hormones) is responsible for 60% of prandial insulin secretion, thus playing a vital role in preventing post-prandial hyperglycemia (2). Disruption of islet innervation by the islet transplantation process may reduce the IR; however, islet exposure to suprasystemic levels of glucagon-like peptide-1 (GLP1) (3) within portal triads could augment IR. The GLP1 analog exenatide has been used with variable success peritransplantation to minimize islet infusion requirements and as salvage therapy in failing intraportal transplants (4–8). This study therefore aimed to evaluate IR to endogenous GLP1 during an oral glucose tolerance test (OGTT) in insulin-independent islet recipients.
The authors report the first evidence that the IR in islet recipients, while reduced by 40% in comparison with non-diabetic controls, is equivalent to that seen in type 2 diabetes mellitus (T2DM). These results therefore provide a rational basis for GLP1 analog therapy early, rather than late post–islet transplantation.
Three insulin-independent islet recipients, three T2DM subjects on metformin±sulfonylureas (withheld 1week before studies), and 10 non-diabetic controls underwent a 4-hour 75-g OGTT with frequent sampling of plasma glucose and insulin (0, 30, 60, 90, 120, 150, 180, and 240 min) and glucometer assessment of whole-blood glucose (every 10 min). Four to six weeks later, participants underwent an isoglycemic intravenous glucose tolerance test (IVGTT) where 20% dextrose was infused at a variable rate to match 10-minute-interval bedside glucose concentrations during the previous OGTT, with plasma glucose and insulin sampled at 0, 30, 60, 90, 120, 150, 180, and 240 minutes. The IR was calculated using the formula: 100%×(AUCinsOGTT−AUCinsIVGTT)/(AUCinsOGTT) (9).
All three islet recipients successfully underwent islet transplantation for type 1 diabetes mellitus (T1DM) with intractable hypoglycemia, receiving a mean of 11,586 islet equivalents per kilogram. They were studied in their first year of insulin independence while on maintenance immune suppression (mycophenolate and tacrolimus 4–5 mg twice daily). None of the recipients were on GLP1 analogs, DPP-IV inhibitors, acarbose, metformin, or other anti-diabetic drugs.
Upon formal testing with OGTT, islet recipients, although insulin independent with HbA1c equal to or less than 6.0% under free-living conditions, were frankly diabetic. The mean IR in islet recipients is significantly lower than controls (48.7% vs. 80.1%, P<0.05) but similar to T2DM subjects (47.4%) (Table 1).
The observation of diminished IR post–islet transplantation is most likely explained by loss of neural inputs secondary to extrinsic±intrinsic denervation of isolated islets during the transplantation process. Extrinsic vagal innervation contributes significantly to cephalic phase (pre-absorptive insulin secretion activated upon contact between glucose and oral cavity) and IR magnitude (2). The intrapancreatic neural network modulates pulsatile insulin secretion, which is essential for normal phasic insulin secretion (10). We postulate that in whole-pancreas recipients who also experience extrinsic denervation, the larger engrafted β-cell mass compensates for loss of neural inputs; however, in islet recipients with a smaller β-cell mass, denervation results in impaired IR.
Alternatively, perhaps islet recipients have either lower GLP1 levels or β-cell “resistance” to GLP1, the main gastrointestinal hormone responsible for IR. Although serum GLP1 was not measured, circulating levels are unlikely to be diminished in islet recipients. IR in T2DM, for example, is impaired despite normal GLP1 concentrations (9). However, the dose-response relationship between GLP1 and its potentiation of glucose-stimulated insulin secretion may be impaired in islet recipients, as has previously been demonstrated in impaired glucose tolerance and T2DM (11, 12). Others have demonstrated reduced insulin secretion in response to exogenous GLP1 in islet recipients (8, 13) and attributed this to “GLP1 resistance” or reduced β-cell mass.
Lastly, IR could be reduced secondary to a smaller engrafted β-cell mass. Rickels et al. have demonstrated that exogenous GLP1’s ability to enhance insulin secretion correlates with β-cell secretory capacity and engrafted β-cell mass (8). It is therefore not unexpected that islet recipients with only 25% normal secretory capacity (8) would have a diminished IR compared with controls and whole-pancreas-transplant recipients (8).
The findings of a diminished IR do not seem to indicate that portal vein GLP1 directly stimulates transplanted islets. Portal vein GLP1 concentrations are 2.5 times higher than peripheral levels (3), thus direct islet exposure would result in normal or supranormal IR. The data, on the other hand, are consistent with hepatic artery revascularization of transplanted islets (14). Animal experiments demonstrating intraportal β-cells secrete insulin and glucagon only with administration of secretagogues via the hepatic artery but not the portal vein, give further credence to this hypothesis (15). Indeed, IR evaluation utilizing conventional means in islet recipients is predicated upon hepatic artery revascularization: if indeed transplanted islets respond to portal vein glucose, IR measurement would necessitate portal vein catheterization during an OGTT.
It can also be inferred that the very presence of an IR in islet recipients indicates that islet denervation is compensated for by gastrointestinal hormones, hence the therapeutic utility of high-dose exenatide posttransplantation.
Importantly, previously published (16) and present expanded observations (Table 1) of reduced oral disposition index (21% normal) and IR (61% normal) but relatively preserved β-cell response to intravenous glucose (84% normal) appear to indicate a functional β-cell secretory abnormality in response to oral but not intravenous glucose in islet recipients. This phenomenon is probably secondary to loss of neurogenic mechanisms that contribute significantly to cephalic phase but do not modulate β-cell response to intravenous glucose.
In conclusion, it was found that IR is restored but diminished post–islet transplantation. Postulated causes include islet denervation, reduced β-cell mass, and GLP1 resistance. These findings may indicate a role for GLP1 analogs in ameliorating defective β-cell responses to oral stimuli early posttransplantation. Randomized controlled trials assessing long-term effects of GLP1 analogs on graft survival are, however, required as exenatide may exacerbate β-cell exhaustion (8).
Shireene R. Vethakkan
Jacqueline M. Walters2
Judith L. Gooley2
Raymond C. Boston3
Thomas W.H. Kay4
David J. Goodman5
Alicia J. Jenkins2
Glenn M. Ward6,7
1 Department of Medicine
University of Malaya
Kuala Lumpur, Malaysia
2 Department of Medicine
St. Vincent’s Hospital Melbourne
University of Melbourne
3 New Bolton Center
University of Pennsylvania
4 St. Vincent’s Institute
5 Department of Nephrology
St. Vincent’s Health
6 Department of Endocrinology & Diabetes
St. Vincent’s Health Melbourne
7 Department of Clinical Chemistry
St. Vincent’s Health Melbourne
The authors thank the patients for their participation. They would also like to acknowledge the invaluable roles played by Margaret Krishnapillai and Kathy Howe in facilitating and coordinating this research effort.
1. Nauck MA, Busing M, Orskov C, et al. Preserved incretin effect in type 1 diabetic patients with end-stage nephropathy treated by combined heterotopic pancreas and kidney transplantation. Acta Diabetol 1993; 30: 39.
2. Holst JJ, Gromada J. Role of the incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab 2004; 287: E199.
3. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev 2007; 87: 1409.
4. Ghofalili KA, Fung M, Ao Z, et al. Effect of exenatide on β-cell function after islet transplantation in type 1 diabetes. Transplantation 2007; 83: 24.
5. Gangemi A, Salehi P, Hatipoglu B, et al. Islet transplantation for brittle type 1 diabetes: the UIC protocol. Am J Transplant 2008; 8: 1250.
6. Froud F, Faradji RN, Pileggi A, et al. The use of exenatide in islet transplant recipients with chronic allograft dysfunction: safety, efficacy, and metabolic effects. Transplantation 2008; 86: 36.
7. Faradji RN, Tharavanij T, Messinger S, et al. Long-term insulin independence and improvement in insulin secretion after supplemental islet infusion under exenatide and etanercept. Transplantation 2008; 86: 1658.
8. Rickels MR, Mueller R, Markmann JF, et al. The effect of glucagon-like peptide-1 on β- and α-cell function in isolated islet and whole pancreas transplant recipients. J Clin Endocrinol Metab 2009; 94: 181.
9. Knop FK, Vilsboll T, Madsbad S, et al. Inappropriate suppression of glucagon during OGTT but not during isoglycaemic i.v. glucose infusion contributes to the reduced incretin effect in type 2 diabetes mellitus. Diabetologia 2007; 50: 797.
10. Meier JJ, Hong-McAtee I, Galasso R, et al. Intrahepatic transplanted islets in humans secrete insulin in a coordinate pulsatile manner directly into the liver. Diabetes 2006; 55: 2324.
11. Fritsche A, Stefan N, Hardt E, et al. Characterisation of beta-cell dysfunction of impaired glucose tolerance: evidence for impairment of incretin-induced insulin secretion. Diabetologia 2000; 43: 852.
12. Hojberg PV, Zander M, Vilsboll T, et al. Near normalisation of blood glucose improves the potentiating effect of GLP-1 on glucose-induced insulin secretion in patients with type 2 diabetes. Diabetologia 2008; 51: 632.
13. Fung M, Thompson D, Shapiro RJ, et al. Effect of glucagon-like peptide-1(7-37) on beta-cell function after islet transplantation in type 1 diabetes. Diabetes Res Clin Pract 2006; 74: 189.
14. Jansson L, Carlsson P-O. Graft vascular function after transplantation of pancreatic islets. Diabetologia 2002; 45: 749.
15. Lau J, Jansson L, Carlsson P-O. Islets transplanted intraportally into the liver are stimulated to insulin and glucagon release exclusively through the hepatic artery. Am J Transplant 2006; 6: 967.
16. Vethakkan SR, Jenkins AJ, Kay TWH, et al. Improved second phase insulin secretion and preserved insulin sensitivity after islet transplantation. Transplantation 2010; 89: 1291.