Increased Plasma Amylin in Type 1 Diabetic Patients After Kidney and Pancreas Transplantation

Abstract

OBJECTIVE -In response to hyperglycemia, ␤-cells release insulin and C-peptide, as well as islet amyloid pancreatic polypeptide, which is involved in glucose homeostasis. After successful pancreas-kidney transplantation (PKT), type 1 diabetic patients may revert to a nondiabetic metabolism without exogenous insulin therapy and re-secrete all ␤-cell hormones. RESEARCH DESIGN AND METHODS-Using mathematical models, we investigated hormone (amylin, insulin, C-peptide) and metabolite (glucose, free fatty acids) kinetics, ␤-cell sensitivity to glucose, and oral glucose insulin sensitivity index (OGIS) in 11 nondiabetic type 1 diabetic patients after PKT (BMI 25 Ϯ 1 kg/m 2 , 47 Ϯ 2 years of age, 4 women/7 men, glucocorticoid-free), 6 matching nondiabetic patients after kidney transplantation (25 Ϯ 1 kg/m 2 , 50 Ϯ 5 years, 3 women/3 men, on glucocorticoids), and 9 matching nondiabetic control subjects (24 Ϯ 1 kg/m 2 , 47 Ϯ 2 years, 4 women/5 men) during a 3-h 75-g oral glucose tolerance test (OGTT).RESULTS -PKT patients had higher fasting amylin (19 Ϯ 3 vs. control subjects: 7 Ϯ 1 pmol/l) and insulin (20 Ϯ 2 vs. control subjects: 10 Ϯ 1 U/ml; each P Ͻ 0.01) levels. Kidney transplant subjects showed increased OGTT plasma insulin at 90 min and C-peptide levels (each P Ͻ 0.05). In PKT patients, plasma glucose from 90 to 150 min was 9 -31% higher (P Ͻ 0.05 vs. control subjects). Amylin clearance was comparable in all groups. Amylin's plasma concentrations and area under the concentration curve were up to twofold higher in PKT patients during OGTT (P Ͻ 0.05). OGIS was not significantly different between groups. ␤-Cell sensitivity to glucose was reduced in PKT patients (Ϫ64%, P Ͻ 0.009). Fasting plasma amylin was inversely associated with ␤-cell sensitivity to glucose (r ϭ Ϫ0.543, P Ͻ 0.004).CONCLUSIONS -After successful PKT, type 1 diabetic patients with nondiabetic glycemia exhibit increased fasting and post-glucose load plasma amylin, which appears to be linked to impaired ␤-cell function. Thus, higher amylin release in proportion to insulin might also reflect impaired ␤-cell function in type 1 diabetic patients after PKT.

Beta cell (dys)function in non-diabetic offspring of diabetic patients

“…Total AUCs during the 2 h OGTT of glucose (glucose AUC), insulin (insulin AUC) and C-peptide (C-peptide AUC) were calculated with the trapezoidal rule. Dynamic AUC (ΔAUC) was calculated as total AUC−basal concentration ×120 min [14,15]. Beta cell function was evaluated as the C-peptide response to the glycaemic stimulus.…”

“…At variance with the classic insulinogenic index, we increased the precision of the measurement by using AUCs instead of a single data point [18]; in addition, we used C-peptide instead of insulin, being interested in the actual response at beta cell level. Hepatic insulin extraction was estimated as [1-(insulin AUC/C-peptide AUC)] as previously described [15].…”

TNF-α acutely upregulates amylin expression in murine pancreatic beta cells

“…Widespread amyloid depositions have been found in transplanted islets in type 1 diabetes patients and mouse models of type 1 diabetes [44,45]. Increased plasma amylin has been reported as a sign of impaired beta cell function in type 1 diabetic patients after kidney and pancreas transplantation [7]. The state of systemic inflammation and the inflammatory mediators have been proposed as causal roles in islet transplantation failure [46].…”

“…Amylin was discovered in 1987 as a major component of amyloid deposits in the pancreas of type 2 diabetes patients [4,5]. Elevated circulating levels of amylin have been detected in patients with severe acute pancreatitis [6], pancreas transplantation [7], obesity and insulin resistance [8][9][10]. Pancreatic amylin mRNA and plasma amylin levels are also elevated in genetically obese, insulin-resistant rats [11].…”

IAPP and type 1 diabetes: implications for immunity, metabolism and islet transplants

“…We previously pointed out the similarities underlying islet dysfunction in T2D and following transplantation, and have proposed that the beta cell dysfunction in islet grafts predisposes to amyloid deposition, as in T2D (Potter et al 2014). IAPP synthesis and secretion is disproportionately elevated (relative to insulin) in dysfunctional beta cells, including those following transplantation (Stadler et al 2006, Rickels et al 2008. We recently found elevated levels of the intermediate hproIAPP in islet transplant recipients (Courtade et al 2017a), suggesting that impaired proIAPP processing may be a characteristic of transplanted islets, as we and others have suggested may be the case for proinsulin (Davalli et al 2008, Fiorina et al 2008).…”