*3.1.4. C-peptide/glucose ratio and C-peptide/glucose\*creatinine ratio*

C-peptide per glucose ratio (CP/G) is also a simple technique to predict islet graft function using blood glucose and C-peptide, similar to the SUITO index [120]. To correct islet graft function in patients with renal dysfunction, C-peptide/glucose\*creatinine ratio has also been proposed. University of Miami group showed that CP/G correlated with 90min glucose level and β score [120].

### *3.1.5. β score*

**3. Clinical assessment of beta cell function**

islet graft function are discussed (Table 5).

**3.1. Blood tests and clinical indices**

180 Type 1 Diabetes

*3.1.1. Glucose tolerance/stimulation test*

University of Pennsylvania group [114].

*3.1.2. HYPO score and LI*

*3.1.3. SUITO index*

Monitoring graft function is a major concern in clinical management of islet recipients since islet graft dysfunction in both acute phase after transplant and chronic phase is an obstacle to its widespread use as a standard care for type 1 diabetes. Furthermore, isolated islets are transplanted via the portal vein into the liver, making it difficult to employ biopsy examina‐ tion of engrafted islets. Hence, several methodologies to predict islet graft function indirect‐ ly have been proposed. In this section, indices currently available for clinical assessment of

Glucose tolerance test (GTT) is a basic assessment method to diagnose diabetes although glucose stimulation; in itself has risk of artificial hyperglycemia for type 1 diabetic patients. Baidal et al reported that acute insulin/C-peptide release, mixed meal stimulation index, time-to-peak C-peptide, 90min glucose level and area under the curve of glucose values could predict islet dysfunction [113]. Arginine stimulation test is also useful for the evalua‐ tion of islet graft function. Glucose-potentiation slope and the maximal response in arginine stimulation test were significantly associated with β cell secretory capacity in a report from

Hypoglycemic (HYPO) score and lability index (LI) are calculated based on patients' jour‐ nals of self-monitoring blood glucose (SMBG) for a month, providing a link to graft function through the quality of glycemic control [115]. These assessment tools are beneficial since a major endpoint of clinical allogeneic islet transplantation is to prevent hypoglycemic events; however, HYPO and LI calculations require a number of glucose measurements and hence

A simple evaluation method using fasting blood glucose and C-peptide levels has been pro‐ posed, called secretory unit of islet transplant objects (SUITO) index [116]. The SUITO index was originally developed using the concept of the homeostasis model assessment for insulin secretion (HOMA-β) model, where healthy person has 100 of SUITO index. The calculation uses serum C-peptide levels instead of insulin levels, since islet recipient may be administer‐ ing exogenous insulin during graft dysfunction and overlapped measurement of endoge‐ nous and exogenous insulin amounts are avoided [117]. SUITO index can provide reference

are only calculated on a monthly or yearly basis using a complex scoring system.

This scoring system uses data on fasting blood glucose, HbA1c, stimulated C-peptide, and absence of insulin or oral diabetic medication, that cover multiple aspect of glycemic control in islet recipients [121]. Correlation between β score and 90 min glucose level after mixed meal tolerance test has also been reported.

### *3.1.6. TEF*

Transplant estimated function (TEF) is calculated by a formula using daily exogenous insu‐ lin requirements and HbA1c, that are routinely measured at clinic, eliminating glucose stim‐ ulation test when compared to β score [122]. TEF correlated well with β score and insulin response to arginine stimulation test.

#### *3.1.7. TFIM model*

Transplanted functional islet mass (TFIM) model is a recently proposed index that is aimed to guide the decision to use a specific islet preparation [123]. TFIM model is composed of transplanted islet volume, increment of insulin secretion, cold ischemia time and exocrine tissue volume transplanted, and can predict islet graft function.

#### **3.2. Clinical image study**

Functional mass of transplanted islets can be observed by the combination of the radioiso‐ tope-labeled grafts using 18F-fluorodeoxyglucose ([18F]FDG) and positron emission tomog‐ raphy with computed tomography (PET/CT) [124, 125]. Although this technique is only applicable to capture early phase of transplantation up to 60 min after transplant, islet graft loss as well as transplanted islet distribution in the liver can be observed. Nano-iron particle also visualizes engrafted islet mass using magnetic resonance imaging (MRI) and allows longer follow-up when compared to PET/CT technique [126, 127].


**3.3. Autologous Islet Transplantation**

prove their quality of life.

**Acknowledgements**

Foundation.

**4. Conclusion**

Patients with refractory chronic pancreatitis undergo total or partial pancreatectomy to alle‐ viate pain and also autologous islet transplantation to retain pancreatic endocrine function after surgery. Islets isolated from pancreas are infused intraportally into the liver. Assess‐ ment of beta cell function in such autologous islet transplant patients typically follows the methods described for allogeneic islet transplantation. For example, the SUITO index can be applicable to autologous islet transplantation and was founded as an excellent predictor of insulin independence [129]. However, no immune response against infused islets is expect‐ ed in these patients. Post-transplant function of autologous islets has been shown to be much better than in allogeneic combination; β cell mass more than 10,000 IEQ/kg of islet yield is considered for a factor of insulin independence in allogeneic transplants while islet yield over 5,000 IEQ/kg is the successful factor in autologous transplantation [130]. After achievement of insulin independent status, patients receiving autologous islets have better long term survival of graft. Most patients also achieve significant relief from pain and im‐

Beta Cell Function After Islet Transplantation http://dx.doi.org/10.5772/ 52952 183

Islet transplantation has been shown to be a very promising treatment that could result in freedom from requirement of exogenous insulin in type 1 diabetic patients. One of the major advantages of islet transplantation is the minimally invasive nature of the procedure when compared to whole organ pancreas transplantation. Despite its wide spread use at several major transplant centers, the volume of patients receiving islet transplants remain low when compared to the number of "brittle" type 1 diabetic patients eligible for this procedure. Re‐ cently impressive gains have been made in the improvement of post-transplant islet func‐ tion. This is primarily due to the use of T-cell depleting immunosuppression during induction phase after transplant followed by use of tacrolimus, rapamycin and or mycophe‐ nolic mofetil during the maintenance phase. In addition several advances made in donor se‐ lection, pancreas procurement, enzymatic digestion, islet purification and islet culture seem to have contributed to this success. Recent completion of a large scale phase III clinical trial sponsored by the NIH has given hope that soon this procedure may be approved for clinical use. In light of these advances, there is optimism that the remaining hurdles could be over‐

This work was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (1R21DK090513-01 to M.F.L.), the Juvenile Diabetes Research Founda‐ tion (#5-2010-668 to B.N. and #3-2011-447 to M.T.) and by the Baylor Health Care System

come to improve the long term function of the transplanted islets.

**Table 5.** Clinical assessment of β cell function

#### **3.3. Autologous Islet Transplantation**

**Method Variables required Advantage Disadvantage Reference**

Direct evaluation of hypoglycemia that is a major outcome in islet transplantation

Simple calculation Easy prediction of graft function corresponding to insulin independence.

To capture multiple aspects of glycemic control

To eliminate glucose stimulation test compared

Calculation using variables that can be collected in standard diabetes care

To follow graft function using isolation results

To allow evaluation of islet graft mass and the distribution in the liver

To allow longitudinal follow

up of islet mass

to β score

clinic

Widely available method in

The risk of hyperglycemia Repeated blood collection

Number of records for monthly basis are required Complex calculation for LI

Limited application to other species

extended outcomes of hypoglycemia

Composite scoring system requiring 4 variables including the results from glucose stimulation test

Adjustment of coefficients by individual patient

Validated using data on islet after kidney transplantation

The measurement only applicable for early phase of transplantation due to half-time of radioisotope Labeling procedure

required

required Iron overload

Labeling procedure

Simple calculation Limited information on

[113, 114]

[118, 119]

[120]

[121]

[122, 128]

[123]

[124, 125]

[126, 127]

[115]

GTT A series of glucose or C-

SUITO index Fasting serum C-peptide and glucose level

CP/G Fasting serum C-peptide and glucose level

β score Fasting glucose, HbA1c, Daily insulin dose, Stimulated C-peptide

TEF A series of records on

amounts

TFIM Model Volume of transplanted

tissue

islets MRI machine

**Table 5.** Clinical assessment of β cell function

Radiologic imaging technique; PET/CT

Radiologic imaging technique; MRI

HbA1c and daily insulin

islets, increment of insulin secretion, cold ischemia time and volume of transplanted exocrine

Radioisotope-labeled islets

Iron-nanoparticle labeled

PET/CT machine

HYPO score and LI

182 Type 1 Diabetes

peptide values during glucose stimulation

Detailed self-recorded journal of glucose levels and hypoglycemic episodes Patients with refractory chronic pancreatitis undergo total or partial pancreatectomy to alle‐ viate pain and also autologous islet transplantation to retain pancreatic endocrine function after surgery. Islets isolated from pancreas are infused intraportally into the liver. Assess‐ ment of beta cell function in such autologous islet transplant patients typically follows the methods described for allogeneic islet transplantation. For example, the SUITO index can be applicable to autologous islet transplantation and was founded as an excellent predictor of insulin independence [129]. However, no immune response against infused islets is expect‐ ed in these patients. Post-transplant function of autologous islets has been shown to be much better than in allogeneic combination; β cell mass more than 10,000 IEQ/kg of islet yield is considered for a factor of insulin independence in allogeneic transplants while islet yield over 5,000 IEQ/kg is the successful factor in autologous transplantation [130]. After achievement of insulin independent status, patients receiving autologous islets have better long term survival of graft. Most patients also achieve significant relief from pain and im‐ prove their quality of life.
