Piero Marchetti

Genetic variants in the gene encoding for transcription factor-7-like 2 (TCF7L2) have been associated with type 2 diabetes (T2D) and impaired beta cell function, but the mechanisms have remained unknown. We therefore studied prospectively the ability of common variants in TCF7L2 to predict future T2D and explored the mechanisms by which they would do this. Scandinavian subjects followed for up to 22 years were genotyped for 3 SNPs (rs7903146, rs12255372, and rs10885406) in TCF7L2, and a subset of them underwent extensive metabolic studies. Expression of TCF7L2 was related to genotype and metabolic parameters in human islets. The CT/TT genotypes of SNP rs7903146 strongly predicted future T2D in 2 independent cohorts (Swedish and Finnish). The risk T allele was associated with impaired insulin secretion, incretin effects, and enhanced rate of hepatic glucose production. TCF7L2 expression in human islets was increased 5-fold in T2D, particularly in carriers of the TT genotype. Overexpression of TCF7L2 in human islets reduced glucose-stimulated insulin secretion. In conclusion, the increased risk of T2D conferred by variants in TCF7L2 involves the enteroinsular axis, enhanced expression of the gene in islets, and impaired insulin secretion.

INTRODUCTION Diabetes Mellitus Diabetes mellitus is one of the most common chronic diseases in the world, with an estimated worldwide prevalence of over 176 million in 2000. Furthermore, the prevalence of the disease is expected to increase in the coming years as industrialized societies become older, more obese, and more sedentary, and it is predicted to rise to 370 million by 2030 (1). Acute metabolic complications of diabetes are associated with high mortality rates; in particular, hyperosmolar hyperglycemia (approximately 15%) and ketoacidosis (up to 5%). The prognosis in these conditions is substantially worse in older patients and those with coma or hypotension (2). Following a review of epidemiologic and pathologic evidence, the American Heart Association has also classified diabetes a major independent risk factor for cardiovascular disease (CVD) (3–8). Manifestations of CVD include atherosclerotic coronary heart disease (CHD), heart failure (diabetic cardiomyopathy), myocardial infarction, stroke, and peripheral vascular disease (7). The risk for stroke has been reported to be two to four times higher in patients with diabetes (7,9). Furthermore, patients with diabetes who develop CVD have a worse prognosis for survival than patients with CVD but without diabetes (8–11). In fact, CVD is listed as the cause of death in approximately 65% of patients with diabetes (12). In addition to the risk for macrovascular complications, diabetes is associated with long-term microvascular complications including neuropathy, retinopathy, nephropathy, and erectile dysfunction. Diabetic nephropathy is the most common single cause of end-stage renal disease in the United States and Europe (13). With respect to retinopathy, after 20 years with the condition, almost all individuals with type 1 diabetes and over 60% with type 2 diabetes have a degree of retinopathy that may progress to loss of vision (14). In fact, diabetes is now considered the leading cause of blindness in developed countries, causing 12,000 to 24,000 new cases each year (15,16). New-Onset Diabetes after Transplantation Diabetes and impaired glucose tolerance occurring as a complication of organ transplantation have been recognized for many years. However, incidence figures for new-onset diabetes after transplantation across different studies have ranged between 2% and 53% (17). Precise figures have been difficult to determine because there has been no consensus regarding the definition of the condition and hence different clinical studies have used a variety of diagnostic criteria. Despite the apparently high incidence of new-onset diabetes after transplantation, transplant patients are for hyperglycemia and the condition is it is that of diabetes after transplantation has for the and the of studies that diabetes after transplantation is associated with and and loss In addition to risk studies that may for a degree of the risk for of diabetes after transplantation However, used in the to diabetes and the of have a major risk for the In diabetes is a complication that the survival of the transplant long-term survival of the and the of is that and of patients and the risk for the Furthermore, and of patients who have developed diabetes the long-term of the the of the the the the and the the New-Onset Diabetes after Transplantation is that of these may in or the incidence and of new-onset diabetes mellitus after The of New-Onset Diabetes after Transplantation Diabetes is one of the most long-term complications of transplantation, the condition is clinical that transplant who develop diabetes are risk of complications, including and Furthermore, the chronic hyperglycemia associated with the condition a long-term risk of microvascular and macrovascular The of new-onset diabetes also of in the United States between and has that the of new-onset diabetes after transplantation are between and higher than for those with no diabetes by the of the year and between and higher by the of the year and prevalence of new-onset diabetes after transplantation The prevalence of new-onset diabetes after transplantation has been in the because of the of a definition for the for diabetes after transplantation are glucose or glucose than and clinical include glucose tolerance to determine the incidence of in transplant has to in the reported incidence of the disease The of many studies are also are and the incidence of the risk of diabetes and patients may develop the condition many years The incidence of new-onset diabetes after transplantation in by incidence of diabetes after transplantation for and transplantation studies reported to be the of 2% to 53% (17). 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diabetes incidence in renal in years. with survival In patients without the survival of to 60% in the to between and In addition to these survival the mortality has to of these be to death with also for of all have that the of diabetes is associated with impaired long-term and survival in transplant have reported that the of diabetes after transplantation associated with a in survival and with and patients with new-onset diabetes after transplantation have been to have impaired by with years survival also worse in patients with diabetes with with new-onset diabetes an independent of loss The of new-onset diabetes after transplantation has also been to in a incidence of in transplant in the The cause of impaired survival and in transplant with new-onset diabetes after transplantation is The of nephropathy is one because it has been that nephropathy and is associated with a high of failure However, nephropathy years to develop and may for the failure that be associated with the of In 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transplantation the for the of patients with type 2 diabetes is that glucose in patients with type 1 or type 2 diabetes in of complications In addition to the of patients the and also be who develop diabetes after transplantation also for the of complications, including retinopathy and may also be to for the of the of has been for the transplant with new-onset the who diabetes after transplantation of The of patients with diabetes to in glucose has the to glucose be an of the of all patients or may also be for patients diabetes is by of the for patients with diabetes the of risk all and in each these and of to the and be year in patients because of in in patients with diabetes and the of of in with patients with diabetes after transplantation have to determine or glucose is with the to the Diabetes and to be used in all cases The of the used and the of the transplant patients diabetes it is that is a is to be to long-term complications but may be difficult to in most may be in most patients but may be to are to an risk for long-term complications, and and of The or may be to different for the of diabetes to the of each it is that an of or higher the for for be that is for of new-onset diabetes after transplantation because it is for Furthermore, in patients with or be with because conditions with the and the may be Diabetic The of new-onset diabetes after transplantation many with type 2 diabetes and it is that transplant who develop new-onset diabetes also be risk of the long-term complications of as retinopathy and it is that all patients with new-onset diabetes are for complications, including an and a The of in the is an of nephropathy in patients with type 1 and type 2 and is a for cardiovascular and is an for for vascular disease and in these to cardiovascular risk (13). for is for all patients with diabetes for type 2 diabetes and after years for type 1 to of nephropathy (13). the of has been in transplant may also be considered in transplant who have developed new-onset diabetes to the of However, it be that many transplant have renal and may have without In may be difficult to in with chronic studies are to the of in transplant with new-onset to diabetes after transplantation of patients with diabetes after transplantation a to that for patients with type 2 diabetes and to of patients with of diabetes after of the most for the of patients with and diabetes after transplantation loss and of loss a as has also been to peripheral and in patients with type 2 diabetes the and are as the in the of type 2 with a of diabetes including of glucose glucose is with and is the to has been the be the of of and of also be The of an may be an is the most used a a or a of each of these is associated with and also the and and of common In the of transplant with impaired it is to the of as with and with is associated with an increase in the risk for CVD and are common with with or are more common with is in the of for transplant patients and be may be the of in the for in transplant patients with renal may be because are in patients with renal or and with be that no of have been in patients to is with a single a of with different of be with the of the are used in the of patients with type 2 or or the of of the also be that of these has been in in transplant may be to or to may be a with or without of and is used in patients with type 2 has been in patients with new-onset diabetes after of may be of is or glucose to than and to than after with an than may be in the of a single of glucose be by the addition of or the by be may also be to are with and of be to glucose be to an or for of and of is that of the risk of chronic heart disease in patients with diabetes all patients with new-onset diabetes after transplantation are high risk of it is that patients also in with the for of to of and In patients with In patients with to be also may be the of in patients with including renal transplant have been the of and as of chronic heart disease are of is reported to the of patients with diabetes in the and is associated with an risk of cardiovascular death a of for the of patients with diabetes have that be in patients to for patients with diabetes in the no studies to have the of in patients with new-onset diabetes after transplantation, an may be expected to be of there is studies of with diabetes and in the that or is associated with a in cardiovascular and a of is for patients with new-onset diabetes after transplantation may be with an with addition of to to the In may to a of in renal no are in transplant studies are to the of these in be to the of to the risk of cardiovascular of new-onset diabetes after transplantation The in the of these the of diabetes as a major complication of transplantation and the that may in However, that a of may the of diabetes in Furthermore, and the long-term complications of the have been developed to a definition and of new-onset diabetes after transplantation and to for of the condition that be used to transplant of these in patients risk of diabetes after transplantation that be in the of these be expected to the risk of new-onset diabetes after transplantation and the long-term associated with the condition of diabetes after

DIRECT (Diabetes Incidence after Renal Transplantation: Neoral C2Monitoring Versus Tacrolimus) was a 6-month, open-label, randomized, multicenter study which used American Diabetes Association/World Health Organization criteria to define glucose abnormalities. De novorenal transplant patients were randomized to cyclosporine microemulsion (CsA-ME, using C2monitoring) or tacrolimus, with mycophenolic acid, steroids and basiliximab. The intent-to-treat population comprised 682 patients (336 CsA-ME, 346 tacrolimus): 567 were nondiabetic at baseline. Demographics, diabetes risk factors and steroid doses were similar between treatment groups. The primary safety endpoint, new-onset diabetes after transplant (NODAT) or impaired fasting glucose (IFG) at 6 months, occurred in 73 CsA-ME patients (26.0%) and 96 tacrolimus patients (33.6%, p = 0.046). The primary efficacy endpoint, biopsy-proven acute rejection, graft loss or death at 6 months, occurred in 43 CsA-ME patients (12.8%) and 34 tacrolimus patients (9.8%, p = 0.211). Mean glomerular filtration rate (Cockcroft–Gault) was 63.6 ± 20.7 mL/min/1.73 m2in the CsA-ME cohort and 65.9 ± 23.1 mL/min/1.73 m2with tacrolimus (p = 0.285); mean serum creatinine was 139 ± 58 and 133 ± 57 μmol/L, respectively (p = 0.005). Blood pressure was similar between treatment groups at month 6, but total cholesterol, LDL-cholesterol and triglyceride levels were significantly higher with CsA than with tacrolimus (total cholesterol:HDL remained unchanged). The profile and incidence of adverse events were similar between treatments. The incidence of NODAT or IFG at 6 months post-transplant is significantly lower with CsA-ME than with tacrolimus without a significant difference in short-term outcome.In this 6-month, open-label, randomized, multicenter study in de novo renal transplant patients, the primary safety endpoint of new-onset diabetes after transplant or impaired fasting glucose was significantly less frequent with cyclosporine microemulsion than tacrolimus, with no significant differences in short-term outcome. See also editorial by Van Hooff in this issue on page 1435. DIRECT (Diabetes Incidence after Renal Transplantation: Neoral C2Monitoring Versus Tacrolimus) was a 6-month, open-label, randomized, multicenter study which used American Diabetes Association/World Health Organization criteria to define glucose abnormalities. De novorenal transplant patients were randomized to cyclosporine microemulsion (CsA-ME, using C2monitoring) or tacrolimus, with mycophenolic acid, steroids and basiliximab. The intent-to-treat population comprised 682 patients (336 CsA-ME, 346 tacrolimus): 567 were nondiabetic at baseline. Demographics, diabetes risk factors and steroid doses were similar between treatment groups. The primary safety endpoint, new-onset diabetes after transplant (NODAT) or impaired fasting glucose (IFG) at 6 months, occurred in 73 CsA-ME patients (26.0%) and 96 tacrolimus patients (33.6%, p = 0.046). The primary efficacy endpoint, biopsy-proven acute rejection, graft loss or death at 6 months, occurred in 43 CsA-ME patients (12.8%) and 34 tacrolimus patients (9.8%, p = 0.211). Mean glomerular filtration rate (Cockcroft–Gault) was 63.6 ± 20.7 mL/min/1.73 m2in the CsA-ME cohort and 65.9 ± 23.1 mL/min/1.73 m2with tacrolimus (p = 0.285); mean serum creatinine was 139 ± 58 and 133 ± 57 μmol/L, respectively (p = 0.005). Blood pressure was similar between treatment groups at month 6, but total cholesterol, LDL-cholesterol and triglyceride levels were significantly higher with CsA than with tacrolimus (total cholesterol:HDL remained unchanged). The profile and incidence of adverse events were similar between treatments. The incidence of NODAT or IFG at 6 months post-transplant is significantly lower with CsA-ME than with tacrolimus without a significant difference in short-term outcome. In this 6-month, open-label, randomized, multicenter study in de novo renal transplant patients, the primary safety endpoint of new-onset diabetes after transplant or impaired fasting glucose was significantly less frequent with cyclosporine microemulsion than tacrolimus, with no significant differences in short-term outcome. See also editorial by Van Hooff in this issue on page 1435.

In an effort to better understand the phenomenon of lipotoxicity in human beta-cells, we evaluated the effects of 48-h preculture with 1.0 or 2.0 mmol/l free fatty acid (FFA) (2:1 oleate to palmitate) on the function and survival of isolated human islets and investigated some of the possible mechanisms. Compared with control islets, triglyceride content was significantly increased and insulin content and glucose-stimulated insulin release were significantly reduced in islets precultured with increased FFA concentrations. These changes were accompanied by a significant reduction of glucose utilization and oxidation. By cell death detection techniques, it was observed that exposure to FFAs induced a significant increase of the amount of dead cells. Electron microscopy showed the involvement of beta-cells, with morphological appearance compatible with the presence of apoptotic phenomena. FFA-induced islet cell death was blocked by inhibition of upstream caspases and partially prevented by inhibiton of ceramide synthesis or serine protease activity, whereas inhibition of nitric oxide synthesis had no effect. RT-PCR studies revealed no major change of iNOS and Bax mRNA expression and a marked decrease of Bcl-2 mRNA expression in the islets cultured with FFA. Thus, prolonged exposure to FFAs has cytostatic and pro-apoptotic effects on human pancreatic beta-cells. The cytostatic action is likely to be due to the FFA-induced reduction of intraislet glucose metabolism, and the proapoptotic effects are mostly caspase mediated, partially dependent on ceramide pathway, and possibly Bcl-2 regulated.