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The development of Type 2 Diabetes (T2D) is a result of a complicated interplay between multiple etiological factors, which include both the prenatal environment and genetics interacting with lifestyle factors on the one hand, and  on the other hand distinct defects of glucose and fat metabolism in many organs. Thus the primary focus and aim of the group is on implementing the rapidly developing metabolic and scientific research technologies of basic science into clinical physiological, integrative metabolic research with the aim of understanding disease mechanisms, and in particular the disease mechanisms underlying T2D etiology and pathophysiology. Science, Technology and Medicine open access publisher.Publish, read and share novel research.
Targeting AMPK for Therapeutic Intervention in Type 2 DiabetesMohamed Kodiha1 and Ursula Stochaj1[1] McGill University, Canada1. For type 1 diabetes (a severe inflammatory disease where insulin-producing cells are destroyed), a possible line of therapy is transplanting islets – a smaller unit of the pancreas which is responsible for insulin production. Now, Ospedale Niguarda Ca’ Granda (Milan, Italy) has succeeded in treating a diabetes patient with a new type of islet transplant. As a result, a 41-year-old man who was diagnosed with type 1 diabetes at age 11 could now stop insulin therapy.
This new technology was developed at the Diabetes Research Institute (DRI) at the University of Miami and could answer part of challenges of islet transplants. Named BioHub, it consists of implanting donor islets in a biodegradable gel-like material made of the patient’s own blood plasma and thrombin (an enzyme involved in blood coagulation).
Similar to the nontransplant settings, the use of fasting plasma glucose (FPG) versus oral glucose tolerance test (OGTT) to define diabetes mellitus also changes the prevalence of NODAT. Among these organs are skeletal muscle, adipose tissue, liver, pancreatic beta-cells, gut, kidney, CNS etc. The liver represents another source of embryologically related tissue that has been transdifferentiated into insulin-expressing cells. Organization of AMPK and regulation of kinase activity by phosphorylation.AMPK is a heterotrimeric enzyme that is activated by phosphorylation on Thr172 of the ? subunit.
AMPK? concentrates in nuclei when cells are exposed to oxidative stress or depleted for energy. IntroductionThis chapter begins with general information on the role of 5’-AMP activated kinase (AMPK) in human physiology and the molecular mechanisms that control this kinase.
In 2000, patients in a trial were able to stop their daily insulin injections after successful transplants (you can read a review of the Islet medtech field here) – a big deal!
This could be a better location for islets to fully develop than the current go-to option – infusion into the liver. Along with technology to create islets in the lab (and bypass the problem of donor shortage), these procedures seem to be the future of treatments for type 1 diabetes. It is used by over 40,000 people monthly to keep a watch on the business and innovations of biotechnologies.
Detection and management of diabetes mellitus in recipients of solid organ transplants 12.1.
Sugested guidelines for pre-transplant baseline evaluation and post-transplant screening for NODAT12.3.
In a prospective study designed to evaluate the use of OGTT for risk-stratifying patients for NODAT, Sharif et al. ObesitySimilar to the general population, obesity has been shown to be associated with the development of NODAT in most studies (Setoguchi et al., 2005). This finding has not yet been validated in either transplant recipients or prospective trials in the general population (Bosch et al., 2006). We work with the conceptual framework that the multiple organ defects in Type 2 Diabetes can be explained by developmental programming as shown in the figure below. AMPK controls the physiology of multiple organs which are critical to type 2 diabetes, obesity and other metabolic diseases.
HeLa cells were treated with diethyl maleate to induce oxidative stress or with a combination of sodium azide and 2-deoxyglucose for energy depletion.
The possible changes induced by the compartment-specific alteration of AMPK activity are depicted. We discuss the functions of AMPK in different tissues and their relationship to type 2 diabetes. There has been scant literature on the incidence of diabetes mellitus after a successful pancreas transplant.
Of interest, ADPKD patients with normal native kidney function have been shown to have insulin resistance and compensatory hyperinsulinemia (Vareesangthip et al., 1997). As such, AMPK regulates both anabolic and catabolic pathways as well as the function and biogenesis of organelles. Some of the tissue-specific reactions regulated by AMPK and relevant to type 2 diabetes are listed. AMPK substrates in different subcellular organelles and compartments are described, and we speculate how the localized action of AMPK could help to control type 2 diabetes. Although not a risk factor per se, increased insulin clearance after a successful kidney transplant can unmask pre-transplant impaired glucose tolerance or pre-existing diabetes mellitus that manifests clinically as NODAT. Although some studies failed to demonstrate an association between obesity and the development of NODAT, obesity and its associated peripheral insulin resistance state is a known risk factor for type 2 diabetes.
The variation in the reported incidence may be due in part to the lack of a standard definition of the condition, the duration of follow-up, the presence of both modifiable and non-modifiable risks factors, and the type of organ transplants among others.
Risk factors for NODATRisk factors for the development of NODAT are categorized as non-modifiable and modifiable or potentially modifiable, the former category to facilitate the identification of high risk individuals, and the latter two categories to optimize the management of NODAT.
Pharmacological managementWhen lifestyle modification fails to achieve adequate glycemic control, medical intervention is recommended. Nonetheless, the pattern of body fat distribution has been suggested to play a contributory role. Orally administered agents can be used either alone or in combination with other oral agents or insulin.
Pham5[1] Department of Medicine, Nephrology Division, Kidney Transplant Program, David Geffen School of Medicine at UCLA, United States of America[2] Department of Medicine, Greater Los Angeles VA Medical Center and David Geffen School of Medicine at UCLA, United States of America[3] Department of Medicine, Cardiology Division, Bay Pines VA Medical Center, Bay Pines, Florida, United States of America[4] Department of Medicine, Division of Cardiovascular Diseases, VA Medical Center, University of Tennessee Health Science Center, Memphis, TN, United States of America[5] Department of Medicine, Nephrology Division, UCLA-Olive View Medical Center and David Geffen School of Medicine, United States of America1. Corticosteroid-associated NODATThe now well-established contributory role of corticosteroid on NODAT was first described by Starlz in 1964 in renal transplant recipients. Studies in healthy women showed that upper body or male-type obesity has a much greater association with insulin resistance and impaired glucose tolerance than lower body or female-type obesity (Kissebah et al., 1982). The choice of pharmacologic therapy is based on the potential advantages and disadvantages associated with the different classes of oral agents. How does the compartment-specific action of AMPK impact cellular functions that are relevant to type 2 diabetes? Introduction New onset diabetes mellitus after transplantation (NODAT) is a serious and common complication following solid organ transplantation. In one single-center study consisting of 126 lung and heart-lung transplant recipients, diabetes has a reported prevalence of 6% at 1 year and 7% at 5 years.
Table 3 summarizes the mechanisms of action and potential advantages and disadvantages of different classes of oral agents.
As a result of these contributions, AMPK is vital to the function of several organs and tissues in metazoans (Fig.
The lower prevalence of diabetes in this study was thought to be due in part to a lower frequency of cystic fibrosis patients (8.7% vs. It is speculated that intra-abdominal fat or waist-to-hip ratio may be more important risk factors for NODAT than total body weight or BMI (Davidson et al., 2003). It should be noted that although in most cases a correlation between treatment and changes in AMPK activity has been demonstrated, the molecular mechanisms are not always fully understood. Kidney transplant recipients who develop NODAT have variably been reported to be at increased risk of fatal and nonfatal cardiovascular events and other adverse outcomes including infection, reduced patient survival, graft rejection, and accelerated graft loss compared with those who do not develop diabetes.
In contrast to the DOPPS study results, in an analysis of the national cohort study consisting of more than 5,000 dialysis patients with type 2 diabetes Brunelli et al. In particular, the low activation state of AMPK could contribute to the increase in type 2 diabetes and obesity (Hardie et al., 2006). Limited clinical studies in liver, heart and lung transplants similarly suggested that NODAT has an adverse impact on patient and graft outcomes. Ischemic heart disease was also found to be associated with an increased incidence of NODAT (Ye et al., 2010b). For some of the treatments, it has yet to be established whether AMPK is essential for the downstream physiological effect. Moreover, as essential regulator of glucose homeostasis and lipid metabolism, AMPK has become an important therapeutic target in type 2 diabetes and obesity. The following chapter presents an overview of the literature on the current diagnostic criteria for NODAT, its incidence after solid organ transplantation, suggested risk factors and potential pathogenic mechanisms. In a single-center study consisting of 97 consecutive adult heart transplant recipients, a family history of diabetes and the need for insulin beyond the first 24 hours after transplantation were shown to be risk factors for the development NODAT (Depczynski et al., 2000). Whether complete withdrawal of chronic low dose corticosteroid therapy (prednisolone 5 mg daily) improves glucose metabolism remains to be studied.
In a recent retrospective analysis consisting of 640 nondiabetic renal transplant recipients Bayer et al.
More recent experiments with knockout cells and animal models will help to fill these gaps (Viollet et al., 2009a).
The impact of NODAT on patient and allograft outcomes and suggested guidelines for early identification and management of NODAT will also be discussed. Nonetheless, in recent years several studies have suggested a potential beneficial effect of steroid-free immunosuppression on NODAT risk reduction (Luan et al., 2011). Multivariate analysis incorporating the individual metabolic syndrome components as covariates demonstrated that of all the pre-transplant metabolic syndrome components, only low-density lipoprotein was independently associated with the development of NODAT.The precise role of the metabolic syndrome or metabolic syndrome component(s) in the development of NODAT remains to be defined. Nonetheless, great caution should be exercised when rosiglitazone is used in the setting of kidney transplantation because all kidney transplant recipients should be regarded as having at least stage II-IV chronic kidney disease. Nonetheless, the overlapping metabolic risk factors for type 2 diabetes and cardiovascular disease (e.g.
Figure 1.Risk Factors for NODATSimilar to type 2 diabetes in the general population, both genetic and environmental factors have been suggested to play a role in the development of NODAT.


The cumulative incidence of NODAT within three years post-transplant were 12.3% in steroid-free vs.
Organization and activation of AMPKAMPK senses a drop in cellular energy as it is induced by a reduction in glucose availability or other metabolic stresses. There is strong evidence suggesting that individuals with a family history of diabetes among first-degree relatives have an increased risk of developing NODAT with one study reporting a seven fold increase in the condition (Davidson et al., 2003).
ProteinuriaEarly report from single-center study suggested an association between proteinuria on day 5 after transplantation and the development of NODAT (Kuypers et al., 2008).
A randomized, placebo-controlled, double-blind, prospective trial to evaluate the safety and efficacy of vildagliptin in patients with NODAT is currently underway (Haidinger et al., 2010). The current WHO and American Diabetes Association (ADA) guidelines for the diagnosis of prediabetic states (IFG and IGT) and diabetes mellitus are provided in Table 1 (modified from Davidson et al., 2003). The increased prevalence of NODAT associated with a family history of diabetes has been documented across all types of solid organ transplantation. Overall, steroid-containing regimens at the time of hospital discharge were associated with a 42% increased risk for NODAT. However, these findings have been challenged because proteinuria on day 5 may just reflect the highly concentrated urine associated with hyperglycemia-induced osmotic diuresis from the early posttransplant use of high dose corticosteroid or residual native kidney proteinuria. Caution should be exercised when these agents are used in the transplant setting, particularly with regards to drug to drug interactions. As a result of AMPK activation, the cellular metabolism switches from anabolic to catabolic processes.
Notably, patients from programs that frequently adopted steroid-free regimens had reduced odds of NODAT compared with those from programs that commonly used steroid-contatining regimens.
Furthermore, it has been shown that immediate posttransplant proteinuria generally resolves several weeks after transplantation (Myslak et al., 2006). Vildagliptin should be avoided in patients with hepatic impairment and stage IV-V chronic kidney disease and the dose of sitagliptin should be adjusted for renal insufficiency. This metabolic shift is accomplished by the AMPK-dependent phosphorylation of multiple targets which are located in different cellular organelles and compartments (see below).The heterotrimeric enzyme AMPK (Fig. Other non-modifiable risk factors include recipient male gender, the presence of certain HLA antigens such as HLA A 30, B27, B42, increasing HLA mismatches, DR mismatch, deceased donor kidneys, male donor, and acute rejection history (Depczynski et al., 2000). The dose dependent diabetogenic effect of corticosteroid was also observed in recipients of nonrenal organ transplants.
Nonetheless, in a subsequent single-center retrospective study designed to evaluate the impact of early proteinuria (3 and 6 months after transplantation) and urinary albumin excretion (UAE) on NODAT, Roland et al.
Adult polycystic kidney disease (ADPKD) has been suggested to confer an increased risk of developing NODAT in some studies but not in others (P.T.
The regulatory ? and ? subunits are encoded by two and three genes, respectively (Hardie et al., 2006). SummaryNODAT is a common complication after solid organ transplantation and has variably been reported to have an adverse impact on patient and allograft outcomes. NODAT-free survival was greater in patients with normoalbuminuria than in those with microalbuminuria, and greater in those with microalbuminuria than in those with macroalbuminuria (p=0.0326). Risk stratification and intervention to minimize risk should be an integral part in the management of the transplant recipients.
The ? subunits (?1, ?2, ?3) bind AMP and ATP in a mutually exclusive fashion, this AMP binding is important to the activation of the enzyme. The authors also demonstrated that pulse pressure was an independent risk factor for NODAT, suggesting that early low-grade proteinuria and pulse pressure may be markers of the metabolic syndrome or vascular damage or both. Clinicians must be familiar with the patients’ immune history prior to manipulating their immunosuppressive therapy.in an attempt to ameliorate NODAT risk.
When lifestyle modification fails to achieve adequate glycemic control, medical intervention is often necessary. Control of AMPK activity by phosphorylation and changes in AMPK concentrationThe importance of AMPK as a key regulator in cellular metabolism requires a tight control of the enzyme. HypomagnesemiaIn the general population, not only has hypomagnesemia been shown to be associated with type 2 diabetes, but numerous studies have also reported an inverse relationship between glycemic control and serum Mg levels (P.C. The routine care of patients with NODAT should include an evaluation of hemoglobin A1C level every three months and regular screening for diabetic complications. It should be noted that hemoglobin A1C cannot be accurately interpreted within the first three months post transplantation due to various factors including possible blood transfusions in the early posttransplant period and the presence of anemia or impaired allograft function. Similar to the nontransplant settings, hypomagenesemia has also been shown to be an independent predictor of NODAT in recipients of renal and liver transplants. Blood transfusions may render the test invalid until new hemoglobin is formed and the presence of anemia and kidney impairment can directly interfere with the A1C assay.
In a single-center retrospective analysis consisting of 254 renal transplant recipients Van Laecke et al.
An artifactual reduction in A1C level has been reported in islet cell transplant recipients taking dapsone for pneumocystis carinii (P. While the association between the use of CNIs was strongly related to hypomagnesemia, NODAT disappeared after adjustment for Mg levels suggesting that the diabetogenic effect of CNIs is at least in part related to hypomagnesemia.
Under these conditions, AMP binding to the regulatory ? subunit promotes the subsequent Thr172 phosphorylation. Furthermore, a lower proportion of CsA-ME patients with NODAT required hypoglycemic medication or dual therapy with insulin and oral hypoglycemic agents compared with their tacrolimus-treated counterparts. Conversely, the use of mTOR inhibitors appeared to be a risk factor for NODAT after adjustment for Mg levels.
In transplant recipients with multiple CVD risk factors, more frequent monitoring of lipid profile should be performed at the discretion of the clinicians. The greater diabetogenic effect of tacrolimus compared to CSA has been reported to occur across renal and nonrenal transplant groups. The same group of authors subsequently demonstrated that both pretransplant hypomagenesemia and hypomagnesemia in the first-month posttransplantation were independent predictors of NODAT in recipients of liver transplants (Van Laecke et al., 2010). Statins or the HMG-CoA reductase inhibitors are the most widely used lipid lowering agents in both the nontransplant and transplant settings. In a meta-analysis to evaluate the reported incidence of NODAT after solid organ transplantation, Heisel and colleagues found a higher incidence of insulin-dependent diabetes mellitus (IDDM) in Tac- vs.
By contrast, a relative small change is observed for the ?3 subunit which is mostly synthesized in glycolytic skeletal muscle.
Whether Mg supplementation and correction of Mg deficiency reduce the incidence of insulin resistance or NODAT remains to be studied. It was proposed that ? subunit myristoylation provides a switch that is a prerequisite for Thr172 phosphorylation (Oakhill et al., 2010). Impaired glucose tolerance before transplantationAbnormal glucose metabolism has been reported to be a risk factor for the development of NODAT in some but not all studies.
This modification is mediated by CaMKK? and particularly important in tissues where LKB1 is not the predominant kinase for Thr172. Nonetheless, not all studies showed that Tac is more diabetogenic than cyclosporine (Meiser et al., 1998). In a single-center study consisting of 45 OLT recipients treated with either CSA (n=9) or high- (n=15) vs. Among patients with IFG pretransplant, 70% had hyperglycemia at one year (IFG 43% and NODAT 27%).
Interaction between tacrolimus and concomitant hepatitis C infection (HCV)In a retrospective study of more than 400 kidney transplant recipients with no known pre-transplant diabetes, Bloom and colleagues have shown that among the HCV(+) cohort, NODAT occurred more often in the Tac- compared with the CSA-treated groups (57.8% vs. HCV-associated NODATThe association between HCV infection and impaired fasting glucose or the development of overt type 2 diabetes mellitus in the general population has long been suggested.
In contrast, among the HCV (-) cohort, the rates of NODAT were similar between the two calcineurin inhibitor (CNI) groups (Tac vs. Potential mechanisms of the diabetogenic effect of HCV infection include insulin resistance, decreased hepatic glucose uptake and glycogenesis, and direct cytopathic effect of the virus on pancreatic ? cells (Bloom & Lake, 2006).
Similar to the non-transplant settings, the link between hepatitis C and the development of NODAT has also been recognized in solid organ transplant recipients.
The tissue-specific regulation of AMPK activity is likely achieved by the combined effects of upstream activating kinases, inactivating phosphatases as well as the synthesis and degradation of AMPK subunits.
For example, LKB1 is particularly important to activate AMPK in skeletal muscle, whereas CaMKK? is crucial in the brain (Ronnett et al., 2009).
Whether concomitant exposure to tacrolimus and HCV plays a synergistic role in the development of NODAT remains speculative.
Clinical studies in recipients of orthotopic liver transplant (OLT) recipients have implicated insulin resistance associated with active HCV infection as a predominant pathogenic mechanism. Effects of sirolimus on glucose metabolismEarly large randomized clinical trials suggested that sirolimus is devoid of diabetogenic effects either used alone or in combination therapy with CNI. Indeed, in a clinical setting AMPK activity is altered with the anti-diabetic drug metformin and other biguanides.
It was suggested that the virus had a direct effect on insulin resistance as no difference in ? cell function or hepatic insulin extraction between the HCV (+) and (-) groups was observed. In one single-center study, tacrolimus and sirolimus combination therapy was found to be associated with a higher incidence of NODAT than tacrolimus alone immunosuppression (Sulanc et al., 2005). Subsequent large registry study also demonstrated an association between sirolimus and the development of NODAT. Cytomegalovirus-associated NODATThe link between cytomegalovirus (CMV) infection and the development of NODAT was first reported in 1985 in a renal transplant recipient (Lehr et al., 1985). In an analysis of the USRDS database consisting of more than 20,000 primary kidney transplant recipients receiving sirolimus (Sir) or CNI (CsA or Tac) or both in various combination therapy with an antimetabolite (MMF or AZA), Johnston et al. Limited studies suggested that both asymptomatic CMV infection and CMV disease are independent risk factors for the development of NODAT.
Phenphormin promotes the LKB1-dependent activation of AMPK by inhibiting mitochondrial complex I (Hawley et al., 2010).


Patients with active CMV infection had a significantly lower median insulin release compared to their CMV negative counterparts, suggesting that impaired pancreatic ? cell insulin release may be involved in the pathogenic mechanism of CMV-associated NODAT. It is speculated that CMV-induced release of proinflammatory cytokines may lead to apoptosis and functional disturbances of pancreatic ?-cells (Hjelmasaeth et al., 2005).
AICAR generates the AMP mimetic 5-amino-4-imidazolecarboxamide ribotide (ZMP) and causes a drop in cellular ATP and ADP, which leads to AMPK activation (Hawley et al., 2010).
Anti-CD25 monoclonal antibodies In a single-center study consisting of 74 stable kidney transplant recipients with 3 month-follow-up, Bayes et al. Aside from drugs that activate AMPK, compound C serves as an ATP-competitive inhibitor of AMPK that has been used widely.
All of the compounds discussed here are established pharmacological tools that alter AMPK activation or enzymatic activity; they have been useful for the analysis of AMPK in vitro, in growing cells and in whole animals. Kidney transplantsClinical studies evaluating the impact of NODAT on patient and allograft outcomes after solid organ transplantation have yielded variable results. The development of NODAT has also been shown to be associated with an adverse impact on patient survival and an increased risk of graft rejection and graft loss, as well as an increased incidence of infectious complications (Ojo, 2006).
Calcineurin inhibitorsImpaired insulin secretion has been suggested to contribute to the development of CNI-associated NODAT (Crutchlow & Bloom, 2007).
The study consisted of >37,000 renal transplant recipients with a functioning transplant for at least 1 year. Risk stratification according to diabetes status (pre-transplant diabetes, NODAT) and acute rejection (AR) at 1 year demonstrated that pre-transplant diabetes is the major predictor of all-cause and cardiovascular mortality whereas acute rejection during the first year is the major predictor of death-censored transplant failure. Of particular importance at the cellular, organ and organismal level is the ability of AMPK to switch from anabolic to catabolic processes when energy supplies are low.
In recipients of pancreas transplants, both calcineurin inhibitors CSA and Tac have been shown to cause reversible toxicity to islet cells.
In contrast, NODAT alone was not associated significantly with any study outcomes (Kuo et al., 2010). AMPK regulates metabolism and other aspects of cell physiology both under normal and disease conditions; studies with different cells or tissues emphasize the significance of AMPK for cellular metabolism and the response to various forms of stress. In a study of 26 pancreas allograft biopsies from 20 simultaneous kidney-pancreas transplant recipients, a significant correlation was seen between the presence of islet cell damage and serum levels of Tac and CSA, as well as with the Tac peak level (Drachenberg et al., 1999). Nonetheless, the study results were regarded as inconclusive due to the wide confidence intervals and the relatively short duration of follow-up. Cytoplasmic swelling and vacuolization, and marked decrease or absence of dense-core secretory granules in ?-cells were demonstrated on electron microscopy.
It is noteworthy that in a large registry study consisting of more than 27,000 primary kidney transplant recipients with graft survival of at least 1 year and with longer-term follow-up, Cole et al. Notably, this signaling in the central nervous system contributes to the regulation of food uptake. Serial biopsies from two patients with hyperglycemia and evidence of islet cell damage receiving Tac immunosuppression demonstrated reversibility of the damage upon discontinuation of tacrolimus. Research with hepatic, skeletal muscle, adipose, pancreatic and kidney cells is particularly important to our understanding of type 2 diabetes as these cell types are crucial to the etiology or pathophysiology of the disease (Fig.
Sirolimus (mTOR inhibitors)Suggested pathogenic mechanisms of sirolimus-induced hyperglycemia include sirolimus-associated impaired insulin-mediated suppression of hepatic glucose production, ectopic triglyceride deposition leading to insulin resistance, and direct ? cell toxicity (Crutchlow & Bloom, 2007).
However, studies on the effects of sirolimus on insulin action and secretion have yielded variable and conflicting results. Whereas the phosphorylation of key enzymes produces a fast downregulation of ATP-consuming metabolic pathways, long-term effects involve changes in the expression of target genes that control metabolism.
Currently existing literature suggests that the effects of sirolimus on glucose metabolism appear to be cell-species- and dose-dependent (Subramanian & Trence, 2007). Since several recently published excellent reviews covered these topics extensively, Table 2 only summarizes the impact of AMPK activation on tissues that are critical to type 2 diabetes. Anti-CD25 monoclonal antibodiesThe pathogenic mechanisms of anti-CD25-induced NODAT have not been established. However, suppression of regulatory T-cells has been suggested to play a contributory role (Aasebo et al., 2010). However, there was no difference in patient survival between the two groups at 1-, 2- and 5-years follow-up. Studies in diabetes-prone mice have shown that anti-IL2-antibody treatment trigger insulinitis and early onset diabetes through inhibition of Foxp3-expressing CD25+ CD4+ regulatory T-cells (Setoguchi et al., 2005). Suggested pathogenic mechanisms of immunosuppressive drug-induced NODAT are summarized in table 2. Subcellular distribution of AMPK substratesThe combination and integration of different subcellular events regulated by AMPK enables cells, tissues and organs to coordinate different metabolic pathways in order to achieve and maintain the proper energy balance of the whole organism. 3 depicts established AMPK substrates according to their presence in different subcellular compartments.
Table 3 expands this information and specifies how the AMPK-dependent phosphorylation of individual substrates alters their functions.It is obvious from Fig.
3 that AMPK phosphorylates a large number of proteins that are associated with distinct organelles or subcellular compartments. Cytoplasmic and mitochondrial substrates of the kinase include enzymes that are involved in fat, protein, glucose and glycogen metabolism.
Pre-transplant baseline evaluationSuggested guidelines for pre-transplant baseline evaluation of potential transplant candidates is shown in Figure 2.
Kinase targets in the plasma membrane consist of ion channels, carriers and receptors, whereas other substrates are linked to the function or trafficking of intracellular membranes.
Patients with evidence of IGT or abnormal OGTT before transplantation should be counseled on lifestyle modifications including weight control, diet, and exercise.
This includes the transport of vesicles containing the glucose transporter GLUT4, because GLUT4 translocation to the plasma membrane is a pre-requisite for efficient glucose uptake in skeletal muscle and other tissues. The goals for the life-style modification involved achieving and maintaining a weight reduction of at least 7 percent of initial body weight through a healthy low-calorie, low-fat diet and at least 150 minutes of physical activity per week.
In the nucleus, the AMPK-mediated modification of transcription factors, transcriptional regulators and a subunit of RNA-polymerase I control the expression of genes that are implicated in specific anabolic and catabolic reactions. Selection of an immunosuppressive regimen should be tailored to each individual patient, weighing the risk of developing diabetes after transplantation against the risk of acute rejection.
The phosphorylation of several of these targets is also critical to the biogenesis of mitochondria and the assembly of ribosomes. Early detection of NODAT after transplantation Studies investigating the best predictive tool for identifying patients at risk for developing NODAT early after transplantation are currently lacking.
While fasting plasma glucose (FPG) is readily available in clinical practice it may be normal in kidney transplant recipients with abnormal glucose homeostasis. It has been suggested that transplant patients have an atypical form of insulin resistance and their plasma glucose often peeks before lunch. See text and Table 3 for details.Given the diverse types of AMPK substrates and their presence in different cellular locations, it is helpful to recapitulate their functions (Table 3a).
This knowledge is a prerequisite to understand how the dynamic association and action of AMPK in different compartments will impact downstream events.Substrates that have been established for AMPK heterotrimers that contain the ?1 or ?2 subunit are shown. For different AMPK substrates the function, effect of AMPK-dependent phosphorylation and the major subcellular localization are depicted.
For some substrates, there are cell-type specific differences, and the effect of AMPK-dependent phosphorylation may not be fully understood or controversial. However, it is noteworthy that while acute rejection has been suggested to increase the risk for NODAT, it usually does not occur before day 5. Obtaining OGTT and FPG at day 5, therefore, may preclude the subset of patients with higher risk of developing NODAT.
Hence, it has been suggested that performing OGTT at 10-12 weeks post-transplantation might be useful as an alternative or supplementary test to day 5 OGTT (P.T. The routine recommendation of performing an OGTT early after transplantation awaits further studies.
Suggested pre-transplant baseline evaluation and post-transplant screening for NODAT is shown in Figure 2. Management of established NODATThe management of NODAT should follow the conventional approach for patients with type 2 diabetes mellitus as recommended by many clinical guidelines established by well-recognized organizations including the American Diabetes Association (ADA).
Nonetheless, it should be noted that the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was discontinued prematurely because of a satistically significant increase in all-cause mortality in the intensive- compared with the standard- glycemic treatment groups (Gerstein et al., 2008). Study similar to that of the ACCORD study in recipients of solid organ transplantation is lacking. Nonetheless, the determination of hemoglobin A1C target levels for solid organ transplant recipients should be individualized based on hypoglycemia risks.
Dietary modification and physical activityThe Diabetes Prevention Program has demonstrated that a structured diet and physical activity program that achieves and maintains modest weight loss for overweight adults with IGT can significantly reduce the development of diabetes.
Defining realistic goals such as a target weight loss of 5-10% of total body weight and patient- centered approach to education may be invaluable in achieving success. Modification of immunosuppressionModification of immunosuppression should be considered in high-risk patients.
Corticosteroid dose reduction has been shown to significantly improve glucose tolerance during the first year after transplantation (Kasiske et al., 2003).
Steroid-sparing regimen or steroid avoidance protocol should be tailored to each individual patient. Tac to CSA conversion therapy in patients who fail to achieve target glycemic control or in those with difficult to control diabetes has yielded variable results. Belatacept -- a selective T cell costimulation blocker, is a promising new immunosuppressant that has been suggested to have better cardiovascular and metabolic risk profiles compared with cyclosporine (lower blood pressure, better lipid profiles and lower NODAT incidence) (Vanrenterghem et al., 2011).



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