Mellitus is a complex illness caused by genetic and environmental
factors that control either energy and nutrient metabolism, or the
susceptibility to the development of an autoimmune process that
destroys the insulin-secreting beta cells of the pancreatic islets,
described further below. Morbidity and mortality are due primarily to
microvascular complications in the retina, kidney and peripheral
nervous system, and to atherosclerosis. Current therapies are now
evolving at rapid rate, however the burden of this illness continues to
increase. The research programs serviced by the Boston Area Diabetes
and Endocrinology Research Center (BADERC) in aggregate, address most
of major problems arising from Diabetes Mellitus and its complications,
across the spectrum from laboratory-based cellular and molecular
biology relevant to metabolic regulation and the function of the immune
system, to animal models of autoimmunity, metabolic dysfunction and
vascular disease, to translational research on human subjects.
Type 1 diabetes is caused by severe insulin deficiency; Type 1A is an autoimmune disease wherein the beta cells of the pancreatic islet are destroyed during an asymptomatic interval of years by a T cell-mediated immune process, whose activity can be detected indirectly and in a qualitative manner by the measurement of circulating antibodies to islet polypeptides e.g., insulin, glutamic acid decarboxylase, etc. and more recently by the detection of pathogenic T cells through the use of MHC tetramers loaded with appropriate peptides. Despite the discovery of AIRE1 transcriptional regulator as the gene mutant in the type 1 autoimmune polyglandular deficiency syndrome, the pathogenesis of autoimmunity in typical human Type 1 diabetes remains elusive. Hyperglycemia develops when the loss of beta cell mass has progressed to well over 90% of initial levels. This syndrome, previously called juvenile diabetes, has a peak incidence in early adolescence, but occurs throughout life and accounts for perhaps ten percent for all diabetes. Prior to the discovery of insulin, Type 1 diabetes was uniformly fatal within days to months from the onset of hyperglycemia; patients expired in a state of skeletal emaciation, drifting into coma from ketoacidosis or succumbing to overwhelming intercurrent infections. Insulin, discovered by Banting and Best in 1921, provided an apparently miraculous cure, restoring nutrient metabolism to near normal, and enabling heretofore doomed subjects to resume nearly normal lives.
By the 1950's, the advent of intermediate-acting insulins, an increasing sophistication in the treatment of diabetic ketoacidosis, the arrival of antibiotics and improvements in obstetric and surgical care led to a public perception that the excessive mortality of Type 1 diabetes had been brought under control. A very different reality, however, confronted patients and physicians as the realization dawned the insulin had not "cured" Type 1 diabetes. Thus, after the passage of 10-15 years, otherwise well-appearing, relatively young Type 1 diabetics experienced an accelerating accumulation of complicating conditions such as ischemic retinopathy leading to blindness, renal failure, myocardial infarction, stroke and the remarkably frequent occurrence of lower limb amputation required for control of neuropathic ulcers complicated by infection and vascular insufficiency. The abrogation of early mortality was now seen to have uncovered the existence of a set of late complications whose impact in suffering was considerable, whose lethality, although delayed still occurred prematurely, and whose burden of medical care in terms of cost was radically greater than that engendered by the rapidly fatal illness of the preinsulin era. Insulin, miraculous as its discovery was, can now in retrospect be seen as the original "halfway" technology of the sort that medical economists speak of with derision; a partial therapy that postpones but does not eliminate disease-specific adverse outcomes, and thereby introduces large new costs. The results of the Diabetes Control and Complications Trial published in 1993 provided the first indisputable evidence in man that control of glycemia will ameliorate the prevalence and progression of the microvascular and neuropathic complications; only recently has followup demonstrated that tight glycemic control also reduces nonfatal MI, stroke and overall cardiovascular mortality to an extent comparable to that achieved for microvascular complications.
Certainly, the introduction during the last two decades of a variety of new insulins and the application of the more aggressive strategies first widely implemented by the DCCT has been accompanied by a significant improvement in hemoglobin A1c levels in the Type 1 population at large. The most widely heralded advance in the treatment of Type 1 diabetes of the last decade was the report in 2000 from the Edmonton group describing their success in achieving insulin-independence after islet transplantation. The “Edmonton” protocol involved improved methods of islet isolation together with a steroid-free immunosuppressive regimen and multiple donors/islet infusions. These modifications, although basically incremental in the context of the evolution of islet transplantation over the past 30 years, were nevertheless reported to yield independence from exogenous insulin in 80% of patients at one year, a rate previously achieved only with whole pancreas transplants or islet isografts into non-autoimmune recipients. The subsequent multicenter trial reported a lesser rate of insulin-independence at one year (16/36, 44%) of whom only 5 remained insulin-independent at two years, rates consistent with our local experience (directed by Dr. E. Cagliero, MGH), in collaboration with H. Auchincloss, MGH). After a lapse, the MGH recruited Dr. James Markmann as clinical director of transplantation; Dr. Markmann has reestablished a vigorous human islet isolation facility on the MGH campus which provides human islets through a JDRF program to investigators in the BADERC and across the country for use in basic research investigations. Moreover, further refinements in pancreas storage, islet isolation and patient preparation proceed.
Neverthess, the viability of islet transplantation for the treatment of Type 1 diabetes remains seriously limited by the low availability of human islets and the need for lifelong immunosuppressive therapy for allo- and autoimmunity. Thus major goals in this area involve the identification of new sources of functional beta cells, together with efforts to overcome transplant rejection as well as cure anti-beta cell autoimmunity through means that avoid the need for life-long immunosuppressive drug therapy. A wide variety of approaches toward these goals are underway, and provide a major focus for several of the investigators whose efforts are amplified by the BADERC. An attractive approach for the development of tolerance is through non-myeloablative methods of generating chimerism, a long term interest of M. Sykes (MGH); her group reported that the induction of mixed hematopoeitic chimerism in the NOD mouse enables the permanent engraftment of islet allo- and (NOD) isografts. Immunomodulatory strategies, such as costimulatory blockade, anti-CD3 mAbs and selective targeting of activated/pathogenic T cells are also widely pursued; BADERC investigators active in this area include D. Faustman (MGH, TNFR2-induced apoptosis of pathogenic CD8+ T effector cells combined with lymphoid “reeducation”), D. Hafler (BWH, IL-4 expression; Th1/Th2 development), H. Weiner (BWH, oral tolerance) and S.B. Wilson (MGH, modulation through CD1-restricted T cell subsets). A critical deficiency in our ability to translate novel therapies directed against beta-cell autoimmunity developed in model systems into the human Type1 diabetic or prediabetic populations is a lack of assays that monitor, in a quantitative way, the activity of T-cell mediated autoimmune attack in vivo. Faustman, is actively developing such assays along with automated, magnetic T cell isolation techniques, and in collaboration with D.M. Nathan (MGH) are applying these isolation techniques and assays of T cell pathogenicity (based on prior work in the NOD system) in a clinical trial of BCG in patients with longstanding T1DM. Independently A. Moore (MGH) and colleagues are developing methods for the in vivo imaging of islet-directed, activated T cells.
A particularly striking result was the finding of D. Faustman and colleagues that reversal of autoimmunity in NOD mice with established hyperglycemia, achieved by an immunomodulatory protocol involving administration of CFA and MHC-1-matched, non-NOD splenocytes, was accompanied by the return of normoglycemia due to the reappearance of functional beta cells, apparently through regeneration; although all investigators detected a recovery of beta cell function in a substantial fraction of NOD mice so treated, Faustman and Mezey found that some of the recovered beta cells had derived from exogenous, spleen-derived precursors, whereas other investigators failed to detect such a contribution; the existence of beta cell precursors in the spleen remains an open question. Nevertheless, it is now clear from this body of work that beta cell regeneration, at least in the diabetic NOD mouse, is a definite occurrence, and is capable of substantial restoration of function if autoimmunity is successfully interrupted. Much effort is ongoing in both these areas-i.e., strategies for permanent interruption of autoimmunity and efforts to understand and harness beta cell regeneration. The mechanism of beta cell neogenesis during normal turnover or in the face of beta cell damage, as well as the nature of the precursor cell are topics of tremendous recent activity as well as great controversy. In addition to the work of Faustman, these questions are central to the research of J. Habener (MGH), BADERC associate director, and D. Melton (Harvard A&S). Habener’s group is pursuing the hypothesis that human beta cells can partially dedifferentiate into a proliferative cohort that can nevertheless resume adult status in vivo or in vitro, given appropriate conditions. Melton and colleagues have demonstrated that “new” beta cells in the adult mouse arise predominantly from the replication of preexisting beta cells, both in unstressed animals and in some models of beta cell ablation; interestingly, this regeneration is suppressed by rapamycin and FK506. Others, e.g S. Bonner-Weir at the Joslin research labs, have pointed the pancreatic duct as the likely source of beta cell precursors and this is well supported in the model of pancreatic duct ligation.The efforts of these groups, together with work from many other investigators here and elsewhere, such as M. Thomas (MGH), working on the developmental biology of the beta cell, on transdifferentiation of acinar cells into beta cells, or on using xenogeneic sources (M. Sykes, MGH) is likely to make strong inroads into the problem of beta cell regeneration and availability for transplantation. It is important to mention that Harvard university has invested heavily in stem cell research through the creation of the Harvard Stem Cell Institute (HSCI), and its Diabetes Program <http://www.hsci.harvard.edu/diabetes-program-overview>, which includes several BADERC investigators, is led by Gordon Weir, director of the Joslin DERC. The HSCI core facilities are located at Joslin, MGH and Boston Children’s hospital, and apart from flow cytometry, provides services largely non-overlapping with those offered by the BADERC cores.
TYPE 2 DIABETES
The vast majority, perhaps 90% of patients with diabetes can be classified as Type 2, or non-insulin dependent diabetes (NIDDM). This is a disease of late-middle and older age, however the increasing prevalence of obesity at all ages has been accompanied by a substantial increase in the prevalence of Type 2 diabetes in adolescents and young adults. Type 2 diabetes affects 1/15 individuals of Caucasian ancestry over age 40, perhaps 1/10 individuals of African-American or Hispanic origin, and nearly 1/3 native Americans (2).
In contrast to the uncertainty as to the pathogenesis of anti-beta cell autoimmunity in Type 1 diabetes, there has been general agreement for some time as to the pathogenesis underlying Type 2 diabetes: a prevalent underlying tendency toward insulin resistance, intensified by the development of obesity and physical deconditioning, combines with an inadequate compensatory beta cell response leading to impaired glucose clearance; mild, initially postprandial hyperglycemia further impairs the beta cell response, so as to generate a positively reinforcing progression toward sustained hyperglycemia. The question as to the “primacy” of insufficient insulin secretion or impaired insulin action had been debated since the work of Himsworth in the 1930’s and was intensified after the pioneering studies of Berson and Yalow showed that insulin levels in Type 2 diabetics were often in excess of those found in nondiabetic individuals . It is now clear that when any degree of abnormal glucose tolerance is present, both impaired insulin secretion and action are detectable, and the development of frank fasting hyperglycemia almost always requires considerable impairment of both insulin secretion and action. In the hyperglycemic Type 2 diabetic, the hyperglycemia itself contributes substantially both to faulty beta cell function and impaired insulin action, but correction of the hyperglycemia leaves behind unmistakable defects in both limbs, as is true in individuals who have only impaired glucose tolerance. Studies of genetically susceptible populations prior to the development of abnormal glucose tolerance has shown evidence for impaired insulin action as the consistent, unequivocal precursor abnormality; evidence for impaired insulin secretion in the prehyperglycemic interval is much less compelling, but certainly available in the form of subnormal beta cell responses to high or low-dose glucose challenge, or altered periodicity in basal insulin release. Such individuals maintain normal glucose tolerance during early life by hypersecreting insulin in response to minimal hyperglycemia, within the “normal” range. With time, insulin resistance worsens due to an excessive caloric intake with the development of obesity, and deconditioning of skeletal muscle metabolism resulting from a progressively sedentary existence. Beta cell responsiveness declines, due to the development of minimal hyperglycemia per se, or due to some toxic concomitant of chronic insulin hypersecretion such as a amylin deposition, or perhaps due to factors that are genetically determined e.g., an intrinsic secretory defect, an initially small beta cell mass, or a limited beta cell replicative capacity, etc. The development of hyperglycemia itself then leads to further impairments in insulin secretion and action, in a positively reinforcing, feed-forward manner. This formulation does not gainsay the potential for a primary role for beta cell deficiency in pathogenesis, a circumstance amply illustrated in several of the MODY syndromes, nor does it address whether the beta cell deficiency arises from the same genetic aberrations as the insulin resistance, entirely independent causes or entirely as a secondary consequence. Nevertheless, insulin resistance is the common, readily detected precursor state in ethnically diverse populations, both in developed and developing countries.
As demonstrated by the Diabetes Prevention Program, the progression from impaired glucose tolerance to Type 2 diabetes, i.e., persistent hyperglycemia, can be interrupted or at least delayed by the adoption of a more physically active, calorically restricted lifestyle, or by the use of Metformin. Once persistent hyperglycemia appears, current treatment involves efforts toward reducing overall calories so as to cause weight loss, thereby reducing the component of insulin resistance attributable to obesity, decreasing or delaying the absorbtion (with a-amylase inhibitors) of the carbohydrate-derived caloric load. The most widely used oral antidiabetic medication is Metformin, which may act in part through activation of the AMP-activated protein kinase; thiazolidinediones, which ameliorate insulin resistance by their ability to serve as an agonist for the PPARg transcriptional regulators, are also significant agents. Supplementing insulin action through administration of additional insulin or by using sulfonylureas, which readjust the threshold for glucose-stimulated insulin secretion, is necessary in the majority of patients.
The most remarkable advance in research relevant to Type 2 diabetes during the past five years has been the discovery, starting in 2007, of genetic loci that occur with increased frequency in T2DM. These loci were identified through Genome-wide association studies, discoveries enabled by the SNP catalogue assembled by HapMap consortium, led by David Altshuler and colleagues, and the consequent elucidation of the bloc structure of the human genome. The excess occurrence of such SNPs in subjects with T2DM presence is presumed to indicate the presence of excess risk ; the strongest effect is observed with the TCF7L2 loci identified by DeCode Genetics, with an excess risk of ~1.4 fold. As the number of genomes analyzed increased, the number of statistically confirmed loci increased in parallel, reaching 17 with the report in 2008 and likely to increase further. All of these confer a lower calculated excess risk, as low as 1.09 fold; moreover, 9/17 loci are clearly intronic and another three are far (7.7-125 kb) outside of coding regions so the biological significance is questioned by some. Thus, the challenge is in establishing the biologic significance of these loci. Notably, the PPARg(P12A) and the predisposing effect of the Kir6.2(E23K) (linked with SUR1(A1396) polymorphisms , previously detected by candidate gene approaches, were also detected in these screens, supporting the likelihood that other loci will prove relevant. Detractors complain that these discoveries do not as yet aid in diagnosis or in the choice of therapies, and further identification of even weaker loci is no longer justified. Advocates argue that the identification of further loci may enable visualization of novel pathways relevant to pathogenesis or drug development, and point to the identification of the MTNR1B (melatonin receptor 1B) as an example of previously unanticipated insights. This is a healthy debate and a formidable challenge; certainly additional GWAS in further diabetes prone populations (e.g., PCOS-C. Welt) will proceed, as well as genomic wide analyses of gene copy number, deletions and microRNA loci. Along with major effort to elucidate the biologic significance of these loci (Altshuler and colleagues at MGH, Broad and beyond), efforts to provide the clinical translation of these discoveries (J. Florez) will accelerate, through the collaboration of geneticists (Altshuler, Florez) with clinical trialists (Nathan) and epidemiologists.
The remarkable increase over recent generations in the incidence of Type 2 DM has provided a startling illustration of the importance of obesity in determining whether this genetic susceptibility will be manifest clinically as hyperglycemia. The science of obesity was transformed with the discovery of Leptin and the subsequent elucidation of the neural circuitry controlling food intake and energy expenditure. Although there is a very active network of obesity investigators in the Boston/Cambridge area, that effort is supported primarily by the Boston Obesity/Nutrition Research Center; the interests of the BADERC investigators are directed primarily toward the problem of how obesity, i.e an overfilled adipocyte depot, promotes insulin resistance and vasculopathy.
A major shift in thinking over the past few years has come from the definition and the development of widespread interest in the Metabolic Syndrome, which has emerged as the essential link between obesity, impaired glucose tolerance and excess atherogenic risk. The most important cause of morbidity and mortality for the Type 2 diabetic patient is the excessive and premature occurrence of athersclerotic cardiovascular disease. It is well known that the risk for atherosclerosis in the nondiabetic population is largely attributable to a set of factors that act in a multiplicative way including (classically) smoking, hypertension and high LDL cholesterol; a low value of HDL cholesterol is now also recognized to confer an independent and powerful risk in addition to that conferred by high LDL cholesterol. Much evidence indicates that obesity also confers an independent risk, even when corrected statistically for the impact of these known intermediates. It is clear from epidemiologic observations that hyperglycemia per se is an independent risk factor for atherogenesis, and experimental studies provide evidence for multiple sites at which hyperglycemia, acting through non-enzymatic glycosylation and perhaps other mechanisms, can affect adversely lipid metabolism, the cellular constituents of the vessel wall, as well as the function of platelets and the clotting and fibrolytic system. Given the high prevalence of the risk factors for atherosclerosis in the population at large, it would not be surprising that the superimposition of sustained hyperglycemia, especially when combined with obesity as is common in the Type 2 syndrome, would be associated with excessive atherogenesis. Nevertheless, this formulation significantly understates the unusually high susceptibility to atherosclerosis experienced by the Type 2 diabetic, especially the female diabetic; the relative protection from atherosclerotic cardiovascular disease seen in women is abolished by diabetes. Moreover, hyperglycemia per se appears to contibute only modestly to the overall atherogenic risk of the Type 2 diabetic, a conclusion presaged by the results of the UGDP study, wherein despite excellent control of fasting glycemia in the treatment group that received insulin in variable dosage, no improvement in any endpoint related to macrovascular disease was observed after 7-10 years follow-up as compared to the hyperglycemic, placebo-treated group; in this group of obese elderly (mostly) females, hyperglycemia per se was a relatively modest contributor to overall cardiovascular risk. Only recently has it been possible to show that cntrol of glycemia has a positive impact on cardiovascular mortality, and then only in the setting of a multi-interventional approach.
Several kinds of evidence indicate that substantial atherogenic risk accrues to the Type 2 population prior to the appearance of hyperglycemia. Many long term studies of populations who exhibit impaired glucose tolerance (IGT), the large majority of whom (60-70%) never progress to exhibit a degree of hyperglycemia sufficient to merit a diagnosis of Type 2 diabetes, have shown that the prevalence of atherosclerosis is at least half of, and often approaches that of populations with frank Type 2 diabetes. Reciprocally, if one begins with populations selected for the occurrence of atherosclerosis, a commonly occurring phenotype emerges, that includes impaired glucose tolerance (IGT), mild hypertension, obesity (especially abdominal obesity), serum lipid abnormalities (high triglycerides, low HDL, small, dense LDL particles, VLDL remnants), and microalbuminuria. Moreover, serum markers typical of a low-grade inflammatory state, such as C-reative protein and IL-6, and hemostatic markers, such as tPA and PAI, are commonly elevated. Thus, the epidemiologic data indicates that this cluster of phenotypes, the “Metabolic syndrome” identifies a population at risk not only for diabetes but for the presence of premature atherosclerotic vascular disease, the primary basis for the excess and premature mortality associated with Type 2 diabetes. The progression to sustained hyperglycemia introduces additional proatherogenic and prothrombotic conditions that further accelerate the atherosclerotic process and entrain the unique microvascular abnormalities shared by Type 1 and Type 2 diabetics.
As to the initiating stimulus for this Metabolic syndrome, Reaven proposed that insulin resistance is the unifying underlying factor. Another, very different and novel hypothesis was offered by Hales and Barker who pointed out the correlation of low birth weight with subsequent atherosclerosis, and proposed a defect in early nutrition as a crucial initiating event, impairing beta cell development and somehow setting in motion the precursors of the insulin resistant/ atherogenic syndrome. Most investigators currently consider central obesity, acting through the provision of excess FFA and adipokines, vasoactive and prothrombotic factors, as the progenitor of the insulin resistant, proinflammatory and prothrombotic state. Nevertheless, among those with the Metabolic Syndrome are a substantial minority of nonobese individuals. Although the factors important to the pathogenesis of insulin resistance in the absence of abdominal obesity are poorly understood, the identification of nonobese, hypertensive, insulin resistant subjects who carry a defective or dominant interfering mutant alleles of PPARg ) indicates that this transcription factor (the receptor for the thiazolidinedione antidiabetic drugs) and its target genes, presumably as well as its coactivators (especially PGCIa, a primary determinant of mitochondrial oxidative capacity,66) and upstream regulators (such as the transcription factors SREBP-1c/ADD-1and FoxO-1 or FOXC2) are likely to be central determinants of insulin sensitivity in vivo, independent of the presence of an elevated BMI. Notably, the PPARg mutations are accompanied by a mild peripheral lipodystrophy, consistent with the role of this transcription factor as a major regulator of adipocyte differentiation. Clearly much more work is needed at all levels to enable a useful understanding of how dysfunction of the adipocyte, particularly those in the visceral depots, whether due to overfilling and/or genetic abnormalities, entrains this prevalent and insidious syndrome of insulin resistance, hypertension and atherogenesis.
The work of the majority of BADERC participants is focussed on the problems surrounding the basis for insulin resistance, the pathogenesis of metabolic syndrome and its vascular sequelae as well as the complications of hyperglycemia. The work in aggregate encompasses studies of the cellular and molecular mechanisms underlying metabolic regulation, insulin resistance and vascular cell function; studies in intact mammalian organisms, often genetically modified, that are necessary to model the complex interorgan feedback systems that control nutrient utilization in vivo or the multicellular interactions that underlie atherogenesis; to studies of human subjects, including genetic analysis, development of new biomarker and imaging methods for the diagnosis of vascular insufficiency or injury, clinical physiology and interventional studies. A large cohort of BADERC participants continue to study the signal transduction pathways that mediate the actions of insulin (Avruch, Ruvkun), or insulin-sensitizing factors such as leptin and adiponectin (Lodish) as well as counter-insulin factors, including nutrient (esp. FFA; Corkey, Ruderman), humoral (such as TNFa; Hotamisligil, Lodish, Seed) and other stresses (Shi (mast cells], Soberman [eicosanoids]). Substantial effort is directed at the mechanism of insulin-stimulated glucose transport (Lodish,), nutrient partitioning in skeletal muscle and its transcriptional regulation (Ruderman, Spiegelman), the recently appreciated importance of the AMP kinase in energy economy in vivo ( Ruderman, Saha), the transcriptional control of adipogenesis (E. Rosen, Spiegelman) and mitochondrial biogenesis and function (Altshuler, Mootha, Lowell, Spiegelman). BADERC investigators work on a variety of problems in vascular biology relevant to diabetes, such as microvascular development (D’Amore) and function in the hyperglycemic milieu (Cohen); the impact of insulin resistance, hyperglycemia and oxidant stress on arterial endothelial function and NO biology, examining both in vitro models and humans in vivo (R. Cohen, Libby, Rosenzweig); in vivo models of atherogenesis, with and emphasis on the role of inflammatory mediators (Freeman, Libby); the molecular basis of the myocardial response to ischemic and other stress (Rosenzweig, Gerszten). Several investigators focus on aspects of renal cell and molecular biology (Arnaout, Bonventre, D. Brown, Lin ). The work of the BADERC investigators designated “translational” is unified by the fact that their research requires direct contact with human subjects, or depends almost entirely on the analysis of materials (usually cells or DNA) obtained from human subjects; nevertheless, the activities of this cohort are diverse. Perhaps the easiest to describe are the human geneticists; the work of D. Altshuler, and colleagues on T2DM at the Broad institute and MGH, was described above; his colleague and former trainee Jose Florez is committed to the clinical translation of these discoveries. As well, the Althsuler group is heavily committed to GWAS focused on cardiovascular diseases and lipid disorders. G. Williams and colleagues are taking a more focused, candidate gene approach to uncover the genetic susceptibilities to premature cardiovascular disease in diabetic populations, starting with their long-term interest in the renin-angiotensin-aldosterone system. C. Welt in collaboration with scientists at DECODE, are engaged in seeking the genes associated with the metabolic syndrome and other phenotypes that characterize the Polycystic Ovarian Syndrome. Other BADERC investigators engage primarily in “clinical physiology”, observational or short term perturbational studies in human subjects relevant to nutrient metabolism or neuroendocrine responses (Grinspoon, Nathan, B.). Finally, several investigators are involved almost exclusively in longer term interventional studies (Cagliero, Nathan, Pittas) or in technology development for diagnosis or therapy (Gerszten). The BADERC, through its core services, has provided a component of the technical support that enables this diverse array of outstanding investigators to contribute effectively to the body of diabetes-related research, and seeks to evolve its services to match the needs that arise.