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Minireview: Pharmacogenetics and Beyond: The Interaction of Therapeutic Response, ß-Cell Physiology, and Genetics in Diabetes

Peninsula Medical School (A.T.H., E.R.P.), Exeter EX2 5DW, United Kingdom; and Ninewells Hospital and Medical School (E.R.P.), Dundee DD1 9SY, Scotland, United Kingdom

Address all correspondence and requests for reprints to: Dr. Andrew T. Hattersley, Peninsula Medical School, Barrack Road, Exeter EX2 5DW, United Kingdom. Email: a.t.hattersley{at}exeter.ac.uk.

	Abstract

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Defining the molecular genetics of diabetes gives new insight into the underlying etiology and so should help improve treatment. The genetic etiology is now known for most patients with ß-cell monogenic diabetes, allowing genetic classification. We review how this genetic knowledge alters treatment. Patients with a glucose-sensing ß-cell defect due to glucokinase mutations have regulated, mild, fasting hyperglycemia. Oral hypoglycemic agents or low-dose insulin rarely improve glycemic control. Patients with hepatic nuclear factor-1 (HNF1) mutations have progressive ß-cell deterioration and require treatment. HNF1 patients are 4 times more sensitive to sulfonylureas than matched type 2 diabetic patients. This is partly due to greater insulin secretion, reflecting the fact that the defect in HNF1 deficiency precedes the K_ATP channel where sulfonylureas act. HNF1ß is expressed in pancreatic stem cells before differentiation into endocrine or exocrine cells, so patients with HNF1ß mutations have reduced pancreatic development, resulting in early-onset diabetes and exocrine dysfunction. These patients usually rapidly require insulin and are not sensitive to sulfonylureas. Thirty-five to 50% of patients diagnosed with diabetes before 6 months have a mutation in Kir6.2. The mutated K_ATP channel in these patients does not close in response to increased ATP concentrations, but can be closed when sulfonylureas bind to the sulfonylurea receptor 1 subunit of the channel by an ATP-independent route. These patients are usually insulin dependent, but have excellent glycemic control on high-dose sulfonylureas tablets. In conclusion, the defining of molecular genetic etiology in monogenic diabetes has identified several specific ß-cell defects, and these are critical in determining the response to treatment.

	Introduction

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DEFINING THE MOLECULAR basis of genetic susceptibility to type 2 diabetes is one approach to trying to define the primary defect(s) of a condition that affects more than 150 million people worldwide. Recent improvements in our ability to analyze large numbers of samples for multiple single nucleotide polymorphisms offer exciting new opportunities in this area of research. The large capital outlay required can be justified by the idea that identified etiological pathways will represent ideal drug targets and may lead to new therapies for treatment and prevention of type 2 diabetes. A similar, but importantly different, concept is that advances in molecular genetics will play a key role in defining heterogeneity between subgroups of diabetic patients. At present, the molecular genetics of type 2 diabetes are incompletely understood, so neither of these possibilities is as yet a reality. However, defining the genes involved in monogenic diabetes has provided clear evidence of improved and individualized treatment.

	Progress in Monogenic Diabetes in Defining Genes and in Pharmacogenetics

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Maturity-onset diabetes of the young (MODY) and neonatal diabetes were clinically defined conditions, but are now recognized as consisting of multiple discrete subtypes defined by genetic etiology. The definition of genetic subtypes has helped, because it has allowed us to define patients who respond well to a particular therapy and those who are unlikely to respond. This allows the possibility of individualizing therapy rather than basing results on a group response for type 1 or type 2 diabetes. This approach is referred to as pharmacogenetics when a different genetic etiology results in a different therapeutic response.

A recent review of pharmacogenetics identified diabetes as one of the few areas in medicine where defining genetic etiology led to a direct improvement in treatment (1). There has been an explosion in defining the genetic etiology of monogenic disorders throughout medicine, so why are there not more examples of a direct therapeutic benefit? There are many different reasons: in some areas etiological and therapeutic advances preceded the definition of the molecular genetics, e.g. in phenolketonuria; the genetic etiology may not be amenable to a pharmacological modification, e.g. a mutated transcription factor altering early development; or there is insufficient profit due to low subject numbers to enable the pharmaceutical industry to justify the costs of new drug development, and there are no established agents.

The aim of this review was to concentrate on what we have learned about the therapeutic response by defining the etiology of monogenic diabetes. This has given many insights into the interaction among the study of molecular genetics, human physiology, and molecular pathophysiology. The emphasis will be on the monogenic ß-cell disorders, which are clinically recognized as MODY and neonatal diabetes. In these examples, the therapeutic response both reflects and improves our understanding about pathophysiology. These monogenic examples are important, because they illustrate that different etiologies of ß-cell defect will respond very differently to therapy. The inaccessibility of the pancreas in humans means that inevitably most mechanistic studies must be performed on cell lines or experimental animals. However, the existence of accidents of nature resulting in ß-cell dysfunction due to mutations in critical ß-cell genes has enormously helped the integration of animal and cellular work with observations in humans (2).

	Progress in Molecular Genetics of Monogenic Diabetes Affecting the ß-Cell

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MODY
MODY was initially recognized as autosomal dominantly inherited diabetes, characterized by ß-cell dysfunction, that despite being diagnosed young (typically before the age of 25 yr), was not insulin dependent (3, 4). Now in the majority of patients, the molecular genetic etiology can be defined (5, 6). Seven genes have been implicated in MODY (see Fig. 1), with by far the most common subgroup resulting from mutations in the genes encoding the glycolytic enzyme glucokinase, and the transcription factor hepatic nuclear factor-1 (HNF1) (7, 8). The definition of the molecular genetics has led to the recognition that the molecular genetic subgroups have different phenotypes (6). In all cases, the clinical phenotype was not recognized until after the genes were defined. The most striking example of this are mutations in the gene encoding HNF1ß that led to the definition of the novel syndrome of renal cysts and diabetes and the recognition that mutations and whole-gene deletions were a common cause of previously undefined renal developmental disorders (9, 10).

View larger version (26K): [in this window] [in a new window]   FIG. 1. Diagram showing how previously clinically defined conditions, 1) MODY and 2) neonatal diabetes, can now be defined by their molecular genetic etiology. [Data for the MODY diagram are from our laboratory, which provides diagnostic and research testing for the United Kingdom (56 ), and additionally from recent reports on carboxyl-ester lipase (CEL) (74 ) (Ellard, S., K. Colcough, S. Flanagan, and A. Hattersley, unpublished observations). Data for neonatal diabetes are from reviews by Singerland and Hattersley (11 ) and Polak and Shield (12 ), with additional information from S. Ellard, J. Minton, S. Flanagan, E. Edghill, A. Hattersley (unpublished observations)].

View larger version (12K): [in this window] [in a new window]   FIG. 2. Insulin secretion rates at different glucose values for different monogenic diabetes, showing that the etiology of the ß-cell defect determines the pathophysiology. [The diagram was adapted from Byrne et al. (21 29 ) and Gloyn et al. (15 ) and unpublished observations from Pearson and Hattersley.]

	Clinical Features, Pathophysiology, and Drug Response in Specific Monogenic Subtypes

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Therapeutic response
Patients with heterozygous glucokinase mutations do not need treatment, because they have only mild hyperglycemia, as reflected in a hemoglobin A_1c (HbA_1c) level that is at or slightly above the upper limit of normal. Patients are usually given treatment when they are misdiagnosed with type 1 or type 2 diabetes, which frequently happens. It also appears that if they are given either insulin or oral hypoglycemic medication, it has little effect on their glycemia. We found no differences in HbA_1c between those patients on and off treatment, and stopping pharmaceutical treatment in glucokinase patients did not result in deterioration of glycemic control. One interesting group that is frequently treated with insulin is mothers with gestational diabetes who have fasting hyperglycemia that does not respond to diet. We found that in the majority of patients, the birth weight of offspring (a surrogate of maternal glycemic control) was not altered regardless of whether the mother was insulin treated, but, in contrast, whether the offspring had inherited the glucokinase mutation made a massive difference in their birth weight (22, 23). Birth weight was only reduced by insulin when doses above a normal replacement dose (>1 U/kg) were used (24).

This work implies that with a pure glucose-sensing defect, as in glucokinase hyperglycemia, insulin and oral agents will have little impact. The key point is that glucose is still regulated, so if a person with a glucokinase mutation is given exogenous insulin, they will reduce their endogenous insulin secretion to maintain their glucose at their homeostatic set point. It will only be possible to lower fasting glucose by giving greater than the replacement doses of insulin. This may be very difficult, because glucokinase also plays a critical role in counterregulation in both the glucagon-secreting -cell and the hypothalamus. When making subjects with glucokinase mutations hypoglycemic with insulin, both the threshold for a counterregulatory response and the threshold at which insulin is secreted are set at higher glucose levels (25) (Spyer, G., A. T. Hattersley, S. Amiel, and K. M. MacLeod, unpublished observations).

	HNF1

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Clinical and pathophysiology
Patients with heterozygous mutations in HNF1 have progressive ß-cell deterioration and usually develop diabetes between 10 and 30 yr of age (20, 26). ß-Cell function declines before diabetes develops (27) and continues to decline after diabetes is diagnosed, resulting in increasing hyperglycemia and increasing treatment requirements (20). Therefore, these patients are at considerable risk of microvascular and macrovascular complications (28). Physiological studies have shown that initially insulin secretion is maintained at normal glucose values, but fails to raise adequately as the glucose concentration is increased (29). This means that in the early stages of the disease, it is possible to maintain fasting blood glucose levels, but when faced with a glucose challenge, the insulin secretion rate increases only slightly, resulting in marked postprandial hyperglycemia (29). This is clearly seen in the dramatic increase in blood glucose during an oral glucose tolerance test, with the 2 h glucose level frequently being more than 6 mmol/liter higher than the fasting level even when fasting glucose values are less than 6 mmol/liter (17).

Therapeutic response
One early observation was that HNF1 mutation patients were extremely sensitive to the hypoglycemic effects of sulfonylureas (30, 31, 32). This could present either with marked symptomatic hyperglycemia on the initiation of sulfonylurea therapy or a dramatic deterioration in glycemic control when sulfonylureas were replaced with the biguanide metformin (32). Initial reports were case reports or small series, but now there is evidence from a randomized cross-over trial in which glycemic responses to the sulfonylurea gliclazide and metformin were compared between patients with HNF1 mutations and patients with type 2 diabetes matched for fasting glucose and body mass index (33). For both medications, the dose was titrated to the maximum tolerated, and the impact on fasting glucose was measured over a 6-wk period. In type 2 diabetes, as predicted from meta-analyses of previous studies, the glycemic response was similar to those to metformin and gliclazide. In contrast, in HNF1, there was a 5-fold greater response to gliclazide than metformin, and the response to the sulfonylurea was 4-fold greater than that in type 2 patients (although the responses to metformin were similar) (33). This represents clear evidence for a pharmacogenetic effect, with mutations in HNF1 being specifically sensitive to the hypoglycemic effects of sulfonylureas. The finding of a specific pharmacogenetic effect enabled us to study patients who had been misdiagnosed with type 1 diabetes and had been treated with insulin from the time of diagnosis. We found that these patients, even after a mean of 20 yr of insulin treatment, were able to discontinue insulin therapy and be treated with sulfonylureas without risk of ketoacidosis (34). In many patients, the glycemic control was as good or better than it had been on insulin. The impact for patients discontinuing insulin therapy were considerable, and the clear financial and social benefits of discontinuing insulin therapy support the case for genetic testing (35).

Physiological studies have suggested that the response to sulfonylureas and the insulin sensitivity in HNF1 mutation patients is similar to, rather than better than, that in normal subjects, at least in most studies (36). Therefore, the improved glycemic response compared with type 2 diabetes reflects an enhanced response to sulfonylureas and normal insulin sensitivity, rather than an improvement in these parameters above that in nondiabetic subjects. Pearson and colleagues (33) investigated the pathophysiology of this observation by investigating the insulin secretory response to iv glucose and iv tolbutamide. They showed that patients with HNF1 mutations were not only more insulin sensitive (less insulin resistant) than type 2 diabetic subjects, but also had a greater insulin secretory response to sulfonylureas (33).

An explanation for the excellent response to sulfonylureas in HNF1 mutation patients is provided by studies performed in knockout animals and also in genetically manipulated cell lines. In studies of the HNF1 knockout animal, it was shown that there was a reduction in the key steps of glucose transport (glucose transporter 2) and metabolism (pyruvate kinase) (37, 38, 39). Studies in ß-cell lines have suggested that in addition to these two steps, mitochondrial metabolism is reduced (40, 41, 42). The key feature of all these defects is that they are upstream of the K_ATP channel. This means that as long as some ATP was present within the ß-cell, sulfonylureas would be able to close the channel, because this is downstream of the primary defect. This explains why these patients are sensitive to the hypoglycemic effects of sulfonylureas, but does not explain the progressive deterioration in ß-cell function that results in increasing hyperglycemia with age. The precise mechanisms for the chronic reduction in functioning ß-cell mass are uncertain.

	HNF1ß Mutations

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Clinical and pathophysiology
There are marked differences in the phenotype between patients with HNF1 and HNF1ß mutations. This is surprising considering the high degree of homology between the two transcription factors and the fact that they have a common binding site, but probably reflects the different timing and sites of expression. Although HNF1ß mutations were originally described as a form of MODY (43), it is now clear that the multiple roles of HNF1ß in early development mean that it is very rare for these patients to present with isolated diabetes (44, 45). In all families described to date, there has been evidence of developmental renal disorders, particularly renal cysts (9, 46, 47, 48, 49, 50). The most common clinical manifestation has therefore been termed renal cysts and diabetes (9). However, it is important to appreciate that this is a heterogeneous condition with other abnormalities, including uterine and genital anomalies, abnormal liver function tests, gout, and hyperuricemia, and possibly abnormalities of the gastrointestinal system, such as pyloric stenosis (9). There is considerable variation in the extent of the multiorgan involvement even with an identical mutation or a whole-gene deletion, including diabetes, which may present before 10 yr or around late middle age (10, 45).

HNF1ß mutations result in diabetes by causing both insulin resistance and ß-cell dysfunction. The insulin resistance is manifest by hyperinsulinemia, elevated triglycerides, and reduced high-density lipoprotein (51) and has been shown to be the result of discrete hepatic insulin resistance (52). There is a more rapid deterioration in ß-cell function than with HNF1 mutations, and diabetic ketoacidosis has been described (49). HNF1ß patients, unlike HNF1 patients, frequently have subclinical exocrine deficiency, and computed tomographic scanning shows marked pancreatic atrophy (53). This is consistent with reduced early development of the pancreas, and recently, it has been shown HNF1ß is highly expressed in pancreatic stem cells before differentiation into endocrine or exocrine cells (54). Additional evidence for an early role of HNF1ß in pancreatic development is that patients can present with neonatal diabetes (55), and reduced birth weight is a consistent finding is keeping with reduced insulin secretion in utero (Edghill, E., S. Ellard, and A. Hattersley, unpublished observations). Therefore, it appears that these patients normally have a reduced ß-cell mass due to reduced fetal development.

Pharmacological response
The difference in pathophysiology between HNF1ß and HNF1 is clearly seen in the response to therapy. HNF1ß mutation patients are more frequently treated with insulin (67%) compared with HNF1 mutation patients (31%) (56), and most patients rapidly require insulin treatment. There are no reported examples of these patients being sensitive to sulfonylureas. We have shown that the response to iv glucose and iv tolbutamide in patients with HNF1ß is similar to that in type 2 diabetic patients, but differs from that in patients with HNF1 mutations. This therapeutic response is consistent with a generalized reduction in ß-cell mass.

	Mutations in Kir6.2

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Clinical and pathophysiology
Mutations in the KCNJ11 gene encoding Kir6.2 have recently been shown to be the most common known cause of neonatal diabetes (15, 16). Heterozygous activating mutations, which are normally spontaneous, have been shown to be present in 30–50% of patients with diabetes diagnosed before 6 months of age. The mutations result in neonatal diabetes by making the K_ATP channel less likely to close in the presence of ATP. This results in reduced potassium efflux, which, in turn, hyperpolarizes the ß-cell membrane, reducing insulin secretion. Mutations that are functionally less severe than those causing permanent diabetes result in transient diabetes that resolves after 12–24 months, but may subsequently relapse (57). The most functionally severe mutations cause neurological features with a clinical picture referred to as DEND syndrome (developmental delay, epilepsy, and neonatal diabetes) (16, 58, 59). Most patients with activating KCNJ11 mutations have diabetes that is insulin dependent; they present with marked hyperglycemia or ketoacidosis, and C peptide is not measurable even when stimulated with glucagon (15). However, it is likely that the insulin deficiency is not absolute, because presentation may occur between 1 and 6 months after birth (16).

Pharmacological response
Before the etiology of their diabetes was defined, all these patients were treated with insulin and responded like type 1 patients, because there was negligible endogenous insulin secretion. Defining the etiology instantly revealed the possibility that these subjects might secrete insulin in response to sulfonylureas, which bind to the sulfonylurea receptor 1 on the K_ATP channel and close the channel through an ATP-independent route. Excitingly, in initial physiological studies these patients had no insulin secretory response to glucose or glucagon, but did secrete insulin in response to tolbutamide (15). Another observation that supported using sulfonylureas in these patients was the observation that one 46-yr-old patient with a KCNJ11 mutation had been treated with sulfonylureas from diagnosis at 3 months of age and had the best glycemic control of any patient in the series (15). Sulfonylurea therapy has been tried in many patients with KCNJ11 mutations. In all reported cases there has been an improvement in glycemic control (60, 61, 62, 63). This has been shown not only by a reduction in long-term glucose concentration, reflected by a fall in HbA_1c levels, but also by a reduction in hypoglycemic episodes. Twenty-four-hour glucose monitoring has shown that many patients have excellent glycemic control during meals, suggesting that the insulin secretion is appropriately responsive to the amount of food eaten (63). This overcame initial concern that sulfonylurea therapy might result in unregulated insulin secretion, because sulfonylurea receptor 1-mediated K_ATP channel closure might prevent the channel from responding to altered ATP concentrations resulting from varying glucose concentrations through the classical pathway. Recent work has found that with sulfonylurea therapy, the insulin response to oral glucose is far greater than that to iv glucose, suggesting that the improved glycemic control is a result of incretins, such as glucagon-like peptide-1, produced by L cells in the gut in response to meals (Pearson, E. R., and A. T. Hattersley, unpublished observations). We propose that sulfonylureas cause partial closure of the K_ATP channel, which means that the ß-cell membrane is no longer fully depolarized, and therefore, it is able to respond to other stimuli, particularly glucagon-like peptide-1, which is released with food. Additional studies are needed, but early results strongly support the idea that incretins and other alternative pathways that stimulate insulin secretion are required for excellent glycemic control.

	Drug Targets and the Genetics of Type 2 Diabetes

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The finding that the genetic predisposition to type 2 diabetes results from variation in a gene suggests that it is unable to compensate for changes in expression or structure of the encoded protein. Therefore, the encoded protein is an ideal target for drug therapy, because altering the action of this protein, in the appropriate direction, could result in an improvement in diabetes even if it is not the primary etiology in this patient. This would mean that defining the susceptibility genes for type 2 diabetes is very important to pharmaceutical companies aiming to develop novel compounds to improve on the present imperfect treatment of type 2 diabetes. If this is a reality, then the reverse should be true, that targets for drugs should be excellent candidate genes for type 2 diabetes. There is strong evidence in favor of this, because the polymorphisms with the best-established roles in susceptibility to type 2 diabetes are the Pro12Ala-coding polymorphism in peroxisomal proliferator-activated receptor-, the target for a class of drugs known as thiazolidinediones (64); and the E23K polymorphism in the KCNJ11 gene encoding Kir6.2, which is a subunit of the K_ATP channel, the target for sulfonylurea therapy (see above) (65, 66). In both cases, large studies and meta-analysis provide very strong evidence that these alleles alter susceptibility to diabetes, with meta-analyses achieving genome-wide significance. Recently, novel hypoglycemic therapy, which acts as a glucokinase activator (67, 68), has been developed on the backdrop of genetic discoveries in monogenic diabetes (69, 70) and hypoglycemia (71, 72). The common glycolytic enzyme glucokinase variant at position –30 alters fasting glucose and, hence, the set point in a similar way as in the monogenic examples (73). The glucokinase activators have been successfully used in animal models, but there have been no human studies reported to date. We can conclude that there is strong evidence that novel type 2 diabetes genes will be potentially exciting pharmaceutical targets.

	What Does the Future Hold for the Interaction between Genetics and Therapeutic Response?

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We need to continue to identify novel causes of monogenic diabetes, which, although they may not be numerically important, will provide crucial insights into patterns of ß-cell dysfunction and the associated therapeutic response. There is no doubt that the next few years will result in novel susceptibility genes for type 2 diabetes being identified. A key point will be to formally assess these, ideally in trials designed to specifically look for pharmacogenetic effects (the variation in response to therapy). It will also be important to recognize that any susceptibility gene for type 2 diabetes or monogenic cause of diabetes should immediately be considered as a potential drug target.

	Acknowledgments

 
We thank our many colleagues in Exeter who contributed enormously to this work.

	Footnotes

 
This work was supported by the Wellcome Trust and Diabetes UK. A.T.H. is a Wellcome Trust Research Leave Fellow. E.P. is a National Health Service Education for Scotland Clinician Scientist Fellowship.

Author Disclosure Summary: A.T.H. and E.R.P. have nothing to declare.

First Published Online March 23, 2006

Abbreviations: HbA_1c, Hemoglobin A_1c; HNF1, hepatic nuclear factor-1; MODY, maturity-onset diabetes of the young.

Received February 6, 2006.

Accepted for publication February 21, 2006.

	References

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1. Royal Society Working Group on Pharmacogenitics 2005 Personalised medicines: hopes and realities. London: Royal Society
2. Hattersley AT 2004 Unlocking the secrets of the pancreatic ß cell: man and mouse provide the key. J Clin Invest 114:314–316[CrossRef][Medline]
3. Tattersall RB 1974 Mild familial diabetes with dominant inheritance. Q J Med 43:339–357[Medline]
4. Tattersall RB, Fajans SS 1975 Prevalence of diabetes and glucose intolerance in 199 offspring of thirty-seven conjugal diabetic parents. Diabetes 24:452–462[Abstract]
5. Fajans SS, Bell GI, Polonsky KS 2001 Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med 345:971–980[Free Full Text]
6. Stride A, Hattersley AT 2002 Different genes, different diabetes: lessons from maturity-onset diabetes of the young. Ann Med 34:207–216[Medline]
7. Froguel P, Zouali H, Vionnet N, Velho G, Vaxillaire M, Sun F, Lesage S, Stoffel M, Takeda J, Passa P 1993 Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. N Engl J Med 328:697–702[Abstract/Free Full Text]
8. Frayling T, Bulman MP, Ellard S, Appleton M, Dronsfield M, Mackie A, Baird J, Kaisaki P, Yamagata K, Bell G, Bain S, Hattersley A 1997 Mutations in the hepatocyte nuclear factor 1 gene are a common cause of maturity-onset diabetes of the young in the United Kingdom. Diabetes 46:720–725[Abstract]
9. Bingham C, Hattersley AT 2004 Renal cysts and diabetes syndrome resulting from mutations in hepatocyte nuclear factor-1ß. Nephrol Dial Transplant 19:2703–2708[Free Full Text]
10. Bellanne-Chantelot C, Clauin S, Chauveau D, Collin P, Daumont M, Douillard C, Dubois-Laforgue D, Dusselier L, Gautier JF, Jadoul M, Laloi-Michelin M, Jacquesson L, Larger E, Louis J, Nicolino M, Subra JF, Wilhem JM, Young J, Velho G, Timsit J 2005 Large genomic rearrangements in the hepatocyte nuclear factor-1ß (TCF2) gene are the most frequent cause of maturity-onset diabetes of the young type 5. Diabetes 54:3126–3132[Abstract/Free Full Text]
11. Slingerland AS, Hattersley AT 2005 Mutations in the Kir6.2 subunit of the KATP channel and permanent neonatal diabetes: new insights and new treatment. Ann Med 37:186–195[CrossRef][Medline]
12. Polak M, Shield J 2004 Neonatal and very-early-onset diabetes mellitus. Semin Neonatol 9:59–65[CrossRef][Medline]
13. Temple IK, Gardner RJ, Mackay DJ, Barber JC, Robinson DO, Shield JP 2000 Transient neonatal diabetes: widening the understanding of the etiopathogenesis of diabetes. Diabetes 49:1359–1366[Abstract]
14. Gardner RJ, Mackay DJ, Mungall AJ, Polychronakos C, Siebert R, Shield JP, Temple IK, Robinson DO 2000 An imprinted locus associated with transient neonatal diabetes mellitus. Hum Mol Genet 9:589–596[Abstract/Free Full Text]
15. Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining GJ, Slingerland AS, Howard N, Srinivasan S, Silva JM, Molnes J, Edghill EL, Frayling TM, Temple IK, Mackay D, Shield JP, Sumnik Z, van Rhijn A, Wales JK, Clark P, Gorman S, Aisenberg J, Ellard S, Njolstad PR, Ashcroft FM, Hattersley AT 2004 Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med 350:1838–1849[Abstract/Free Full Text]
16. Hattersley AT, Ashcroft FM 2005 Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. Diabetes 54:2503–2513[Abstract/Free Full Text]
17. Stride A, Vaxillaire M, Tuomi T, Barbetti F, Njolstad PR, Hansen T, Costa A, Conget I, Pedersen O, Sovik O, Lorini R, Groop L, Froguel P, Hattersley AT 2002 The genetic abnormality in the ß cell determines the response to an oral glucose load. Diabetologia 45:427–435[CrossRef][Medline]
18. Sturis J, Kurland IJ, Byrne MM, Mosekilde E, Froguel P, Pilkis SJ, Bell GI, Polonsky KS 1994 Compensation in pancreatic ß-cell function in subjects with glucokinase mutations. Diabetes 43:718–723[Abstract]
19. Velho G, Blanche H, Vaxillaire M, Bellanne-Chantelot C, Pardini VC, Timsit J, Passa P, Robert JJ, Weber IT, Marotta D, Pilkis SJ, Lipkind GM, Bell GI, Froguel P 1997 Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families. Diabetologia 40:217–224[CrossRef][Medline]
20. Pearson ER, Velho G, Clark P, Stride A, Shepherd M, Frayling TM, Bulman MP, Ellard S, Froguel P, Hattersley AT 2001 ß-Cell genes and diabetes: quantitative and qualitative differences in the pathophysiology of hepatic nuclear factor-1 and glucokinase mutations. Diabetes 50:S101–S107
21. Byrne MM, Sturis J, Clement K, Vionnet N, Pueyo ME, Stoffel M, Takeda J, Passa P, Cohen D, Bell GI, Velho G, Froguel P, Polonsky KS 1994 Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations. J Clin Invest 93:1120–1130[Medline]
22. Hattersley AT, Beards F, Ballantyne E, Appleton M, Harvey R, Ellard S 1998 Mutations in the glucokinase gene of the fetus in reduced birthweight. Nat Genet 19:268–270[CrossRef][Medline]
23. Spyer G, Ballantyne E, Shepherd M, Allen L, Macleod K, Ellard S, Hattersley AT 2000 Fetal growth is altered by fetal genotype and not insulin treatment of maternal hyperglycaemia in gestational diabetes due to mutations in the glucokinase gene. Diabetic Med 17(Suppl):A40
24. Spyer G, Hattersley AT, Sykes JE, Sturley RH, MacLeod KM 2001 Influence of maternal and fetal glucokinase mutations in gestational diabetes. Am J Obstet Gynecol 185:240–241[Medline]
25. Guenat E, Seematter G, Philippe J, Temler E, Jequier E, Tappy L 2000 Counterregulatory responses to hypoglycemia in patients with glucokinase gene mutations. Diabetes Metab 26:377–384[Medline]
26. Frayling TM, Evans JC, Bulman MP, Pearson E, Allen L, Owen K, Bingham C, Hannemann M, Shepherd M, Ellard S, Hattersley AT 2001 ß-Cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors. Diabetes 50:S94–S100
27. Stride A, Ellard S, Clark P, Shakespeare L, Salzmann M, Shepherd M, Hattersley AT 2005 ß-Cell dysfunction, insulin sensitivity, and glycosuria precede diabetes in hepatocyte nuclear factor-1 mutation carriers. Diabetes Care 28:1751–1756[Abstract/Free Full Text]
28. Isomaa B, Henricsson M, Lehto M, Forsblom C, Karanko S, Sarelin L, Haggblom M, Groop L 1998 Chronic diabetic complications in patients with MODY3 diabetes. Diabetologia 41:467–473[CrossRef][Medline]
29. Byrne MM, Sturis J, Menzel S, Yamagata K, Fajans SS, Dronsfield MJ, Bain SC, Hattersley AT, Velho G, Froguel P, Bell GI, Polonsky KS 1996 Altered insulin secretory responses to glucose in diabetic and nondiabetic subjects with mutations in the diabetes susceptibility gene MODY3 on chromosome 12. Diabetes 45:1503–1510[Abstract]
30. Heiervang E, Folling I, Sovik O, Sandnes T, Myrmael T, Moen T, Myking O 1989 Maturity-onset diabetes of the young: studies in a Norwegian family. Acta Paediatr Scand 78:74–80[Medline]
31. Sovik O, Njolstad P, Folling I, Sagen J, Cockburn BN, Bell GI 1998 Hyperexcitability to sulphonylurea in MODY3. Diabetologia 41:607–608[CrossRef][Medline]
32. Pearson ER, Liddell WG, Shepherd M, Corrall RJ, Hattersley AT 2000 Sensitivity to sulphonylureas in patients with hepatocyte nuclear factor 1 gene mutations: evidence for pharmacogenetics in diabetes. Diabetic Med 17:543–545[CrossRef][Medline]
33. Pearson ER, Starkey BJ, Powell RJ, Gribble FM, Clark PM, Hattersley AT 2003 Genetic cause of hyperglycaemia and response to treatment in diabetes. Lancet 362:1275–1281[CrossRef][Medline]
34. Shepherd M, Pearson ER, Houghton J, Salt G, Ellard S, Hattersley AT 2003 No deterioration in glycemic control in HNF1 maturity-onset diabetes of the young following transfer from long-term insulin to sulphonylureas. Diabetes Care 26:3191–3192[Free Full Text]
35. Shepherd M, Hattersley AT 2004 ‘I don’t feel like a diabetic any more’: the impact of stopping insulin in patients with maturity onset diabetes of the young following genetic testing. Clin Med 4:144–147[Medline]
36. Sagen JV, Pearson ER, Johansen A, Spyer G, Sovik O, Pedersen O, Njolstad PR, Hattersley AT, Hansen T 2005 Preserved insulin response to tolbutamide in hepatocyte nuclear factor-1 mutation carriers. Diabetic Med 22:406–409[CrossRef][Medline]
37. Dukes ID, Sreenan S, Roe MW, Levisetti M, Zhou YP, Ostrega D, Bell GI, Pontoglio M, Yaniv M, Philipson L, Polonsky KS 1998 Defective pancreatic ß-cell glycolytic signaling in hepatocyte nuclear factor-1-deficient mice. J Biol Chem 273:24457–24464[Abstract/Free Full Text]
38. Pontoglio M, Sreenan S, Roe M, Pugh W, Ostrega D, Doyen A, Pick AJ, Baldwin A, Velho G, Froguel P, Levisetti M, Bonner-Weir S, Bell GI, Yaniv M, Polonsky KS 1998 Defective insulin secretion in hepatocyte nuclear factor 1-deficient mice. J Clin Invest 101:2215–2222[Medline]
39. Shih DQ, Screenan S, Munoz KN, Philipson L, Pontoglio M, Yaniv M, Polonsky KS, Stoffel M 2001 Loss of HNF1 function in mice leads to abnormal expression of genes involved in pancreatic islet development and metabolism. Diabetes 50:2472–2480[Abstract/Free Full Text]
40. Wang H, Antinozzi PA, Hagenfeldt KA, Maechler P, Wollheim CB 2000 Molecular targets of a human HNF1 mutation responsible for pancreatic ß-cell dysfunction. EMBO J 19:4257–4264[CrossRef][Medline]
41. Wang H, Maechler P, Hagenfeldt KA, Wollheim CB 1998 Dominant-negative suppression of HNF1 function results in defective insulin gene transcription and impaired metabolism-secretion coupling in a pancreatic ß-cell line. EMBO J 17:6701–6713[CrossRef][Medline]
42. Wollheim CB 2000 ß-Cell mitochondria in the regulation of insulin secretion: a new culprit in type II diabetes. Diabetologia 43:265–277[CrossRef][Medline]
43. Horikawa Y, Iwasaki N, Hara M, Furuta H, Hinokio Y, Cockburn B, Lindner T, Yamagata K, Ogata M, Tomonaga O, Kuroki H, Kasahar T, Iwamoto Y, Bell GI 1997 Mutation in hepatocyte nuclear factor-1b gene (TCF2) associated with MODY. Nat Genet 17:384–385[CrossRef][Medline]
44. Beards F, Frayling T, Bulman M, Horikawa Y, Allen L, Appleton M, Bell GI, Ellard S, Hattersley AT 1998 Mutations in hepatocyte nuclear factor 1ß are not a common cause of maturity-onset diabetes of the young in the U.K. Diabetes 47:1152–1154[Medline]
45. Edghill EL, Bingham C, Ellard S, Hattersley AT 2006 Mutations in hepatocyte nuclear factor-1ß and their related phenotypes. J Med Genet 43:84–90[Abstract/Free Full Text]
46. Bingham C, Ellard S, Allen L, Bulman M, Shepherd M, Frayling T, Berry PJ, Clark PM, Lindner T, Bell GI, Ryffel GU, Nicholls AJ, Hattersley AT 2000 Abnormal nephron development associated with a frameshift mutation in the transcription factor hepatocyte nuclear factor-1ß. Kidney Int 57:898–907[CrossRef][Medline]
47. Bingham C, Bulman MP, Ellard S, Allen LI, Lipkin GW, Hoff WG, Woolf AS, Rizzoni G, Novelli G, Nicholls AJ, Hattersley AT 2001 Mutations in the hepatocyte nuclear factor-1ß gene are associated with familial hypoplastic glomerulocystic kidney disease. Am J Hum Genet 68:219–224[CrossRef][Medline]
48. Bingham C, Ellard S, Cole TR, Jones KE, Allen LI, Goodship JA, Goodship TH, Bakalinova-Pugh D, Russell GI, Woolf AS, Nicholls AJ, Hattersley AT 2002 Solitary functioning kidney and diverse genital tract malformations associated with hepatocyte nuclear factor-1ß mutations. Kidney Int 61:1243–1251[CrossRef][Medline]
49. Bingham C, Ellard S, van’t Hoff WG, Simmonds HA, Marinaki AM, Badman MK, Winocour PH, Stride A, Lockwood CR, Nicholls AJ, Owen KR, Spyer G, Pearson ER, Hattersley AT 2003 Atypical familial juvenile hyperuricemic nephropathy associated with a hepatocyte nuclear factor-1ß gene mutation. Kidney Int 63:1645–1651[CrossRef][Medline]
50. Harries LW, Ellard S, Jones RW, Hattersley AT, Bingham C 2004 Abnormal splicing of hepatocyte nuclear factor-1ß in the renal cysts and diabetes syndrome. Diabetologia 47:937–942[CrossRef][Medline]
51. Pearson ER, Badman MK, Lockwood CR, Clark PM, Ellard S, Bingham C, Hattersley AT 2004 Contrasting diabetes phenotypes associated with hepatocyte nuclear factor-1 and -1ß mutations. Diabetes Care 27:1102–1107[Abstract/Free Full Text]
52. Brackenridge A, Pearson ER, Shojaee-Moradie F, Hattersley AT, Russell-Jones D, Umpleby AM 2006 Contrasting insulin sensitivity of endogenous glucose production rate in subjects with hepatocyte nuclear factor-1ß and -1 mutations. Diabetes 55:405–411[Abstract/Free Full Text]
53. Bellanne-Chantelot C, Chauveau D, Gautier JF, Dubois-Laforgue D, Clauin S, Beaufils S, Wilhelm JM, Boitard C, Noel LH, Velho G, Timsit J 2004 Clinical spectrum associated with hepatocyte nuclear factor-1ß mutations. Ann Intern Med 140:510–517[Abstract/Free Full Text]
54. Maestro MA, Boj SF, Luco RF, Pierreux CE, Cabedo J, Servitja JM, German MS, Rousseau GG, Lemaigre FP, Ferrer J 2003 Hnf6 and Tcf2 (MODY5) are linked in a gene network operating in a precursor cell domain of the embryonic pancreas. Hum Mol Genet 12:3307–3314[Abstract/Free Full Text]
55. Yorifuji T, Kurokawa K, Mamada M, Imai T, Kawai M, Nishi Y, Shishido S, Hasegawa Y, Nakahata T 2004 Neonatal diabetes mellitus and neonatal polycystic, dysplastic kidneys: phenotypically discordant recurrence of a mutation in the hepatocyte nuclear factor-1ß gene due to germline mosaicism. J Clin Endocrinol Metab 89:2905–2908[Abstract/Free Full Text]
56. Frayling TM, Evans JC, Bulman MP, Pearson E, Allen L, Owen K, Bingham C, Hannemann M, Shepherd M, Ellard S, Hattersley AT 2001 ß-Cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors. Diabetes 50:S94–S100
57. Gloyn AL, Reimann F, Girard C, Edghill EL, Proks P, Pearson ER, Temple IK, Mackay DJ, Shield JP, Freedenberg D, Noyes K, Ellard S, Ashcroft FM, Gribble FM, Hattersley AT 2005 Relapsing diabetes can result from moderately activating mutations in KCNJ11. Hum Mol Genet 14:925–934[Abstract/Free Full Text]
58. Proks P, Antcliff JF, Lippiat J, Gloyn AL, Hattersley AT, Ashcroft FM 2004 Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features. Proc Natl Acad Sci USA 101:17539–17544[Abstract/Free Full Text]
59. Proks P, Girard C, Haider S, Gloyn AL, Hattersley AT, Sansom MS, Ashcroft FM 2005 A gating mutation at the internal mouth of the Kir6.2 pore is associated with DEND syndrome. EMBO Rep 6:470–475[CrossRef][Medline]
60. Codner E, Flanagan S, Ellard S, Garcia H, Hattersley AT 2005 High-dose glibenclamide can replace insulin therapy despite transitory diarrhea in early-onset diabetes caused by a novel R201L Kir6.2 mutation. Diabetes Care 28:758–759[Free Full Text]
61. Klupa T, Edghill EL, Nazim J, Sieradzki J, Ellard S, Hattersley AT, Malecki MT 2005 The identification of a R201H mutation in KCNJ11, which encodes Kir6.2, and successful transfer to sustained-release sulphonylurea therapy in a subject with neonatal diabetes: evidence for heterogeneity of ß cell function among carriers of the R201H mutation. Diabetologia 48:1029–1031[CrossRef][Medline]
62. Sagen JV, Raeder H, Hathout E, Shehadeh N, Gudmundsson K, Baevre H, Abuelo D, Phornphutkul C, Molnes J, Bell G, Gloyn AL, Hattersley AT, Molven A, Sovik O, Njolstad PR 2004 Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy. Diabetes 53:2713–2718[Abstract/Free Full Text]
63. Zung A, Glaser B, Nimri R, Zadik Z 2004 Glibenclamide treatment in permanent neonatal diabetes mellitus due to an activating mutation in Kir6.2. J Clin Endocrinol Metab 89:5504–5507[Abstract/Free Full Text]
64. Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl M-C, Nemesh J, Lane CR, Schaffner F, Bolk S, Brewer C, Tuomi T, Gaudet D, Hudson TJ, Daly M, Groop L, Lander ES 2000 The common PPAR Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 26:76–80[CrossRef][Medline]
65. Gloyn AL, Weedon MN, Owen KR, Turner MJ, Knight BA, Hitman G, Walker M, Levy JC, Sampson M, Halford S, McCarthy MI, Hattersley AT, Frayling TM 2003 Large-scale association studies of variants in genes encoding the pancreatic ß-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes. Diabetes 52:568–572[Abstract/Free Full Text]
66. Florez J, Burtt N, de Bakker P, Almgren P, Tuomi T, Holmkvist J, Gaudet D, Hudson T, Schaffner S, Daly M, Hirschhorn J, Groop L, Altshuler D 2004 Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region. Diabetes 53:1360–1368[Abstract/Free Full Text]
67. Grimsby J, Sarabu R, Corbett WL, Haynes NE, Bizzarro FT, Coffey JW, Guertin KR, Hilliard DW, Kester RF, Mahaney PE, Marcus L, Qi L, Spence CL, Tengi J, Magnuson MA, Chu CA, Dvorozniak MT, Matschinsky FM, Grippo JF 2003 Allosteric activators of glucokinase: potential role in diabetes therapy. Science 301:370–373[Abstract/Free Full Text]
68. Matschinsky FM, Magnuson MA, Zelent D, Jetton TL, Doliba N, Han Y, Taub R, Grimsby J 2006 The network of glucokinase-expressing cells in glucose homeostasis and the potential of glucokinase activators for diabetes therapy. Diabetes 55:1–12[Abstract/Free Full Text]
69. Hattersley AT, Turner RC, Permutt MA, Patel P, Tanizawa Y, Chiu KC, O’Rahilly S, Watkins PJ, Wainscoat JS 1992 Linkage of type 2 diabetes to the glucokinase gene. Lancet 339:1307–1310[CrossRef][Medline]
70. Njolstad P, Sovik O, Cuesta-Munoz A, Bjorkhaug L, Massa O, Barbetti F, Undlien D, Shiota C, Magnuson M, Molven A, Matschinsky F, Bell G 2001 Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med 344:1588–1592[Free Full Text]
71. Glaser B, Kesavan P, Haymen M, Davies E, Cuesta A, Buchs A, Stanley CA, Thornton PS, Permutt MA, Matschinsky FM, Herold KC 1998 Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med 338:226–230[Free Full Text]
72. Gloyn AL, Noordam K, Willemsen MA, Ellard S, Lam WW, Campbell IW, Midgley P, Shiota C, Buettger C, Magnuson MA, Matschinsky FM, Hattersley AT 2003 Insights into the biochemical and genetic basis of glucokinase activation from naturally occurring hypoglycemia mutations. Diabetes 52:2433–2440[Abstract/Free Full Text]
73. Weedon MN, Frayling TM, Shields B, Knight B, Turner T, Metcalf BS, Voss L, Wilkin TJ, McCarthy A, Ben-Shlomo Y, Davey Smith G, Ring S, Jones R, Golding J, Byberg L, Mann V, Axelsson T, Syvanen AC, Leon D, Hattersley AT 2005 Genetic regulation of birth weight and fasting glucose by a common polymorphism in the islet cell promoter of the glucokinase gene. Diabetes 54:576–581[Abstract/Free Full Text]
74. Raeder H, Johansson S, Holm PI, Haldorsen IS, Mas E, Sbarra V, Nermoen I, Eide SA, Grevle L, Bjorkhaug L, Sagen JV, Aksnes L, Sovik O, Lombardo D, Molven A, Njolstad PR 2006 Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. Nat Genet 38:54–62[CrossRef][Medline]

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