Opinion
Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.
EDITORIAL
Insights From Monogenic Diabetes and Glycemic Treatment Goals for Common Types of Diabetes Jose C. Florez, MD, PhD
The “glucose hypothesis,” which held that bringing ambient glucose levels into the near-normal range would help prevent the onset of diabetic complications, was first supported by findings from the Diabetes Control and Complications Trial.1 Related article page 279 Intensive glucose control resulting in a mean glycated hemoglobin (HbA1c) level near 7% had discernible and sustained effects on both microvascular2-4 and macrovascular5 end points. An appeal of type 1 diabetes as a model for studying hyperglycemic effects is its clear-cut phenotype, in which autoimmune destruction of pancreatic beta cells causes hyperglycemia as the main triggering vascular insult at disease onset, typically unconfounded by other potential or established cardiovascular risk factors such as hyperinsulinemia, hyperlipidemia, and hypertension. Achieving a similar level of evidence for type 2 diabetes has been more difficult. Although the UK Prospective Diabetes Study showed improvement in microvascular end points at the conclusion of the active phase of the trial,6 and of macrovascular end points after extended follow-up,7 recent randomized clinical trials have failed to demonstrate that intensive glycemic control confers any cardiovascular benefit,8-10 although modest benefit was seen in some meta-analyses.11-13 Thus, in contrast to low-density lipoprotein cholesterol, for glucose it has not been proven that “lower is always better.” Indeed, the higher mortality rate seen in the intensive group of the Action to Control Cardiovascular Risk in Diabetes trial8 triggered an as yet unresolved controversy regarding reasonable glycemic targets, with the issuing of multiple competing professional guidelines and expert statements that have generated confusion for practitioners.14-17 The appropriate target for HbA1c remains controversial. Given the concerns with severe hypoglycemia and potential cardiovascular risk from overly aggressive glucoselowering regimens, the key question remains: how high can ambient glycemia be allowed to rise before the rate of complications becomes unacceptable? That is, what is the maximally tolerable average glucose level that still is associated with avoidance of microvascular and macrovascular complications? Nature, in the form of a genetic experiment, has provided some clues to solve that riddle. Maturity-onset diabetes of the young (MODY) type 2 results from inactivating or loss of function mutations in GCK, the gene that encodes glucokinase.18-20 Glucokinase acts as the central glucose sensor in pancreatic beta cells; its activity is dependent on glucose concentration, and
it catalyzes the phosphorylation of glucose into glucose-6phosphate as the rate-limiting step that initiates the cascade of glucose-dependent insulin secretion. The presence of inactivating mutations in GCK requires higher glucose concentrations to trigger insulin release. Thus, while the secretory machinery is intact, ambient glucose levels are higher because of a “reset glucostat” that keeps fasting glucose levels between 100 and 150 mg/dL and HbA1c as high as 7.5%. Other than during pregnancy, patients with glucokinase MODY seldom require pharmacological therapy, as they respond adequately to carbohydrate loads in terms of insulin output required to manage the glucose challenge.21 Therefore, glucokinase MODY can be viewed as the natural experiment by which humans are exposed to permanent levels of mild hyperglycemia in an isolated or “pure” framework, ie, without other contributing factors such as obesity, hyperlipidemia, hypertension, or even autoimmunity. In this issue of JAMA, Steele and colleagues22 leverage the known pathophysiology of glucokinase MODY to determine whether exposure to modest levels of hyperglycemia since birth leads to diabetic complications. In a clever and informative study design, the authors identified 99 GCK mutation carriers (median age, 48 years) and compared them with 89 related noncarriers (median age, 52 years) and 83 other participants with early-onset type 2 diabetes (diagnosed before age 45 years), establishing the prevalence of microvascular and macrovascular complications in a cross-sectional examination. Mean known duration of diabetes was 48 years in participants with glucokinase MODY and 17 years in those with type 2 diabetes. Of note, retinopathy was ascertained by fundus photography and scored by 2 independent reviewers according to a standardized grading system used in the United Kingdom, a significant improvement over prior studies. Cardiovascular disease was ascertained by questionnaire and 12lead electrocardiography, supplemented by medical records. As expected, the 3 groups differed in their glycemia at the time of the study: nondiabetic controls had an HbA1c of 5.8%, GCK mutation carriers had an HbA1c of 6.9%, and participants with early-onset type 2 diabetes had an HbA1c of 7.8%. The latter weighed more and had higher values for fasting glucose, systolic blood pressure, and triglycerides. They more frequently used antidiabetic, antihypertensive, and lipidlowering medications and had higher rates of smoking, along with lower high-density and low-density lipoprotein cholesterol levels and shorter duration of hyperglycemia. The authors found that severe complications (eg, proteinuria, proliferative retinopathy, macular edema, ischemic heart disease)
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were generally absent in GCK mutation carriers (rates ranging from 0% to 4%), and mild complications (eg, microalbuminuria, neuropathy) were rare (1%-2%) in GCK mutation carriers and typically comparable with rates seen in the nondiabetic controls. One exception was background retinopathy, present in 30% of the GCK mutation carriers and 14% of the nondiabetic controls (63% of participants with type 2 diabetes had any retinopathy, 35% of whom were classified as severe). The majority of GCK mutation carriers with background retinopathy (81%) had fewer than 5 microaneurysms. The authors conclude that maintaining a blood glucose that yields an HbA1c level of 7%, as recommended currently by major professional organizations, is not associated with a clinically significant rate of diabetes complications. This study contributes to the ongoing debate over glycemic targets in the general population of patients with diabetes by providing the longest and largest follow-up of individuals who have been exposed to stable mild hyperglycemia since birth. By comparing GCK mutation carriers with unaffected relatives, it is as if the investigators had collaborated with nature to perform a randomized clinical trial of mild hyperglycemia, with randomization occurring at the time of allele assortment in meiosis. That the incidence of complications over a median of 48 years is nearly indistinguishable among those with GCK mutations vs nondiabetic controls (with the possible exception of mild background retinopathy, not requiring laser therapy) is indeed reassuring. On the other hand, Steele et al22 readily acknowledge the limitations of this paradigm, which cannot be fully extrapolated to people with type 1 or type 2 diabetes. Carriers of GCK mutations have more stable glucose levels than people with either common form of diabetes and typically lack the other risk factors that accompany the metabolic
ARTICLE INFORMATION Author Affiliations: Center for Human Genetic Research, Massachusetts General Hospital, Boston; Diabetes Research Center, Diabetes Unit, Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts. Corresponding Author: Jose C. Florez, MD, PhD, Center for Human Genetic Research, Diabetes Unit, Massachusetts General Hospital, 185 Cambridge St, Simches Research Bldg–CPZN 5.250, Boston, MA 02114 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Florez reported having received consulting fees from Eli Lilly, Pfizer, and Novartis. REFERENCES 1. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14): 977-986. 250
syndrome, such as visceral adiposity, dyslipidemia, hypertension, insulin resistance, and hyperinsulinemia. The MODY cohort studied by the authors is younger than the general population with type 2 diabetes, and exposure to hyperglycemia may have more deleterious effects at later stages in life. The lifelong hyperglycemia seen in patients with MODY could also trigger compensatory responses early in development, rendering cells and tissues slightly more impervious to glucotoxicity, with such plasticity absent at later stages. The cohort of participants with type 2 diabetes studied here, with a mean age at diagnosis of 40 years, may have had a particularly aggressive form of the disease. In other words, although an HbA1c level of 7% may be perfectly fine in the absence of any other cardiovascular risk factors and during the first 5 decades of life, this report does not answer conclusively whether that is an optimal goal for older adults who have other comorbidities, who experience more severe spikes in glucose levels, and in whom the onset of hyperglycemia is relatively recent. Nevertheless, this study by Steele et al22 sheds light on the extent to which decades of isolated mild hyperglycemia promote diabetes complications, and with key caveats expressed here, this study supports current treatment goals and lays the groundwork for more extended follow-up of this unique population. In particular, determining whether the observed higher degree of background retinopathy evolves into proliferative retinopathy or clinically significant macular edema is a relevant lingering question. Overall, it is clear that despite the low frequency of glucokinase MODY, knowledge of its natural course has implications for the management of common forms of diabetes, and it illustrates how clinical insights gained from the study of monogenic syndromes can improve understanding of complex diseases.
2. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000;342(6):381-389.
6. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837-853.
3. Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA. 2002;287(19):2563-2569.
7. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577-1589.
4. Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA. 2003;290(16):2159-2167. 5. Nathan DM, Cleary PA, Backlund JY, et al; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353(25):2643-2653.
8. Gerstein HC, Miller ME, Byington RP, et al; Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):25452559. 9. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-2572. 10. Duckworth W, Abraira C, Moritz T, et al; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360(2):129-139. 11. Ray KK, Seshasai SR, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes
JAMA January 15, 2014 Volume 311, Number 3
Copyright 2014 American Medical Association. All rights reserved.
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Editorial Opinion
mellitus: a meta-analysis of randomised controlled trials. Lancet. 2009;373(9677):1765-1772. 12. Kelly TN, Bazzano LA, Fonseca VA, Thethi TK, Reynolds K, He J. Systematic review: glucose control and cardiovascular disease in type 2 diabetes. Ann Intern Med. 2009;151(6):394-403. 13. Turnbull FM, Abraira C, Anderson RJ, et al; Control Group. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009;52(11):2288-2298. 14. Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: update regarding thiazolidinediones: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2008;31(1):173-175. 15. Nathan DM, Buse JB, Davidson MB, et al; American Diabetes Association; European Association for Study of Diabetes. Medical management of hyperglycemia in type 2 diabetes:
a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32(1):193-203. 16. Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract. 2009;15(6):540-559. 17. Inzucchi SE, Bergenstal RM, Buse JB, et al; American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35(6):1364-1379. 18. Froguel P, Vaxillaire M, Sun F, et al. Close linkage of glucokinase locus on chromosome 7p to early-onset
jama.com
non-insulin-dependent diabetes mellitus. Nature. 1992;356(6365):162-164. 19. Vionnet N, Stoffel M, Takeda J, et al. Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus. Nature. 1992;356(6371):721-722. 20. Froguel P, Zouali H, Vionnet N, et al. Familial hyperglycemia due to mutations in glucokinase: definition of a subtype of diabetes mellitus. N Engl J Med. 1993;328(10):697-702. 21. Stride A, Shields B, Gill-Carey O, et al. Cross-sectional and longitudinal studies suggest pharmacological treatment used in patients with glucokinase mutations does not alter glycaemia. Diabetologia. 2014;57(1):54-56. 22. Steele AM, Shields BM, Wensley KJ, Colclough K, Ellard S, Hattersley AT. Prevalence of vascular complications among patients with glucokinase mutations and prolonged mild hyperglycemia. JAMA. doi:10.1001/jama.2013.283980.
JAMA January 15, 2014 Volume 311, Number 3
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/18/2015
251
Editorials represent the opinions of the authors and JAMA and not those of the American Medical Association.
EDITORIAL
Insights From Monogenic Diabetes and Glycemic Treatment Goals for Common Types of Diabetes Jose C. Florez, MD, PhD
The “glucose hypothesis,” which held that bringing ambient glucose levels into the near-normal range would help prevent the onset of diabetic complications, was first supported by findings from the Diabetes Control and Complications Trial.1 Related article page 279 Intensive glucose control resulting in a mean glycated hemoglobin (HbA1c) level near 7% had discernible and sustained effects on both microvascular2-4 and macrovascular5 end points. An appeal of type 1 diabetes as a model for studying hyperglycemic effects is its clear-cut phenotype, in which autoimmune destruction of pancreatic beta cells causes hyperglycemia as the main triggering vascular insult at disease onset, typically unconfounded by other potential or established cardiovascular risk factors such as hyperinsulinemia, hyperlipidemia, and hypertension. Achieving a similar level of evidence for type 2 diabetes has been more difficult. Although the UK Prospective Diabetes Study showed improvement in microvascular end points at the conclusion of the active phase of the trial,6 and of macrovascular end points after extended follow-up,7 recent randomized clinical trials have failed to demonstrate that intensive glycemic control confers any cardiovascular benefit,8-10 although modest benefit was seen in some meta-analyses.11-13 Thus, in contrast to low-density lipoprotein cholesterol, for glucose it has not been proven that “lower is always better.” Indeed, the higher mortality rate seen in the intensive group of the Action to Control Cardiovascular Risk in Diabetes trial8 triggered an as yet unresolved controversy regarding reasonable glycemic targets, with the issuing of multiple competing professional guidelines and expert statements that have generated confusion for practitioners.14-17 The appropriate target for HbA1c remains controversial. Given the concerns with severe hypoglycemia and potential cardiovascular risk from overly aggressive glucoselowering regimens, the key question remains: how high can ambient glycemia be allowed to rise before the rate of complications becomes unacceptable? That is, what is the maximally tolerable average glucose level that still is associated with avoidance of microvascular and macrovascular complications? Nature, in the form of a genetic experiment, has provided some clues to solve that riddle. Maturity-onset diabetes of the young (MODY) type 2 results from inactivating or loss of function mutations in GCK, the gene that encodes glucokinase.18-20 Glucokinase acts as the central glucose sensor in pancreatic beta cells; its activity is dependent on glucose concentration, and
it catalyzes the phosphorylation of glucose into glucose-6phosphate as the rate-limiting step that initiates the cascade of glucose-dependent insulin secretion. The presence of inactivating mutations in GCK requires higher glucose concentrations to trigger insulin release. Thus, while the secretory machinery is intact, ambient glucose levels are higher because of a “reset glucostat” that keeps fasting glucose levels between 100 and 150 mg/dL and HbA1c as high as 7.5%. Other than during pregnancy, patients with glucokinase MODY seldom require pharmacological therapy, as they respond adequately to carbohydrate loads in terms of insulin output required to manage the glucose challenge.21 Therefore, glucokinase MODY can be viewed as the natural experiment by which humans are exposed to permanent levels of mild hyperglycemia in an isolated or “pure” framework, ie, without other contributing factors such as obesity, hyperlipidemia, hypertension, or even autoimmunity. In this issue of JAMA, Steele and colleagues22 leverage the known pathophysiology of glucokinase MODY to determine whether exposure to modest levels of hyperglycemia since birth leads to diabetic complications. In a clever and informative study design, the authors identified 99 GCK mutation carriers (median age, 48 years) and compared them with 89 related noncarriers (median age, 52 years) and 83 other participants with early-onset type 2 diabetes (diagnosed before age 45 years), establishing the prevalence of microvascular and macrovascular complications in a cross-sectional examination. Mean known duration of diabetes was 48 years in participants with glucokinase MODY and 17 years in those with type 2 diabetes. Of note, retinopathy was ascertained by fundus photography and scored by 2 independent reviewers according to a standardized grading system used in the United Kingdom, a significant improvement over prior studies. Cardiovascular disease was ascertained by questionnaire and 12lead electrocardiography, supplemented by medical records. As expected, the 3 groups differed in their glycemia at the time of the study: nondiabetic controls had an HbA1c of 5.8%, GCK mutation carriers had an HbA1c of 6.9%, and participants with early-onset type 2 diabetes had an HbA1c of 7.8%. The latter weighed more and had higher values for fasting glucose, systolic blood pressure, and triglycerides. They more frequently used antidiabetic, antihypertensive, and lipidlowering medications and had higher rates of smoking, along with lower high-density and low-density lipoprotein cholesterol levels and shorter duration of hyperglycemia. The authors found that severe complications (eg, proteinuria, proliferative retinopathy, macular edema, ischemic heart disease)
jama.com
JAMA January 15, 2014 Volume 311, Number 3
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/18/2015
249
Opinion Editorial
were generally absent in GCK mutation carriers (rates ranging from 0% to 4%), and mild complications (eg, microalbuminuria, neuropathy) were rare (1%-2%) in GCK mutation carriers and typically comparable with rates seen in the nondiabetic controls. One exception was background retinopathy, present in 30% of the GCK mutation carriers and 14% of the nondiabetic controls (63% of participants with type 2 diabetes had any retinopathy, 35% of whom were classified as severe). The majority of GCK mutation carriers with background retinopathy (81%) had fewer than 5 microaneurysms. The authors conclude that maintaining a blood glucose that yields an HbA1c level of 7%, as recommended currently by major professional organizations, is not associated with a clinically significant rate of diabetes complications. This study contributes to the ongoing debate over glycemic targets in the general population of patients with diabetes by providing the longest and largest follow-up of individuals who have been exposed to stable mild hyperglycemia since birth. By comparing GCK mutation carriers with unaffected relatives, it is as if the investigators had collaborated with nature to perform a randomized clinical trial of mild hyperglycemia, with randomization occurring at the time of allele assortment in meiosis. That the incidence of complications over a median of 48 years is nearly indistinguishable among those with GCK mutations vs nondiabetic controls (with the possible exception of mild background retinopathy, not requiring laser therapy) is indeed reassuring. On the other hand, Steele et al22 readily acknowledge the limitations of this paradigm, which cannot be fully extrapolated to people with type 1 or type 2 diabetes. Carriers of GCK mutations have more stable glucose levels than people with either common form of diabetes and typically lack the other risk factors that accompany the metabolic
ARTICLE INFORMATION Author Affiliations: Center for Human Genetic Research, Massachusetts General Hospital, Boston; Diabetes Research Center, Diabetes Unit, Massachusetts General Hospital, Boston; Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts. Corresponding Author: Jose C. Florez, MD, PhD, Center for Human Genetic Research, Diabetes Unit, Massachusetts General Hospital, 185 Cambridge St, Simches Research Bldg–CPZN 5.250, Boston, MA 02114 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Florez reported having received consulting fees from Eli Lilly, Pfizer, and Novartis. REFERENCES 1. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14): 977-986. 250
syndrome, such as visceral adiposity, dyslipidemia, hypertension, insulin resistance, and hyperinsulinemia. The MODY cohort studied by the authors is younger than the general population with type 2 diabetes, and exposure to hyperglycemia may have more deleterious effects at later stages in life. The lifelong hyperglycemia seen in patients with MODY could also trigger compensatory responses early in development, rendering cells and tissues slightly more impervious to glucotoxicity, with such plasticity absent at later stages. The cohort of participants with type 2 diabetes studied here, with a mean age at diagnosis of 40 years, may have had a particularly aggressive form of the disease. In other words, although an HbA1c level of 7% may be perfectly fine in the absence of any other cardiovascular risk factors and during the first 5 decades of life, this report does not answer conclusively whether that is an optimal goal for older adults who have other comorbidities, who experience more severe spikes in glucose levels, and in whom the onset of hyperglycemia is relatively recent. Nevertheless, this study by Steele et al22 sheds light on the extent to which decades of isolated mild hyperglycemia promote diabetes complications, and with key caveats expressed here, this study supports current treatment goals and lays the groundwork for more extended follow-up of this unique population. In particular, determining whether the observed higher degree of background retinopathy evolves into proliferative retinopathy or clinically significant macular edema is a relevant lingering question. Overall, it is clear that despite the low frequency of glucokinase MODY, knowledge of its natural course has implications for the management of common forms of diabetes, and it illustrates how clinical insights gained from the study of monogenic syndromes can improve understanding of complex diseases.
2. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000;342(6):381-389.
6. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837-853.
3. Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA. 2002;287(19):2563-2569.
7. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577-1589.
4. Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA. 2003;290(16):2159-2167. 5. Nathan DM, Cleary PA, Backlund JY, et al; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353(25):2643-2653.
8. Gerstein HC, Miller ME, Byington RP, et al; Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):25452559. 9. Patel A, MacMahon S, Chalmers J, et al; ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560-2572. 10. Duckworth W, Abraira C, Moritz T, et al; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360(2):129-139. 11. Ray KK, Seshasai SR, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes
JAMA January 15, 2014 Volume 311, Number 3
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/18/2015
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Editorial Opinion
mellitus: a meta-analysis of randomised controlled trials. Lancet. 2009;373(9677):1765-1772. 12. Kelly TN, Bazzano LA, Fonseca VA, Thethi TK, Reynolds K, He J. Systematic review: glucose control and cardiovascular disease in type 2 diabetes. Ann Intern Med. 2009;151(6):394-403. 13. Turnbull FM, Abraira C, Anderson RJ, et al; Control Group. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009;52(11):2288-2298. 14. Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: update regarding thiazolidinediones: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2008;31(1):173-175. 15. Nathan DM, Buse JB, Davidson MB, et al; American Diabetes Association; European Association for Study of Diabetes. Medical management of hyperglycemia in type 2 diabetes:
a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32(1):193-203. 16. Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract. 2009;15(6):540-559. 17. Inzucchi SE, Bergenstal RM, Buse JB, et al; American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35(6):1364-1379. 18. Froguel P, Vaxillaire M, Sun F, et al. Close linkage of glucokinase locus on chromosome 7p to early-onset
jama.com
non-insulin-dependent diabetes mellitus. Nature. 1992;356(6365):162-164. 19. Vionnet N, Stoffel M, Takeda J, et al. Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus. Nature. 1992;356(6371):721-722. 20. Froguel P, Zouali H, Vionnet N, et al. Familial hyperglycemia due to mutations in glucokinase: definition of a subtype of diabetes mellitus. N Engl J Med. 1993;328(10):697-702. 21. Stride A, Shields B, Gill-Carey O, et al. Cross-sectional and longitudinal studies suggest pharmacological treatment used in patients with glucokinase mutations does not alter glycaemia. Diabetologia. 2014;57(1):54-56. 22. Steele AM, Shields BM, Wensley KJ, Colclough K, Ellard S, Hattersley AT. Prevalence of vascular complications among patients with glucokinase mutations and prolonged mild hyperglycemia. JAMA. doi:10.1001/jama.2013.283980.
JAMA January 15, 2014 Volume 311, Number 3
Copyright 2014 American Medical Association. All rights reserved.
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251
