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Can Diabetes Be Cured?: Potential Biological and Mechanical Approaches

Can Diabetes Be Cured?: Potential Biological and Mechanical Approaches To feel our ills is one thing, but to cure them is another.—Ovid (Publius Ovidius Naso) Epistolae For individuals with diabetes, the ultimate hope is cure. But how will this cure ever be realized? If the answer was obvious, all effort would be directed to it, and a Manhattan Project model would succeed. But not knowing where the cure will be found, a series of diverse approaches must be pursued, with the hope that at least one will prove successful. The broad paths to a cure may be considered either biological and surgical or mechanical. Biological and Surgical Approaches When successful, whole-organ allographic pancreas transplant is a state-of-the-art biological cure, normalizing blood glucose levels. About 400 to 500 pancreas transplantations are performed per year in the United States. But how successful is this “cure”? Pancreas transplants require major surgery, the best outcomes being achieved when a kidney transplantation is performed simultaneously. Recipients must be immunosuppressed for the rest of their lives, with all the attendant complications. According to one analysis, 10-year graft survival rates remain less than 50%; 40% of failures are due to technical complications and 15% due to acute rejection.1 While some clinicians would recommend pancreas transplantation to treat severe glucose instability or hypoglycemia unawareness, most consider this operation to be indicated only in the setting of established or impending end-stage renal disease.2 Pancreas transplantation is far from a perfect cure. Islet cell transplantation is a simpler clinical procedure than whole-organ transplantation and can require a less toxic immunosuppressive regimen. An initial report2 documented success, defined as insulin independence for 4 to 15 months in 7 patients, using a glucocorticoid-free immunosuppression regimen. However, longer-term follow-up in an international trial of 36 islet cell transplants found that 66% of recipients required conventional insulin therapy within a year and 75% after 2 years.3 Islet cell transplantation now requires multiple donors to achieve insulin independence, as well as repeated transplantation every several years, with continued immunosuppression. There is evidence, furthermore, that transplant rejection may be caused by the same autoimmune process that initially causes type 1 diabetes.3 Another innovative approach to blocking immune destruction of transplanted tissue is to place the islets inside a protective membrane or microcapsule.4 The sequestered islets are exposed to ambient glucose levels, and their insulin secretion passes through the protective membrane into the blood. However, the membrane does not allow beta cells to be destroyed by humoral or cellular immune mediators. The ultimate goal of transplant biology would be a xenograft transplantation with unlimited organ procurement of, for example, pig pancreases, with successfully established immune tolerance obviating the need for immunosuppression. Stem cells, adult or embryonic, represent another direction in the search for a biological cure. In vitro, stem cells have been induced to produce insulin and to respond to ambient glucose.5 But a great deal of basic science must be successfully pursued before scientists can even begin to consider safety and efficacy trials. Specifically, conditions must be developed to harvest enough stem cell–derived beta cells and to demonstrate that those cells can survive in vivo. Through regenerative biology, residual pancreatic beta cells might be regenerated, reversing the decline of beta cell mass that is basic to the pathophysiology of both type 1 and type 2 diabetes. Even in type 1 diabetes, there is often demonstrable residual insulin secretion. Regenerative biology as a science, while promising,6 is still in its infancy. Another approach for preventing or curing type 1 diabetes is interruption of the autoimmune destruction of beta cells as soon as that process starts. A proof-of-principle report in 20027 spawned a number of new trials with a series of blocking antibodies.8 None of these antibodies has proven successful as yet, but the hope is eventually to be able to interrupt the specific immune process that attacks pancreatic beta cells in type 1 diabetes. As Couri et al9 report in this issue of JAMA, the autoimmune process may be able to be eliminated by autologous nonmyeloablative hematopoietic stem cell transplantation if performed within 6 weeks of diagnosing type 1 diabetes and in the absence of a history of ketoacidosis. Among 23 patients with the autologous transplant, 12 remained insulin-free for a mean of 31 months. The second pathophysiologic pillar of type 2 diabetes—insulin resistance—can be addressed pharmacologically or surgically. Thiazolidinediones are a start at correcting insulin resistance but are only partially effective, with well-established adverse effects. The most effective way to induce a remission of type 2 diabetes at present is not pharmacologic but surgical. Bariatric surgery, particularly when gastric banding is effectively applied, results in rapid and massive weight loss that reduces insulin resistance.10 Roux-en-Y procedures, however, may act via the enteropancreatic (incretin) hormone axis, causing diabetes to remit even before weight loss.11 However, bariatric surgery has adverse effects and complications, as it enforces a major alteration of lifestyle. Surgically reduced stomach volume restricts how much food the individual can ingest without significant discomfort. Long-established eating habits are necessarily changed. Mechanical Approaches Another approach to the cure of diabetes may be purely mechanical. The closed-loop artificial pancreas is, in essence, a glucose sensor, an insulin pump, and algorithms to link the 2. External insulin pumps (without a glucose sensor) have been available for decades. Just in the past few years, continuous glucose monitoring has become a viable treatment option, with a large trial demonstrating that simply wearing a glucose sensor can improve diabetic control.12 However, the algorithms connecting the sensor to the pump are not as straightforward as might be thought. The challenge is more complicated than just translating a glucose level, or change in level, into an insulin delivery rate. The normal pancreas responds not only to increasing blood glucose levels but to intestinal and cephalic stimuli that signal the pancreatic alpha cells as well as beta cells that a meal is on the way. These early signals support the first phase, acute insulin release. Therefore, insulin delivered in response only to an increasing blood glucose level is too little and too late. A study that compared the results of giving an insulin pulse before blood glucose level increased vs waiting for postmeal hyperglycemia found that giving the early signal improved glycemic response to the meal.13 There are other challenges to achieving a mechanical cure. Current pumps and sensors are worn externally, with a small delivery catheter or sensor filament placed transcutaneously into the subcutaneous space. These devices can only be used in the short term, must be replaced every 3 to 5 days, and demand significant patient attention. Implanted pumps that last more than 5 years and deliver insulin more physiologically are more user-friendly and have had demonstrable success.14 Industry has chosen not to continue the development of implanted insulin pumps, however. The ideal mechanical cure would be a robust, accurate, long-term “closed-loop” system. With the perfectly designed device, life for individuals with diabetes potentially could have only minimal restrictions. The ideal system would be fully implanted under the skin. To be safe and effective, however, the ideal requirements are daunting: absolute reliability to eliminate the chance of serious over- or underdelivery of insulin; durability to reduce the need for frequent changes or calibrations; linking algorithms that are fine-tuned enough to replicate a complex normal physiology; and a fully autopilot mode of action. While achieving the mechanical cure will be challenging, in a broad sense it requires only more sophisticated applied engineering, not basic science breakthroughs. Conclusions If both biological and mechanical approaches to finding a cure for diabetes are worth pursuing but not likely to be definitively successful any time soon, what can be done now? The answer is: a great deal. Many studies have proven that good diabetes care is effective, and the metrics are available to assess good care. Hemoglobin A1c levels of less than 7% substantially reduce the risk of diabetic retinopathy, nephropathy, and neuropathy. Statins reduce the risk of cardiovascular disease in persons with diabetes. Blood pressure control is effective, as is laser therapy for retinopathy. Diabetes self-management training helps patients practice good self-care and promotes a more informed relationship with clinicians. Why, then, does the toll of diabetes morbidity and mortality continue to increase? Because the evidence-based therapies are not reaching the patients in need. The mean hemoglobin A1c level for persons with diabetes in the United States is higher than 7%, and success in meeting most risk factor targets is alarmingly low.15 A great deal of the morbidity and reduced quality of life among patients with diabetes, as well as substantial societal expense, could be avoided or reduced by taking full advantage of therapies available today. It is not easy to manage diabetes using currently available tools. All manner of barriers inhibit good care, from the individual patient psyche to the health care system. Thus, a cure is needed, but it will probably not come from a single breakthrough. More likely, the cure will be a gradual process, building over years. Biological approaches will improve incrementally, with the procedures becoming more effective with fewer adverse effects. Mechanical cures will also improve, gradually becoming more robust, less demanding of attention, and more effective. Both the biological and mechanical paths must be vigorously pursued. And for now, patients, health care professionals, and health system planners can team up, making use of what is available to prevent and reduce the ravages of diabetes immediately, even as work continues toward finding a cure. Back to top Article Information Corresponding Author: Christopher D. Saudek, MD, Osler 575, Johns Hopkins Hospital, 700 N Wolfe St, Baltimore, MD 21287 (csaudek@jhu.edu). Financial Disclosures: Dr Saudek reports serving on the medical advisory board for Array Biopharma and serving as a consultant to MicroCHIPS Inc (both developers of glucose sensors). References 1. Waki K, Kadowaki T. An analysis of long-term survival from the OPTN/UNOS pancreas transplant registry. Clin Transpl. 2007;9-1718637455PubMedGoogle Scholar 2. Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in 7 patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med. 2000;343(4):230-23810911004PubMedGoogle ScholarCrossref 3. Shapiro AM, Ricordi C, Hering BJ, et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med. 2006;355(13):1318-133017005949PubMedGoogle ScholarCrossref 4. Mallett AG, Korbutt GS. Alginate modification improves long-term survival and function of transplanted encapsulated islets [published online ahead of print October 24, 2008]. Tissue Eng Part A18950258PubMedGoogle Scholar 5. Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature. 2008;455(7213):627-63218754011PubMedGoogle ScholarCrossref 6. Bonner-Weir S, Inada A, Yatoh S, et al. Transdifferentiation of pancreatic ductal cells to endocrine beta-cells. Biochem Soc Trans. 2008;36(pt 3):353-35618481956PubMedGoogle ScholarCrossref 7. Herold KC, Hagopian W, Auger JA, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med. 2002;346(22):1692-169812037148PubMedGoogle ScholarCrossref 8. Bollyky J, Sanda S, Greenbaum CJ. Type 1 diabetes mellitus: primary, secondary, and tertiary prevention. Mt Sinai J Med. 2008;75(4):385-39718729155PubMedGoogle ScholarCrossref 9. Couri CEB, Oliveira MCB, Stracieri ABPL, et al. C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA. 2009;301(15):1573-1579Google ScholarCrossref 10. Dixon JB, O’Brien PE, Playfair J, et al. Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial. JAMA. 2008;299(3):316-32318212316PubMedGoogle ScholarCrossref 11. Rubino F, Forgione A, Cummings DE, et al. The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes. Ann Surg. 2006;244(5):741-74917060767PubMedGoogle ScholarCrossref 12. Tamborlane WV, Beck RW, Bode BW.Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. Continuous glucose monitoring and intensive treatment of type 1 diabetes. N Engl J Med. 2008;359(14):1464-147618779236PubMedGoogle ScholarCrossref 13. Weinzimer SA, Steil GM, Swan KL, Dziura J, Kurtz N, Tamborlane WV. Fully automated closed-loop insulin delivery vs semiautomated hybrid control in pediatric patients with type 1 diabetes using an artificial pancreas. Diabetes Care. 2008;31(5):934-93918252903PubMedGoogle ScholarCrossref 14. Saudek CD, Duckworth WC, Giobbie-Hurder A, et al; Department of Veterans Affairs Implantable Insulin Pump Study Group. Implantable insulin pump vs multiple-dose insulin for non-insulin-dependent diabetes mellitus: a randomized clinical trial. JAMA. 1996;276(16):1322-13278861991PubMedGoogle ScholarCrossref 15. Resnick HE, Foster GL, Bardsley J, Ratner RE. Achievement of American Diabetes Association clinical practice recommendations among US adults with diabetes, 1999-2002: the National Health and Nutrition Examination Survey. Diabetes Care. 2006;29(3):531-53716505501PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

Can Diabetes Be Cured?: Potential Biological and Mechanical Approaches

JAMA , Volume 301 (15) – Apr 15, 2009

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American Medical Association
Copyright
Copyright © 2009 American Medical Association. All Rights Reserved.
ISSN
0098-7484
eISSN
1538-3598
DOI
10.1001/jama.2009.508
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Abstract

To feel our ills is one thing, but to cure them is another.—Ovid (Publius Ovidius Naso) Epistolae For individuals with diabetes, the ultimate hope is cure. But how will this cure ever be realized? If the answer was obvious, all effort would be directed to it, and a Manhattan Project model would succeed. But not knowing where the cure will be found, a series of diverse approaches must be pursued, with the hope that at least one will prove successful. The broad paths to a cure may be considered either biological and surgical or mechanical. Biological and Surgical Approaches When successful, whole-organ allographic pancreas transplant is a state-of-the-art biological cure, normalizing blood glucose levels. About 400 to 500 pancreas transplantations are performed per year in the United States. But how successful is this “cure”? Pancreas transplants require major surgery, the best outcomes being achieved when a kidney transplantation is performed simultaneously. Recipients must be immunosuppressed for the rest of their lives, with all the attendant complications. According to one analysis, 10-year graft survival rates remain less than 50%; 40% of failures are due to technical complications and 15% due to acute rejection.1 While some clinicians would recommend pancreas transplantation to treat severe glucose instability or hypoglycemia unawareness, most consider this operation to be indicated only in the setting of established or impending end-stage renal disease.2 Pancreas transplantation is far from a perfect cure. Islet cell transplantation is a simpler clinical procedure than whole-organ transplantation and can require a less toxic immunosuppressive regimen. An initial report2 documented success, defined as insulin independence for 4 to 15 months in 7 patients, using a glucocorticoid-free immunosuppression regimen. However, longer-term follow-up in an international trial of 36 islet cell transplants found that 66% of recipients required conventional insulin therapy within a year and 75% after 2 years.3 Islet cell transplantation now requires multiple donors to achieve insulin independence, as well as repeated transplantation every several years, with continued immunosuppression. There is evidence, furthermore, that transplant rejection may be caused by the same autoimmune process that initially causes type 1 diabetes.3 Another innovative approach to blocking immune destruction of transplanted tissue is to place the islets inside a protective membrane or microcapsule.4 The sequestered islets are exposed to ambient glucose levels, and their insulin secretion passes through the protective membrane into the blood. However, the membrane does not allow beta cells to be destroyed by humoral or cellular immune mediators. The ultimate goal of transplant biology would be a xenograft transplantation with unlimited organ procurement of, for example, pig pancreases, with successfully established immune tolerance obviating the need for immunosuppression. Stem cells, adult or embryonic, represent another direction in the search for a biological cure. In vitro, stem cells have been induced to produce insulin and to respond to ambient glucose.5 But a great deal of basic science must be successfully pursued before scientists can even begin to consider safety and efficacy trials. Specifically, conditions must be developed to harvest enough stem cell–derived beta cells and to demonstrate that those cells can survive in vivo. Through regenerative biology, residual pancreatic beta cells might be regenerated, reversing the decline of beta cell mass that is basic to the pathophysiology of both type 1 and type 2 diabetes. Even in type 1 diabetes, there is often demonstrable residual insulin secretion. Regenerative biology as a science, while promising,6 is still in its infancy. Another approach for preventing or curing type 1 diabetes is interruption of the autoimmune destruction of beta cells as soon as that process starts. A proof-of-principle report in 20027 spawned a number of new trials with a series of blocking antibodies.8 None of these antibodies has proven successful as yet, but the hope is eventually to be able to interrupt the specific immune process that attacks pancreatic beta cells in type 1 diabetes. As Couri et al9 report in this issue of JAMA, the autoimmune process may be able to be eliminated by autologous nonmyeloablative hematopoietic stem cell transplantation if performed within 6 weeks of diagnosing type 1 diabetes and in the absence of a history of ketoacidosis. Among 23 patients with the autologous transplant, 12 remained insulin-free for a mean of 31 months. The second pathophysiologic pillar of type 2 diabetes—insulin resistance—can be addressed pharmacologically or surgically. Thiazolidinediones are a start at correcting insulin resistance but are only partially effective, with well-established adverse effects. The most effective way to induce a remission of type 2 diabetes at present is not pharmacologic but surgical. Bariatric surgery, particularly when gastric banding is effectively applied, results in rapid and massive weight loss that reduces insulin resistance.10 Roux-en-Y procedures, however, may act via the enteropancreatic (incretin) hormone axis, causing diabetes to remit even before weight loss.11 However, bariatric surgery has adverse effects and complications, as it enforces a major alteration of lifestyle. Surgically reduced stomach volume restricts how much food the individual can ingest without significant discomfort. Long-established eating habits are necessarily changed. Mechanical Approaches Another approach to the cure of diabetes may be purely mechanical. The closed-loop artificial pancreas is, in essence, a glucose sensor, an insulin pump, and algorithms to link the 2. External insulin pumps (without a glucose sensor) have been available for decades. Just in the past few years, continuous glucose monitoring has become a viable treatment option, with a large trial demonstrating that simply wearing a glucose sensor can improve diabetic control.12 However, the algorithms connecting the sensor to the pump are not as straightforward as might be thought. The challenge is more complicated than just translating a glucose level, or change in level, into an insulin delivery rate. The normal pancreas responds not only to increasing blood glucose levels but to intestinal and cephalic stimuli that signal the pancreatic alpha cells as well as beta cells that a meal is on the way. These early signals support the first phase, acute insulin release. Therefore, insulin delivered in response only to an increasing blood glucose level is too little and too late. A study that compared the results of giving an insulin pulse before blood glucose level increased vs waiting for postmeal hyperglycemia found that giving the early signal improved glycemic response to the meal.13 There are other challenges to achieving a mechanical cure. Current pumps and sensors are worn externally, with a small delivery catheter or sensor filament placed transcutaneously into the subcutaneous space. These devices can only be used in the short term, must be replaced every 3 to 5 days, and demand significant patient attention. Implanted pumps that last more than 5 years and deliver insulin more physiologically are more user-friendly and have had demonstrable success.14 Industry has chosen not to continue the development of implanted insulin pumps, however. The ideal mechanical cure would be a robust, accurate, long-term “closed-loop” system. With the perfectly designed device, life for individuals with diabetes potentially could have only minimal restrictions. The ideal system would be fully implanted under the skin. To be safe and effective, however, the ideal requirements are daunting: absolute reliability to eliminate the chance of serious over- or underdelivery of insulin; durability to reduce the need for frequent changes or calibrations; linking algorithms that are fine-tuned enough to replicate a complex normal physiology; and a fully autopilot mode of action. While achieving the mechanical cure will be challenging, in a broad sense it requires only more sophisticated applied engineering, not basic science breakthroughs. Conclusions If both biological and mechanical approaches to finding a cure for diabetes are worth pursuing but not likely to be definitively successful any time soon, what can be done now? The answer is: a great deal. Many studies have proven that good diabetes care is effective, and the metrics are available to assess good care. Hemoglobin A1c levels of less than 7% substantially reduce the risk of diabetic retinopathy, nephropathy, and neuropathy. Statins reduce the risk of cardiovascular disease in persons with diabetes. Blood pressure control is effective, as is laser therapy for retinopathy. Diabetes self-management training helps patients practice good self-care and promotes a more informed relationship with clinicians. Why, then, does the toll of diabetes morbidity and mortality continue to increase? Because the evidence-based therapies are not reaching the patients in need. The mean hemoglobin A1c level for persons with diabetes in the United States is higher than 7%, and success in meeting most risk factor targets is alarmingly low.15 A great deal of the morbidity and reduced quality of life among patients with diabetes, as well as substantial societal expense, could be avoided or reduced by taking full advantage of therapies available today. It is not easy to manage diabetes using currently available tools. All manner of barriers inhibit good care, from the individual patient psyche to the health care system. Thus, a cure is needed, but it will probably not come from a single breakthrough. More likely, the cure will be a gradual process, building over years. Biological approaches will improve incrementally, with the procedures becoming more effective with fewer adverse effects. Mechanical cures will also improve, gradually becoming more robust, less demanding of attention, and more effective. Both the biological and mechanical paths must be vigorously pursued. And for now, patients, health care professionals, and health system planners can team up, making use of what is available to prevent and reduce the ravages of diabetes immediately, even as work continues toward finding a cure. Back to top Article Information Corresponding Author: Christopher D. Saudek, MD, Osler 575, Johns Hopkins Hospital, 700 N Wolfe St, Baltimore, MD 21287 (csaudek@jhu.edu). Financial Disclosures: Dr Saudek reports serving on the medical advisory board for Array Biopharma and serving as a consultant to MicroCHIPS Inc (both developers of glucose sensors). References 1. Waki K, Kadowaki T. An analysis of long-term survival from the OPTN/UNOS pancreas transplant registry. Clin Transpl. 2007;9-1718637455PubMedGoogle Scholar 2. Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in 7 patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med. 2000;343(4):230-23810911004PubMedGoogle ScholarCrossref 3. Shapiro AM, Ricordi C, Hering BJ, et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med. 2006;355(13):1318-133017005949PubMedGoogle ScholarCrossref 4. Mallett AG, Korbutt GS. Alginate modification improves long-term survival and function of transplanted encapsulated islets [published online ahead of print October 24, 2008]. Tissue Eng Part A18950258PubMedGoogle Scholar 5. Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature. 2008;455(7213):627-63218754011PubMedGoogle ScholarCrossref 6. Bonner-Weir S, Inada A, Yatoh S, et al. Transdifferentiation of pancreatic ductal cells to endocrine beta-cells. Biochem Soc Trans. 2008;36(pt 3):353-35618481956PubMedGoogle ScholarCrossref 7. Herold KC, Hagopian W, Auger JA, et al. Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus. N Engl J Med. 2002;346(22):1692-169812037148PubMedGoogle ScholarCrossref 8. Bollyky J, Sanda S, Greenbaum CJ. Type 1 diabetes mellitus: primary, secondary, and tertiary prevention. Mt Sinai J Med. 2008;75(4):385-39718729155PubMedGoogle ScholarCrossref 9. Couri CEB, Oliveira MCB, Stracieri ABPL, et al. C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA. 2009;301(15):1573-1579Google ScholarCrossref 10. Dixon JB, O’Brien PE, Playfair J, et al. Adjustable gastric banding and conventional therapy for type 2 diabetes: a randomized controlled trial. JAMA. 2008;299(3):316-32318212316PubMedGoogle ScholarCrossref 11. Rubino F, Forgione A, Cummings DE, et al. The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes. Ann Surg. 2006;244(5):741-74917060767PubMedGoogle ScholarCrossref 12. Tamborlane WV, Beck RW, Bode BW.Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. Continuous glucose monitoring and intensive treatment of type 1 diabetes. N Engl J Med. 2008;359(14):1464-147618779236PubMedGoogle ScholarCrossref 13. Weinzimer SA, Steil GM, Swan KL, Dziura J, Kurtz N, Tamborlane WV. Fully automated closed-loop insulin delivery vs semiautomated hybrid control in pediatric patients with type 1 diabetes using an artificial pancreas. Diabetes Care. 2008;31(5):934-93918252903PubMedGoogle ScholarCrossref 14. Saudek CD, Duckworth WC, Giobbie-Hurder A, et al; Department of Veterans Affairs Implantable Insulin Pump Study Group. Implantable insulin pump vs multiple-dose insulin for non-insulin-dependent diabetes mellitus: a randomized clinical trial. JAMA. 1996;276(16):1322-13278861991PubMedGoogle ScholarCrossref 15. Resnick HE, Foster GL, Bardsley J, Ratner RE. Achievement of American Diabetes Association clinical practice recommendations among US adults with diabetes, 1999-2002: the National Health and Nutrition Examination Survey. Diabetes Care. 2006;29(3):531-53716505501PubMedGoogle ScholarCrossref

Journal

JAMAAmerican Medical Association

Published: Apr 15, 2009

Keywords: diabetes mellitus,diabetes mellitus, type 2

References