Early Vascular Risk Factor Modification in Type 1 Diabetes
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《新英格兰医药杂志》
The discovery of insulin some 80 years ago changed type 1 diabetes from an imminently lethal disease to a chronic condition, and clinical care evolved from preventing death to preventing disability. Large-scale studies defined the natural history of the development of early retinal lesions and their progression to loss of vision, leading to interventions such as laser-photocoagulation therapy to help prevent vision loss.1 Similar work identified the fundamental importance of microalbuminuria as a sign of incipient kidney disease and defined some of the necessary interventions to prevent progression of diabetic nephropathy to impairment of renal function and end-stage renal disease.2,3 However, the third member of the triad of chronic microvascular diseases, diabetic neuropathy, has somehow evaded a comparable degree of basic understanding in terms of accurate diagnosis, prevention, and treatment. The report by Tesfaye et al. in this issue of the Journal4 begins to correct this deficit.
Damage to the peripheral nervous system in people with diabetes is a complex process, both clinically and biologically. The complexity begins with the diverse clinical presentation. The neuropathies associated with diabetes fall into two broad categories — focal and generalized neuropathies. The focal neuropathies include the mononeuropathies such as carpal tunnel syndrome, palsy of the peroneal nerve, palsy of the third cranial nerve, and proximal nerve conditions (e.g., diabetic amyotrophy). Diabetic sensorimotor polyneuropathy is by far the most common generalized neuropathy among the neurologic complications of diabetes. For this reason, despite the many other presentations of neuropathy associated with diabetes, the simplified term "diabetic neuropathy" usually replaces "diabetic sensorimotor polyneuropathy" in the general medical literature.
Diabetic neuropathy is a polyneuropathy because of the diffuse damage to all peripheral nerve fibers — motor, sensory, and autonomic. Such damage occurs insidiously and progressively. It usually begins as a generalized and asymptomatic symmetrical dysfunction of the peripheral nerves, depending on the length of the involved nerves. Nerve damage is characterized at first by sensory loss and later by loss of motor function, in a stocking-and-glove distribution.
Tesfaye et al. consider diabetic neuropathy at this stage to be "pure" peripheral neuropathy, but the full syndrome of the polyneuropathy may progress to involve clinical evidence of autonomic dysfunction, which may include such conditions as gastroparesis, cardiac autonomic neuropathy, and erectile dysfunction. Therefore, research studies such as the one by Tesfaye et al. must capture all these elements in their functional definition of diabetic neuropathy. The presence of pure peripheral neuropathy usually suggests earlier disease, as compared with disease involving autonomic features. Although not in full accordance with expert criteria,5 the definition used by Tesfaye et al. is an excellent surrogate that is useful for epidemiologic study and appears to agree quite well with objective studies of nerve conduction.6
Whether associated with autonomic features or not, diabetic peripheral neuropathy is of profound importance because it potentiates severe sequelae, including skin ulceration of the feet and legs, faulty healing, and gangrene. Furthermore, peripheral neuropathy is sufficient to cause exquisite pain, imbalance, and Charcot's foot. These sequelae dramatically affect the quality of life and, from a public health perspective, generate an immense economic burden.7
Tesfaye et al. define the magnitude of diabetic neuropathy; nearly one third of the young patients with type 1 diabetes in the European Diabetes Prospective Complications Study cohort had profound diabetic neuropathy when a cross-sectional analysis was done, and advanced neuropathy developed within a relatively short time frame in almost one fourth of the remaining participants, who did not have such advanced neuropathy at baseline. This information about the natural history alone emphasizes the urgent need for research to identify a clinical indicator of incipient diabetic neuropathy. We need an indicator of early nerve damage before the development of diabetic neuropathy, akin to early retinal changes as an indicator of risk for retinopathy or microalbuminuria as an indicator of risk for nephropathy. Scores derived from simple physical examination maneuvers (such as evaluation of pressure sensation with a monofilament or evaluation of vibration perception with a 128-Hz tuning fork) that can be performed in the clinic may be suitable for defining incipient diabetic neuropathy but require confirmation.8
Current evidence emphasizes the role of intensive glycemic control in all patients with type 1 diabetes in order to prevent microvascular complications9 and macrovascular injury,10 although recommendations for modifying vascular risk factors are too often delivered to patients who have already had diabetes for many years.11 Tesfaye et al. provide convincing evidence that even slight improvements in lipid variables, blood pressure, and body mass are associated with a significantly lower risk of the onset of diabetic neuropathy, and that this effect is similar to that of better glycemic control on neuropathy. These data suggest that vascular risk factors may accelerate the adverse effects of hyperglycemia on the peripheral nerves in patients with diabetes. Although no mechanism is known with certainty, the hyperglycemia-induced formation of reactive oxygen species, in the setting of increased levels of low-density lipoprotein cholesterol, may induce lipid oxidization, which in turn may intensify the injurious effect of hyperglycemia alone.12
We are rapidly learning through clinical and epidemiologic research that vascular factors traditionally associated with type 2 diabetes also play an important role in the natural history of microvascular complications in patients with type 1 diabetes.13,14,15 The focus on glycemic control9 should not obscure the attention owed to modifications of vascular risk factors in clinical trials in patients with type 1 diabetes. Indeed, it may be time for a multifactorial intervention trial similar to the design of clinical trials in patients with type 2 diabetes that incorporate glycemic control, smoking cessation, blood-pressure control, and dyslipidemia interventions.16 Furthermore, in light of the results reported by Tesfaye et al., such a clinical trial should include diabetic neuropathy as a primary outcome.
Source Information
From the Divisions of Endocrinology and Metabolism (B.A.P.) and Urology (V.B.), University of Toronto, Toronto.
References
Fundus photographic risk factors for progression of diabetic retinopathy: ETDRS report number 12. Ophthalmology 1991;98:Suppl:823-833.
Krolewski AS, Laffel LMB, Krolewski M, Quinn M, Warram JH. Glycosylated hemoglobin and the risk of microalbuminuria in patients with insulin-dependent diabetes mellitus. N Engl J Med 1995;332:1251-1255.
Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329:1456-1462.
Tesfaye S, Chaturvedi N, Eaton SEM, et al. Vascular risk factors and diabetic neuropathy. N Engl J Med 2005;352:341-350.
Consensus statement: report and recommendations of the San Antonio conference on diabetic neuropathy. Diabetes Care 1988;11:592-597.
Boulton AJ, Malik RA, Arezzo JC, Sosenko JM. Diabetic somatic neuropathies. Diabetes Care 2004;27:1458-1486.
Gordois A, Scuffham P, Shearer A, Oglesby A, Tobian JA. The health care costs of diabetic peripheral neuropathy in the US. Diabetes Care 2003;26:1790-1795.
Perkins BA, Olaleye D, Zinman B, Bril V. Simple screening tests for peripheral neuropathy in the diabetes clinic. Diabetes Care 2001;24:250-256.
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;329:977-986.
The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus. N Engl J Med 2003;348:2294-2303.
Haffner SM. Dyslipidemia management in adults with diabetes. Diabetes Care 2004;27:Suppl 1:S68-S71.
Feldman EL. Oxidative stress and diabetic neuropathy: a new understanding of an old problem. J Clin Invest 2003;111:431-433.
DeFronzo RA, Hendler R, Simonson D. Insulin resistance is a prominent feature of insulin-dependent diabetes. Diabetes 1982;31:795-801.
Perkins BA, Ficociello LH, Silva KH, Finkelstein DM, Warram JH, Krolewski AS. Regression of microalbuminuria in type 1 diabetes. N Engl J Med 2003;348:2285-2293.
Lyons TJ, Jenkins AJ, Zheng D, et al. Diabetic retinopathy and serum lipoprotein subclasses in the DCCT/EDIC cohort. Invest Ophthalmol Vis Sci 2004;45:910-918.
Gaede P, Vedel P, Larsen N, Jensen GVH, Parving H-H, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-393.(Bruce A. Perkins, M.D., M)
Damage to the peripheral nervous system in people with diabetes is a complex process, both clinically and biologically. The complexity begins with the diverse clinical presentation. The neuropathies associated with diabetes fall into two broad categories — focal and generalized neuropathies. The focal neuropathies include the mononeuropathies such as carpal tunnel syndrome, palsy of the peroneal nerve, palsy of the third cranial nerve, and proximal nerve conditions (e.g., diabetic amyotrophy). Diabetic sensorimotor polyneuropathy is by far the most common generalized neuropathy among the neurologic complications of diabetes. For this reason, despite the many other presentations of neuropathy associated with diabetes, the simplified term "diabetic neuropathy" usually replaces "diabetic sensorimotor polyneuropathy" in the general medical literature.
Diabetic neuropathy is a polyneuropathy because of the diffuse damage to all peripheral nerve fibers — motor, sensory, and autonomic. Such damage occurs insidiously and progressively. It usually begins as a generalized and asymptomatic symmetrical dysfunction of the peripheral nerves, depending on the length of the involved nerves. Nerve damage is characterized at first by sensory loss and later by loss of motor function, in a stocking-and-glove distribution.
Tesfaye et al. consider diabetic neuropathy at this stage to be "pure" peripheral neuropathy, but the full syndrome of the polyneuropathy may progress to involve clinical evidence of autonomic dysfunction, which may include such conditions as gastroparesis, cardiac autonomic neuropathy, and erectile dysfunction. Therefore, research studies such as the one by Tesfaye et al. must capture all these elements in their functional definition of diabetic neuropathy. The presence of pure peripheral neuropathy usually suggests earlier disease, as compared with disease involving autonomic features. Although not in full accordance with expert criteria,5 the definition used by Tesfaye et al. is an excellent surrogate that is useful for epidemiologic study and appears to agree quite well with objective studies of nerve conduction.6
Whether associated with autonomic features or not, diabetic peripheral neuropathy is of profound importance because it potentiates severe sequelae, including skin ulceration of the feet and legs, faulty healing, and gangrene. Furthermore, peripheral neuropathy is sufficient to cause exquisite pain, imbalance, and Charcot's foot. These sequelae dramatically affect the quality of life and, from a public health perspective, generate an immense economic burden.7
Tesfaye et al. define the magnitude of diabetic neuropathy; nearly one third of the young patients with type 1 diabetes in the European Diabetes Prospective Complications Study cohort had profound diabetic neuropathy when a cross-sectional analysis was done, and advanced neuropathy developed within a relatively short time frame in almost one fourth of the remaining participants, who did not have such advanced neuropathy at baseline. This information about the natural history alone emphasizes the urgent need for research to identify a clinical indicator of incipient diabetic neuropathy. We need an indicator of early nerve damage before the development of diabetic neuropathy, akin to early retinal changes as an indicator of risk for retinopathy or microalbuminuria as an indicator of risk for nephropathy. Scores derived from simple physical examination maneuvers (such as evaluation of pressure sensation with a monofilament or evaluation of vibration perception with a 128-Hz tuning fork) that can be performed in the clinic may be suitable for defining incipient diabetic neuropathy but require confirmation.8
Current evidence emphasizes the role of intensive glycemic control in all patients with type 1 diabetes in order to prevent microvascular complications9 and macrovascular injury,10 although recommendations for modifying vascular risk factors are too often delivered to patients who have already had diabetes for many years.11 Tesfaye et al. provide convincing evidence that even slight improvements in lipid variables, blood pressure, and body mass are associated with a significantly lower risk of the onset of diabetic neuropathy, and that this effect is similar to that of better glycemic control on neuropathy. These data suggest that vascular risk factors may accelerate the adverse effects of hyperglycemia on the peripheral nerves in patients with diabetes. Although no mechanism is known with certainty, the hyperglycemia-induced formation of reactive oxygen species, in the setting of increased levels of low-density lipoprotein cholesterol, may induce lipid oxidization, which in turn may intensify the injurious effect of hyperglycemia alone.12
We are rapidly learning through clinical and epidemiologic research that vascular factors traditionally associated with type 2 diabetes also play an important role in the natural history of microvascular complications in patients with type 1 diabetes.13,14,15 The focus on glycemic control9 should not obscure the attention owed to modifications of vascular risk factors in clinical trials in patients with type 1 diabetes. Indeed, it may be time for a multifactorial intervention trial similar to the design of clinical trials in patients with type 2 diabetes that incorporate glycemic control, smoking cessation, blood-pressure control, and dyslipidemia interventions.16 Furthermore, in light of the results reported by Tesfaye et al., such a clinical trial should include diabetic neuropathy as a primary outcome.
Source Information
From the Divisions of Endocrinology and Metabolism (B.A.P.) and Urology (V.B.), University of Toronto, Toronto.
References
Fundus photographic risk factors for progression of diabetic retinopathy: ETDRS report number 12. Ophthalmology 1991;98:Suppl:823-833.
Krolewski AS, Laffel LMB, Krolewski M, Quinn M, Warram JH. Glycosylated hemoglobin and the risk of microalbuminuria in patients with insulin-dependent diabetes mellitus. N Engl J Med 1995;332:1251-1255.
Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329:1456-1462.
Tesfaye S, Chaturvedi N, Eaton SEM, et al. Vascular risk factors and diabetic neuropathy. N Engl J Med 2005;352:341-350.
Consensus statement: report and recommendations of the San Antonio conference on diabetic neuropathy. Diabetes Care 1988;11:592-597.
Boulton AJ, Malik RA, Arezzo JC, Sosenko JM. Diabetic somatic neuropathies. Diabetes Care 2004;27:1458-1486.
Gordois A, Scuffham P, Shearer A, Oglesby A, Tobian JA. The health care costs of diabetic peripheral neuropathy in the US. Diabetes Care 2003;26:1790-1795.
Perkins BA, Olaleye D, Zinman B, Bril V. Simple screening tests for peripheral neuropathy in the diabetes clinic. Diabetes Care 2001;24:250-256.
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;329:977-986.
The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus. N Engl J Med 2003;348:2294-2303.
Haffner SM. Dyslipidemia management in adults with diabetes. Diabetes Care 2004;27:Suppl 1:S68-S71.
Feldman EL. Oxidative stress and diabetic neuropathy: a new understanding of an old problem. J Clin Invest 2003;111:431-433.
DeFronzo RA, Hendler R, Simonson D. Insulin resistance is a prominent feature of insulin-dependent diabetes. Diabetes 1982;31:795-801.
Perkins BA, Ficociello LH, Silva KH, Finkelstein DM, Warram JH, Krolewski AS. Regression of microalbuminuria in type 1 diabetes. N Engl J Med 2003;348:2285-2293.
Lyons TJ, Jenkins AJ, Zheng D, et al. Diabetic retinopathy and serum lipoprotein subclasses in the DCCT/EDIC cohort. Invest Ophthalmol Vis Sci 2004;45:910-918.
Gaede P, Vedel P, Larsen N, Jensen GVH, Parving H-H, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-393.(Bruce A. Perkins, M.D., M)