Vinik AI, Milicevic Z: Recent advances in the diagnosis and treatment of diabetic neuropathy. Thus, emphasizing tight control for individuals with autonomic dysfunction should also include increased vigilance in glycemic monitoring and reeducation of the patient with regard to hypoglycemia.
Autonomic neuropathy: its diagnosis and prognosis - PubMed Bacterial overgrowth due to stasis of the bowel may contribute to diarrhea, in which case broad-spectrum antibiotics (e.g., tetracycline and metronidazole) are useful. Cardiovascular autonomic function testing may help differentiate CAN from other causes of weakness, lightheadedness, dizziness, or fatigue and promote appropriate therapeutic intervention (62). (31) reported a 2.5-year mortality rate of 27.5\% that increased to 53\% after 5 years in diabetic patients with abnormal autonomic function tests compared with a mortality rate of only 15\% over the 5-year period among diabetic patients with normal autonomic function test results. There is a predominately peripheral component, but pain generates a centrally mediated response. Dysautonomia, also called autonomic dysfunction or autonomic neuropathy, is relatively common. Several different factors have been implicated in this pathogenic process. The ANS is typically divided into two divisions: the parasympathetic and the sympathetic systems on the basis of anatomical and functional differences.
Tests for early diagnosis of cardiovascular autonomic neuropathy Identifying individuals at risk is only the first step in managing patients and ultimately affecting outcomes. A search of PubMed using the Mesh terms "diabetes," "type 1," "insulin-dependent," "T1DM," and "diabetic autonomic neuropathy" was performed to find relevant primary literature. E:I ratios are based on the fact that inspiration shortens R-R intervals while expiration lengthens them. Freeman R: The peripheral nervous system and diabetes. Smooth muscle microvasculature in the periphery reacts sympathetically to a number of stressor tasks. If the cause of orthostatic hypotension is CAN, treatment goals should not only consist of therapies to increase the standing blood pressure, balanced against preventing hypertension in the supine position (61), but should also provide education to patients so that they avoid situations (e.g., vasodilation from hot showers) that result in the creation of symptoms (i.e., syncopal episodes). Autonomic neuropathy can be a complication of many diseases and conditions and can be a side effect from some medications. Roy TM, Peterson HR, Snider HL, Cyrus J, et al. (109) showed that a simple bedside test that measured 1-min HRV during deep breathing was a good predictor of all-cause mortality for 185 patients (17.8% with diabetes) after a first MI. In 1992, a second jointly sponsored conference was convened to review the state-of-the-art of diabetic neuropathy measures used in epidemiological and clinical studies including cross-sectional, longitudinal, and therapeutic trials. In fact, researchers have confirmed the presence of autonomic neuropathy at presentation (24). Two separate population-based studies have also examined the association of CAN and mortality. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB: Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. BP, blood pressure; CVD, cardiovascular disease; E:I difference = mean expiration to inspiration difference in R-R intervals over six consecutive breaths; R-R interval, time interval between successive ECG R-waves; sBP, systolic blood pressure. Diabetic neuropathies, including cardiac autonomic neuropathy (CAN), are a common chronic complication of type 1 and type 2 diabetes and confer high morbidity and mortality to patients with diabetes.1 Diabetic autonomic neuropathy is among the least recognised and understood complications of diabetes, despite its signicant negative . As some researchers have reported, the incidence of reduced HRV (measured using PSA) has been shown to be 15% in children (176). In practical terms, the risk is minimal because comparable intrathoracic pressures occur in the performance of daily activities.
Incidence, Prevalence, and Long-Term Consequences of Small Fiber Neuropathy Javorka K, Javorkova J, Petraskova M, et al. In healthy subjects, the reflex response to the Valsalva maneuver includes tachycardia and peripheral vasoconstriction during strain, followed by an overshoot in blood pressure and bradycardia after release of strain. Relative risk decreased from 4.03 to 1.37 after controling for duration, renal disease, hypertension, and coronary heart disease. It is a well-standardized test and evaluates the distribution of sweat by a change in color of an indicator powder on the skin after exposure to infrared light. Indeed, because the vagus nerve (the longest of the ANS nerves) accounts for 75% of all parasympathetic activity (4), and DAN manifests first in longer nerves, even early effects of DAN are widespread.
What is the life expectancy of someone with autonomic dysfunction Diabetic cystopathy manifests as an increase in threshold of occurrence of a detrusor reflex contraction. Given that CAN may be life-threatening and the assessment for its presence can be easily performed, testing for cardiovascular autonomic dysfunction is suggested for individuals with diabetes.
Autonomic Neuropathy | ADA - American Diabetes Association For example, in a community-based population study of diabetic neuropathy in Oxford, England, the prevalence of autonomic neuropathy as defined by one or more abnormal heart rate variability (HRV) test results was 16.7% (38). Case-control study of transplant recipients (pancreas-kidney or kidney alone). and Risk) were based on standardized testing of 205 normal subjects and 3,516 patients with type 1 or type 2 diabetes from 42 centers. Diabetic patients with CAN are predisposed to a lack of the normal nighttime decrease in blood pressure because of an increased prevalence of sympathetic activity (100). Marchant B, Umachandran V, Stevenson R, Kopelman PG, Timmis AD: Silent myocardial ischemia: role of subclinical neuropathy in patients with and without diabetes. In people with diabetes, the body's capability to use or produce insulin, a hormone that assists .
Diabetic Neuropathy - Types, Causes, Symptoms & Prevention Burgos LG, Ebert TJ, Asiddao C, Turner LA, et al. As their Autonomics continue to malfunction, Autonomic testing reveals increased Low HRV (Heart Rate Variability). Hormonal evaluation (luteinizing hormone, testosterone, free testosterone, prolactin), Psychological evaluation (Minnesota Multiphasic Personality Inventory [MMPI]). Constipation is the most common lower-GI symptom but can alternate with episodes of diarrhea. Rather, it is a complication or side-effect caused by disrupted signals between the brain and the nervous system. An impaired ability to recognize hypoglycemia and impaired recovery from hypoglycemic episodes due to defective endocrine counterregulatory mechanisms are also potential reasons for death (36). Improved nutrition and reduced alcohol and tobacco consumption are additional options available to patients with diabetes who are identified with autonomic nerve dysfunction. The evaluation might include the following: Postvoid ultrasound to assess residual volume and upper-urinary tract dilation, Cystometry and voiding cystometrogram to measure bladder sensation and volume pressure changes associated with bladder filling with known volumes of water and voiding. Jermendy G, Davidovits Z, Khoor S: Silent coronary artery disease in diabetic patients with cardiac autonomic neuropathy. The time-domain values were found to correlate very strongly with high-frequency spectral indexes, especially the Valsalva and 30:15 ratios (linear regression gave R2 values of 0.85 and 0.90, respectively). Cryer PE, Silverberg AB, Santiago JV, Shah SD: Plasma catecholamines in diabetes: the syndromes of hypoadrenergic and hyperadrenergic postural hypotension. Many health conditions can cause autonomic neuropathy. Some people have mild symptoms. The clinical literature has consistently identified these five tests as they have been widely used in a variety of studies. Sawicki PT, Bender DR, Berger M: Prolonged QT interval as a predictor of mortality in diabetic nephropathy. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RE, Lachin JM, Walker EA, Nathan DM: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. One-half of patients with known or suspected CAD, Both HRV during deep breathing and 30:15 ratio were abnormal, Authors did not indicate whether only one or both tests were abnormal. At least two of these three tests should be performed to provide adequate diagnostic information and to support reimbursement claims. Borst C, Weiling W, van Brederode JFM, Hond A, DeRijk LG, Dunning AJ: Mechanisms of initial heart rate response to postural change. Positive Schillings test may be diagnostic of bacterial overgrowth. Low PA, Walsh JC, Huang CY, McLeod JG: The sympathetic nervous system in diabetic neuropathy: a clinical and pathological study. Delay in instituting appropriate interventions can only increase the likelihood of developing advanced neuropathies. This paper was peer-reviewed, modified, and approved by the Professional Practice Committee, January 2003. Gde P, Oellgaard J, Carstensen B, et al. Fanelli C, Pampanelli S, Lalli C, Del Sindaco P, Ciofetta M, Lepore M, Porcellati F, Bottini P, Di Vincenzo A, Brunetti P, Bolli GB: Long-term intensive therapy of IDDM patients with clinically overt autonomic neuropathy: effects on hypoglycemia awareness and counterregulation. : Autonomic influence on cardiovascular performance in diabetic subjects. In a study by Levitt et al. Pfeifer MA, Weinberg CR, Cook DL, Reenan A, Halter JB, Ensinck JW, Porte D Jr: Autonomic neural dysfunction in recently diagnosed diabetic subjects. Life Expectancy Of Someone With Autonomic Neuropathy. The test, typically done by recording from the forearm and three lower-extremity skin sites, has high sensitivity, specificity, and reproducibility, with a coefficient of variation of 20% if performed by trained personnel. Occasionally, anorectal manometry and other specialized tests typically performed by the gastroenterologist may be helpful. Glucose is the main source of energy for the body's cells and is obtained from the food we consume. Therefore, assessment modalities that are used to measure other forms of diabetic peripheral neuropathy, such as tests of sensory or motor nerve fiber function (e.g., monofilament probe, quantitative sensory tests, or nerve conduction studies) and tests of muscle strength, may not be effective in detecting the cardiovascular involvement that autonomic function tests detect at early stages of emergence. It comprises sympathetic, parasympathetic, and enteric nervous systems, which are three anatomically distinct divisions. Assessment of colonic segmental transit time. These studies have consistently provided evidence for an increased mortality risk among diabetic individuals with CAN compared with individuals without CAN (Table 3). It causes a reduction in heart rate and blood pressure, facilitates the digestion and absorption of nutrients, and facilitates the excretion of waste products from the body.
Life Expectancy Of Someone With Diabetic Neuropathy - Epainassist The three tests recommended were heart rate response to 1) deep breathing, 2) standing, and 3) the Valsalva maneuver. DAN frequently coexists with other peripheral neuropathies and other diabetic complications, but DAN may be isolated, frequently preceding the detection of other complications. Female sexual dysfunction (e.g., loss of vaginal lubrication), Hypoglycemia-associated autonomic failure, Pupillomotor function impairment (e.g., decreased diameter of dark-adapted pupil).
Small Fiber Sensory Neuropathy - Hopkins Medicine Can diabetic neuropathy go away? - remodelormove.com The patient is connected to an electrocardiogram (ECG) monitor while lying down and then stands to a full upright position. Sacral outflow (S2, S3, and S4) assessment, which represents the sacral parasympathetic divisions: anal sphincter tone, perianal sensation, anal wink, and bulbocavernous reflex are clinical features of denervation of the important nerve supply that enable erections to occur. PDF | Aims Diabetic neuropathy (DN) represents an important complication of diabetes mellitus. Poor glycemic control may also be a consequence of DAN (e.g., gastroparesis that goes unidentified). Long-term poor glycemic control can only increase the risk of developing advanced diabetic neuropathy, although long-term follow-up studies are lacking (117). Horowitz M, Edelbroek M, Fraser R, Maddox A, Wishart J: Disordered gastric motor function in diabetes mellitus: recent insights into prevalence, pathophysiology, clinical relevance and treatment. Other investigators have noted explanations for the high mortality rate as an interaction with other concomitant disorders that also carry high risks of mortality. Langer A, Freeman MR, Josse RG, Armstrong PW: Metaiodobenzylguanidine imaging in diabetes mellitus: assessment of cardiac sympathetic denervation and its relation to autonomic dysfunction and silent myocardial ischemia. To help them burn away dangerous fat from their . In most individuals with hypoglycemic unawareness, raising the target may be necessary to prevent repeat episodes. Diabetic autonomic neuropathy may lead to a silent myocardial infarction, which is a condition of the heart. Intrasubject comparisons were achieved through multiple linear regression analysis for which the predicted spectral power was plotted against the actual time-domain values. Treatment focuses on managing the symptoms of autonomic neuropathy. Relative risks and 95% CIs for association between CAN and mortality in 15 studies. Some patients may experience burning pain or coldness and electric shock-like brief painful sensations. Two of the meetings (the San Antonio Conference on Diabetic Neuropathy held in 1988 and a second conference in 1992) were jointly sponsored by the American Diabetes Association and AAN. Association of CAN and silent myocardial infarction (SMI) in 12 studies. This is due, in part, to the long-term commitment that must be made to the practice of preventive measures. Comparing the silent ischemia group (n = 16) with the group who did experience angina (n = 36) revealed impaired autonomic function in the silent ischemia group, with statistically lower 30:15 ratios. Activation of the muscarinic, cholinergic, and postganglionic pelvic nerve fibers result in contraction of the urinary bladder.
Autoimmune Autonomic Ganglionopathy and Autoimmune Autonomic Neuropathy Other antioxidants such as vitamin E have been shown to improve the ratio of cardiac sympathetic to parasympathetic tone in type 2 diabetic individuals with CAN (186) but may mitigate the effects of statins and niacin in treating or preventing macrovascular disease. The presence of autonomic neuropathy may accelerate the rate of progression of diabetic glomerulopathy by mechanisms not completely understood (36). Diabetic cardiovascular autonomic . 1. Beylot M, Marion D, Noel G: Ultrasonographic determination of residual urine in diabetic subjects: relationship to neuropathy and urinary tract infection. For example, in the DCCT, the presence of autonomic neuropathy correlated with male sex along with age and duration (178). Kong MF, Horowitz M, Jones KL, Wishart JM, Harding PE: Natural history of diabetic gastroparesis. Pharmacological blockade studies using atropine, phentolamine (an -adrenergic antagonist), and propranolol (a nonspecific -adrenergic blocker) confirm dual involvement of autonomic nerve branches for the response to this maneuver by demonstrating the drugs varied effects of attenuation or augmentation of the hemodynamic response to the maneuver at specific times during the response (162). The most common painful neuropathies are diabetic neuropathy and postherpetic neuralgia, for which epidemiological data are available [7, 33, 49]. The severe and intermittent nature of diabetic diarrhea makes treatment and assessment difficult. These changes ultimately contribute to the development of ulcers, gangrene, and limb loss. A total of 16 individuals did not experience angina, and 10 of these had diabetes. Noninvasive validated measures of autonomic neural reflexes should be used as specific markers of autonomic neuropathy if end-organ failure is carefully ruled out and other important factors such as concomitant illness, drug use, and age are taken into account. ECG tracings are used to determine the 30:15 ratio, calculated as the ratio of the longest R-R interval (found at about beat 30) to the shortest R-R interval (found at about beat 15). Thus, children may pose some challenges related to performance (such as the attainment of the expiration pressure target required for the Valsalva maneuver and the performance of metronomic breathing) and the cooperation and attention requirements of the test situation. Although the relationship between features of autonomic neuropathy and hypoglycemic unawareness is complex and there is overlap, it is recognized that autonomic neuropathy may cause or contribute to the development of hypoglycemic unawareness. Worldwide, it affects more than 70 million people. Pfeifer MA, Schumer MP, Gelber DA: Aldose reductase inhibitors: the end of an era or the need for different trial designs? It's a rare disorder that usually occurs in adults over the age of 40. . Neurovascular dysfunction resulting from DAN contributes to a wide spectrum of clinical disorders including erectile dysfunction, loss of skin integrity, and abnormal vascular reflexes. Therefore, they suggested that although CAN could be a contributing factor, it was not a significant independent cause of sudden death. Autonomic neuropathy is a collection of diseases and syndromes in which autonomic nervous system, parasympathetic, sympathetic or both are affected. (50) showed that some diabetic patients with autonomic neuropathy have a reduced hypoxic-induced ventilatory drive. Neuropathy can also be caused by other health conditions and certain medications. In some cases, no cause can be identified and this is termed idiopathic neuropathy. In, Smith SA, Smith SE: Assessment of pupillary function in diabetic neuropathy. Small fiber neuropathy of the autonomic nervous system can also cause additional symptoms, such as dizziness, dry mouth and eyes, G.I. In people with diabetes, the body's capability to utilize or produce insulin, a hormone . (Heart,. This [] Aaron I. Vinik, Raelene E. Maser, Braxton D. Mitchell, Roy Freeman; Diabetic Autonomic Neuropathy . Chen HS, Hwu CM, Kuo BI, Chiang SC, Kwok CF, Lee SH, Lee YS, Weih MJ, Hsiao LC, Lin SH, Ho LT: Abnormal cardiovascular reflex tests are predictors of mortality in type 2 diabetes mellitus. Major clinical features of this disorder are early satiety, anorexia, nausea, vomiting, epigastric discomfort, and bloating. Pacher P, Liaudet L, Soriano FG, Mabley JG, Szabo E, Szabo C: The role of poly(ADP-ribose) polymerase activation in the development of myocardial and endothelial dysfunction in diabetes. (161) redefined the maximum/minimum 30:15 ratio as the longest R-R interval during beats 2040 divided by the shortest R-R interval during beats 525. Glucose is the main source of energy for the body's cells and is acquired from the food we consume. Cryer PE: Hypoglycemia-associated autonomic failure in diabetes. If reflex pathways are defective, blood pressure falls markedly with hemodynamic pooling. The influence of autonomic function was assessed via heart rate variation during deep breathing (beats/min), Valsalva maneuver, 30:15 ratio, and blood pressure response to standing. The panel in 1992 also revised its recommendation to include three tests for the longitudinal testing of the cardiovascular ANS: 1) heart rate response during deep breathing, 2) Valsalva maneuver, and 3) postural blood pressure testing (157). Diabetic Autonomic Neuropathy Life Expectancy. In men, DAN may cause loss of penile erection and/or retrograde ejaculation. Among individuals who died, there was no difference in duration of diabetes between those with and without autonomic neuropathy. Dysautonomia can be mild to serious in severity and even fatal (rarely). Healthy patients develop tachycardia and peripheral vasoconstriction during the strain and an overshoot in blood pressure and bradycardia on release. Hypotheses concerning the multiple etiologies of diabetic neuropathy include a metabolic insult to nerve fibers, neurovascular insufficiency, autoimmune damage, and neurohormonal growth factor deficiency (8). Murray DP, OBrien T, Mulrooney R, OSullivan DJ: Autonomic dysfunction and silent myocardial ischaemia on exercise testing in diabetes mellitus. Hemodynamic changes occur during surgery for individuals with and without diabetes. Bottini P, Boschetti E, Pampanelli S, Ciofetta M, Del Sindaco P, Scionti L, Brunetti P, Bolli GB: Contribution of autonomic neuropathy to reduced plasma adrenaline responses to hypoglycemia in IDDM: evidence for a nonselective defect. (155) demonstrated the effect of autonomic neuropathy on the risk of developing a foot ulcer independent of other measures of sensory neuropathy. Answer (1 of 12): Yes. Gerritsen J, Dekker JM, ten Voorde BJ, Kostense PJ, Heine RJ, Bouter LM, Heethaar RM, Stehouwer CD: Impaired autonomic function is associated with increased mortality, especially in subjects with diabetes, hypertension, or a history of cardiovascular disease: the Hoorn Study. The heart rate power spectrum is typically divided into two frequency bands: low (0.040.15 Hz) and high (0.150.4 Hz). This can lead to the death of almost 25 percent to 50 percent of people suffering from diabetic neuropathy, within a period as short as 5 to 10 years. This is seen as a blunted heart rate response and sometimes as a lower-than-normal decline in blood pressure during strain, followed by a slow recovery after release. Despite the increased association with mortality, the causative relationship between CAN and the increased risk of mortality has not been conclusively established. Sochett E, Daneman D: Early diabetes-related complications in children and adolescents with type 1 diabetes: implications for screening and intervention. Relative risk = 2.25 (1.134.45); diabetic subjects (, Unique diagnostic criteria defined by scoring 3 or more, Copyright American Diabetes Association. Intensive insulin therapy has been shown to be effective at preventing multiple complications in patients with type 1 diabetes and is postulated to be effective for patients with type 2 diabetes, although clinical studies are underway in the latter. With performance of the Valsalva maneuver, there is a transient increase in intraocular and intracranial pressure, creating a small theoretical risk of intraocular hemorrhage and lens dislocation (163). McCulloch DK, Campbell IW, Wu FC, Prescott RJ, Clarke BF: The prevalence of diabetic impotence. Low PA, Nickander KK: Oxygen free radical effects in sciatic nerve in experimental diabetes.
What is the life expectancy of someone with neuropathy? More recent data suggest that the presence of autonomic neuropathy further attenuates the epinephrine response to hypoglycemia in diabetic individuals after recent hypoglycemic exposure (144146). This can result in wide swings of glucose levels and unexpected episodes of postprandial hypoglycemia and apparent brittle diabetes. Therefore, gastroparesis should be suspected in patients with erratic glucose control. The neurogenic bladder, also called cystopathy, may be due to DAN (62). Other forms of autonomic neuropathy can be evaluated with specialized tests, but these are less standardized and less available than commonly used tests of cardiovascular autonomic function, which quantify loss of HRV. Neither age nor type of diabetes are limiting factors in its emergence, being found in young individuals with newly diagnosed type 1 diabetes and older individuals newly diagnosed with type 2 diabetes (5,24,40,44,113,114). Reduced heart rate variation is the earliest indicator of CAN (44). In its entirety, the evidence supports the contention that all patients with diabetes, regardless of metabolic control, are at risk for autonomic complications. cardiovascular autonomic . If history and examination suggest small bowel disease, hydrogen breath test and Schillings test are required. A study by Marchant et al. Freeman R: Cardiovascular autonomic neuropathy. Its importance has been clarified in recent years during which the extent of autonomic control over all areas of body function has been defined. Advances in technology, built on decades of research and clinical testing, now make it possible to objectively identify early stages of CAN with the use of careful measurement of autonomic function. Address correspondence and reprint requests to Aaron I. Vinik, MD, PhD, Director, Strelitz Diabetes Research Institutes, Eastern Virginia Medical School, 855 W. Brambleton Ave., Norfolk, VA 23510. Those with CAN had greater prevalence of other complications, but in multivariate analysis, CAN was the most important predictor of mortality. The efferent fibers innervate the heart and muscle, resulting in increased cardiac output, blood pressure, and heart rate. Diabetes affects more than million worldwide. By opposing the sympathetic stimulus, they may restore the parasympathetic-sympathetic balance. Subjects were newly diagnosed with diabetes. Other investigators have also shown independent associations of autonomic dysfunction with markers of cardiovascular risk (e.g., elevated blood pressure [98], body weight, glycosylated hemoglobin, and overt albuminuria [99]). The perception of angina was severely impaired in the diabetic patients, allowing these individuals to exercise longer after the onset of myocardial ischemia. : Diabetic autonomic neuropathy: the prevalence of impaired heart rate variability in a geographically defined population. Hikita H, Kurita A, Takase B, Nagayoshi H, Uehata A, Nishioka T, Mitani H, Mizuno K, Nakamura H: Usefulness of plasma beta-endorphin level, pain threshold and autonomic function in assessing silent myocardial ischemia in patients with and without diabetes mellitus. Veves A, King GL: Can VEGF reverse diabetic neuropathy in human subjects? Clinical signs and symptoms of autonomic dysfunction do not always progress. Another study by Howorka et al. I have breathing issues and arithmia's. My doctor refuses to discuss life expectancy. Autonomic neuropathy is not a single condition. Ambepityia G, Kopelman PG, Ingram D, Swash M, Mills PG, Timmis AD: Exertional myocardial ischemia in diabetes: a quantitative analysis of anginal perceptual threshold and the influence of autonomic function. The association of cardiovascular autonomic dysfunction in the absence of coronary disease and cardiomyopathy requires further study. The defect is associated with a reduction in the amplitude of vasomotion and resembles premature aging (153). Examination features include mild sensory deficits to pain and temperature. Diagnostic approaches should rule out autonomic dysfunction and the well-known causes such as neoplasia. Given the potential for impaired exercise tolerance, it has been suggested that diabetic patients who are likely to have CAN have cardiac stress testing before undertaking an exercise program (45). Autophagy is considered to be potentially involved in the. Pfeifer MA, Schumer MP: Clinical trials of diabetic neuropathy: past, present, and future. Another study group observed nearly an identical prevalence rate (16.6%) for individuals with insulin-dependent diabetes (39). These results, however, recapitulate that prevalence rates will vary depending on 1) different patient cohorts studied, 2) varied testing modalities utilized, and 3) different criteria used to define autonomic dysfunction. One of the most overlooked of all serious complications of diabetes is cardiovascular autonomic neuropathy (CAN), 1-3 which encompasses damage to the autonomic nerve fibers that innervate the heart and blood vessels, resulting in abnormalities in heart rate control and vascular dynamics. Additionally, risk factors for type 2 .