- Email: [email protected]
Current and future strategies for treatment of diabetic neuropathy
Speech Abstracts / Diabetes Research and Clinical Practice 120S1 (2016) S1–S39
Approximately 30% of diabetic subjects have chronic kidney disease (CKD). The choice of anti-diabetic agents in patients with CKD faces special challenges because CKD alters insulin sensitivity and clearance, glucose transport, and metabolism of anti-diabetic agents. CKD is also associated with increased CV and other complications. Inappropriate selection and dosage often aggravate renal dysfunction, cause hypoglycemia, morbidity and mortality, particularly CV diseases. The glycemic goal in CKD still is not defined. The KDOQI 2012 guidelines suggest a goal HbA1C of 7% to delay the progression of CKD. The Dialysis Outcomes and Practice Patterns Study (DOPPS) indicated that mortality increased when HbA1C moved from 7–7.9%. Apparently, the glycemic goal in diabetes with CKD is in this range. To reach this target, it is crucial to evaluate potential side effects of all anti-diabetic agents according to their safety, efficacy, renal metabolism and pharmacokinetics. Based on numerous trials, the dose of these anti-diabetic agents needs to be adjusted in patients with varying stages of CKD. Suggested dose adjustments are: 1. 2.
3. 4. 5. 6.
7.
8.
9.
Metformin: Discontinued if eGFR < 30 mL/min, <1,000 mg/ day if eGFR 30–45 mL/min/1.73 m2. Glimepiride, Glyburide (Glibenclamide): avoid use if eGFR <60 mL/min/1.73 m2. Gliclazide: Reduce dose if eGFR <30 mL/min, avoid use if eGFR <15 mL/min/1.73 m2. Glipizide: No dose adjustment required. Repaglinide: Reduce dose if eGFR <30 mL/min; Nateglinide: Caution if eGFR <30 mL/min. Acarbose: Avoid use if eGFR <30 mL/min; Miglitol: Avoid use if eGFR <30 mL/min. Pioglitazone: No dose adjustment required, but caution if CKD, CHF and hypervolemia. Exenatide: Avoid use if eGFR <30 mL/min, reduce dose if eGFR 30–50 mL/min/1.73 m2. Liraglutide: No dose adjustment required if eGFR >30 mL/ min/1.73 m2. Lixisenatide: Caution if eGFR <50 mL/min/1.73 m2. Sitagliptin: 100 mg/day if eGFR >50 mL/min, 50 mg if eGFR 30–50, 25 mg if eGFR <30. Saxagliptin: 2.5–5 mg/day if eGFR >50 mL/min, 2.5 mg/day if eGFR <50 mL/min/1.73 m2. Aloglitiptin: 25 mg/day if eGFR >50 mL/min, 12.5 mg if eGFR 30–50 mL/min, and 6.25 mg if eGFR <30 mL/min or ESRD. Linagliptin: No dose adjustment required. Canagliflozin: Reduce dose if eGFR 45–59/min; Empagliflozin: Caution if eGFR <45 mL/min; Dapagliflozin: Avoid use if eGFR <60 mL/min/1.73 m2. Insulin: No dose adjustment if eGFR >50 mL/min, 25% or 50% reduction of total daily dose if eGFR 10–50 mL/min or <10 mL/min/1.73 m2.
Diabetic Neuropathy: Clinical Update S21-1 How to approach the patient with diabetic neuropathy – Screening and diagnosis Sung-Tsang HSIEH1,2. 1Department of Neurology, National Taiwan University Hospital, 10002, 2Department of Anatomy and Cell Biology, National Taiwan University, Taipei, 10051, Taiwan Diabetic neuropathy is one of the most frequent neuropathy in clinical practice. The manifestations of diabetic neuropathy are very diverse ranging from focal involvement of carpal tunnel syndrome to systemic sensorimotor polyneuropathy and autonomic neuropathy. Major symptoms of diabetic neuropathy include reduced sensation which may lead to painless injury of the body, neuropathic pain of different characters such as burning or tingling, and
S13
veracious autonomic symptoms of gastroparesis, orthostatic hypotension, chronic diarrhea, and sexual dysfunctions etc. Efficient screening and accurate diagnosis of diabetic neuropathy are challenging tasks for clinical practice. Screening instruments include questionnaires and thermal thresholds on quantitative sensory testing which provide the first-line assessments of potential neuropathy. Further confirmation of neuropathy, in particular, degeneration of nerve fibers can be diagnosed with conventional nerve conduction studies for large-diameter nerves. Over the past decade, our group has developed a technique of skin biopsy to examine smalldiameter sensory nerves which are responsible for thermal and nociceptive sensations. With a 3 mm punch and special staining on skin biopsy sections, nociceptive nerve fibers could be demonstrated and quantified, i.e. intraepidermal nerve fiber density (Eur J Neurol 17:903–912, 2010). This approach has become the standard for diagnosing small fiber neuropathy. Patients with diabetic neuropathy frequently had different types of neuropathic pain for example burning over the limbs or even the trunk. We tackled this issue by establishing contact heat evoked potential (Diabetes Care 33:2654–2659, 2010) and heat-activated functional magnetic resonance imaging (fMRI) (Hum Brain Mapp 34:2733–2746, 2013). These examinations demonstrated enhanced brain activations due to peripheral nerve degeneration. These assessments provide foundations for prescribing centralacting drugs for neuropathic pain, such as antidepressants and anticonvulsants as documented in various guidelines for neuropathic pain. This talk will focus on the recent advancements in screening and diagnosis of diabetic neuropathy. S21-2 Current and future strategies for treatment of diabetic neuropathy Jiro NAKAMURA1. 1Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan Diabetic neuropathy is the most common complication in diabetic patients. The symptom of diabetic neuropathy may cause various problems in daily life and affect the prognosis of diabetic patients. Therefore, it is important to prevent the development and progression of diabetic neuropathy at an early stage. It is obvious that the primary cause of diabetic neuropathy is hyperglycemia itself, and previous clinical trials such as DCCT, Kumamoto Study and EDIC Study demonstrated that strict glycemic control could prevent the development and progression of diabetic neuropathy. However, it is difficult to keep normal glucose levels for 24 hours in diabetic patients, especially in type 1 diabetic patients. Short-term hyperglycemia can switch on the pathogenic mechanisms. In addition, therefore, interventions to the pathogenic mechanisms beyond glucose are required. Various factors such as the metabolic factors, vascular factors, and neurotrophic factors have been proposed to explain the pathogenesis of diabetic neuropathy. Among these factors, the role of metabolic factors has been most extensively investigated. Metabolic factors include polyol pathway hyperactivity, altered protein kinase C activity, increased oxidative stress, and enhanced non-enzymatic glycation. Each metabolic deficit was originally derived from an independent background. However, recent studies have reported close relationships between these abnormalities, and it is now clear that polyol pathway hyperactivity leads to other three metabolic deficits. Based on previous studies, furthermore, polyol pathway hyperactivity plays the major role in the development of diabetic neuropathy. Therefore, from the viewpoint of preventing diabetic neuropathy or treatment of mild diabetic neuropathy, aldose reductase inhibition would be the best therapeutic strategy. However, advanced
S14
Speech Abstracts / Diabetes Research and Clinical Practice 120S1 (2016) S1–S39
neuropathy with established nerve degeneration and capillary occlusion cannot be ameliorated only by aldose reductase inhibition, and further interventions with regenerative medicine would be required. Previous studies reported that introduction of NGF, HGF or VEGF genes is a useful regenerative therapy of diabetic neuropathy. We reported the usefulness of local injection of basic FGF protein with cross-linked gelatin gel and transplantation of various kinds of progenitor cells such as endothelial progenitor cells (EPCs), mononuclear cells (MNCs), bone marrowderived mesenchymal stem cells (MSCs), and iPS cell-derived neural crest cells (NCCs) on diabetic neuropathy with diabetic animal models. In addition, we have investigated the possibilities of incretin-related agents to regenerate nerve fibers. In this session, an overview of current and future strategies for treatment of diabetic neuropathy will be presented.
Diabetes is a major public health problem affecting 415 million people worldwide in 2015 and the number is expected to rise to 642 million by 2040. In 2010, approximately a third of those with diabetes were found to have signs of DR and of these, a further one third were found to have vision-threatening DR, including diabetic macular edema (DME). With the rising prevalence of diabetes (in particular type 2), ageing of the population and increased life expectancy, number of persons with diabetic retinopathy (DR) is also expected to increase substantially. In view of the increasing burden of diabetes and DR, there has been significant global public attention and research in recent years on understanding the epidemiology of diabetes and DR, in an effort to develop long-term strategies to manage this major public health problem. This talk will highlight the recent trends in the epidemiology of DR with a particular focus on the burden, awareness, population differences, risk factors, and screening of DR/DME.
S21-3 Recent management of diabetic distal symmetric polyneuropathy Nigishi HOTTA1. 1Japan Organization of Occupational Health and Safety, Chubu Rosai Hospital, Nagoya, Japan
S25-2 The pathogenesis and risk factors of diabetic retinopathy and macular edema Gavin TAN1. 1Singapore Eye Research Institute, Singapore
Diabetic peripheral neuropathy is a very common complication of diabetes often associated with considerable morbidity and mortality. It appears relatively early in the disease process. The most common manifestation is a distal symmetric polyneuropathy, but many patterns of nerve impairment can occur. Diabetic neuropathy is not a single entity, but includes several neuropathic syndrome. Autonomic neuropathy may effect almost every system of our body, and once it is well established in the patients with diabetes, it is very difficult to treat for us. The treatment of diabetic neuropathy is classified to symptomatic- and causal-therapy. Current strategies for the treatment of distal symmetric polyneuropathy are based on the following: ①reduction of risk factors including poor glycemic control, ②treatment based on pathogenetic mechanisms, ③symptomatic treatment for such being neuropathic pain, and ④treatment of diabetic foot, autonomic and other complications. The previous three topics are talked over in my presentation. There are some differences of risk factors between type1 and type2 diabetes but mostly similar. Major factors are poor glycemic control with age and duration of diabetes but the development of diabetic neuropathy is also partly associated with hypertension, hyperlipidemia, obesity and cigarette smoking. Recently, there are the new appearance of useful drugs for diabetic painful neuropathy such as pregabalin and duloxetine. As the treatment based on pathogenetic mechanisms, many drugs have developed till today. However, unfortunately, most of their clinical trials have failed to show its efficacy. Only epalrestat, an aldose reductase inhibitor and α-lipoic acid, an anti-oxidant are available in clinical use at limited countries. We need for further experimental and clinical researches to find more effective, novel compounds being able to slow, prevent and/or reverse diabetic neuropathy.
S25-3 Diabetic eye diseases Chung-May YANG1. 1National Taiwan University Hospital, Taipei, Taiwan
The understanding of the pathogenesis of diabetic retinopathy is constantly evolving with new research. The major risk factors for diabetic retinopathy include duration of diabetes, hyperglycemia, and hypertension, but these account for only a small amount of the variation in the risk of diabetic retinopathy. Studies have shown that factors such as dyslipidemia, ethnicity, genetics, nephropathy myopia and ocular surgery contribute to the risk. Chronic exposure to hyperglycemia and other known risk factors results in a cascade of biochemical and physiologic changes that ultimately lead to microvascular damage and retinal dysfunction. Implicated pathways include the accumulation of sorbitol and advanced glycation end-products, oxidative stress, protein kinase C activation, inflammation, and upregulation of the reninangiotensin system and vascular endothelial growth factor.
The eye is one of the major organs affected by diabetic mellitus. Structural and functional changes can be seen from the cornea through the crystalline lens to the vitreo-retinal tissues. Diabetic vitreoretinopathy is the most important category related to diabetic eye diseases. The basic pathogenesis of diabetic vitreoretinopathy involves retinal vascular permeability changes and vascular occlusion, which cause macular edema and the development of retinal fibrovascular proliferation through the excessive production of various angiogenic factors. The progression of fibrovascular proliferation may induce vitreous hemorrhage, traction macular elevation and traction retinal detachment, leading to severe bilateral visual loss. In this presentation, clinical manifestations, update treatment strategies and outcome will be briefly reviewed.
Diabetic Eye Disease: Early Detection, and Treatment
Diabetes Foot: Learning from Diabetes Foot Care Program
S25-1 Epidemiology of diabetic retinopathy, diabetic macular edema and vision loss due to diabetes Charumathi SABANAYAGAM1. 1Far Eastern Memorial Hospital, New Taipei, Taiwan
S31-1 Diabetic foot problems and education programme on the diabetic foot in Western Pacific Region Shigeo KONO1. 1National Hospital Organization, Kyoto Medical Center, Kyoto, Japan
Approximately 30% of diabetic subjects have chronic kidney disease (CKD). The choice of anti-diabetic agents in patients with CKD faces special challenges because CKD alters insulin sensitivity and clearance, glucose transport, and metabolism of anti-diabetic agents. CKD is also associated with increased CV and other complications. Inappropriate selection and dosage often aggravate renal dysfunction, cause hypoglycemia, morbidity and mortality, particularly CV diseases. The glycemic goal in CKD still is not defined. The KDOQI 2012 guidelines suggest a goal HbA1C of 7% to delay the progression of CKD. The Dialysis Outcomes and Practice Patterns Study (DOPPS) indicated that mortality increased when HbA1C moved from 7–7.9%. Apparently, the glycemic goal in diabetes with CKD is in this range. To reach this target, it is crucial to evaluate potential side effects of all anti-diabetic agents according to their safety, efficacy, renal metabolism and pharmacokinetics. Based on numerous trials, the dose of these anti-diabetic agents needs to be adjusted in patients with varying stages of CKD. Suggested dose adjustments are: 1. 2.
3. 4. 5. 6.
7.
8.
9.
Metformin: Discontinued if eGFR < 30 mL/min, <1,000 mg/ day if eGFR 30–45 mL/min/1.73 m2. Glimepiride, Glyburide (Glibenclamide): avoid use if eGFR <60 mL/min/1.73 m2. Gliclazide: Reduce dose if eGFR <30 mL/min, avoid use if eGFR <15 mL/min/1.73 m2. Glipizide: No dose adjustment required. Repaglinide: Reduce dose if eGFR <30 mL/min; Nateglinide: Caution if eGFR <30 mL/min. Acarbose: Avoid use if eGFR <30 mL/min; Miglitol: Avoid use if eGFR <30 mL/min. Pioglitazone: No dose adjustment required, but caution if CKD, CHF and hypervolemia. Exenatide: Avoid use if eGFR <30 mL/min, reduce dose if eGFR 30–50 mL/min/1.73 m2. Liraglutide: No dose adjustment required if eGFR >30 mL/ min/1.73 m2. Lixisenatide: Caution if eGFR <50 mL/min/1.73 m2. Sitagliptin: 100 mg/day if eGFR >50 mL/min, 50 mg if eGFR 30–50, 25 mg if eGFR <30. Saxagliptin: 2.5–5 mg/day if eGFR >50 mL/min, 2.5 mg/day if eGFR <50 mL/min/1.73 m2. Aloglitiptin: 25 mg/day if eGFR >50 mL/min, 12.5 mg if eGFR 30–50 mL/min, and 6.25 mg if eGFR <30 mL/min or ESRD. Linagliptin: No dose adjustment required. Canagliflozin: Reduce dose if eGFR 45–59/min; Empagliflozin: Caution if eGFR <45 mL/min; Dapagliflozin: Avoid use if eGFR <60 mL/min/1.73 m2. Insulin: No dose adjustment if eGFR >50 mL/min, 25% or 50% reduction of total daily dose if eGFR 10–50 mL/min or <10 mL/min/1.73 m2.
Diabetic Neuropathy: Clinical Update S21-1 How to approach the patient with diabetic neuropathy – Screening and diagnosis Sung-Tsang HSIEH1,2. 1Department of Neurology, National Taiwan University Hospital, 10002, 2Department of Anatomy and Cell Biology, National Taiwan University, Taipei, 10051, Taiwan Diabetic neuropathy is one of the most frequent neuropathy in clinical practice. The manifestations of diabetic neuropathy are very diverse ranging from focal involvement of carpal tunnel syndrome to systemic sensorimotor polyneuropathy and autonomic neuropathy. Major symptoms of diabetic neuropathy include reduced sensation which may lead to painless injury of the body, neuropathic pain of different characters such as burning or tingling, and
S13
veracious autonomic symptoms of gastroparesis, orthostatic hypotension, chronic diarrhea, and sexual dysfunctions etc. Efficient screening and accurate diagnosis of diabetic neuropathy are challenging tasks for clinical practice. Screening instruments include questionnaires and thermal thresholds on quantitative sensory testing which provide the first-line assessments of potential neuropathy. Further confirmation of neuropathy, in particular, degeneration of nerve fibers can be diagnosed with conventional nerve conduction studies for large-diameter nerves. Over the past decade, our group has developed a technique of skin biopsy to examine smalldiameter sensory nerves which are responsible for thermal and nociceptive sensations. With a 3 mm punch and special staining on skin biopsy sections, nociceptive nerve fibers could be demonstrated and quantified, i.e. intraepidermal nerve fiber density (Eur J Neurol 17:903–912, 2010). This approach has become the standard for diagnosing small fiber neuropathy. Patients with diabetic neuropathy frequently had different types of neuropathic pain for example burning over the limbs or even the trunk. We tackled this issue by establishing contact heat evoked potential (Diabetes Care 33:2654–2659, 2010) and heat-activated functional magnetic resonance imaging (fMRI) (Hum Brain Mapp 34:2733–2746, 2013). These examinations demonstrated enhanced brain activations due to peripheral nerve degeneration. These assessments provide foundations for prescribing centralacting drugs for neuropathic pain, such as antidepressants and anticonvulsants as documented in various guidelines for neuropathic pain. This talk will focus on the recent advancements in screening and diagnosis of diabetic neuropathy. S21-2 Current and future strategies for treatment of diabetic neuropathy Jiro NAKAMURA1. 1Division of Diabetes, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan Diabetic neuropathy is the most common complication in diabetic patients. The symptom of diabetic neuropathy may cause various problems in daily life and affect the prognosis of diabetic patients. Therefore, it is important to prevent the development and progression of diabetic neuropathy at an early stage. It is obvious that the primary cause of diabetic neuropathy is hyperglycemia itself, and previous clinical trials such as DCCT, Kumamoto Study and EDIC Study demonstrated that strict glycemic control could prevent the development and progression of diabetic neuropathy. However, it is difficult to keep normal glucose levels for 24 hours in diabetic patients, especially in type 1 diabetic patients. Short-term hyperglycemia can switch on the pathogenic mechanisms. In addition, therefore, interventions to the pathogenic mechanisms beyond glucose are required. Various factors such as the metabolic factors, vascular factors, and neurotrophic factors have been proposed to explain the pathogenesis of diabetic neuropathy. Among these factors, the role of metabolic factors has been most extensively investigated. Metabolic factors include polyol pathway hyperactivity, altered protein kinase C activity, increased oxidative stress, and enhanced non-enzymatic glycation. Each metabolic deficit was originally derived from an independent background. However, recent studies have reported close relationships between these abnormalities, and it is now clear that polyol pathway hyperactivity leads to other three metabolic deficits. Based on previous studies, furthermore, polyol pathway hyperactivity plays the major role in the development of diabetic neuropathy. Therefore, from the viewpoint of preventing diabetic neuropathy or treatment of mild diabetic neuropathy, aldose reductase inhibition would be the best therapeutic strategy. However, advanced
S14
Speech Abstracts / Diabetes Research and Clinical Practice 120S1 (2016) S1–S39
neuropathy with established nerve degeneration and capillary occlusion cannot be ameliorated only by aldose reductase inhibition, and further interventions with regenerative medicine would be required. Previous studies reported that introduction of NGF, HGF or VEGF genes is a useful regenerative therapy of diabetic neuropathy. We reported the usefulness of local injection of basic FGF protein with cross-linked gelatin gel and transplantation of various kinds of progenitor cells such as endothelial progenitor cells (EPCs), mononuclear cells (MNCs), bone marrowderived mesenchymal stem cells (MSCs), and iPS cell-derived neural crest cells (NCCs) on diabetic neuropathy with diabetic animal models. In addition, we have investigated the possibilities of incretin-related agents to regenerate nerve fibers. In this session, an overview of current and future strategies for treatment of diabetic neuropathy will be presented.
Diabetes is a major public health problem affecting 415 million people worldwide in 2015 and the number is expected to rise to 642 million by 2040. In 2010, approximately a third of those with diabetes were found to have signs of DR and of these, a further one third were found to have vision-threatening DR, including diabetic macular edema (DME). With the rising prevalence of diabetes (in particular type 2), ageing of the population and increased life expectancy, number of persons with diabetic retinopathy (DR) is also expected to increase substantially. In view of the increasing burden of diabetes and DR, there has been significant global public attention and research in recent years on understanding the epidemiology of diabetes and DR, in an effort to develop long-term strategies to manage this major public health problem. This talk will highlight the recent trends in the epidemiology of DR with a particular focus on the burden, awareness, population differences, risk factors, and screening of DR/DME.
S21-3 Recent management of diabetic distal symmetric polyneuropathy Nigishi HOTTA1. 1Japan Organization of Occupational Health and Safety, Chubu Rosai Hospital, Nagoya, Japan
S25-2 The pathogenesis and risk factors of diabetic retinopathy and macular edema Gavin TAN1. 1Singapore Eye Research Institute, Singapore
Diabetic peripheral neuropathy is a very common complication of diabetes often associated with considerable morbidity and mortality. It appears relatively early in the disease process. The most common manifestation is a distal symmetric polyneuropathy, but many patterns of nerve impairment can occur. Diabetic neuropathy is not a single entity, but includes several neuropathic syndrome. Autonomic neuropathy may effect almost every system of our body, and once it is well established in the patients with diabetes, it is very difficult to treat for us. The treatment of diabetic neuropathy is classified to symptomatic- and causal-therapy. Current strategies for the treatment of distal symmetric polyneuropathy are based on the following: ①reduction of risk factors including poor glycemic control, ②treatment based on pathogenetic mechanisms, ③symptomatic treatment for such being neuropathic pain, and ④treatment of diabetic foot, autonomic and other complications. The previous three topics are talked over in my presentation. There are some differences of risk factors between type1 and type2 diabetes but mostly similar. Major factors are poor glycemic control with age and duration of diabetes but the development of diabetic neuropathy is also partly associated with hypertension, hyperlipidemia, obesity and cigarette smoking. Recently, there are the new appearance of useful drugs for diabetic painful neuropathy such as pregabalin and duloxetine. As the treatment based on pathogenetic mechanisms, many drugs have developed till today. However, unfortunately, most of their clinical trials have failed to show its efficacy. Only epalrestat, an aldose reductase inhibitor and α-lipoic acid, an anti-oxidant are available in clinical use at limited countries. We need for further experimental and clinical researches to find more effective, novel compounds being able to slow, prevent and/or reverse diabetic neuropathy.
S25-3 Diabetic eye diseases Chung-May YANG1. 1National Taiwan University Hospital, Taipei, Taiwan
The understanding of the pathogenesis of diabetic retinopathy is constantly evolving with new research. The major risk factors for diabetic retinopathy include duration of diabetes, hyperglycemia, and hypertension, but these account for only a small amount of the variation in the risk of diabetic retinopathy. Studies have shown that factors such as dyslipidemia, ethnicity, genetics, nephropathy myopia and ocular surgery contribute to the risk. Chronic exposure to hyperglycemia and other known risk factors results in a cascade of biochemical and physiologic changes that ultimately lead to microvascular damage and retinal dysfunction. Implicated pathways include the accumulation of sorbitol and advanced glycation end-products, oxidative stress, protein kinase C activation, inflammation, and upregulation of the reninangiotensin system and vascular endothelial growth factor.
The eye is one of the major organs affected by diabetic mellitus. Structural and functional changes can be seen from the cornea through the crystalline lens to the vitreo-retinal tissues. Diabetic vitreoretinopathy is the most important category related to diabetic eye diseases. The basic pathogenesis of diabetic vitreoretinopathy involves retinal vascular permeability changes and vascular occlusion, which cause macular edema and the development of retinal fibrovascular proliferation through the excessive production of various angiogenic factors. The progression of fibrovascular proliferation may induce vitreous hemorrhage, traction macular elevation and traction retinal detachment, leading to severe bilateral visual loss. In this presentation, clinical manifestations, update treatment strategies and outcome will be briefly reviewed.
Diabetic Eye Disease: Early Detection, and Treatment
Diabetes Foot: Learning from Diabetes Foot Care Program
S25-1 Epidemiology of diabetic retinopathy, diabetic macular edema and vision loss due to diabetes Charumathi SABANAYAGAM1. 1Far Eastern Memorial Hospital, New Taipei, Taiwan
S31-1 Diabetic foot problems and education programme on the diabetic foot in Western Pacific Region Shigeo KONO1. 1National Hospital Organization, Kyoto Medical Center, Kyoto, Japan