Advanced glycation end products and diabetic complications

Diabetic complications are major cause of morbidity and mortality in patients with diabetes. While the precise pathogenic mechanism(s) underlying conditions such as diabetic retinopathy, diabetic nephropathy and increased risk of atherosclerosis remain ill-defined, it is clear that hyperglycaemia is a primary factor that initiates and promotes complications. Formation of advanced glycation end products (AGEs) correlate with glycaemic control, and these reactive adducts form on DNA, lipids and proteins where they represent pathophysiological modifications that precipitate dysfunction at a cellular and molecular level. Many of these adducts form rapidly during diabetes and promote progression of a raft of diabetes-related complications. Recent evidence also suggests an important interaction with other pathogenic mechanisms activated within the diabetic milieu. This review outlines the nature of AGE formation in biological systems and highlights accumulative evidence that implicates these adducts in diabetic complications. As more therapeutic agents are developed to inhibit AGE formation or limit their pathogenic influence during chronic diabetes, it is becoming clear that these anti-AGE strategies have an important role to play in the treatment of diabetic patients.     

Advanced glycation end products and diabetic complications

Diabetic complications are major cause of morbidity and mortality in patients with diabetes. While the precise pathogenic mechanism(s) underlying conditions such as diabetic retinopathy, diabetic nephropathy and increased risk of atherosclerosis remain ill-defined, it is clear that hyperglycaemia is a primary factor that initiates and promotes complications. Formation of advanced glycation end products (AGEs) correlate with glycaemic control, and these reactive adducts form on DNA, lipids and proteins where they represent pathophysiological modifications that precipitate dysfunction at a cellular and molecular level. Many of these adducts form rapidly during diabetes and promote progression of a raft of diabetes-related complications. Recent evidence also suggests an important interaction with other pathogenic mechanisms activated within the diabetic milieu. This review outlines the nature of AGE formation in biological systems and highlights accumulative evidence that implicates these adducts in diabetic complications. As more therapeutic agents are developed to inhibit AGE formation or limit their pathogenic influence during chronic diabetes, it is becoming clear that these anti-AGE strategies have an important role to play in the treatment of diabetic patients.     

Evolving strategies for insulin delivery and therapy

It has now been conclusively proven that adequate control of blood glucose delays or prevents the progression of diabetic complications. In order to achieve the suggested targets for glycaemic control necessary to reduce the incidence of diabetic complications, it has been established that a more intensive insulin regimen requiring multiple insulin injections is required for patients with type 1 diabetes mellitus. For patients with type 2 diabetes, oral antidiabetic therapy is generally used initially, but given the natural history of type 2 diabetes and the need to achieve improved glycaemic control, earlier use of insulin has been promoted. However, the use of insulin in more intensive regimens for the patient with type 1 diabetes or for earlier treatment of the patient with type 2 diabetes is not routine. Many factors are responsible for this observation. Nevertheless, available device options such as insulin pens or insulin pumps are routinely available for implementation of intensive insulin therapy. However, a major limitation for advancing to intensive insulin therapy is that the only viable way to administer insulin is through injection. Delivery options that use dermal, nasal and oral approaches have been explored. The oral approach may include gastrointestinal, buccal or pulmonary uptake. Recent evidence shows that delivery of insulin via the oral cavity with uptake occurring in the pulmonary alveoli may be the most viable clinical option in the future.     

Cost-effectiveness of oral hypoglycaemic agents for the treatment of type 2 diabetes mellitus

Diabetes is a public health problem worldwide. Its treatment includes controlling hyperglycaemia, initially through changes in lifestyle such as diet, exercise and weight loss. UK Prospective Diabetes Study results showed that intensive treatment to achieve glycaemic control in patients with type 2 diabetes reduces the risk of diabetes-related complications. Typically, patients initially receive monotherapy with oral hypoglycaemic agents but usually progress to combination therapy or insulin. In the short term, the cost of achieving glycaemic control can be substantial, particularly when combination therapy is required. However, additional treatment costs of achieving recommended glycaemic control levels are predicted to be at least partially offset in the long term by the reduction of diabetes-related complications and their related management costs.     

The therapeutic potential of islet cell transplant in the treatment of diabetes

Diabetic patients requiring insulin treatment are at an increased risk of developing chronic complications affecting the eye, kidney and heart as well as other disabilities, such as neurological and vascular disease. The Diabetes Control and Complications Trial (DCCT) showed that the development of these complications can be profoundly reduced or even prevented by strict glycaemic control through intensive insulin therapy. The DCCT study, which was concluded in 1993, administered intensive insulin treatment either by multiple (three or four per day) insulin injections or by an external insulin pump. However, it is both stressful and difficult to achieve effective glycaemic control by these methods. Furthermore, intensive insulin administration imposes a significant danger of hypoglycaemia to patients receiving this treatment. Biological replacement of the destroyed insulin-producing B-cells of pancreatic islets, with normal functioning islet transplants, remains the best option with which to achieve strict glycaemic control in diabetic patients requiring insulin treatment. The ultimate goal in transplantation is the unlimited availability of organs/tissues to be transplanted in a simple procedure that requires little or no immunosuppression. Other obstacles have also contributed to the delay in islet transplantation becoming a clinical reality. There are now good methods for isolating long-term functional islets, and it has been proposed that these islets can be immunoisolated by microencapsulation to prevent transplant rejection, an approach that could easily lead to the use of islet xenografts in human diabetic patients. Therefore, the development of microencapsulated islets promises to solve the two major obstacles to clinical islet transplantation, transplant rejection and shortage of human islets. This technique has enormous potential as a viable treatment for diabetic patients requiring insulin therapy to achieve glycaemic control.     

The therapeutic potential of islet cell transplant in the treatment of diabetes

Diabetic patients requiring insulin treatment are at an increased risk of developing chronic complications affecting the eye, kidney and heart as well as other disabilities, such as neurological and vascular disease. The Diabetes Control and Complications Trial (DCCT) showed that the development of these complications can be profoundly reduced or even prevented by strict glycaemic control through intensive insulin therapy. The DCCT study, which was concluded in 1993, administered intensive insulin treatment either by multiple (three or four per day) insulin injections or by an external insulin pump. However, it is both stressful and difficult to achieve effective glycaemic control by these methods. Furthermore, intensive insulin administration imposes a significant danger of hypoglycaemia to patients receiving this treatment. Biological replacement of the destroyed insulin-producing B-cells of pancreatic islets, with normal functioning islet transplants, remains the best option with which to achieve strict glycaemic control in diabetic patients requiring insulin treatment. The ultimate goal in transplantation is the unlimited availability of organs/tissues to be transplanted in a simple procedure that requires little or no immunosuppression. Other obstacles have also contributed to the delay in islet transplantation becoming a clinical reality. There are now good methods for isolating long-term functional islets, and it has been proposed that these islets can be immunoisolated by microencapsulation to prevent transplant rejection, an approach that could easily lead to the use of islet xenografts in human diabetic patients. Therefore, the development of microencapsulated islets promises to solve the two major obstacles to clinical islet transplantation, transplant rejection and shortage of human islets. This technique has enormous potential as a viable treatment for diabetic patients requiring insulin therapy to achieve glycaemic control.     

Management of type 2 diabetes: long-awaited evidence of benefits after blood sugar control

(1) The UKPDS trial was a very large, complex, comparative study with methodological weaknesses such as the absence of blinding. It showed that lowering the blood glucose level in patients with type 2 diabetes reduces the risk of clinical complications, especially diabetic microangiopathy. (2) In contrast, glycaemic control had no statistically significant impact on mortality. (3) Contrary to findings in a previous trial, glucose-lowering sulphonylureas and insulin did not increase cardiovascular morbidity or mortality in the UKPDS study. (4) Glibenclamide was the only drug tested that yielded a statistically significant reduction in the risk of clinical complications linked to type 2 diabetes. (5) Strict glycaemic control with a glucose-lowering sulphonylurea or insulin was associated with hypoglycaemic episodes in approximately a quarter of patients each year. (6) Metformin gave conflicting results that are difficult to explain: metformin reduced mortality in overweight patients with type 2 diabetes; but in diabetic patients poorly controlled by glucose-lowering sulphonylureas, mortality was higher in the group treated with the sulphonylurea + metformin combination than in the group that continued treatment with a sulphonylurea alone. (7) Currently, the results of the UKPDS trial are the only available clinical data on which to base the choice of treatment for type 2 diabetic patients aged between 25 and 65 years. When a glucose-lowering drug is considered necessary and is not contraindicated, the first-line choice is glibenclamide for diabetics who are not overweight, and metformin for those who are.     

西洛他唑、前列地尔等联合治疗糖尿足54例疗效观察

目的加深对糖尿病慢性并发症的认识,要认识到糖尿病足等慢性并发症的难治性和治疗的长期性,认识到良好的血糖控制和坚持不懈的治疗对于提高患者生活质量的重要性。方法对54例不同程度的糖尿病足的患者,随机分为两组。治疗组28例,对照组26例。两组患者在年龄、性别、糖尿病病程、平均血糖、糖尿病足严重程度、外周血管狭窄程度及血脂情况经统计学处理,均无显著性差异(P>0.05)。两组患者在治疗期间均给予糖尿病饮食,据药敏选用有效抗生素,局部清创,维生素B1 1mg im(1次/日),血塞通400mg每日静滴一次,同时给予每日四次皮下注射胰岛素(甘舒霖R、甘舒霖N);治疗组加用西洛他唑、前列地尔、甲钴胺、进行治疗60d,并观察疗效。结果多数患者都有程度不等的效果。总有效率达85.7%。结论使用西洛他唑、前列地尔、甲钴胺等治疗糖尿病足可以收到较为良好的治疗效果,糖尿病足的治疗关键在于长期坚持清创换药,应用敏感抗生素和良好的血糖控制,并恰当选用营养神经、扩张血管、促进血液循环的药物。     

Strategies for better diabetes control in the US

Recent surveys in the US have indicated that 71% of the total diabetes care is delivered by primary care physicians, and that current management practices in terms of the point of initiation of pharmacological treatment fall considerably short of the American Diabetes Association's recommendations. In part, this delay in initiating treatment is due to a fear of provoking hypoglycaemia, which in itself results from a general avoidance of blood glucose monitoring on the part of patients. As a consequence of this apparent disregard for diabetes care, blood glucose concentrations are not adequately controlled in the US and this is reflected in a high incidence of chronic complications, particularly diabetic neuropathy. This is likely to have major cost implications in the future. In an effort to improve the standard of diabetes care, a number of US authorities have begun producing guidelines for primary care physicians, and in the State of Texas, treatment algorithms that incorporate recommendations based on the current US registration trial data have been developed. These recommendations, which have now been adopted by the State of Texas and form part of the minimum standard of care mandated by the State Department of Health's Diabetes Council, provide guidance on the selection and use of oral antidiabetic drugs (including sulphonylureas, metformin, troglitazone, repaglinide and acarbose) in patients with type 2 diabetes, both for glycaemic control and for prevention of cardiovascular complications. It is hoped that organised implementation of these treatment algorithms will produce better control of diabetes and its complications than the current ad hoc strategies used by individual practitioners.     

Factors affecting self‐care activities,postprandial plasma glucose and HbA1c in patients with type 2 diabetes

Adherence to diabetes self‐care activities can reduce the risk of developing complications Results from this study of type 2 diabetic patients attending a hospital outpatient clinic indicated that 82 per cent of the patients had poor diet behaviour and 52 per cent of the patients had poor exercise behaviour High haemaglobin A1c levels or high postprandial blood glucose levels were associated with younger age, more days with a high fat diet, lower general education, higher number of diabetes medications, increased concerns about medications and increased barriers to diet and exercise Patients exhibiting these features should be targeted for disease management interventions     

Beneficial Effects of Clonidine in Streptozotocin-induced Diabetes and DOCA-hypertensive Rats

This investigation was undertaken to study the effects of chronic treatment with clonidine on cardiovascular complications in streptozotocin-induced diabetes and DOCA-hypertensive rats. Injection of streptozotocin induced glucosuria, hyperglycaemia, hypoinsulinaemia, hypothyroidism, hypercholesterolaemia, hypertriglyceridaemia, bradycardia and a decrease in left ventricular developed pressure (LVDP). DOCA by itself did not induce any change in blood-glucose levels in non-diabetic animals. However, in diabetic animals DOCA significantly reduced blood-glucose levels. Treatment of diabetic and diabetic hypertensive animals with clonidine (25 μg kg^? every day for six weeks) significantly prevented diabetes-induced loss of body weight, bradycardia, cardiac hypertrophy and hypothyroidism. It also partially, but significantly, prevented diabetes-induced hyperglycaemia and hypoinsulinaemia in both diabetic and diabetic-hypertensive animals. There was a significant reduction in diabetes-induced elevation of cholesterol and triglyceride levels and an improvement in LVDP at higher filling pressure in diabetic and diabetic hypertensive animals. This investigation shows that chronic treatment with clonidine produces a number of beneficial effects such as prevention of hyperlipidaemia and hypothyroidism and improvement in cardiomyopathy and glycaemic control in diabetic and diabetic hypertensive rats.     

Beneficial and detrimental effects of intensive glycaemic control, with emphasis on type 2 diabetes mellitus

Diabetes mellitus is a major health problem in the world. Several clinical trials have shown that some of the major complications of diabetes mellitus can be partially prevented or delayed by intensive glycaemic control. However, there are benefits and risks in aiming for near normal blood glucose levels. Intensive glycaemic control delays the onset and progression of retinopathy, nephropathy and neuropathy. Epidemiological and observational studies have shown that cardiovascular events may be correlated with the severity and duration of diabetes mellitus, but major randomised trials have only shown weak and nonsignificant benefits of intensive glycaemic management in decreasing event rates. A modest improvement in lipid profile results from blood glucose control although, in the majority of cases, not enough to reach current targets. Detrimental effects of intensive glycaemic control include bodyweight gain and hypoglycaemia. Controversial issues in the management of patients with diabetes mellitus include the unproven increase in cardiovascular morbidity from sulphonylureas and hyperinsulinaemia, and the still unknown long term effects of newer oral antihyperglycaemic agents alone or in combination with traditional therapies (such as sulphonylureas and metformin). It is important to individualise management in setting glycaemic goals. Control of cardiovascular risk factors through blood pressure and lipid control and treatment with aspirin (acetylsalicylic acid) and ACE inhibitors have consistently shown benefits in the prevention of both macro- and microvascular complications in patients with diabetes mellitus; these measures deserve priority.     

Management of type 2 diabetes mellitus in the elderly: special considerations

The principles of managing type 2 diabetes mellitus in the elderly are no different from those in younger patients, but the priorities and therapeutic strategies need to be cautiously individualised. The objectives of treatment are to improve glycaemic control in a stepwise approach that involves nonpharmacological methods including diet and exercise, and pharmacological therapy including mixtures of oral antihyperglycaemic agents alone or in combination with insulin. Although the goals of treatment may be the same for elderly and younger patients, certain aspects of type 2 diabetes in the elderly require special consideration. Treatment decisions are influenced by age and life expectancy, comorbid conditions and severity of the vascular complications. Adherence to dietary therapy, physical activity, and medication regimens may be compromised by comorbid conditions and psychosocial limitations. Drug-induced hypoglycaemia has been the main consideration and the most serious potential complication. In addition, the long term macrovascular and microvascular complications of type 2 diabetes are a source of significant morbidity and mortality. Indeed, vascular and neuropathic complications are already present at the time of diagnosis in a significant number of patients, and the impact of improved diabetes control depends on the age and life expectancy of the patient. Age-related changes in pharmacokinetics and the potential for adverse effects and drug interactions should also be considered when choosing appropriate pharmacological therapy. In general, a conservative and stepwise approach to the treatment of the elderly patient with type 2 diabetes is suggested; treatment may be initiated with monotherapy, followed by early intervention with a combination of oral agents including a sulphonylurea as a foundation insulin secretagogue in addition to a supplemental insulin sensitiser. Insulin therapy is eventually required if significant hyperglycaemia [glycosylated haemoglobin (HbA1c) >8%] persists despite oral combination therapy. Combination therapy with evening insulin and a long-acting sulphonylurea such as glimepiride is an effective strategy to improve hyperglycaemia in the elderly patient with type 2 diabetes in whom polypharmacy with oral agents is unsuccessful. In addition, such a regimen is simple to follow for the patient who may not be able to adhere to a more complicated insulin regimen. Hyperglycaemia in the elderly can be managed well with practical intervention and a straightforward treatment plan to enhance compliance. Optimal glycaemic control should be possible for every patient if treatment is individualised; however, strict glycaemic control may not be achievable in all patients or even desirable in many elderly patients.     

Effectiveness of acarbose,an alpha-glucosidase inhibitor,in uncontrolled non-obese non-insulin dependent diabetes

Summary The effect of acarbose, an alpha-glucosidase inhibitor, on glycaemic control, was compared with placebo in a double-blind, randomised, group comparison study during 16 weeks in 20 non-obese non-insulin dependent diabetic patients in whom sulphonylurea treatment had been withdrawn.There was significant deterioration in glycaemic control as assessed by HbA₁ following withdrawal of the sulphonylurea. There was no significant improvement in HbA₁ between weeks 0 and 16 in either the acarbose (11.3% and 12.4% respectively) or the placebo group (10.6% and 12.2% respectively). In both the acarbose and placebo treated groups fasting glucose and insulin concentrations were unaltered.This study also suggests that acarbose was not an effective substitute for sulphonylureas in non-obese Type 2 diabetes uncontrolled by diet alone.     

Matching diabetes treatment and lifestyle

Strict glycaemic control reduces the likelihood of complications in patients with type 1 or type 2 diabetes mellitus. However, achieving such control as part of normal daily life can be difficult and may be further complicated by changes to daily routine. Here we highlight key ways of achieving good control without unduly restricting the patient's day-to-day activities. We also discuss the impact exercise, travel, changes in working patterns, and fasting can have on diabetic control and consider what practical advice healthcare professionals can offer to individuals facing such lifestyle changes.     

Acarbose. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential

Acarbose delays the production of monosaccharides (notably glucose) by inhibiting the alpha-glucosidases associated with the brush-border membrane of the small intestine which are responsible for the digestion of complex polysaccharides and sucrose. In healthy subjects acarbose 100 to 200 mg significantly inhibits postprandial glucose, insulin and triglyceride responses, with some evidence of carbohydrate malabsorption with the higher dose. Clinical trials in patients with non-insulin-dependent diabetes mellitus showed that acarbose improved diabetic control, especially postprandial blood glucose levels, independent of whether the patients were receiving concomitant oral antidiabetic drugs in addition to dietary management. In comparative studies acarbose was significantly superior to placebo, and comparable to biguanides, when used alone or as an adjuvant to sulphonylurea therapy. Trials in patients requiring insulin to control their diabetes demonstrated that acarbose significantly reduced postprandial blood glucose concentrations, resulting in a smoother diurnal blood glucose-time curve and improved symptoms associated with nocturnal hypoglycaemia. Daily insulin requirements were sometimes reduced. In large multicentre trials acarbose up to 600 mg/day for 3 to 12 months improved glycaemic control in approximately 55% of patients with non-insulin-dependent or insulin-dependent diabetes mellitus. Apart from its use in diabetes, encouraging preliminary results have been obtained with acarbose in other therapeutic areas such as dumping syndrome, reactive hypoglycaemia, and types IIb and IV hyperlipoproteinaemias--however, further clinical experience is needed in these settings before clear conclusions can be drawn. No serious side effects have been reported during treatment with acarbose, although it is associated with a high incidence of troublesome gastrointestinal symptoms such as flatulence, abdominal distension, borborygmus and diarrhoea. The incidence of these reactions usually decreases with time. Thus, acarbose represents the first of a new class of oral antidiabetic drugs--the alpha-glucosidase inhibitors. It has proven useful for improving glycaemic control when used as an adjunct to standard therapy involving dietary restriction, oral antidiabetic drugs and/or subcutaneous insulin. That being the case, acarbose should provide the clinician with an interesting treatment option which can be used in a broad range of patients with diabetes mellitus in whom 'traditional' management approaches produce suboptimal glycaemic control.     

Rosiglitazone

Type 2 diabetes mellitus is characterised by impaired insulin secretion, diminished peripheral insulin action and increased hepatic glucose production. Clinical trials have indicated that near-normal glucose control may reduce the risk for microvascular and - to a lesser extent - macrovascular complications in Type 2 diabetic patients. Thiazolidinediones improve insulin action by activating a nuclear receptor, PPARgamma. Therefore, these drugs are often referred to as 'insulin sensitisers'. Rosiglitazone is the second compound of this group. Clinical studies with rosiglitazone have shown that it is effective in lowering blood glucose levels in Type 2 diabetic patients treated with either diet alone, sulphonylurea or metformin. Preliminary studies suggest that rosiglitazone also improves glycaemic control in insulin-treated patients while even slightly decreasing insulin dose. The magnitude of the effects is, however, moderate. In diet-treated patients, the reduction of HbA1c levels amounted on average 0.5 - 1.5% and addition to existing sulphonylurea therapy decreased HbA1c by 1.0 - 1.2%. The clinical relevance of additional beneficial effects, i.e., on blood pressure and microalbuminuria, needs to be determined further. Rosiglitazone does not cause hypoglycaemia or gastrointestinal side effects. There is however some concern related to fluid retention, which seems to be an effect of all PPARgamma agonists. In patients treated with rosiglitazone, no severe hepatotoxic side effects have been noticed until now. In the treatment of our patients with Type 2 diabetes, drugs like rosiglitazone which directly reduce insulin resistance are very welcome but more data on its combined use with insulin are needed. Additional studies will also explore its long-term effects in sparing beta-cell function and reducing diabetes-related complications and atherosclerosis.     

Present condition of diabetes and its treatment--from the perspective of a hospital pharmacist

In Japan, the number of diabetic patients has increased steadily. According to a 2007 report by the Ministry of Health, Labour and Welfare, the number of diabetic patients and its reserves is estimated to be 22 million, or a fifth of adults. On a global scale, the number of deaths due to diabetes is almost equivalent to that due to AIDS. Therefore, in 2006, WHO designated November 14 as World Diabetes Day and began a worldwide campaign to increase people's awareness of diabetes. Diabetic patients usually fluctuate between good and bad data of SMBG (self-monitoring of blood glucose). However, the main goal of diabetes treatment is to not only keep good data of SMBG but also prevent diabetes-related complications from arising, because such complications have a major impact on patients' QOL and medical costs. At medical institutions, CDEJs (Certified Diabetes Educator of Japan, a qualification awarded to health care professionals such as nurses, dietitians, pharmacists, laboratory technicians, and physiotherapists) provide information to diabetic patients in order to increase their knowledge of the disease; such professionals also assist with patients' medical treatments. I would like to discuss frequently used diabetes medications, the latest treatments for diabetes, the problems faced by diabetic patients, and so on, from the perspective of a hospital pharmacist.     

Cost-utility analysis in a UK setting of self-monitoring of blood glucose in patients with type 2 diabetes

BACKGROUND: Self-monitoring of blood glucose (SMBG) in type 2 diabetes patients has been shown in meta-analyses of randomized trials to improve HbA(1c) by approximately 0.4% when compared to no SMBG. However, the cost of testing supplies is high, improvements in health utility due to improved glycaemic control may be possible and cost-effectiveness has not been evaluated. METHODS: A peer-reviewed validated model projected improvements in lifetime quality-adjusted life years (QALYs), long-term costs and cost-effectiveness of SMBG versus no SMBG. Markov/Monte Carlo modelling simulated the progression of complications (cardiovascular, neuropathy, renal and eye disease). Transition probabilities and HbA(1c)-dependent adjustments came from the United Kingdom Prospective Diabetes Study (UKPDS) and other major studies. Effects of SMBG on HbA(1c) came from clinical studies, meta-analyses and population studies, but can only be considered 'moderate' levels of evidence. Costs of complications were retrieved from published sources. Direct costs of diabetes complications and SMBG were projected over patient lifetimes from a UK National Health Service perspective. Outcomes were discounted at 3.5% annually. Extensive sensitivity analyses were performed. RESULTS: Depending on the type of diabetes treatment (diet and exercise/oral medications/insulin), improvements in glycaemic control with SMBG improved discounted QALYs anywhere from 0.165 to 0.255 years, with increased total costs of 1013 pounds sterlings- 2564 pounds sterlings/patient, giving incremental cost-effectiveness ratios of 4508 pounds sterlings: 15,515 pounds sterlings/QALY gained, well within current UK willingness-to-pay limits. Results were robust under a wide range of plausible assumptions. CONCLUSIONS: Based on the moderate level of clinical evidence available to date, improvements in glycaemic control with interventions, including SMBG, can improve patient outcomes, with acceptable cost-effectiveness ratios in the UK setting.