Lipids and lipoproteins in patients with type 2 diabetes

Insulin resistance and type 2 diabetes are associated with a clustering of interrelated plasma lipid and lipoprotein abnormalities, which include reduced HDL cholesterol, a predominance of small dense LDL particles, and elevated triglyceride levels. Each of these dyslipidemic features is associated with an increased risk of cardiovascular disease. Increased hepatic secretion of large triglyceride-rich VLDL and impaired clearance of VLDL appears to be of central importance in the pathophysiology of this dyslipidemia. Small dense LDL particles arise from the intravascular processing of specific larger VLDL precursors. Typically, reduced plasma HDL levels in type 2 diabetes are manifest as reductions in the HDL(2b) subspecies and relative or absolute increases in smaller denser HDL(3b) and HDL(3c). Although behavioral interventions such as diet and exercise can improve diabetic dyslipidemia, for most patients, pharmacological therapy is needed to reach treatment goals. There are several classes of medications that can be used to treat lipid and lipoprotein abnormalities associated with insulin resistance and type 2 diabetes, including statins, fibrates, niacin, and thiazolidinediones. Clinical trials have shown significant improvement in coronary artery disease after diabetic dyslipidemia treatment.     

Management of dyslipidemia in NIDDM

Coronary heart disease is the leading cause of death among patients with non-insulin-dependent diabetes mellitus (NIDDM). NIDDM patients have a high frequency of dyslipidemia, which along with obesity, hypertension, and hyperglycemia may contribute significantly to accelerated coronary atherosclerosis. Because risk factors for coronary heart disease are additive and perhaps multiplicative, even mild degrees of dyslipidemia may enhance coronary heart disease risk. Therefore, therapeutic strategies for management of NIDDM should give equal emphasis to controlling hyperglycemia and dyslipidemia. The National Cholesterol Education Program recently issued guidelines for treatment of hyperlipidemia in adults including diabetic patients. Because of the unique features of diabetic dyslipidemia, however, we suggest that certain modifications in these guidelines be made to meet specific needs of diabetic patients. For example, therapeutic goals for serum cholesterol reduction should be lower in diabetic patients than in nondiabetic subjects. Particular emphasis should be given to weight reduction in NIDDM patients. In some diabetic patients, monounsaturated fatty acids may be a better replacement for saturated fatty acids than carbohydrates. The target for cholesterol lowering should include both very-low-density lipoprotein and low-density lipoprotein (LDL) (non-high-density lipoprotein) rather than LDL alone. To obtain a substantial reduction of cholesterol levels, drug therapy may be required in many patients. However, first-line drugs for nondiabetic patients (nicotinic acid and bile acid sequestrants) may be less desirable in NIDDM patients than hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors and even fibric acids. In fact, HMG CoA reductase inhibitors may be the drugs of choice for NIDDM patients with elevated LDL cholesterol and borderline hypertriglyceridemia, whereas gemfibrozil appears preferable for NIDDM patients with severe hypertriglyceridemia.     

Dyslipidemia in patients with type 2 diabetes. relationships between lipids, kidney disease and cardiovascular disease.

Type 2 diabetes mellitus is a leading cause of morbidity and mortality. Cardiovascular disease (CVD) is the most prevalent complication and primarily accounts for the excess morbidity and mortality in diabetic patients, but microvascular complications, such as kidney disease and retinopathy, are frequent and contribute to the total disease burden. Lipid abnormalities in patients with type 2 diabetes are a major problem and associated with the increased risk of CVD. The most common pattern of dyslipidemia in these patients consists of elevated levels of triglycerides and low levels of high-density lipoprotein cholesterol. Low-density lipoprotein levels in these patients are often similar to that of the nondiabetic population, although there may be important qualitative differences in the pattern that contribute to the increased risk of CVD. Abnormal levels of urinary albumin occur in 30-40% of patients with type 2 diabetes and the presence of kidney disease enhances the mortality from CVD. Microalbuminuria, an early marker of diabetic nephropathy, is an independent risk factor for CVD. The increased levels of urinary albumin secretion may represent a more generalized vascular damage than renal microvascular injury alone. This Review focuses on the significance of diabetic dyslipidemia and microalbuminuria to CVD risk as well as to kidney complications. We also discuss the role of aggressive therapy to ameliorate vascular injury in the diabetic patient and reduce or prevent the cardiovascular and renal consequences of the disease.     

Diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions

Diabetes in humans accelerates cardiovascular disease caused by atherosclerosis. The relative contributions of hyperglycemia and dyslipidemia to atherosclerosis in patients with diabetes are not clear, largely because there is a lack of suitable animal models. We therefore have developed a transgenic mouse model that closely mimics atherosclerosis in humans with type 1 diabetes by breeding low-density lipoprotein receptor-deficient mice with transgenic mice in which type 1 diabetes can be induced at will. These mice express a viral protein under control of the insulin promoter and, when infected by the virus, develop an autoimmune attack on the insulin-producing beta cells and subsequently develop type 1 diabetes. When these mice are fed a cholesterol-free diet, diabetes, in the absence of associated lipid abnormalities, causes both accelerated lesion initiation and increased arterial macrophage accumulation. When diabetic mice are fed cholesterol-rich diets, on the other hand, they develop severe hypertriglyceridemia and advanced lesions, characterized by extensive intralesional hemorrhage. This progression to advanced lesions is largely dependent on diabetes-induced dyslipidemia, because hyperlipidemic diabetic and nondiabetic mice with similar plasma cholesterol levels show a similar extent of atherosclerosis. Thus, diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions.     

Management of mixed dyslipidemia in patients with or at risk for cardiovascular disease: a role for combination fibrate therapy

Background: Lowering low-density lipoprotein cholesterol (LDL-C) is the primary focus of the management of dyslipidemia in patients with or at risk for cardiovascular disease. However, use of a statin alone may be insufficient for the treatment of mixed dyslipidemia, which is characterized by low levels of high-density lipoprotein cholesterol and elevated levels of triglycerides, with or without elevated levels of LDL-C. Objective: This report reviews the evidence for the efficacy and tolerability of different combination treatments for the management of mixed dyslipidemia, as supported by clinical-trial data and recommended by national guidelines. Methods: Using the terms lipid-modifying therapy, combination therapy, combination statin-fibrate therapy, and mixed dyslipidemia, a search of PubMed was conducted (completed in April 2007, updated to October 2007) to identify English-language publications and pertinent studies of fibrate combination therapy in patients with mixed dyslipidemia, including those with diabetes or the metabolic syndrome. Results: National guidelines recommend the addition of either niacin (nicotinic acid) or a fibrate to statin therapy in patients with mixed dyslipidemia to achieve better overall lipid control. Fibrates do not have detrimental effects on uric acid levels or glycemic control in patients with diabetes or the metabolic syndrome. Based on data from the US Food and Drug Administration Adverse Event Reporting System indicating that gemfibrozil plus a statin was associated with a 15-fold higher risk of rhabdomyolysis than fenofibrate plus a statin, fenofibrate may be the fi-brate of choice for use in combination with a statin. As reported by the Fenofibrate Intervention and Event Lowering in Diabetes study, fenofibrate treatment has also been associated with microvascular benefits in patients with type 2 diabetes, which is consistent with preliminary evidence from the Diabetes Atherosclerosis Intervention Study. Conclusion: The addition of fenofibrate to statin therapy may be a useful strategy for the management of mixed dyslipidemia in patients with or at risk for cardiovascular disease.     

Preventing, stopping, or reversing coronary artery disease--triglyceride-rich lipoproteins and associated lipoprotein and metabolic abnormalities: the need for recognition and treatment

A substantial number of treated patients with or at high risk for coronary artery disease continue to have fatal and nonfatal coronary artery events in spite of significant reduction of elevated levels of low-density lipoprotein cholesterol. Other lipoprotein abnormalities besides an elevated level of low-density lipoprotein cholesterol contribute to risk of coronary artery disease and coronary artery events, and the predominant abnormalities that appear to explain much of this continued risk are an elevated serum triglyceride level and a low level of high-density lipoprotein cholesterol. Most patients with coronary artery disease have a mixed dyslipidemia with hypertriglyceridemia, which is associated and metabolically intertwined with other atherogenic risk factors, including the presence of triglyceride-rich lipoprotein remnants, low levels of high-density lipoprotein cholesterol, small, dense, low-density lipoprotein particles, postprandial hyperlipidemia, and a prothrombotic state. Aggressive treatment of these patients needs to focus on these other lipoprotein abnormalities as much as on low-density lipoprotein cholesterol. Combination drug therapy will usually be required. Reliable assessment of risk of coronary artery disease from lipoprotein measurements and response to therapy requires inclusion of all atherogenic lipoproteins in laboratory measurements and treatment protocols. At present this may be best accomplished by use of non-high-density lipoprotein cholesterol (total cholesterol minus high-density lipoprotein cholesterol) calculated from standard laboratory lipoprotein values. Ultimately, a more comprehensive assessment of coronary artery disease risk and appropriate therapy may include measurement of lipoprotein subclass distribution including determination of low-density lipoprotein particle concentration and sizes of the various lipoprotein particles.     

Managing cardiovascular risk in patients with metabolic syndrome

Metabolic syndrome consists of a cluster of cardiovascular (CV) and metabolic risk factors (e.g., abdominal obesity, hypertension, elevated levels of fasting plasma glucose and triglycerides, and low levels of high-density lipoprotein cholesterol [HDL-C]) and is associated with an increased risk for type 2 diabetes mellitus (DM) and cardiovascular disease (CVD). Because the risks for CVD and type 2 DM are highly variable among patients with metabolic syndrome, it is essential to assess a patient's risks before identifying specific treatment or lifestyle interventions. The major risk factors for CVD are smoking, hypertension, elevated levels of total and low-density lipoprotein cholesterol, low levels of HDL-C, and older age. In patients at low risk for CV events, lifestyle interventions (i.e., weight loss and increased physical activity) may be sufficient to control the components of metabolic syndrome and to reduce the risk for type 2 DM and CVD. Patients who are at high risk, however, must receive aggressive drug therapy in addition to lifestyle interventions. The following factors need to be targeted: obesity (particularly abdominal obesity), dyslipidemia, hypertension, and prothrombotic/proinflammatory states. Drugs with various and complementary mechanisms of action, including drugs targeting lipid metabolism, may be effective in controlling these factors and thereby delaying or preventing CV events and type 2 DM.     

Successful control of dyslipidemia in patients with metabolic syndrome: focus on lifestyle changes

Approaches to controlling dyslipidemia in patients with metabolic syndrome must take into consideration a patient's individual characteristics and underlying lipid disorder. Some patients will require pharmacologic therapy, whereas others can be controlled with lifestyle changes alone. The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines recommend that patients with at least 3 of the following clinical variables be designated as having metabolic syndrome: abdominal obesity as reflected in increased waist circumference; a low high-density lipoprotein cholesterol (HDL-C) level; an elevated triglyceride level; elevated blood pressure or treatment with antihypertensive medications; and/or elevated fasting plasma glucose or treatment with antidiabetic medications. Unless patients with metabolic syndrome change their lifestyle, existing cardiovascular and metabolic risk factors will worsen or new risk factors will develop. This helps explain why these patients are at increased risk for developing type 2 diabetes mellitus (DM) and coronary heart disease (CHD). The lifestyle changes recommended by NCEP ATP III for controlling dyslipidemia (i.e., elevated levels of triglycerides and decreased levels of HDL-C) in patients with metabolic syndrome or type 2 DM include (1) reduced intake of saturated fats and dietary cholesterol, (2) intake of dietary options to enhance lowering of low-density lipoprotein cholesterol, (3) weight control, and (4) increased physical activity. If lifestyle changes are not successful for individuals at high risk of developing CHD, or for those who currently have CHD, a CHD risk equivalent, or persistent atherogenic dyslipidemia, then pharmacotherapy may be necessary as defined by NCEP ATP III guidelines.     

Targets for intervention in dyslipidemia in diabetes

Treatment for dyslipidemia in diabetes reduces cardiovascular events. Diabetes is associated with major abnormalities in fatty acid metabolism. The resulting disturbance results in an abnormal lipoprotein cascade from the large chylomicron through to the small HDL particle. This suggests that drugs that alter formation of the chylomicron particle might have a very important role in diabetic dyslipidemia. Achieving normal glycemia will reverse the abnormalities in fatty acid metabolism, but this is difficult, particularly as the disease progresses. Genes that regulate cholesterol absorption and excretion have been described (Niemann Pick C1-like 1 [NPC1-L1] and ATP binding cassette proteins [ABC] G5 and G8). An effective NPC1-L1 inhibitor (ezetimibe) improves the reduction in cholesterol caused by statins. Agonists of ABCG5 and G8 may become important in the treatment of dyslipidemia. Microsomal triglyceride transfer protein (MTP) is responsible for the assembly of the chylomicron and VLDL particles. New MTP inhibitors, acting only on the intestine, are exciting possible treatments. The advisability of sitosterol-enriched foods to lower cholesterol may have to be reassessed for patients with diabetes, since these products may lead to an increase in chylomicron sitosterol in diabetic patients. More successful treatment of diabetic dyslipidemia is essential if we are to reduce the burden of cardiovascular disease so commonly found in diabetes.     

PCSK9 and resistin at the crossroads of the atherogenic dyslipidemia

The atherogenic dyslipidemia is a pathophysiological lipid triad, composed of high triglycerides and low-density lipoprotein and low high-density lipoprotein. The dyslipidemia is highly prevalent in individuals who are obese, insulin resistant and those with Type 2 diabetes and is the major contributing factor to the high atherosclerotic cardiovascular disease risk in these subjects. The primary initiating event in atherogenic dyslipidemia development is the hepatic overproduction of very-low-density lipoprotein (VLDL). The intracellular and extracellular protein triggers of hepatic VLDL production were not known until the recent identification of the causal roles of PCSK9 and resistin. Both PCSK9 and resistin act in large part by targeting and reducing the hepatic degradation of VLDL apoB through distinctly different mechanisms. In the current review, we discuss both the individual roles and the interaction of these proteins in driving atherogenic dyslipidemia, and thus, atherosclerotic cardiovascular disease progression in humans. We further explore the important therapeutic implications of these findings.     

Stroke prevention in diabetes and obesity

Stroke is an important cause of morbidity and mortality, and is an economic burden. Diabetes and obesity are two important modifiable risk factors for stroke. Patients with diabetes have a higher incidence of stroke and a poorer prognosis after stroke. Risk-factor modification is the most important aspect of prevention of stroke in diabetes and obesity. This includes lifestyle modifications and different therapeutic modalities to control conditions, such as diabetes, hypertension, dyslipidemia and arrhythmia. Recent landmark studies have shown the beneficial effects of statins in diabetic patients even with close to normal or normal low-density lipoprotein cholesterol. Obesity, which is a risk factor for diabetes, hypertension and hyperlipidemia has been shown to be an independent risk factor for stroke. Increased leptin, dysregulation of adipocyte proteins, increased insulin resistance and C-reactive protein may be factors involved in the increased incidence of cardiovascular morbidity and mortality directly related to obesity. Visceral fat is a much bigger health risk than subcutaneous fat. Lifestyle interventions and pharmacotherapeutic agents have been used to manage obesity. In morbidly obese patients, surgical intervention seems to be the best method of treatment with a long-lasting favorable metabolic outcome. In the 21st Century, with the advanced medical knowledge and the therapeutic modalities available, it should be possible to reduce the incidence of stroke associated with diabetes and obesity.     

Glycation of lipoproteins and accelerated atherosclerosis in non-insulin-dependent diabetes mellitus

Summary We used a new and remarkably simple method to examine the extent of in vivo lipoprotein glycation in type II diabetic patients with atherosclerosis and diabetic patients with no complications. Serum glycated lipoprotein levels were determined by agarose gel film electrophoresis in 48 non-diabetic control subjects and 39 diabetic patients, of whom 26 had no complications and 13 had atherosclerotic heart disease. Fasting serum glucose, glycohemoglobin and serum fructosamine concentrations (indicators of glycemia) and total cholesterol, triglyceride, low-density lipoprotein-, very low-density lipoprotein-and high-density lipoprotein-cholesterol concentrations and the low-density lipoprotein/high-density lipoprotein ratio (serum lipid profile) were also detewrmined in the control and diabetic subjects. Glycated low-density lipoprotein and very low-density lipoprotein concentrations were significantly increased in diabetic patients compared with controls; but only glycated very low-density lipoprotein was significantly increased in atherosclerotic patients compared with diabetics without complications. The lipid profile parameters were not significantly increased in patients compared with controls. In diabetics, especially those with poorly controlled hyperglycemia and atherosclerosis, glycation of lipoprotein fractions might be more important than serum lipid and lipoprotein abnormalities. The significant correlation between atherosclerosis and glycated very low-density lipoprotein, suggests that very low-density lipoprotein glycation could be responsible for the development of atherosclerosis in diabetes.     

Abnormal high-density lipoprotein composition in women with insulin-dependent diabetes

To determine whether alterations in lipoprotein phospholipid composition might be an unrecognized factor that contributes to the unexplained acceleration of atherogenesis and the loss of sex-related protection from the development of coronary heart disease in women with insulin-dependent diabetes mellitus, we have estimated levels of neutral lipids, apolipoproteins (A-I, A-II, B), and free cholesterol (FC) in plasma and the four major phospholipid constituents of the very low-density lipoprotein + low-density lipoprotein and high-density lipoprotein (HDL) fractions in 12 ambulatory female patients with varying degrees of diabetic control. Although levels of triglyceride, cholesterol, HDL-cholesterol, and lipoprotein phospholipids in whole plasma of the patients with diabetes were similar to those in controls, their FC levels and FC/lecithin ratio, a recently described index of cardiovascular risk, both were abnormally increased (p less than 0.01). In the HDL-containing plasma fraction, concentrations of sphingomyelin, lecithin, and lysolecithin all were significantly reduced (p less than 0.05; p less than 0.01, and p less than 0.02, respectively). These compositional changes may be potentially atherogenic, because a reduction in the phospholipid content of HDL may impair its capacity to promote the efflux of cholesterol from cells, and the transfer of cholesterol ester from HDL to the larger apo-B-containing lipoproteins is inhibited when their content of FC is increased relative to phospholipid. These previously unrecognized qualitative defects, which are inapparent in the routine estimation of plasma lipids, may compromise reverse cholesterol transport and thereby promote atherogenesis in women with insulin-dependent diabetes mellitus.     

Increased plasma urotensin-II levels are associated with diabetic retinopathy and carotid atherosclerosis in Type 2 diabetes

Human U-II (urotensin-II), the most potent vasoconstrictor peptide identified to date, is associated with cardiovascular disease. A single nucleotide polymorphism (S89N) in the gene encoding U-II (UTS2) is associated with the onset of Type 2 diabetes and insulin resistance in the Japanese population. In the present study, we have demonstrated a relationship between plasma U-II levels and the progression of diabetic retinopathy and vascular complications in patients with Type 2 diabetes. Eye fundus, IMT (intima-media thickness) and plaque score in the carotid artery, BP (blood pressure), FPG (fasting plasma glucose), HbA(1c) (glycated haemoglobin), U-II, angiogenesis-stimulating factors, such as VEGF (vascular endothelial growth factor) and heregulin-beta(1), and lipid profiles were determined in 64 patients with Type 2 diabetes and 24 non-diabetic controls. FPG, HbA(1c) and VEGF levels were significantly higher in patients with Type 2 diabetes than in non-diabetic controls. Diabetes duration, insufficient glycaemic and BP control, plasma U-II levels, IMT, plaque score and nephropathy grade increased significantly across the subjects as follows: non-diabetic controls, patients with Type 2 diabetes without retinopathy (group N), patients with Type 2 diabetes with simple (background) retinopathy (group A) and patients with Type 2 diabetes with pre-proliferative and proliferative retinopathy (group B). The prevalence of obesity and smoking, age, low-density lipoprotein, triacylglycerols (triglycerides) and heregulin-beta(1) were not significantly different among the four groups. In all subjects, U-II levels were significantly positively correlated with IMT, FPG, and systolic and diastolic BP. Multiple logistic regression analysis revealed that, of the above parameters, U-II levels alone had a significantly independent association with diabetic retinopathy. In conclusion, the results of the present study provide the first evidence that increased plasma U-II levels may be associated with the progression of diabetic retinopathy and carotid atherosclerosis in patients with Type 2 diabetes.     

Management of hypertriglyceridemia

Hypertriglyceridemia is associated with an increased risk of cardiovascular events and acute pancreatitis. Along with lowering low-density lipoprotein cholesterol levels and raising high-density lipoprotein cholesterol levels, lowering triglyceride levels in high-risk patients (e.g., those with cardiovascular disease or diabetes) has been associated with decreased cardiovascular morbidity and mortality. Although the management of mixed dyslipidemia is controversial, treatment should focus primarily on lowering low-density lipoprotein cholesterol levels. Secondary goals should include lowering non-high-density lipoprotein cholesterol levels (calculated by subtracting high-density lipoprotein cholesterol from total cholesterol). If serum triglyceride levels are high, lowering these levels can be effective at reaching non-high-density lipoprotein cholesterol goals. Initially, patients with hypertriglyceridemia should be counseled about therapeutic lifestyle changes (e.g., healthy diet, regular exercise, tobacco-use cessation). Patients also should be screened for metabolic syndrome and other acquired or secondary causes. Patients with borderline-high serum triglyceride levels (i.e., 150 to 199 mg per dL [1.70 to 2.25 mmol per L]) and high serum triglyceride levels (i.e., 200 to 499 mg per dL [2.26 to 5.64 mmol per L]) require an overall cardiac risk assessment. Treatment of very high triglyceride levels (i.e., 500 mg per dL [5.65 mmol per L] or higher) is aimed at reducing the risk of acute pancreatitis. Statins, fibrates, niacin, and fish oil (alone or in various combinations) are effective when pharmacotherapy is indicated.     

Autoantibodies to oxidized low-density lipoprotein in patients with type 2 diabetes mellitus

BACKGROUND: Oxidation of low-density lipoprotein (LDL) is a crucial step in atherogenesis. There is an urgent need for direct measures of in vivo oxidative stress. Autoantibodies against oxidized low-density lipoprotein (Ab against Ox-LDL) are a direct measure of oxidative stress and predict cardiovascular disease. Our aim was to evaluate an ELISA for Ab against Ox-LDL in Type 2 diabetes, a condition with increased oxidative stress. METHODS: Ab against Ox-LDL were measured by ELISA and expressed as a ratio of Ox-LDL to native LDL (N-LDL). Samples were obtained from 45 Type 2 diabetic patients and 25 matched controls before and after supplementation with alpha tocopherol (AT, 1200 IU/day). RESULTS: The assay had good precision. While there was no interference with bilirubin and hemolysis, triglycerides 500 mg/dl increased antibody titer, which was abrogated by airfuging. Compared to controls, significantly increased titers of Ab against Ox-LDL were found in diabetics (diabetes mellitus Type 2) with macrovascular disease (DM2-MV), but not without macrovascular disease (DM2) (DM2: 1.32+/-0.33; DM2-MV: 1.48+/-0.44 vs. controls, 1.21+/-0.28; p<0.05). AT supplementation significantly decreased titers of Ab against Ox-LDL in both diabetic groups (p<0.01). CONCLUSION: This assay may serve as a future test for the assessment of cardiovascular risk especially in patients with increased oxidative stress.     

Effectiveness of long-term treatment with pantethine in patients with dyslipidemia

A one-year clinical trial with pantethine was conducted in 24 patients with established dyslipidemia of Fredrickson's types II A, II B, and IV, alone or associated with diabetes mellitus. The treatment was well tolerated by all patients with no subjective complaints or detectable side effects. Blood lipid assays repeated after 1, 3, 6, 9, and 12 months of treatment revealed consistent and statistically significant reductions of all atherogenic lipid fractions (total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B) with parallel increases of high-density lipoprotein cholesterol and apolipoprotein A. The results were equally good in patients with uncomplicated dyslipidemia and in those with associated diabetes mellitus. The authors conclude that pantethine (a drug entity related to the natural compound, pantetheine) represents a valid therapeutic support for patients with dyslipidemia not amenable to satisfactory correction of blood lipids by diet alone.     

Perspective of dietary management and exercise therapy in diabetes mellitus

Diet and exercise are basic measures of treatment of diabetes mellitus. To prevent the development and progression of atherosclerotic disease as well as microangiopathy, diet management should be focused on the reductions of conventional risk factors for atherosclerosis such as hyperglycemia, dyslipidemia, and hypertension. To control the these risk factors, both total energy and fat intake should be reduced. A diet high in mono- and poly-unsaturated fatty acids, and dietary fibers are recommended to diabetic patients, but the ideal ratio of saturated, monounsaturated, and polyunsaturated fatty acids should be determined from clinical and epidemiological studies in the future. A high concentration of plasma homocysteine is a new risk factor for atherosclerotic disease in diabetic patients. To reduce plasma homocysteine, diet enriched in folate and vitamin B12 may be recommended. A high intake of flavonoid, one of antioxidants, may be also recommended in diabetic patients because of its counteraction against increased oxidative stress in diabetes mellitus. Exercise therapy is an effective measure for improving glycemic control in Type 2 diabetic patients. However, the most appropriate kinds and strength of exercise in diabetic patients with complications or elderly diabetic patients still remain unknown. The dietary regimen or exercise of diabetic patients should be determined individually according to the risk factors, complications, and psychological and socioeconomic conditions.