Clinical significance of cardiovascular dysmetabolic syndrome

Although diabetes mellitus is predominantly a metabolic disorder, recent data suggest that it is as much a vascular disorder. Cardiovascular complications are the leading cause of death and disability in patients with diabetes mellitus. A number of recent reports have emphasized that many patients already have atherosclerosis in progression by the time they are diagnosed with clinical evidence of diabetes mellitus. The increased risk of atherosclerosis and cardiovascular complications in diabetic patients is related to the frequently associated dyslipidemia, hypertension, hyperglycemia, hyperinsulinemia, and endothelial dysfunction. The evolving knowledge regarding the variety of metabolic, hormonal, and hemodynamic abnormalities in patients with diabetes mellitus has led to efforts designed for early identification of individuals at risk of subsequent disease. It has been suggested that insulin resistance, the key abnormality in type II diabetes, often precedes clinical features of diabetes by 5–6 years. Careful attention to the criteria described for the cardiovascular dysmetabolic syndrome should help identify those at risk at an early stage. The application of nonpharmacologic as well as newer emerging pharmacologic therapies can have beneficial effects in individuals with cardiovascular dysmetabolic syndrome and/or diabetes mellitus by improving insulin sensitivity and related abnormalities. Early identification and implementation of appropriate therapeutic strategies would be necessary to contain the emerging new epidemic of cardiovascular disease related to diabetes.

Related papers:

title: MORTALITY FROM CORONARY HEART DISEASE IN SUBJECTS WITH TYPE 2 DIABETES AND IN NONDIABETIC SUBJECTS WITH AND WITHOUT PRIOR MYOCARDIAL INFARCTION
abstract: s of articles published since 1993. Single articles and past issues of the Journal can also be ordered for a fee through the Internet (http://www.nejm.org/customer/).

title: The changing face of macrovascular disease in non-insulin-dependent diabetes mellitus: an epidemic in progress
abstract: Cardiovascular disease (CVD) is the most common complication of non-insulin-dependent diabetes mellitus (NIDDM) in Europeans,“z and accounts for at least 66% of deaths in NIDDM patients.3 People with diabetes have a risk of CVD two to five times that of nondiabetic individuals.‘,‘,’ Macrovascular disease, in both diabetic and nondiabetic people, was thought to be rare in developing countries that are undergoing large cultural transitions, but there is now evidence that this theory may need revision.ls5 The main implication of macrovascular diabetic disease, from the public-health perspective, is the human distress and disability associated with it, and the socioeconomic costs from premature morbidity and mortality.” Although CVD risk is consistently increased in people with diabetes, it reflects the prevalence of CVD in the non-diabetic members of that population.‘Thus, even in a low-prevalence nation, such as Japan, a person with diabetes has a CVD risk twice that of the non-diabetic person. This risk, however, is still only a fraction of the risk of a non-diabetic person from a western culture.’ But exposure to ‘westernised’ environments rapidly raises the atherosclerotic risk in people from lowprevalence nations.’ Most of the increase in atherosclerotic risk has occurred in newly industrialised nati0ns.Q’ These findings call for a reassessment of the impact of macrovascular complications, since they were rare in these populations when they lived a ‘traditional’ way of life.5,8

title: Insulin Resistance, Hyperinsulinemia, and Coronary Artery Disease: A Complex Metabolic Web
abstract: Diabetes mellitus is commonly associated with systolic and diastolic hypertension, and a wealth of epidemiological data suggest that this association is independent of age and obesity. Much evidence indicates that the link between diabetes and essential hypertension is hyperinsulinemia. Thus, when hypertensive patients, whether obese or of normal body weight, are compared with age- and weight-matched normotensive controls, a heightened plasma insulin response to a glucose challenge is found consistently. A state of cellular resistance to insulin action subtends the observed hyperinsulinism. Using the insulin/glucose clamp technique in combination with tracer glucose infusion and indirect cal-orimetry, it has been demonstrated that the insulin resistance of essential hypertension is located in peripheral tissues (muscle), is limited to nonoxidative pathways of glucose disposal (glycogen synthesis), and correlates directly with the severity of hypertension. The reasons for the association of insulin resistance and essential hypertension can be sought in at least four general types of mechanisms: sodium retention, sympathetic nervous system overactivity, disturbed membrane ion transport, and proliferation of vascular smooth-muscle cells. Physiological maneuvers, such as caloric restriction (in the overweight patient) and regular physical exercise, can improve tissue sensitivity to insulin; good evidence indicates that these maneuvers also can lower blood pressure in both normotensive and hypertensive individuals. Insulin resistance and hyperinsulinemia also are associated with an atherogenic plasma lipid profile. Elevated plasma insulin concentrations enhance very-low-density lipoprotein (VLDL) synthesis, leading to hypertriglyceridemia. Progressive elimination of lipid and apolipoproteins from the VLDL particle leads to an increased formation of intermediate density and low-density lipoproteins, both of which are atherogenic. Last, insulin per se, independent of its effects on blood pressure and plasma lipids, is known to be atherogenic. The hormone enhances cholesterol transport into arteriolar smooth-muscle cells and increases endogenous lipid synthesis by these cells. Insulin also stimulates the proliferation of arteriolar smooth-muscle cells, augments collagen synthesis in the vascular wall, increases the formation of and decreases the regression of lipid plaques, and stimulates the production of a variety of growth factors. In summary, insulin resistance appears to be a syndrome that is associated with a clustering of metabolic disorders, including type II diabetes mellitus, obesity, hypertension, lipid abnormalities, and atherosclerotic cardiovascular disease.

title: Hyperinsulinemia as an independent risk factor for ischemic heart disease.
abstract: Prospective studies suggest that hyperinsulinemia may be an important risk factor for ischemic heart disease. However, it has not been determined whether plasma insulin levels are independently related to ischemic heart disease after adjustment for other risk factors, including plasma lipoprotein levels.



In 1985 we collected blood samples from 2103 men from suburbs of Quebec City, Canada, who were 45 to 76 years of age and who did not have ischemic heart disease. A first ischemic event (angina pectoris, acute myocardial infarction or death from coronary heart disease) occurred in 114 men (case patients) between 1985 and 1990. Each case patient was matched for age, body-mass index, smoking habits, and alcohol consumption with a control selected from among the 1989 men who remained free of ischemic heart disease during follow-up. After excluding men with diabetes, we compared fasting plasma insulin and lipoprotein concentrations at base line in 91 case patients and 105 controls.



Fasting insulin concentrations at base line were 18 percent higher in the case patients than in the controls (P<0.001). Logistic-regression analysis showed that the insulin concentration remained associated with ischemic heart disease (odds ratio for ischemic heart disease with each increase of 1 SD in the insulin concentration, 1.7; 95 percent confidence interval, 1.3 to 2.4) after adjustment for systolic blood pressure, use of medications, and family history of ischemic heart disease. Further adjustment by multivariate analysis for plasma triglyceride, apolipoprotein B, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol concentrations did not significantly diminish the association between the insulin concentration and the risk of ischemic heart disease (odds ratio, 1.6; 95 percent confidence interval, 1.1 to 2.3).



High fasting insulin concentrations appear to be an independent predictor of ischemic heart disease in men.

title: Diabetic and Hypertensive Heart Disease
abstract: Diabetes mellitus and hypertensiontwo disorders that frequently coexist in the same patientlead to structural and functional cardiac impairments that accelerate progression to cardiovascular illness and death from cardiovascular causes [1, 2]. Clinical and experimental studies suggest that the presence of diabetes and hypertension in the same patient results in more severe cardiomyopathy than would be expected with either condition alone [3, 4]. We summarize the features of heart disease in patients with diabetes and hypertension.  We searched the MEDLINE database for English-language articles published between 1980 and January 1996; we used the terms diabetes mellitus, hypertension or blood pressure, and heart. We also reviewed pertinent articles cited in the identified papers. The term diabetes mellitus included insulin-dependent and noninsulin-dependent diabetes mellitus; however, in some studies, the type of diabetes was not specified. We indicate the type of diabetes if this information was available. We divided the articles into those that addressed coronary artery disease or myocardial ischemia and those that addressed nonischemic cardiomyopathy and its sequelae. Articles about cardiac complications that result from the combination of diabetes mellitus and hypertension were emphasized.  Diabetic Heart Disease Long-standing diabetes has been documented to cause structural and functional cardiac impairment and to lead to ischemic heart disease, cardiomyopathy, and congestive heart failure. Ischemic Heart Disease Diabetes mellitus is an independent risk factor for the development of coronary artery disease [5, 6]. At coronary angiography or autopsy, diabetic patients have a higher incidence of double- and triple-vessel disease and a lower incidence of single-vessel disease than do their nondiabetic counterparts [5, 7]. In one large study , 83% of patients with noninsulin-dependent diabetes mellitus had severe two- or three-vessel involvement at autopsy. Of patients who had no known coronary artery disease, 31% had severe narrowing of at least one major coronary artery. The presence of diabetes mellitus reduces survival after myocardial infarction. The 5-year mortality rate after acute myocardial infarction can be as great as 55% in diabetic patients but only reaches 30% in patients without diabetes, and the rate of reinfarction may be as much as 60% higher in diabetic than in nondiabetic patients . In a recent study of Mexican-American and non-Hispanic white persons, Orlander and coworkers  found higher short-term and long-term mortality rates and a higher rate of pump failure in persons with diabetes mellitus than in persons without the disease. The effect of noninsulin-dependent diabetes mellitus on mortality and morbidity in coronary heart disease is more marked in women than in men [11]. Accelerated atherosclerosis in patients with diabetes mellitus may be related to lipid disorders, hyperinsulinemia, and poor glycemic control. Hyperinsulinemia, particularly from exogenous insulin, may exert both a beneficial effect (by reducing hypoglycemia) and an adverse effect (by directly promoting atherogenesis, thrombogenesis, or both) [12, 13]. In addition to accelerating atherosclerosis, diabetes mellitus is associated with abnormal platelet function, coagulation, fibrinolysis, and endothelial function that may favor coronary thrombosis [14]. Autonomic neuropathy related to diabetes mellitus also contributes to the occurrence of ischemic myocardial events. Diabetic autonomic neuropathy initially involves the parasympathetic nerve fibers, leading to a relative increase in sympathetic tone with tachycardia at rest and exaggerated coronary vasoconstriction and, later (in advanced diabetic autonomic neuropathy), to sympathetic dysfunction with postural hypotension . Autonomic neuropathy in patients with diabetes is also associated with an increased rate of sudden death caused by ventricular arrhythmia [16]. Ventricular arrhythmia may be secondary to silent myocardial ischemia or to the combination of a prolonged QT interval and increased sympathetic tone [16-18]. Diabetic patients have a decreased perception of ischemic pain, which contributes to a high prevalence of silent ischemia. Nesto and colleagues  showed that during ischemia on thallium exercise testing, angina is less common in diabetic patients than in nondiabetic patients. The time interval from the onset of ST-segment depression to the occurrence of angina is longer in diabetic than in nondiabetic patients and correlates with the extent of autonomic nervous dysfunction [20]. Asymptomatic infarction is almost twice as common in diabetic patients as in nondiabetic patients [21, 22]. These data are consistent with autopsy results showing that myocardial scars, in the absence of a history of infarction, are three times more common in diabetic patients than in nondiabetic patients [23]. Diabetic Cardiomyopathy Several clinical and experimental studies [2, 24-33] have indicated that diabetes mellitus is associated with cardiomyopathy that is independent of atherosclerotic coronary artery disease. Macroscopic changes include muscular hypertrophy with pale appearance and firmness to palpation. Microscopic changes include thickening of the capillary basement membranes, intimal proliferation of small myocardial arterioles and capillary microaneurysms, and focal myocardial fibrosis with an accumulation of interstitial glycoprotein and collagen [34]. Electron microscopy shows perivascular damage with loss of contractile myocardial elements and deposition of either glycoprotein or material that is positive on periodic acid-Schiff stain . Various metabolic derangements [35-53] that can contribute to the development of diabetic cardiomyopathy are beyond the scope of this review. Microvascular Disease Small-vessel coronary artery disease frequently occurs in patients with diabetes [34]. On the basis of necropsy findings, Hamby and associates [28] suggested that changes in small vessels of the myocardium are responsible for diabetic cardiomyopathy. Fein and Sonnenblick [51] reported that patients with diabetes have increased sensitivity to catecholamines, which may cause myocardial ischemia through the focal vasoconstriction of small coronary arteries. Altered Cardiac Function Structural changes in patients with diabetes are associated. with impaired ventricular performance. Using echocardiography, Shapiro [54] found abnormal diastolic function in patients with diabetes mellitus who did not have heart disease. Diabetes mellitus seems to have less effect on systolic function, as was shown in a study by Borow and colleagues  in which indices of contractility and contractile reserve after stimulation with dobutamine were normal. Structural changes suggestive of cardiomyopathy can be detected with echocardiography on the basis of quantitative backscatter imaging, even before ventricular function is impaired [56]. Mustonen and coworkers  found similar resting ejection fractions in diabetic patients and controls. However, during 4 years of follow-up, the left ventricular ejection fraction at rest markedly decreased only in the patients with noninsulin-dependent diabetes mellitus. Several studies have shown that ejection fractions after myocardial infarction are lower in diabetic than in nondiabetic patients [10, 58, 59]. Contractile abnormalities are more pronounced in postmenopausal diabetic women than in diabetic men [58]. Not surprisingly, congestive heart failure is a common and serious complication of diabetes mellitus. Data from the Framingham study showed that men with diabetes had a 2.4-fold greater risk for heart failure than did men without diabetes . Hypertensive Heart Disease Sustained hypertension can cause structural and functional cardiac abnormalities that lead to myocardial ischemia, congestive heart failure, and sudden cardiac death. Ischemic Heart Disease in Patients with Hypertension Myocardial ischemia is common in patients with hypertension [60, 61]. Pathogenic mechanisms that may lead to myocardial ischemia include the following. First, long-standing hypertension accelerates arteriosclerosis in systemic and coronary arteries [62]. Second, an increase in arterial pressure increases left ventricular wall stress, wall tension, and stroke work. Third, resistance of the coronary microvasculature (microvascular angina) is abnormally elevated in hypertensive patients even in the absence of left ventricular hypertrophy [63]. Fourth, long-standing hypertension causes left ventricular hypertrophy, which is associated with an increase in the diameter of myocardial cells without a proportional proliferation of the capillary vasculature; this leads to an increased diffusion distance [64]. Fifth, vasodilator reserve appears to be compromised in the coronary circulation of hearts in patients with left ventricular hypertrophy [65, 66]. Finally, left ventricular hypertrophy itself (that is, the increased myocardial muscle mass seen with this condition) requires an enhanced supply of oxygen to the myocardium. It should be noted that hypertensive patients, especially those with left ventricular hypertrophy, are as susceptible to silent myocardial ischemia as patients with diabetes [67-69]. Hypertensive Cardiomyopathy The classic cardiac adaptation to a sustained pressure overload is concentric left ventricular hypertrophy. Hemodynamic factors offer a reasonable explanation for increased left ventricular mass; however, in several groups of patients with uncomplicated essential hypertension, physicians' measurements of blood pressure have been only weakly related to left ventricular mass on echocardiography [70]. Therefore, such nonhemodynamic factors as sodium intake, activity of growth-promoting hormones (such as insulin and thyroxine), activity of the sympathetic nervous system, renin angiotensin systems, whole-blood visco

title: Fasting hyperinsulinism, insulin resistance syndrome, and coronary artery disease in men and women.
abstract: A large segment of the population gradually develops insulin resistance, and the related metabolic syndrome is one of the most frequent causes of atherosclerosis. Searching for a practical indicator of insulin resistance, we studied the correlations between fasting serum insulin level, the general manifestations of insulin resistance syndrome, and various aspects of coronary artery disease in 797 men and 322 women. After we classified patients according to the quartiles of serum insulin level, we noted in the top quartile the presence of practically all manifestations of insulin resistance syndrome in persons of both sexes (e.g., increased waist/hip ratio, body mass index, glucose, uric acid, triglycerides, apolipoprotein B and decreased high-density lipoprotein cholesterol levels as well as apolipoprotein A-I/B ratios, and so forth). We also noted a higher prevalence of hypertension, diabetes mellitus, and type IV hyperlipidemia. Significantly more women in the fourth than in the first quartile had angiographically documented significant stenosis of the coronary arteries (p = 0.0016, odds ratio 2.9, 95% confidence interval 1.5 to 5.6) and previous myocardial infarction (p = 0.0297, odds ratio 2.1, 95% confidence interval 1.1 to 4.1). Men in both the first and the fourth quartile had a more disturbed lipid profile and a higher prevalence of significant stenoses of coronary arteries and/or previous myocardial infarction than women; there was a tendency toward a lower prevalence of alcohol consumption (p = 0.0503), a higher prevalence of gout (p = 0.0634), and previous myocardial infarction (p = 0.0791) in men in the fourth than in the first quartile.(ABSTRACT TRUNCATED AT 250 WORDS)

title: Cardiovascular risk continuum: implications of insulin resistance and diabetes.
abstract: Although low-density lipoprotein (LDL) cholesterol is a critically important factor in the development of atherosclerosis, nearly half the patients with coronary artery disease have LDL cholesterol levels within the National Cholesterol Education Program (NCEP) guidelines. Therefore, attention has focused on other modifiable risk factors that could strongly impact the development of coronary artery disease. Type 2 diabetics have a 3-fold increased risk of coronary artery disease; prediabetics, without chronic hyperglycemia, have a 2-fold increased risk compared with normal subjects. Insulin resistance has also been implicated as the cause of atherosclerosis. Insulin resistance is associated with hyperinsulinemia and a constellation of other factors, some of which are themselves independent risk factors for coronary artery disease. These include reduced levels of high-density lipoprotein (HDL) cholesterol, hypertriglyceridemia, increased small dense LDL particles, hypertension, visceral obesity, and increased levels of plasminogen activator inhibitor-1 (PAI-1). Hyperinsulinemia and insulin resistance at the vascular level also may contribute to vascular injury and the atherosclerotic process. Current studies suggest that controlling hyperglycemia, LDL cholesterol, and blood pressure are important to protect the diabetic from atherosclerosis. A key question, particularly in type 2 diabetes, is to define the best regimen for glucose control that will protect the vasculature. Sulfonylureas, metformin, and troglitazone have direct vascular actions. Metformin lowers LDL cholesterol and triglycerides, while troglitazone reverses many of the components associated with the insulin resistance syndrome. Clinical trials focusing on coronary artery disease outcomes are now warranted to prevent coronary artery disease, the major vascular complication and cause of mortality in diabetes.

title: The cardiovascular dysmetabolic syndrome.
abstract: Aclustering of metabolic abnormalities associated with cardiovascular disease has been recognized since at least 1988. This clustering has been given many names including Syndrome X, The Deadly Quartet, and The Insulin Resistance Syndrome. For various reasons each of these names is unsatisfactory. The Western Working Group believes that cardiovascular dysmetabolic syndrome (CDS) is the name that best describes this group of abnormalities, because it emphasizes the cardiovascular consequences of these abnormalities, recognizes that they are distinguishable abnormalities, and indicates that any given patient may have some or all of the components of the syndrome. The CDS is summarized in Table 1. The mnemonic D-R-O-P stands for Dyslipidemia, insulin Resistance, Obesity, and high blood Pressure. Other abnormalities that may be associated include elevated serum uric acid and elevated plasminogen activator inhibitor-1 (PAI-1) levels. Insulin resistance is thought to be central to the metabolic abnormalities, but all of the mechanisms are not established and other etiologies are possible. A diagnosis of CDS requires the presence of criteria for at least 2 of the first 3 components (dyslipidemia, insulin resistance, and obesity). Any component is a risk factor for macrovascular (coronary, cerebral, or peripheral vascular) disease. Additional components confer additional risk, although some, such as diabetes mellitus, confer more risk than others. These risk factors are in addition to, but not necessarily completely independent of, other traditional risk factors, such as established vascular disease, smoking, age, gender, elevated LDL cholesterol, sedentary lifestyle, and positive family history of vascular disease. All risk factors do not convey equal risk of atherosclerotic cardiovascular disease. Existing vascular disease increases risk of a subsequent event 5-fold compared to a patient without pre-existing vascular disease. Diabetes mellitus increases the risk of macrovascular disease 2-fold in men and 4 –5-fold in women. Thus, women with diabetes lose the protective effect of their gender and are at equally high risk of coronary artery disease (CAD) as men of the same age with the same additional risk factors. Hyperinsulinemia has been shown to be associated with CAD in multiple studies in nondiabetic men, but most studies in women have not shown a significant relationship. Recently, the Atherosclerosis Risk in Communities study has shown a significant relationship between plasma insulin levels and CAD in women. The relationship between CAD risk and increased plasma insulin levels is stronger in younger compared to older individuals. Whether hyperinsulinemia is a marker for insulin resistance and/or causative of atherosclerosis is unclear. Insulin resistance (which is harder to document than frank diabetes mellitus) is more highly correlated with atherosclerotic cardiovascular disease than is elevated insulin, per se. This may be because insulin levels are affected by many factors and elevated plasma insulin is only a surrogate for insulin resistance, and/or because insulin resistance impairs insulin-dependent production of nitric oxide (NO), which is anti-atherogenic, without affecting insulin-dependent vascular smooth muscle cell growth and migration, which are pro-atherogenic. Insulin resistance, rather than hyperglycemia, appears to be the primary factor in endothelial dysfunction in type 2 diabetes. Furthermore, insulin potentiates angiotensin II–stimulated production of PAI-1, which may contribute to a prothrombotic effect. Adequate studies are lacking regarding whether different insulin regimens—and specifically the 4 classes of oral hypoglycemic agents— have different effects on morbidity and mortality due to cardiovascular disease. Insulin resistance is difficult to detect clinically, although the extreme of type 2 diabetes mellitus is well defined. Fasting plasma glucose $110 mg/dL identifies persons who have insulin resistance. Diabetes mellitus affects approximately 6% of the US population, yet only 50% of those individuals have been diagnosed. These patients have predominantly type 2 diabetes mellitus. Significant sequelae often develop prior to diagnosis; at the time of diagnosis of type 2 diabetes, 20% of patients have retinopathy, 8% have nephropathy, and 9% have neuropathy. In addition to these microvascular complications, the prevalence of macrovascular complications is similar to that in diagnosed type 2 diabetes. The new classification promulgated by the American Diabetes Association (ADA) divides diabetes mellitus into type 1 (absolute insulin deficiency) and type 2 (insulin resistance with inadequate compensatory insulin secretory response), as well as gestational diabetes and From the Departments of Medicine and Pharmacology, University of Arizona College of Medicine, Tucson, Arizona; Cardiology Division, Department of Medicine, University of California, San Francisco, San Francisco, California; Stanford University Medical Center, Palo Alto, California. Requests for reprints should be addressed to Timothy C. Fagan, MD, University Health Care at Ventana Vista, 5620 North Kolb Road, Suite 166, Tucson, Arizona 85750.

title: The new diagnostic criteria for diabetes: the impact on management of diabetes and macrovascular risk factors.
abstract: The American Diabetes Association (ADA) has recently revised the system of classification and criteria for diagnosis of diabetes to help remedy the problem of undiagnosed diabetes, as well as to move away from a system of diagnosis based on treatment used toward a system based on disease etiology. The ADA report identifies 4 major categories of diabetes: (1) type 1 (absolute insulin deficiency); (2) type 2 (insulin resistance with an insulin secretory defect); (3) other specific types; and (4) gestational diabetes mellitus. The major changes are establishing a fasting glucose > or = 126 mg/dL for the diagnosis of diabetes and the suggestion that oral glucose tolerance tests are not needed in routine practice for the diagnosis of diabetes. The report stresses that the degree and type of diabetes can change over time and underscores the importance of early recognition and management of glycemic disorders. More aggressive screening, using fasting plasma glucose (FPG) concentrations of > or = 110 mg/dL as a marker of insulin resistance, should help identify not only patients with hyperglycemia but also those with insulin resistance without significant hyperglycemia. Even if hemoglobin A1c levels are in the normal range, patients in this category are at increased risk for developing macrovascular complications and may benefit from active intervention to reduce cardiac risk factors.

title: Metabolic effects of metformin in non-insulin-dependent diabetes mellitus.
abstract: The metabolic effects and mechanism of action of metformin are still poorly understood, despite the fact that it has been used to treat patients with non-insulin-dependent diabetes mellitus (NIDDM) for more than 30 years.



In 10 obese patients with NIDDM, we used a combination of isotope dilution, indirect calorimetry, bioimpedance, and tissue-balance techniques to assess the effects of metformin on systemic lactate, glucose, and free-fatty-acid turnover; lactate oxidation and the conversion of lactate to glucose; skeletal-muscle glucose and lactate metabolism; body composition; and energy expenditure before and after four months of treatment.



Metformin treatment decreased the mean (+/- SD) glycosylated hemoglobin value from 13.2 +/- 2.2 percent to 10.5 +/- 1.6 percent (P < 0.001) and reduced fasting plasma glucose concentrations from 220 +/- 41 to 155 +/- 28 mg per deciliter (12.2 +/- 0.7 to 8.6 +/- 0.5 mmol per liter) (P < 0.001). Although resting energy expenditure did not change, the patients lost 2.7 +/- 1.3 kg of weight (P < 0.001), 88 percent of which was adipose tissue. The mean (+/- SE) rate of plasma glucose turnover (hepatic glucose output and systemic glucose disposal) decreased from 2.8 +/- 0.2 to 2.0 +/- 0.2 mg per kilogram of body weight per minute (15.3 +/- 0.9 to 10.8 +/- 0.9 mumol per kilogram per minute) (P < 0.001), as a result of a decrease in hepatic glucose output; systemic glucose clearance did not change. The rate of conversion of lactate to glucose (gluconeogenesis) decreased by 37 percent (P < 0.001), whereas lactate oxidation increased by 25 percent (P < 0.001). There were no changes in the plasma lactate concentration, plasma lactate turnover, muscle lactate release, plasma free-fatty-acid turnover, or uptake of glucose by muscle.



Metformin acts primarily by decreasing hepatic glucose output, largely by inhibiting gluconeogenesis. It also seems to induce weight loss, preferentially involving adipose tissue.

title: Metformin associated lactic acidosis.
abstract: A case of lactic acidosis occurring in association with inappropriate and excessive metformin therapy and a high serum metformin concentration is described. In the other 23 cases of metformin associated lactic acidosis reported to December 1977, renal, cardiovascular and liver disease were common. Although metformin is less likely to cause lactic acidosis than phenformin, neither drug should be prescribed in the presence of renal, hepatic or cardiovascular disease.

title: Suppression of hepatic gluconeogenesis in long-term Troglitazone treated diabetic KK and C57BL/KsJ-db/db mice.
abstract: The orally effective antidiabetic agent Troglitazone (CS-045) exerts hypoglycemic effects in various insulin-resistant obese and/or diabetic animals. Since increased hepatic gluconeogenesis is a major cause of hyperglycemia in these diabetic animals, we evaluated the effect of long-term Troglitazone treatment on hepatic gluconeogenesis. Troglitazone was administered for 7 days to normal ddY mice, diabetic KK mice, diabetic C57BL/KsJ-db/db mice, and its heterozygote, db/+ mice, as a 0.1% or 0.2% food admixture. Troglitazone significantly decreased plasma glucose in diabetic KK and db/db mice, but not in normal ddY and db/+ mice. 14C incorporation into blood glucose from NaH14CO3 was measured to assess hepatic gluconeogenesis in diabetic KK and normal ddY mice. Hepatic gluconeogenesis was significantly increased in diabetic KK mice (P < .01) as compared with normal mice, and was significantly suppressed (P < .05) after 7 days of Troglitazone treatment (approximately 200 mg/kg/d). Glucose-6-phosphate (G6P) and fructose-6-phosphate (F6P) were significantly decreased but fructose-1,6-bisphosphate (FBP) was not significantly increased in the liver of diabetic db/db mice treated with Troglitazone for 7 days (approximately 80 mg/kg/d) as compared with control db/db mice. These changes in G6P, F6P, and FBP corresponded with the activity of fructose-1,6-bisphosphatase (Fru-1,6P2ase) and 6-phosphofructo-1-kinase (6-PF-1K), which determined the content of F6P and FBP. Namely, Fru-1,6P2ase was significantly decreased in Troglitazone-treated db/db mice as compared with control mice, whereas 6-PF-1K activity was not affected by Troglitazone treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

title: Troglitazone inhibits vascular smooth muscle cell growth and intimal hyperplasia.
abstract: Vascular smooth muscle cell (VSMC) proliferation and migration are responses to arterial injury that are highly important to the processes of restenosis and atherosclerosis. In the arterial balloon injury model in the rat, platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) are induced in the vessel wall and regulate these VSMC activities. Novel insulin sensitizing agents, thiazolidinediones, have been demonstrated to inhibit insulin and epidermal growth factor-induced growth of VSMCs. We hypothesized that these agents might also inhibit the effect of PDGF and bFGF on cultured VSMCs and intimal hyperplasia in vivo. Troglitazone (1 microM), a member of the thiazolidinedione class, produced a near complete inhibition of both bFGF-induced DNA synthesis as measured by bromodeoxyuridine incorporation (6.5+/-3.9 vs. 17.6+/-4.3% cells labeled, P < 0.05) and c-fos induction. This effect was associated with an inhibition (by 73+/-4%, P < 0.01) by troglitazone of the transactivation of the serum response element, which regulates c-fos expression. Inhibition of c-fos induction by troglitazone appeared to occur via a blockade of the MAP kinase pathway at a point downstream of MAP kinase activation by MAP kinase kinase. At this dose, troglitazone also inhibited PDGF-BB-directed migration of VSMC (by 70+/-6%, P < 0.01). These in vitro effects were operative in vivo. Quantitative image analysis revealed that troglitazone-treated rats had 62% (P < 0.001) less neointima/media area ratio 14 d after balloon injury of the aorta compared with injured rats that received no troglitazone. These results suggest troglitazone is a potent inhibitor of VSMC proliferation and migration and, thus, may be a useful agent to prevent restenosis and possibly atherosclerosis.

title: Metabolic Effects of New Oral Hypoglycemic Agent CS-045 in NIDDM Subjects
abstract: To study the metabolic effects of a new oral antidiabetic agent, CS-045, in subjects with non-insulin-dependent diabetes mellitus (NIDDM).  Eleven NIDDM subjects (mean age 59 yr and body mass index 32.3) were treated with 400 mg/day CS-045 for 6-12 wk. Patients were hospitalized before and at the end of the drug-treatment period for metabolic studies, including oral glucose tolerance test (OGTT), meal tolerance test (MTT), euglycemic glucose-clamp studies, and lipid analyses.  Eight subjects showed a marked clinical response to the drug, whereas 3 were nonresponders. The data were analyzed both for the total group and for the responders. Fasting plasma glucose (FPG) fell from 12.5 ± 0.7 to 10.7 ± 1.0 mM in the total group but fell more dramatically from 12.7 ± 0.5 to 8.3 ± 0.6 mM in the responder group. The area under the OGTT glucose curve improved by 17% in the total group and by 29% in the responders. The area under the MTT glucose curve improved by 38 and 52%, respectively. MTT levels of insulin, free fatty acids, and glucagon were significantly lower after treatment. Glucose disposal rates during glucose-clamp studies were increased in all subjects after CS-045 treatment. Mean increases were 63% at 120 mU · m−2 · min−1 and 41% at 300 mU · m−2 · min−1. Basal hepatic glucose production fell by 17% in the total group and by 28% in the responders.  CS-045 improves insulin resistance, reduces insulinemia, lowers hepatic glucose production, and improves both fasting and postprandial glycemia in NIDDM subjects. CS-045 may represent a new therapeutic option for NIDDM.