Complications In Non-insulin-dependent Diabetes Mellitus Research Articles

Hypertension and macrovascular disease—the killing fields of NIDDM

Diabetes mellitus and particularly non-insulin-dependent diabetes mellitus (NIDDM) increases the risk for all manifestations of: (a) atherosclerotic vascular disease; (b) coronary heart disease (CHD); (c) cerebrovascular disease; and (d) peripheral vascular disease. NIDDM is known to be associated with several adverse cardiovascular risk factors, including: (i) hypertension; (ii) obesity; (iii) central obesity; (iv) hyperinsulinemia; and (v) serum lipid and lipoprotein abnormalities, characterized mainly by elevated serum total triglycerides and low high-density lipoprotein cholesterol. This review will discuss the prevalence of hypertension in NIDDM, the role of hypertension to increase the risk for macrovascular complications in NIDDM and finally trial evidence for the beneficial effect of blood pressure lowering in patients with NIDDM.

Angiotensin blockade improves cardiac and renal complications of type II diabetic rats.

Using Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a new model of human non-insulin-dependent diabetes mellitus (NIDDM), we examined the role of local angiotensin II in cardiovascular and renal complications of NIDDM. OLETF rats were orally given cilazapril (an angiotensin-converting enzyme inhibitor, 1 or 10 mg/kg), E4177 (an angiotensin AT1 receptor antagonist, 10 mg/kg), or vehicle for 26 or 40 weeks (from the age of 20 to 46 or 60 weeks). Cardiac mRNAs were measured by Northern blot analysis, and the thickening of the coronary arterial wall and the degree of perivascular fibrosis were determined by an image analyzer. Cilazapril or E4177 did not significantly affect body weight or plasma glucose and insulin levels of OLETF rats, indicating the minor effects on diabetes itself. However, both drugs significantly and similarly prevented coronary microvascular remodeling (the increase in wall thickening and perivascular fibrosis in coronary arterioles and small coronary arteries) in OLETF rats, and they were associated with the suppression of cardiac transforming growth factor-beta1 expression. Both drugs suppressed not only the increase in left ventricular weight but also the downregulation of cardiac alpha-myosin heavy chain expression in OLETF rats. Glomerulosclerosis and glomerular hypertrophy in OLETF rats were improved by cilazapril and E4177 to a comparable extent. These results, taken together with the fact that OLETF rats show normal plasma renin levels, support that the AT1 receptor is involved in the pathogenesis of cardiac and renal complications in NIDDM.

Implications of the diabetes control and complications trial for persons with non-insulin-dependent diabetes mellitus.

The Diabetes Control and Complications Trial has conclusively established that intensive control of insulin-dependent diabetes mellitus in persons aged 19 to 26 years (almost exclusively white, normotensive, nondyslipidemic, of normal weight, and insulin sensitive) reduces by +/- 50% the likelihood of retinopathy, nephropathy, and neuropathy. In contrast, persons with non-insulin-dependent diabetes mellitus (NIDDM) are older, overweight, hypertensive, dyslipidemic, and insulin resistant. Glycemia is only one of their risk factors, and they die of macrovascular disease. Review of studies supporting glycemic control versus risk factor reduction as management of NIDDM suggests a clear need to address risk factors besides glycemic control for successful prevention of complications of NIDDM. A new schematic proposal for intervention based upon risk factor reduction is presented.

Associations of hypertension and complications in non-insulin-dependent diabetes mellitus

Hypertension is a common comorbidity with non-insulin-dependent diabetes mellitus (NIDDM). Data are somewhat inconsistent as to whether hypertension exacerbates diabetic complications in this population. Therefore, we examined the relationship between hypertension and vascular complications of NIDDM in the 950 patients enrolled in the prospective and randomized Appropriate Blood Pressure Control in Diabetes (ABCD) study. We found both systolic and diastolic hypertension to be associated with diabetic nephropathy ( P < .001) as well as with its macrovascular complications ( P < .05). Our present results also demonstrated that there was a significant relationship between hypertension and peripheral vascular disease ( P < .05), and left ventricular hypertrophy ( P < .001). There was, however, no apparent relationship between hypertension and diabetic neuropathy. Thus, arterial pressure may be a major determinant of complications in NIDDM.

Metabolic Control and Prevalent Cardiovascular Disease in Non-Insulin-dependent Diabetes Mellitus (NIDDM): The NIDDM Patient Outcomes Research Team

PURPOSE: Cardiovascular disease is a major cause of morbidity and death in non–insulin-dependent diabetes mellitus (NIDDM). While hyperglycemia is clearly related to diabetic microvascular complications, its contribution to large-vessel atherosclerosis is controversial.PATIENTS AND METHODS: We performed an analysis of the association between glycemic control and prevalent cardiovascular disease in 1,539 participants in the NIDDM Patient Outcomes Research Team study who were under usual care in a health maintenance organization. Prevalent cardiovascular disease and its risk factors were identified by self-administered questionnaire. Cardiovascular disease was defined by the presence of coronary heart disease, peripheral vascular disease, and/or cerebrovascular disease. Glycohemoglobin and lipid levels were obtained from a computerized laboratory database.RESULTS: The mean age of participants was 63 years (range 31 to 91); 51% were women. The mean duration of NIDDM was 9 years (range <1 to 50), 35% took insulin, and 48% took sulfonylureas. Mean glycohemoglobin was 10.6%. Sixty percent had hypertension, 16% currently smoked cigarettes, and the mean total high-density lipoprotein (HDL) cholesterol ratio was 5.7. Fifty-one percent had cardiovascular disease. Cardiovascular disease prevalence remained constant across increasing quartiles of glycohemoglobin for both men and women. In contrast, prevalent cardiovascular disease was associated with established cardiovascular disease risk factors including age (67 versus 59 years, P <0.0001), hypertension (66% versus 54%, P <0.0001), current cigarette smoking (17% versus 13%, P <0.005), and total/HDL cholesterol ratio (5.9 versus 5.6, P <0.05). Cardiovascular disease was also associated with duration of NIDDM (11 versus 8 years, P <0.0001). In multiple logistic regression analysis controlling for established cardiovascular disease risk factors and diabetes duration and therapy, glycohemoglobin remained unassociated with cardiovascular disease.CONCLUSIONS: Glycemic control is not associated with prevalent cardiovascular disease in this large population of individuals with NIDDM. Conventional cardiovascular disease risk factors are independently associated with cardiovascular disease and may be a more promising focus for clinical intervention to reduce atherosclerotic complications in NIDDM.

Forum Two: Unanswered Research Questions about Metabolic Control in Non-Insulin-dependent Diabetes Mellitus

The participants of Forum Two addressed the unanswered research questions about metabolic control and non-insulin-dependent diabetes mellitus (NIDDM). The most compelling issue was the effect of metabolic control on both the development and progression of macrovascular disease in patients with NIDDM. Associated questions that could be answered by a well-controlled clinical trial related to the goal of blood glucose control in NIDDM in the elderly and in persons with clinical vascular disease. The specific suggestion was a trial similar to the Veterans Affairs Cooperative Study on Glycemic Control and Complications in NIDDM. Another important research issue that was discussed was the benefit of treating other risk factors such as hypertension and hyperlipidemia in diabetic patients. Yet another area discussed was the study of health services delivery to examine the best care-delivery methods for diabetes and other chronic diseases. Other areas of discussion centered on basic research, that is, the fundamental cause of insulin resistance and the genetics of NIDDM and the loss of protection against atherosclerosis in postmenopausal women with diabetes.

Section Review: Oncologic, Endocrine &amp; Metabolic: Thiazolidinediones

To date, the treatment of Non-Insulin Dependent Diabetes Mellitus (NIDDM) has focused primarily on attempts to correct some of the metabolic abnormalities commonly associated with the disease. Insulin and/or insulin secretagogues, such as sulphonylureas, are frequently used to lower blood sugar; however, there is a significant risk of hypoglycaemia. Moreover, the use of insulin or insulin secretagogues in patients who are already hyperinsulinaemic may accelerate some of the cardiovascular complications of NIDDM, and further aggravate insulin resistance. Other therapeutic strategies have focused on aberrations in glucose metabolism or absorption, including biguanides, such as metformin, or glucosidase inhibitors, such as acarbose. While these agents have been efficacious to a degree, they do not have a direct impact on the underlying pathology of insulin resistance. A novel therapeutic strategy involves the use of insulin-sensitising agents, such as the thiazolidinediones. These compounds appear to improve...

Serum amyloid A protein in patients with non-insulin-dependent diabetes mellitus

We determined the serum amyloid A protein (SAA) levels in patients with non-insulin-dependent diabetes mellitus (NIDDM), and investigated the possible association between SAA and the complications of NIDDM. The concentrations of SAA were measured in the plasma of 105 patients with NIDDM (52 men and 53 women, age mean ± SD, 61 ± 13 years) and 91 healthy subjects (37 men and 54 women, aged 57 ± 11 years). SAA concentrations were assayed by enzyme-linked immunosorbent assay. SAA concentrations in the patients with NIDDM were significantly higher than those in healthy subjects (2.1 ± 1.3 vs. 1.2 ± 0.5 mg/L). There were no obvious relationships between SAA lebels and duration of diabetes, type of therapy, or control of blood sugar in the patients with NIDDM. However, SAA levels in patients with NIDDM increased significantly, with increase of urinary albumin excretion ( p = 0.027). The increase of SAA in the patients with NIDDM did not influence the serum concentrations of lipid or lipoprotein. The SAA concentration in NIDDM was unrelated to the type of treatment, but seemed to be related to the development of diabetic nephropathy.

Impact of obesity on neuropathic late complications in NIDDM.

This cross-sectional study was aimed to investigate the isolated influence of obesity on peripheral sensorimotor and autonomic neuropathy in patients with long-term non-insulin-dependent diabetes mellitus (NIDDM). Ninety-one long-term NIDDM patients with a mean duration of 13.6 +/- 1.0 years and a mean age of 60.4 +/- 1.0 years were divided into two groups according to their body mass index (BMI) (lean with a BMI < 26.5: n = 41, age = 58.6 +/- 1.7 years, BMI = 23.7 +/- 0.3 kg/m2; and obese with a BMI > or = 26.5: n = 50, age = 61.9 +/- 1.2 years, BMI = 30.5 +/- 0.5 kg/m2). The two groups were not different in age, duration, gender, current parameters of glycemic control, number of smokers, cholesterol, triglycerides, and systolic and diastolic blood pressure. Neuropathic late complications were scrutinized by a standardized clinical examination that delivers a neuropathy score, pupillary autonomic neuropathy assessed by pupillometry, and cardiovascular autonomic neuropathy using a standardized test battery. One-way analysis of variance revealed that obese patients had poor results in the clinical neuropathy test (overall score in obese vs. lean: 71.1 +/- 2.9 vs. 80.6 +/- 3.0 points, 2P = 0.0266; 100 points were absolutely normal). This was particularly true for the discrimination perception (obese vs. lean: 67.0 +/- 4.0 vs. 81.7 +/- 3.3 points, 2P = 0.0073) and the reflex status (obese vs. lean: 57.4 +/- 4.0 vs. 71.8 +/- 4.3 points, 2P = 0.0164). Furthermore, obese patients had a poor result in the respiratory sinus arrhythmia (RSA) test, one of six autonomic function tests (RSA: obese vs. lean in average RSA percentile: 36.9 +/- 4.9 vs. 54.0 +/- 5.9%, 2P = 0.0264). Obesity influences sensorimotor and autonomic neuropathic late complications. The poor result in RSA in obesity may indicate an interrelation between pathogenesis of obesity and disorders of the respiratory and heart rhythm-generating control centers in the brain stem. Moreover, it could be due to intrathoracic fat deposits that alter lung mobility. Body mass control may be an important approach to reduce neuropathic complications. Beyond that, it seems necessary to control for body mass when comparing neuropathy in two groups of patients with NIDDM.

New pharmacological approaches to insulin and lipid metabolism.

Obesity and diabetes mellitus are 2 of the most important metabolic disorders. In particular, noninsulin-dependent diabetes mellitus (NIDDM) accounts for over 75% of all cases of diabetes mellitus and has a prevalence of 0.5 to 2.0% in most Western populations (Alberti & Hockaday 1987). Obesity is even more common and, since diabetic and overweight patients experience much higher rates of cardiovascular morbidity and mortality than normal (Kannel et al. 1967), the underlying metabolic derangements have obvious clinical implications. Standard drug therapies for both conditions are far from ideal. For example, sulphonylurea drugs, which have been the mainstay of oral treatment for NIDDM for over 30 years, are associated with a 40% rate of secondary failure (Shen & Bressler 1987). Since defective insulin action is thought to be more important than failure of insulin secretion in the development of NIDDM, this raises doubts about the intrinsic suitability of antidiabetic treatment that is based entirely upon stimulation of insulin release. In obesity, many of the pharmacological agents are only transiently effective and carry risks of habituation as well as adverse cardiovascular and psychomotor reactions. Although various pathophysiological mechanisms contribute to the aetiology and complications of NIDDM and obesity, recent therapeutic developments have focused on pharmacological modulation of insulin-dependent pathways of glucose and lipid metabolism. Thus, a number of new drugs are now entering clinical evaluation with potential applications in NIDDM, obesity and possibly some forms of dyslipidaemia (table I).

Accelerated cholesteryl ester transfer in noninsulin-dependent diabetes mellitus

Alterations in core lipid composition of lipoproteins in noninsulin-dependent diabetes mellitus (NIDDM) patients have suggested that the heteroexchange of neutral lipids between HDL and the apo B-containing lipoproteins may be enhanced. For this reason, we studied cholesteryl ester transfer (CET) in ten sulfonylurea-treated patients with stable NIDDM. CET measured in all NIDDM subjects with an assay of mass transfer was significantly greater than that of controls at 1 and 2 h ( P < 0.001); the transfer of radiolabeled CE also was increased in a subset of four of the NIDDM group (NIDDM k = 0.21 ± 0.04 vs. control k = 0.10 ± 0.05; P < 0.05). A weak correlation was demonstrable between the mass of CE transferred at 1 h and diabetic control expressed as plasma fructosamine ( r = 0.58, P < 0.09). To characterize this disturbance in CET further, the donor (HDL + VHDL) and acceptor (VLDL + LDL) lipoprotein fractions were isolated by ultracentrifugation at d 1.063 g/ml from NIDDM and control plasma and a series of recombination experiments were performed. Combining NIDDM acceptor with control donor fractions that contained HDL and CETP and not the combination of NIDDM donor and control acceptor lipoproteins resulted in an accelerated CET response identical to that observed in NIDDM whole plasma. This observation indicated that the abnormality in CET in NIDDM was associated with the VLDL + LDL fraction. To discern which lipoprotein class was dysfunctional, VLDL ( d < 1.006 g/ml) and LDL ( d 1.006-1.063 g/ml) from NIDDM and control subjects were isolated and combined with the d > 1.063 g/ml fractions of their respective control at the same triglyceride concentration for VLDL and cholesterol for LDL. These experiments revealed that NIDDM VLDL and not LDL promoted CET. Concentrations of cholesteryl ester transfer protein (CETP) did not differ in the two groups (NIDDM 1.63 ± 0.36 μg/ml vs. control 1.33 ± 0.36). These findings indicate that CET is increased in the plasma of NIDDM patients, and this abnormality appears to result from dysfunction of VLDL. Since this abnormality may promote the generation of increased numbers of potentially atherogenic cholesteryl ester-enriched apo B-containing lipoproteins, it may be a previously unrecognized risk factor that contributes to the development of macrovascular complications in NIDDM.

Apolipoprotein E phenotype is related to macro- and microangiopathy in patients with non-insulin-dependent diabetes mellitus

The role of apolipoprotein E (apo E) in modulating the susceptibility of individuals with non-insulin-dependent diabetes mellitus (NIDDM) to atherosclerotic vascular disease was studied in 143 male and 128 female patients with NIDDM. The data show that the apolipoprotein phenotype E2 somehow protects from macrovascular complications in NIDDM both in men and women. E2 also tends to protect from microvascular complications. In contrast, apo E phenotypes E4/4 and E4/3 tend to increase the risk for macroangiopathy in NIDDM patients. The lower prevalence, of macroangiopathy in the subjects with E2 was associated with lower plasma total and LDL cholesterol concentrations and low plasma lipoprotein(a) levels. Overall, this study demonstrates the role of the apo E phenotype to modulate the risk for diabetic complications in patients with NIDDM. The confirmation of the association of apo E polymorphism with diabetic complications warrants, however, long-term follow-up studies.

Microvascular Complications of NIDDM in Hispanics and Non-Hispanic Whites: San Luis Valley Diabetes Study

The goal of this article was to examine the differences in the rates of microvascular complications of non-insulin-dependent diabetes mellitus (NIDDM) in Hispanic and non-Hispanic white subjects. This was a geographically based case-control study where prevalent cases of NIDDM were identified in medical records. Subjects attended a 4-h clinic to confirm NIDDM diagnosis and assess complication end points. Retinopathy was defined by stereofundus photographs. Distal symmetric neuropathy was determined by standardized clinical examination. Nephropathy was indicated by serum creatinine level, urine protein-creatinine ratio, and urine albumin concentration. This study consisted of 279 NIDDM subjects confirmed by oral glucose tolerance test and World Health Organization criteria aged 20-74 yr (187 Hispanic and 92 non-Hispanic white subjects). Duration-adjusted prevalence of retinopathy was significantly higher in non-Hispanic white subjects (54.1 per 100, 95% confidence interval [CI] 44.4-63.7) than in Hispanics (41.8 per 100, 95% CI 34.8-48.8). This excess occurred only in non-Hispanic white subjects with background retinopathy but not in those with more severe retinopathy. Hispanics and non-Hispanic white subjects did not differ significantly for the prevalence of neuropathy (31.6 per 100 in non-Hispanic white subjects and 26.3 per 100 in Hispanics) or nephropathy by any measure. There were no significant differences in duration of diabetes or mean glycohemoglobin levels between ethnic groups. Microvascular complications of NIDDM are not in excess among Colorado Hispanics, and retinopathy may be somewhat more common in non-Hispanic white people.

Current status of non-insulin-dependent diabetes mellitus (type II): Management with gliclazide

Non-insulin-dependent diabetes mellitus (NIDDM) is a major cause of morbidity and mortality worldwide, with a prevalence of 3–7% in most Western countries. Decreased insulin secretion and diminished tissue insulin sensitivity are both implicated in the pathogenesis of the disease; both may be exacerbated by persistent hyperglycemia and improved by normalization of blood sugar levels. Measures to control hyperglycemia, hypertension, and hyperlipidemia are important in the management of NIDDM and prevention of its long-term complications. The effects of dietary modification, exercise, and antihypertensive and antiplatelet therapy, as well as of pharmacologic control of blood sugar, on the vascular and renal complications of NIDDM have been investigated. Gliclazide is a second-generation sulfonylurea drug whose efficacy in the treatment of NIDDM, alone or in combination with insulin, has been widely demonstrated. Studies of the use of gliclazide, reported at recent symposia, are summarized in this review.

Will Sulfonylurea Treatment of Impaired Glucose Tolerance Delay Development and Complications of NIDDM?

The chronic hyperglycemia of non-insulin-dependent diabetes mellitus (NIDDM) evolves gradually and is usually preceded by more transient hyperglycemia, classified as impaired glucose tolerance (IGT). Already in this phase, there is an increased risk of cardiovascular complications, and many IGT subjects, like NIDDM patients, often display several of the metabolic and circulatory disturbances that are associated with hyperglycemia, e.g., insulin resistance, hyperinsulinemia and/or hyperproinsulinemia, delayed insulin release, dyslipidemia, and hypertension. Therefore, and because untreated hyperglycemia is a self-perpetuating condition, early detection and early intervention may be necessary to prevent the progression and complications of NIDDM. This in turn would necessitate screening procedures, and the therapeutic goal should include both euglycemia and normalization of plasma insulin, plasma lipids, and blood pressure. A study in the German Democratic Republic indicated that the mortality in screening-detected NIDDM patients did not differ from that in patients detected in routine care. In a Swedish study on screening-detected NIDDM subjects, only those who had IGT rather than manifest NIDDM could maintain fasting blood glucose less than or equal to 6 mM for 5 yr by hypocaloric dietary regulation alone. In those with screening-detected NIDDM, the delayed acute insulin release and net postprandial hyperglycemia were improved by addition of glipizide, and most managed to attain and maintain fasting blood glucose less than or equal to 6 mM for approximately 2 yr after such addition. However, after 4 yr, there was an increase in blood glucose, suggesting that preventive intervention either may not be possible or may have to start in the IGT phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Complements in non-insulin-dependent diabetes mellitus with complications

A relation of the complement system to the development of complications in non-insulin-dependent diabetes mellitus (NIDDM) was evaluated by measuring some components of the complement system. CH50, C3, C4 and C3bINA were significantly elevated in subjects with NIDDM as compared with healthy non-diabetic controls. However, CH50 and C3 did not differ between diabetics with and without complications. C4 was higher in diabetics with retinopathy as well as with retinopathy and neuropathy than in diabetics without these complications. ACH50, beta 1Hg1 and C3d were similar in subjects with NIDDM and non-diabetics, and not associated with complications of NIDDM. C3d/C3 in NIDDM without complications was lower than in healthy subjects, but did not significantly differ between the types of complications. These results suggest that the high level of complements in NIDDM might be due to enhanced production of complements and the development of diabetic complications would be related to the elevated level of complements.