Microalbuminuria in non-insulin-dependent diabetes mellitus. Implications for renal survival

Microvascular and macrovascular disease cause considerable mortality and morbidity both among patients with non-insulin-dependent diabetes mellitus and those with insulin-dependent diabetes mellitus. Furthermore, non-insulin-dependent and insulin-dependent diabetes mellitus overlap in their pathogenesis as well as short- and long-term complications. In the diabetic patient, genetic susceptibility as well as other factors, ie, microalbuminuria, hypertension, high protein intake, blood glucose control, etc, ultimately culminate in a diffuse disease process, eg, diabetic vascular and/or renal disease. Early predictors of susceptibility for development of renal disease in diabetic subjects would help focus our treatment strategies. The role of microalbuminuria as a prognostic marker for the major complications of insulin-dependent diabetes mellitus has been previously reviewed. We reviewed the role of microalbuminuria as prognostic marker for progression of diabetic renal disease in subjects with non-insulin-dependent diabetes mellitus. We examined treatment strategies to lower microalbuminuria and its associated impact on disease progression.     

The Diabetes Atherosclerosis Intervention Study (DAIS): a study conducted in cooperation with the World Health Organization. The DAIS Project Group

The incidence of coronary artery disease is greatly increased in those with diabetes mellitus. The largest number of those who have coronary artery disease have non-insulin-dependent diabetes (NIDDM). Lipoprotein abnormalities have been identified among the several risk factors that could account for this increase in atherosclerosis. There have been many studies demonstrating that correction of dyslipoproteinaemias will reduce the risk of coronary disease in non-diabetic populations. Current advice to those with diabetes is based on extrapolations from such studies. However, the justification for this, and the treatment targets are unclear as there has been no direct test of the lipid hypothesis in diabetes. This paper describes the protocol of the first intervention trial designed to examine directly whether correcting dyslipoproteinaemia in men and women with NIDDM will reduce their coronary artery disease. The Diabetes Atherosclerosis Intervention Study (DAIS), is a multinational angiographic study using the 200 mg micronized form of fenofibrate in a double-blind, placebo-controlled protocol.     

Plasma endothelin-1 levels in non-insulin dependent diabetes mellitus patients with macrovascular disease

BACKGROUND: Endothelin-1 (ET-1) with its well-known vasoconstrictive and mitogenic action and through its interaction with insulin, blood glucose, and lipids might play an important role in the accelerated atherogenic process in diabetes mellitus. OBJECTIVE: To determine whether ET-1 levels are indicative of macrovascular disease in diabetes mellitus. METHODS: In the present cross-sectional study, plasma ET-1 concentrations were measured in members of three groups. The first group consisted of 20 patients (15 men and five women; aged 56.3 +/- 12.5 years) with non-insulin-dependent diabetes mellitus and coronary artery disease, the second group of 20 patients (16 men and four women, aged 56.9 +/- 11.2 years) with coronary artery disease only, and the third group of 10 healthy subjects who served as controls. ET-1 levels were determined by a radioimmunoassay. RESULTS: The mean plasma ET-1 levels for the three groups were 3.59 +/- 1.88, 4.31 +/- 1.32, and 4.42 +/- 1.01 pmol/l respectively, and there was no statistically significant difference among the groups (P = 0.23). There was also no correlation between the plasma ET-1 concentration and age, sex, body mass index, triglyceride, total cholesterol, high-, low- and very-low density lipoprotein levels, for all groups, and, for the first group, hemoglobin A1c (HbA1c), the duration of diabetes mellitus. CONCLUSION: The plasma ET-1 concentration is not elevated in non-insulin-dependent diabetes mellitus patients with macrovascular disease, which might reflect the fact that its action occurs in a paracrine or an autocrine rather than an endocrine fashion and suggests that ET-1 levels are not necessarily indicative of macrovascular disease in diabetes mellitus.     

More uniform diurnal blood glucose control and a reduction in daily insulin dosage on addition of glibenclamide to insulin in type 1 diabetes mellitus: role of enhanced insulin sensitivity

Combination therapy with insulin and sulphonylurea has gained acceptance in management of subjects with Type 2 (non-insulin-dependent) diabetes mellitus. However, its role in management of Type 1 (insulin-dependent) diabetes mellitus remains controversial. In this study, the effect of combination therapy with insulin and glibenclamide on metabolic control, daily insulin dosage, and insulin sensitivity was assessed in subjects with Type 1 diabetes mellitus. Ten men with Type 1 diabetes mellitus participated in a randomized, double-blind, crossover, clinical trial with three treatment regimens, namely (1) insulin alone, (2) insulin and placebo, (3) insulin and glibenclamide, each lasting 3 months. Combination therapy induced: (1) reduction in daily insulin dosage; (2) more uniform blood glucose control as reflected by a lower average 24 h blood glucose level, a smaller difference between mean preprandial and 2 h postprandial blood glucose concentrations, decreased 24 h urine glucose excretion, and a decline in number of hypoglycaemic events; (3) improved insulin sensitivity as expressed by more rapid plasma glucose disappearance rate, without a significant alteration in fasting plasma glucagon and 1h postprandial serum C-peptide levels; when compared with treatment with either insulin alone or with insulin and placebo. Therefore, it is apparent that the addition of glibenclamide to insulin reduces daily insulin dosage and renders a greater uniformity to diurnal blood glucose control, most probably secondary to enhancement of insulin sensitivity.     

Glucose and lipid metabolism during long-term antihypertensive treatment with indapamide in non-insulin-dependent diabetic patients

Thirty-nine patients with diabetes and hypertension were treated with indapamide for 24 weeks to study the effects of that drug on glucose and lipid metabolism. The drug was administered at a dose of 2 mg once per day in the morning as a single drug (26 patients) or in combination with other antihypertensive drugs (13 patients), including calcium antagonists, angiotensin-converting enzyme inhibitors, an alpha-blocker, or a beta-blocker. Blood pressure was reduced in both groups during treatment, and no alteration of glycemic control or lipid metabolism was observed. One patient complained of a mild headache, but treatment was continued. The results indicate that indapamide is useful for the long-term treatment of hypertension in diabetic patients, either alone or in combination with other antihypertensive agents.     

Cellular Ca2+ ATPase activity in diabetes mellitus

Basal and maximal Ca2+ ATPase activity was studied in erythrocytes of 29 healthy controls, 15 patients with insulin-dependent diabetes mellitus (IDDM) and 22 patients with non-insulin-dependent diabetes mellitus (NIDDM). Basal and maximal Ca2+ ATPase activity was significantly decreased in insulin-dependent diabetes mellitus (8.4 +/- 0.5 and 22.5 +/- 1.1 pmol/10(6) RBC/min) and non-insulin-dependent diabetes mellitus (7.3 +/- 1.0 and 18.6 +/- 1.8 pmol/10(6) RBC/min) compared to healthy controls (9.3 +/- 1.0 and 24.6 +/- 1.1 pmol/10(6) RBC/min). Maximal Ca2+ ATPase activity showed a significant correlation to systolic blood pressure in both insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus. There was no significant correlation of maximal Ca2+ ATPase activity to fasting serum glucose concentration and to HbA1 levels. Maximal Ca2+ ATPase activity was significantly correlated to creatinine clearance in non-insulin-dependent diabetes mellitus, but not in insulin-dependent diabetes mellitus. It is concluded that a decreased cellular Ca2+ ATPase activity may predispose to the development of hypertension in diabetes mellitus.     

Extracellular matrix changes in human corneas after radial keratotomy

It has been shown that an adenine (A) to guanine (G) transition at position 3243 of the mitochondrial transfer RNA(tRNA)leu(UUR) gene is associated with a subgroup of diabetes mellitus. Therefore, we screened for this transition in 86 patients with non-insulin-dependent diabetes mellitus (NIDDM) in which two or three generations were affected with diabetes, in 14 patients with insulin-dependent diabetes mellitus, and in 9 families with diabetes mellitus and/or associated disorders suggesting mitochondrial gene abnormalities. We failed to identify the mutation in 100 diabetic patients, 86 NIDDM and 14 insulin-dependent diabetes mellitus (IDDM). Out of the latter 9 families, we identified an A to G transition in 14 individuals in 5 families. Diabetes mellitus was shown to be maternally inherited in one family. In 9 of 14 patients with the mutation, insulin was required to treat diabetes mellitus, indicating impaired insulin secretion. A hyperglycemic clamp test performed in one subject revealed significant impairment of insulin secretion, whereas euglycemic clamp test showed normal insulin sensitivity in this patient. The heteroplasmy of the mutant mitochondrial DNA (mtDNA) in leukocytes does not appear to correlate with the severity of diabetes in terms of the insulin therapy required. Body mass index of the affected individuals was less than 23.3. In one family, in addition to diabetes mellitus and hearing loss, hypoparathyroidism was associated with the mutation, suggesting that hypoparathyroidism is caused by the impaired processing and/or secretion of proparathyroid hormone due to the mutation. In addition, the affected subjects presented with proteinuria at the time of diagnosis of diabetes mellitus which appeared not to be related with diabetic nephropathy.     

Troglitazone

Troglitazone decreases insulin resistance (improves insulin sensitivity), which results in reduced plasma glucose and insulin levels in patients with non-insulin-dependent diabetes mellitus (NIDDM). Risk factors for cardiovascular disease such as elevated proinsulin and triglyceride levels are also reduced by troglitazone. In clinical trials, troglitazone 200 to 800 mg daily (alone or in combination with other oral antidiabetic agents or insulin) reduced plasma or serum glucose levels and glycosylated haemoglobin compared with both baseline and placebo in patients with NIDDM refractory to other oral antidiabetic agents (usually sulphonylureas). Troglitazone was generally well tolerated in clinical trials. In patients in the US, the incidence of adverse events in troglitazone recipients was similar to that in placebo recipients.     

Obesity is a health problem

Obesity is a very common and an increasing nutritional problem in Finland and in other western countries and also in circumpolar areas. Dietary factors like high intakes of fat and alcohol, and physical inactivity predispose to obesity. Childhood obesity increases the risk of obesity in adulthood. Obesity is associated with cardiovascular diseases, non-insulin-dependent diabetes mellitus and musculoskeletal disorders which cause work disability. Prevention of obesity should be more focused because treatment of obesity is difficult and the long-term result generally poor. Multidisciplinary co-work is needed to find out how the factors of childhood are related to obesity in adulthood.     

Effect of cilazapril therapy on glucose and lipid metabolism in patients with hypertension

The effects of long-term monotherapy with cilazapril, an angiotensin-converting enzyme inhibitor, on blood pressure, glucose tolerance, and serum lipid profiles were prospectively investigated in 66 patients with hypertension: 23 with normal glucose tolerance and 43 with glucose intolerance (including 9 patients with non-insulin-dependent diabetes mellitus). The levels of plasma glucose, serum insulin, serum lipids, glycated hemoglobin A(lc) (Hb A(lc)), and fructosamine were determined before and during long-term (mean +/- SD, 26.2 +/- 1.2 weeks) therapy with cilazapril. A 75-g oral glucose tolerance test was performed before and during treatment. Significant reductions in both systolic and diastolic blood pressures in both patient groups were maintained during the study. Neither fasting nor post-glucose load venous plasma glucose levels were altered in either group of patients, and no patient with normal glucose tolerance developed diabetes mellitus during the study. There was no significant change in the insulinogenic index (delta serum insulin/delta venous plasma glucose at 30 minutes post-glucose load) in either group, and glucose intolerance was slightly improved with significant reductions (P < 0.01) in Hb A(lc) and fructosamine in the patient group with impaired glucose tolerance. Serum total cholesterol (TC), low-density lipoprotein cholesterol, and triglyceride levels were significantly (P < 0.01) decreased and high-density lipoprotein cholesterol levels increased in patients with hypercholesterolemia (TC levels > or = 5.69 mmol/L). These results suggest that long-term cilazapril therapy may improve glucose and lipid metabolism in hypertensive patients with impaired glucose tolerance. Cilazapril also appears to be useful as an antihypertensive agent for hypertensive patients with either impaired glucose tolerance or hypercholesterolemia.     

Tumour necrosis factor beta alleles and hyperinsulinaemia in coronary artery disease

BACKGROUND: Hyperinsulinaemia and dyslipoproteinaemia are markers and risk factors for coronary artery disease (CAD) and non-insulin-dependent diabetes mellitus (NIDDM). We investigated the influence of a tumour necrosis factor beta (TNF-beta) gene polymorphism on serum parameters related to these metabolic disorders in patients with CAD. METHODS: A total of 199 patients with CAD and 81 control subjects with angiographically normal coronary arteries were studied. A digestion of amplified DNA with NcoI revealed three fragment patterns: homozygosity for TNF-beta *1 or TNF-beta *2 and heterozygosity (TNF-beta *1/*2). RESULTS: Patients with CAD who had increased serum insulin or C-peptide (fasting and after glucose load) were predominantly heterozygous for TNF-beta (72% vs. 47%) and less frequently homozygous for TNF-beta *2 (22% vs. 43%, P = 0 x 0.03). CONCLUSION: This study demonstrates an association of TNF-beta alleles with the risk factor hyperinsulinaemia in CAD. Genomic variants of TNF-beta may therefore contribute to the complex susceptibility for the metabolic syndrome in patients with CAD.     

The contribution of non-insulin-dependent diabetes to lower-extremity amputation in the community

BACKGROUND: Despite the significant public health burden of lower-extremity amputations in diabetes mellitus, few data are available on the epidemiology of lower-extremity amputations in diabetes mellitus in the community setting. METHODS: A retrospective incidence cohort study based in Rochester, Minn, was conducted. RESULTS: Among the 2015 diabetic individuals free of lower-extremity amputation at the diagnosis of diabetes mellitus, 57 individuals underwent 79 lower-extremity amputations (incidence, 375 per 100,000 person-years; 95% confidence interval, 297 to 467). Among the 1826 patients with non-insulin-dependent diabetes mellitus, 52 underwent 73 lower-extremity amputations, and the subsequent incidence of lower-extremity amputation among these residents was 388 per 100,000 person-years (95% confidence interval, 304 to 487). Of the 137 insulin-dependent diabetic patients, four subsequently underwent five lower-extremity amputations (incidence, 283 per 100,000 person-years; 95% confidence interval, 92 to 659). Twenty-five years after the diagnosis of diabetes mellitus, the cumulative risk of one lower-extremity amputation was 11.2% in insulin-dependent diabetes mellitus and 11.0% in non-insulin-dependent diabetes mellitus. When compared with lower-extremity amputation rates for Rochester residents without diabetes, patients with non-insulin-dependent diabetes mellitus were nearly 400 times more likely to undergo an initial transphalangeal amputation (rate ratio, 378.8) and had almost a 12-fold increased risk of a below-knee amputation (rate ratio, 11.8). In this community, more than 60% of lower-extremity amputations were attributable to non-insulin-dependent diabetes mellitus. CONCLUSIONS: These population-based data document the magnitude of the elevated risk of lower-extremity amputation among diabetic individuals. Efforts should be made to identify more precisely risk factors for amputation in diabetes and to intervene in the processes leading to amputation.     

Histochemical detection of lymphatic drainage pathways in the middle nasal meatus

AIM: Assessment of the antihypertensive effect of doxazosin, alpha-1 blocker, as well as its action on lipid and carbohydrate metabolism, microcirculation and platelet function in patients with non-insulin-dependent diabetes mellitus (NIDDM). MATERIALS AND METHODS: Doxazosin (tonocardin) treatment was given for 11 weeks to 33 NIDDM patients with concomitant hypertension. The clinical examination comprised evaluation of central hemodynamics, vessels of the fundus of eye, lipid and carbohydrate metabolism, renal function, platelet aggregation. RESULTS: Tonocardin produced a fall in the systolic blood pressure (BP) by 14%, in the diastolic BP--by 17%. The 24-h profile of BP, lipid and purine metabolism, microcirculation of the vessels of the fundus of eye also improved. Total peripheral vascular resistance, left ventricular myocardial mass and platelet aggregation. Carbohydrate metabolism remained unchanged. CONCLUSION: Monotherapy with tonocardin (2-8 mg/day) is effective and safe in the treatment of arterial hypertension in NIDDM patients.     

Detection of prostaglandin E2 and matrix metalloproteinases in implant crevicular fluid

OBJECTIVE: To compare the effects of a calcium antagonist (nitrendipine) and an angiotensin converting enzyme inhibitor (enalapril) with those of placebo on left ventricular mass in patients with non-insulin-dependent diabetes mellitus and hypertension. DESIGN: A double-blind randomized, placebo-controlled trial. SETTING: General practitioners referred patients to the trial physician. PATIENTS: The study population comprised 121 patients with non-insulin-dependent diabetes mellitus. Inclusion criteria for blood pressure were diastolic blood pressure 90-115 mmHg and systolic blood pressure < or = 200 mmHg, while subjects were not being administered blood-pressure-lowering drugs for 3 weeks. INTERVENTION: Patients were randomly allocated to receive nitrendipine (n = 40), enalapril (n = 40) or placebo (n = 41). The treatment period was 48 weeks. MAIN OUTCOME MEASURES: The effect of nitrendipine was defined as the difference in change in left ventricular mass index from baseline between nitrendipine treatment and placebo after 48 weeks of treatment. The effects of nitrendipine compared with that of enalapril and of enalapril compared with placebo were defined similarly. Left ventricular mass was measured by M-mode echocardiography. RESULTS: Use of nitrendipine and enalapril led to significant and almost identical reductions in systolic and diastolic blood pressures. During 48 weeks left ventricular mass index decreased by 5% for patients in the nitrendipine group (decrease by 12 g/m2, 95% confidence interval 1-23), remained about the same for patients in the enalapril group (decrease by 1 g/m2, 95% confidence interval decrease by 10 to increase by 9) and increased by 9% for patients in the placebo group (increase by 9 g/m2, 95% confidence interval 2-16). CONCLUSION: These results indicate that administration of nitrendipine to patients with non-insulin-dependent diabetes mellitus and hypertension reduces left ventricular mass index. Enalapril appears not to induce regression, but perhaps prevents progression with an effect that is intermediate between those of nitrendipine and placebo.     

Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidaemia and atherosclerosis

Insulin resistance syndrome (IRS) has the potential to explain a large group of common metabolic and cardiovascular disorders [e.g., obesity, non-insulin-dependent diabetes mellitus (NIDDM), hypertension, hyperlipidaemia, hypercoagulability] which are all in themselves cardiovascular risk factors. This contribution firstly reviews the convincing evidence from glucose-clamp studies that all of these conditions are characterised by the presence of combined insulin resistance and hyperinsulinaemia, and secondly examines the relationships of the components of this syndrome to coronary artery disease and to the rational choice of antihypertensive therapy.     

Time for more active lipid-lowering treatment of patients with diabetes. Negative effect of hyperlipidemia on beta-cells is a neglected field

Type 2 diabetes mellitus is a common metabolic disorder whose prevalence is increasing in the western world. The ravaging complications of the disease constitute a major cause of hospitalisation and cardiovascular morbidity, and despite intensive research the pathogenic mechanism remain unknown. The article summarises some recent advances in the field of islet beta-cell dysfunction caused by hyperlipidaemia in the diabetic state, which results in perturbed insulin secretory capacity and overt glucose intolerance. In contrast to hyperglycaemia, the detrimental effects of hyperlipidaemia have been a relatively neglected area of diabetes research. However, the direct inhibitory effects of long-term hyperlipidaemia on beta-cell function, 'lipotoxicity,' should form the basis of a more active approach to lipid screening and pharmacological treatment of hyperlipidaemia in diabetes patients. Intervention in the leptin pathway may prove beneficial in future treatment strategies.     

Outcome of trigger finger treatment in diabetes

Trigger finger is an underdiagnosed hand disorder causing disability in longstanding diabetic patients. Sixty diabetic patients [39 insulin-dependent diabetes mellitus (IDDM) and 21 non-insulin-dependent diabetes mellitus (NIDDM)] and 60 nondiabetic patients were examined. All were initially treated by steroid injections: failure to alleviate symptoms was the indication for surgery. The incidence of multiple digit involvement was higher in IDDM patients as compared with the control group (p < 0.001). The diffuse type was 1.45 times more frequent in IDDM and NIDDM than in nondiabetic patients (p < 0.008). The diabetic patients had a relatively longer duration of symptoms (p < 0.003). Significantly, a higher recovery rate upon steroid injection was achieved in control patients as compared with the diabetic ones (p < 0.001). IDDM patients required more surgery compared with NIDDMs and, in 13.3% of diabetic patients, the surgical outcome was not successful. Diabetic patients should be diagnosed early for multiple and diffuse types of trigger digits. Steroid injection as the first mode of therapy is highly recommended although not always successful. Surgery is the definitive treatment but requires a long course of physiotherapy and may be associated with some complications.     

The antidyslipoproteinemic activity of ufibrate in patients with non-insulin-dependent diabetes mellitus

Ufibrate (150 mg daily) was found to have a beneficial effect on main parameters characterizing lipid metabolism, with no effect being exerted on carbohydrate metabolism, as evidenced by three months' follow-up of 24 patients aged 42 to 65 presenting with insulin-nondependent type II diabetes mellitus and hyperlipidemia. Ufibrate appeared to be a most efficacious long-term drug treatment option, particularly so in those patients presenting with initially high blood levels of a great many of lipid fractions.     

Clinical significance of insulin resistance

Insulin resistance has emerged in the last 20 years as a concept familiar to clinicians in many specialties. No easily performed laboratory test is available to assess insulin action in routine clinical practice. Several rare syndromes of severe insulin resistance are recognized but most clinicians will encounter insulin resistance as a manifestation of common diseases. Physiological and treatment induced changes in insulin sensitivity influence insulin doses required in insulin-dependent diabetes mellitus. In non-insulin-dependent diabetes mellitus insulin resistance is fundamental to pathogenesis but it is also influenced by standard dietary and pharmacological treatment, and probably mediated by changes in prevailing glycaemia. Antihypertensive agents appear to have diverse effects on the insulin resistance of essential hypertension though the long term significance of these remains unclear. The importance of insulin as a risk factor for coronary heart disease and the concept of an insulin resistance syndrome as a common precursor of conditions with increased vascular risk remains controversial.