Therapeutic interventions for nephropathy in type I diabetes mellitus

Diabetic nephropathy is the single most common cause of end-stage renal disease in the United States. Recently, several major therapeutic interventions have been developed and shown to slow or halt the progression of renal failure in patients with diabetes and diabetic kidney disease. Studies have shown that in patients with insulin-dependent diabetes and proteinuria, lowering systemic blood pressure slows the rate of decline in renal function and improves patients' survival. In the recently completed trial of angiotensin converting enzyme (ACE) inhibition in diabetic nephropathy, ACE inhibitors were specifically shown to decrease dramatically the risk of doubling of serum creatinine or reaching a combined outcome of end-stage renal disease or death independent of their effect on systemic blood pressure. In studies with small numbers of patients, dietary protein restriction has also been shown to slow the rate of decline of renal function. New potential interventions currently undergoing study include treatment with aldose reductase inhibitors, treatment with inhibitors of the formation of advanced glycosylation end-products, treatment of dyslipidemia, and a variety of other less well-studied interventions.     

Non-insulin-dependent diabetes: from physiopathology to treatment

Non-insulin-dependent (or type 2) diabetes mellitus is a common, underdiagnosed and growing disease in our society. It is responsible for increased morbidity and mortality and represents an important public health problem. This polygenic disease is often expressed late in life and its evolution is accelerated by environmental factors leading to obesity. It combines defects in both insulin secretion and insulin action, and such defects are present in various proportions according to the type of patient and the stage of the disease. Diet and physical activity recommendations are the basis of the treatment. Current pharmacological approaches aim at improving insulin secretion and/or insulin cellular action. After secondary failure to oral drugs, insulin therapy should be initiated, the patient becoming "insulin-requiring". A synergy should be searched in the combination of various therapeutic modalities in order to improve the glycaemic control.     

The HLA system and diabetes mellitus

There is a significant positive association between insulin dependent diabetes, irrespective of age of onset, and the HLA system, whereas there is no association of HLA antigens with non-insulin dependent diabetes. There is a significant concordance value for HLA antigen frequencies in insulin dependent diabetics from three different centres, indicating that the genes (s) conferring susceptibility to this type of diabetes is possibly present in all "juvenile-onset" diabetics and is in linkage disequilibrium with all the B locus alleles.     

Autonomy of the renin system in type II diabetes mellitus: dietary sodium and renal hemodynamic responses to ACE inhibition

OBJECTIVE: To characterize the cytomorphologic features of pilomatrixoma. STUDY DESIGN: Aspirate findings in nine cases of PMX were correlated with clinical data and subsequent histology. This relatively large volume of case material afforded an opportunity to test the cytologic criteria that have been proposed as diagnostic of pilomatrixoma in the case reports published previously. RESULTS: Ghost cells, basaloid cells and calcium deposits were the features found to be most characteristic of PMX and were observed in all four cases in which a correct diagnosis was made originally. CONCLUSION: The presence of ghost cells seems to be the key to recognizing PMX. These cells are visible in the majority of air-dried smears but seldom in alcohol-fixed smears. Adequate cytologic sampling and the routine use of both wet-fixed and air-dried smears should preclude an incorrect diagnosis.     

DNA polymorphisms in the ACE gene, serum ACE activity and the risk of nephropathy in insulin-dependent diabetes mellitus

BACKGROUND: To determine the relationship between DNA polymorphisms in the angiotensin I converting enzyme (ACE) gene, serum ACE activity and the risk of diabetic nephropathy. METHODS: A case-control study was carried out in a population of Jewish insulin-dependent diabetes mellitus (IDDM) patients. Cases (77 IDDM patients with diabetic nephropathy) and controls (89 IDDM patients with normoalbuminuria) were genotyped with PCR protocols for detecting two DNA polymorphisms in the ACE gene: one in intron 7 detected with the restriction enzyme PstI and the other in intron 16 identified as an insertion/deletion (I/D). RESULTS: The risk of nephropathy was increased only in patients homozygous for the allele with the PstI site. These homozygotes had a nephropathy risk that was 2.3 times (95% C.I.: 1.2-4.5) that of the other genotypes. Furthermore, these individuals did not have elevated serum ACE activity. CONCLUSIONS: The results of this study are evidence that the risk of diabetic nephropathy in IDDM is influenced by genetic variability at the ACE locus, but the responsible variant is not the I/D polymorphism in intron 16. Our findings require further studies in other populations.     

Diabetes mellitus, arterial hypertension and serum levels of renin

Plasmatic renin levels were measured in 17 adults patients with diagnosis of diabetes mellitus and systemic arterial hypertension. None of them was under antihypertensive therapy. The results obtained showed lessening of renin levels in 13 cases, normal levels in two cases, no valuable results in one and Significative increase in other. Renal biopsy was performed in 8 patients and in all cases nephropathies were demonstrated; only one of them had normal renin levels. We have concluded that more than 75% of our cases were hyporeninemic hypertensive patients. Our findings are according with other medical papers that have been published before. Finally, we try to explain the mechanisms upon which theorethical causes are based.     

Non-insulin-dependent diabetes mellitus in New Zealand Maori: a relationship with Class I but not Class II histocompatibility locus antigens

AIMS: To investigate the possibility of a relationship between the major histocompatibility complex (MHC) and non-insulin-dependent diabetes mellitus (NIDDM) in Maori. Such relationships have previously been shown in non-European races with a high incidence of NIDDM. METHODS: We performed serological Class I and PCR-SSP Class II HLA typing on 44 Maori with NIDDM and renal failure and compared the results with normal Maori. RESULTS: A strong relationship with the HLA-B40 groups of antigens (relative risk 5.1 chi 2 = 16.8, p < 0.001) was found; this was mainly attributable to HLA-B48 and HLA-B60. There was no HLA Class II relationship. CONCLUSION: The relationship with HLA-B40 antigens suggests that the MHC or other genes on chromosome 6 play a role in NIDDM in Maori.     

Angiotensin-converting enzyme gene polymorphism in non-insulin dependent diabetes mellitus and its relationship with diabetic nephropathy

The effects of prolactin (PRL) on proliferation of cultured human uterine leiomyoma-derived smooth muscle cells (SMC) and its mechanism of action were investigated. PRL stimulated DNA synthesis and the expression of PRL receptor was identified by ribonuclease protection assay. Moreover, the regulation of mitogen-activated protein (MAP) kinase by PRL in leiomyoma-derived SMC was investigated. PRL stimulated MAP kinase activity, as detected by 32P incorporation into MAP-2, in a dose-dependent manner. PRL also rapidly stimulated MAP kinase phosphorylation as detected by in vivo phosphorylation using 32P labeling and phosphotyrosine immunoblotting. These results suggest that PRL stimulates the proliferation of human leiomyoma cells via the MAP kinase cascade.     

Gestational diabetes mellitus and subsequent development of overt diabetes mellitus

GDM develops in 1-3% of all pregnancies. Women with GDM are characterized by a relatively diminished insulin secretion coupled with a pregnancy-induced insulin resistance primary located in skeletal muscle tissue. The cellular background for this insulin resistance is not known. The binding of insulin to its receptor and the subsequent activation of the insulin receptor tyrosine kinase have significant importance for the cellular effect of insulin. Thus, the pathogenesis to the insulin resistance was studied by investigating insulin receptor binding and tyrosine kinase activity in skeletal muscle biopsies from women with GDM and pregnant controls. No major abnormalities were found in GDM wherefore it is likely that the insulin resistance is caused by intracellular defects distal to the activation of the tyrosine kinase. Glucose tolerance returns to normal postpartum in the majority of women with GDM. However, previous studies, in populations quite different from a Danish population, have shown that women with previous GDM have a high risk of developing overt diabetes mellitus later in life. Hence, we aimed to investigate the prognosis of women with previous GDM with respect to subsequent development of diabetes and also to identify predictive factors for the development of overt diabets in these women. A follow-up study of diet treated GDM women diagnosed during 1978 to 1985 at the Rigshospital, Copenhagen was performed. Glucose tolerance was evaluated in 241 women (81% of the GDM population) 2-11 years after pregnancy. Abnormal glucose tolerance was found in 34.4% of the women (3.7% IDDM, 13.7% NIDDM, 17% IGT) in contrast to a control group where none had diabetes and 5.3% had IGT. Logistic regression analysis identified the following independent risk factors for later development of diabetes: a high fasting glucose level at diagnosis of GDM, a delivery more than 3 weeks before term, and an abnormal OGTT 2 months postpartum. Low insulin secretion at diagnosis of GDM was also an independent risk factor. The presence of ICA and GAD-autoantibodies in pregnancy was associated with later development of IDDM. In another study the following techniques: hyperinsulinaemic euglycaemic clamp, indirect calorimetry and tritiated glucose infusion were used to evaluate insulin sensitivity in glucose tolerant nonobese women with previous GDM and controls. A decreased insulin sensitivity due to a decreased non-oxidative glucose metabolism in skeletal muscle was found in women with previous GDM. Hence, the activity of three key enzymes in intracellular glucose metabolism (GS, HK and PFK) was studied in skeletal muscle biopsies obtained in the basal state and after 3 h hyperinsulinaemia, with the aim to identify the cellular defects causing the decreased insulin sensitivity. However, no abnormalities in enzyme activity was found. The same group of previous GDM women had a relatively reduced insulin secretion evaluated by the IVGTT. A longitudinal study of 91 GDM women showed a relatively reduced insulin secretion to oral glucose in pregnancy, postpartum as well as 5-11 years later. Thus the present review has shown that even nonobese glucose tolerant women with previous GDM are characterized by the metabolic profile of NIDDM i.e. insulin resistance and impaired insulin secretion. Hence, the combination of this finding together with the significantly increased risk for development of diabetes indicates that all women with previous GDM should have a regular assessment of their glucose tolerance in the years after pregnancy. The first OGTT should be performed around 2 months postpartum in order to diagnose women already diabetic and to identify women with the highest risk for later development of overt diabetes. Women with previous GDM comprise a target group for future intervention trials with the aim to prevent or delay development of NIDDM and IDDM.     

Zinc and diabetes mellitus

In patients with type 1 and 2 diabetes was frequently found: low blood zinc levels, high zincuria, severe and ubiquitous cellular depletion of zinc, increased basal and after loading blood mineral clearance, and hyperglycaemia due to the reduction of pancreatic insulin secretion and to the reduced biological action of the hormone on liver, as a consequence of chronic zinc deficit. Strong endocellular zinc depletion in diabetics; low insulin secretion; insulin biological action decrease for zinc deficit; IG-I concentration decrease, that happens in this condition; insulin and IGF-I resistance; insulin and IGF-I receptors depletion in diabetics: are strong arguments for zinc pharmacological supplementation, in gastric protective formulation, to avoid gastroenteric problems.     

Smoking and diabetes mellitus

Diabetic patients die mostly from chronic vascular complications, in particular ischaemic heart disease (specially type II diabetics) and renal failure associated with diabetic nephropathy (in particular type I diabetics). Smoking--one of the basic risk factors of atherosclerosis and its complications--accelerates in diabetics the atherosclerotic process and enhances the risk of cardiovascular complications. Smoking causes endothelial dysfunction, as well as deterioration of diabetic nephropathy and retinopathy. Smoking accelerates by various mechanisms the coagulation process and causes thus deterioration of the hypercoagulation state in diabetics. Anti-smoking intervention should be along with a diabetic diet the basic step in non-pharmacological treatment of diabetics.