Current concepts of renal hemodynamics in diabetes

Glomerular hyperfiltration has long been recognized in insulin-dependent diabetes, and has been more recently recognized in patients with non-insulin dependent diabetes mellitus as well. Experimentally, glomerular hyperfiltration has been shown to result from elevations in the glomerular capillary blood flow and the glomerular capillary hydraulic pressure (PGC). Of the hemodynamic determinants of hyperfiltration, it is glomerular hypertension that is most damaging to the glomerulus. Experimental and clinical studies have confirmed that antihypertensive agents that lower PGC more consistently slow the progression of injury than do those that fail to control glomerular hypertension. The pathogenesis of diabetic hyperfiltration is multifactoral. Many mediators have been proposed, including changes due to the altered metabolic milieu, and alterations in endogenous levels of such vasoactive mediators as atrial natriuretic peptide, endothelial-derived relaxing factor, angiotensin II, prostaglandins, thromboxanes, and kinins, among others. It has more recently been suggested that local renal tissue levels, rather than circulating levels, play the more profound role in hemodynamic regulation. For example, the renin-angiotensin system (RAS) appears to be disproportionately active in the renal tissue, potentially explaining the renal vascular responsiveness to angiotensin-converting enzyme inhibition despite absence of systemic RAS activation. Little is yet known of the mechanisms by which glomerular hypertension leads to injury. Innovative new in vitro systems have been developed to address this question. These studies postulate that glomerular hemodynamic factors (shear stress, pulsatile flow) modify the growth and activity of glomerular component cells, inducing the expression of cytokines and other mediators, which then stimulate matrix production and promote structural injury.     

Ocular arterial flow hemodynamics in patients with diabetes mellitus

The purpose of this study was to investigate ocular blood flow hemodynamics in patients with diabetes mellitus. We used color Doppler sonography, in 22 normal subjects and 52 patients with (n = 25) or without (n = 27) diabetic retinopathy, to determine blood flow velocities and the resistive index of the central retinal artery. The resistive index of the central retinal artery in patients with diabetic retinopathy (0.85 +/- 0.09) was significantly greater (P < 0.01) than that in normal subjects (0.72 +/- 0.08) and in patients without diabetic retinopathy (0.81 +/- 0.09). The resistive index of the central retinal artery in the patients without diabetic retinopathy was also significantly greater than that of normal subjects (P < 0.01). The resistive index of ocular arterial flow was increased in the patients with diabetes mellitus and further increased in the presence of retinopathy. Increased resistance in the peripheral ocular vascular bed contributes to diabetic retinopathy, and this change is present before the appearance of overt diabetic retinopathy.     

Serum protein changes in diabetes mellitus

AIM: To evaluate the serum protein pattern in a wide sample of diabetic patients using the simple method of electrophoresis, identifying the characteristics for each condition and correlating the various components. EXPERIMENTAL DESIGN: A retrospective study was made using medical records. SETTING: The Institute of Clinical Medicine I at Palermo University Hospital during the years 1990, 1991 and 1992. PATIENTS: 156 patients suffering from diabetes mellitus, of whom 68 were Type 1 (IDDM) and 88 Type 2 (NIDDM). The latter were divided into non-obese (NO-NIDDM), obese (O-NIDDM) and "secondary failures" (SF-NIDDM) to oral hypoglycemic agents (receiving mixed treatment, TM-NIDDM, or insulin alone, I-NIDDM). PARAMETERS: In addition to personal and anthropometric data and clinical data, in particular dysmetabolic data, an electropherogram was performed in each patient. RESULTS: Higher serum albumin concentrations were found in patients with IDDM, NIDDM compared to I-NIDDM, with an overall inverse correlation between the duration of diabetes and albumin serum levels. On the contrary, serum levels of alpha-2 globulins were higher in I-NIDDM patients compared to IDDM, and directly correlated with the age and duration in the overall series. beta-globulin levels were lower in IDDM patients compared to all other groups, and were directly correlated with age and body mass index (BMI) in the overall series. No statistical significance or correlation was found between the two groups in relation to alpha 1 and gamma-globulins. CONCLUSIONS: The study showed a characteristic serum protein pattern for each group of diabetic patients examined, analysing the role of insulin but also the duration and typical pathological events of the natural history of diabetes on protein metabolism, not only with regard to the amino acid metabolism but also on the distribution of circulating proteins.     

Renal structural-functional relationships in early diabetes mellitus

To define the earliest renal morphological changes in patients with type I diabetes, we studied renal function and morphometric analysis of renal biopsies in 59 patients with diabetes for 5-12 years and normal blood pressure, normal creatinine clearance (CCr), and negative dipstick urinary protein. Arteriolar hyalinization and intimal fibrous thickening were noted in 43%. Glomerular basement membrane thickness and fractional mesangial volume were increased in 51% and 56%, respectively. The pre-pubertal and post-pubertal years of diabetes were associated with similar degrees of renal structural changes, but during the pre-pubertal years normal urinary albumin excretion (UAE) was seen. Principal factor analysis of morphometric structural parameters yielded four clusters of variables: "glomerular size" correlated with patient age, CCr, and UAE; "peripheral capillary decrease" correlated with glycosylated hemoglobin, diastolic blood pressure, glomerular filtration rate, and UAE; "mesangial increase" correlated with UAE; and "interstitial scarring" correlated with diastolic blood pressure. This study provides unique documentation of renal structural abnormalities which precede clinically evident renal functional abnormalities and documents that these early structural abnormalities are present in the pre-pubertal years of diabetes as well as postpuberty, and are associated with each other in constellations that correspond to postulated mechanisms in diabetic nephropathy.     

Effect of experimental diabetes mellitus on gentamicin-induced acute renal functional changes in the anaesthetized rat

1. Rats with streptozotocin (STZ) diabetes are protected from gentamicin (GEN) nephrotoxicity. Because the chronic renal damage from GEN is preceded by acute renal functional changes (notably hypercalciuria), the present study aims to determine whether diabetes may also protect against the acute effects of the drug. If there is a link between the rapid physiological actions of GEN and its subsequent nephrotoxicity, the former may also be affected by the diabetic condition. 2. Standard renal clearance techniques were performed on anaesthetized rats that had been injected with STZ or vehicle 2 weeks previously. All animals were infused with 0.9% NaCl for 5 h and then either GEN (0.28 mg/kg per min) or 0.9% NaCl alone for 2 h. 3. Baseline fractional calcium excretion (FE(Ca)) of diabetic rats was three-fold that of control animals (6.6+/-0.2 vs 2.2+/-0.2%, respectively; P<0.01, MANOVA). Following GEN infusion, a comparable increase in FE(Ca) occurred in control and diabetic rats (5.3+/-0.6 vs 5.3+/-0.8%, respectively; NS). 4. Streptozotocin diabetes, therefore, does not alter the acute hypercalciuric response to GEN. This may suggest that the acute effects of GEN on renal calcium handling do not contribute to the subsequent nephrotoxicity. However, the higher baseline FE(Ca) seen in diabetic rats may afford protection against the renal injury caused by gentamicin.     

Acute renal failure in patients with type 1 diabetes mellitus

Acute renal failure (ARF) is a serious condition which still carries a mortality of around 50%. People with diabetes may be at increased risk of developing ARF, either as a complication of diabetic ketoacidosis or hyperosmolar coma, increased incidence of cardiovascular disease, or due to increased susceptibility of the kidney to adverse effects in the presence of underlying diabetic renal disease. During the period 1956-1992, 1,661 cases of ARF have been treated at Leeds General Infirmary. Of these, we have identified 26 patients also having type 1 diabetes. ARF due to diabetic ketoacidosis is surprisingly uncommon (14 cases out of 23 patients whose notes were reviewed). All cases of ARF complicating ketoacidosis in the last decade have been associated with particularly severe illness requiring intensive care unit support, rather than otherwise 'uncomplicated' ketoacidosis. We discuss the conditions that may result in ARF in patients with diabetes and the particular difficulties that may be encountered in management.     

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.     

Gestational diabetes mellitus and hypertension in pregnancy: hemodynamics and diurnal arterial pressure profile

We characterised the 24-h arterial pressure (AP) profile and the left ventricular (LV) structures and functions in pregnant women with pregnancy-induced hypertension (PIH) or gestational diabetes mellitus (GDM). Thirty pregnant women after 20 weeks' gestation--(10 normotensive; 10 with PIH; and 10 with GDM)--were investigated haemodynamically using 24-h AP monitoring and Doppler echocardiography for determination of LV structures and functions, both systolic and diastolic. The PIH women had significantly higher AP determinations throughout the 24 h, with no change in the diurnal variation, ie, nocturnal decline and early morning peaks. The LV mass was greater in PIH and GDM than in the normotensive women, despite normal AP in GDM. The increased LV mass in GDM was mainly due to LV dilatation and not to increased thickness of its walls. In PIH, the increase in AP was due to peripheral vasoconstriction, while cardiac output was preserved. The LV systolic functions did not differ among the three groups. However, a slight reduction in the myocardial contractility was found in PIH and GDM. The LV relaxation was significantly impaired in both PIH and GDM. Thus, GDM and PIH, although differing in their 24-h AP profile, are characterised by LV hypertrophy and reduction in diastolic function.     

Reversible diabetes mellitus during growth hormone therapy in chronic renal failure

A 12-year-old girl with short stature due to idiopathic Fanconi syndrome and chronic renal failure was treated with recombinant human growth hormone (rhGH). There was no family history of diabetes mellitus and the glucose tolerance before treatment was normal. Intravenous glucose tolerance tests were performed before, during and after treatment. Two months after starting rhGH the early phase of insulin secretion (1-+3-min values) was diminished, and the patient developed manifest diabetes mellitus with hyperglycemia and an elevated hemoglobin A1c. Following discontinuation of rhGH, glucose tolerance slowly returned to normal.     

Pharmacokinetics of oral glyburide in subjects with non-insulin-dependent diabetes mellitus and renal failure

There is considerable controversy about the distal clearance margin that needs to be maintained beyond the extent of a rectal tumor in order to reduce the risk of local recurrence. We investigated the rate of local recurrence, distant metastases and survival in 87 patients who had undergone radical restorative resection of the rectum for cancer and had been followed up for a median period of over 6 years, and we analyzed the statistical relation (log-rank test for trend) with the length of the distal margin. The distal margin length was divided into three categories: 1 cm, 2 cm, and > or = 3 cm. No significant correlation was found between the length of the distal clearance margin and the oncologic outcome. Taken together, our data suggest that if the resection line distally falls on healthy tissue, there is no need to resect additional rectum in order to achieve a better outcome.     

Clinical predictors of non-diabetic renal disease in patients with non-insulin dependent diabetes mellitus

BACKGROUND: Several studies had suggested that non-diabetic renal disease (NDRD) was common among non-insulin dependent diabetes mellitus (NIDDM) patients with renal involvement. METHODS: We prospectively studied the prevalence of NDRD among a Chinese NIDDM population. Renal biopsy specimens were evaluated with light-, immunohistological and electron-microscopy. The cohort consisted of 51 patients who had NIDDM and proteinuria > 1 g/24 h. RESULTS: Patients with both isolated diabetic nephropathy (DN, n = 34) and NDRD (n = 17) had comparable duration of DM, creatinine clearance, serum creatinine, albumin and glycosylated haemoglobin levels, as well as incidences of retinopathy, neuropathy and hypertension. Significantly more patients with NDRD had microscopic haematuria (P = 0.043) or non-nephrotic proteinuria (P = 0.004). IgA nephropathy accounted for 59% of the NDRD identified. CONCLUSIONS: In this study, microscopic haematuria and non-nephrotic proteinuria predicted the presence of NDRD among NIDDM patients presenting with renal disease.     

Mood changes associated with blood glucose fluctuations in insulin-dependent diabetes mellitus.

Examined relationships between blood glucose (BG) levels and self-reported mood in 34 19–68 yr old insulin-independent diabetes mellitus patients. Four times each day, Ss completed a mood/symptom checklist before a self-measurement of BG until 40 checklists had been completed. Half the items of the checklist described physical symptoms, and half described mood states. Within-S correlations and regressions showed that moods were related to BG for the majority of Ss and that, like physical symptoms, mood–BG relationships were idiosyncratic. Low BG levels were associated with negative mood states; positive mood items were almost always associated with high BG. High BG levels also frequently correlated with negative mood states, although the negative mood items that related to high glucose (anger, sadness) differed from those that tended to relate to low BG. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Microalbuminuria: a marker to increased renal and cardiovascular risk in diabetes mellitus

The presence of persistent microalbuminuria in IDDM is strongly predictive of the future development of end stage renal failure and of cardiovascular disease to a lesser extent. Screening for microalbuminuria is an essential component of modern diabetes practice, as effective antihypertensive therapy, and particularly, the use of angiotensin converting enzyme inhibitors is of proven benefit in retarding progression of renal disease. Cost benefit analysis justifies the expense of microalbuminuria screening programmes and early intervention. It has been estimated that the use of angiotensin converting enzyme inhibitors in microalbuminuric IDDM will save 5200 Pounds-11,000 Pounds per year of life saved. Angiotensin converting enzyme inhibitors are not free of side-effects, and it is therefore essential, given the intrinsic variability of the albumin excretion rate, and the regression to normoalbuminuria of a significant proportion of patients, to confirm the diagnosis of microalbuminuria by repeated measurements prior to the commencement of treatment. The value of intensive glycaemic control is unproven, and further prospective studies are required. There are no proven therapies for the prevention of macrovascular disease in IDDM, although the value of cessation of smoking and aggressive blood pressure control are undoubted in the non-diabetic population. Controversy persists about the value of lipid lowering therapy, especially in young patients, although even in this group there is an increased risk of cardiovascular disease. Microalbuminuria is the strongest known predictor of cardiovascular disease in NIDDM; in contrast to the situation in the non-diabetic population, active lipid lowering therapy is not of proven cardiac benefit, but intervention seems justifiable when taken in the context of the very high prevalence of cardiovascular disease. Microalbuminuria is also predictive of end stage renal disease in NIDDM. Although intervention with angiotensin converting enzyme inhibitors has not been proven to prevent end stage renal disease, stabilisation of albumin excretion rate and creatinine clearance have been demonstrated in normotensive NIDDM, and it seems likely that longer term follow-up studies will confirm the benefit of angiotensin converting enzyme inhibitors in the prevention of end-stage renal disease. The observed predictive power of microalbuminuria as regards both cardiac and renal risk in NIDDM when considered in conjunction with the preliminary results of the benefits of angiotensin converting enzyme inhibition lend further support to the employment of microalbuminuria screening in NIDDM.     

Large-scale screening for early diagnosis of gestational diabetes mellitus (GDM)

The aim of study was to evaluate incidence of GDM in Poland. All 1500 pregnant women between 24-28 week's gestation consulted in 4 centers were offered a 50 g oral glucose test (screening test). Capillary blood glucose was measured at 60 min after glucose ingestion. When blood glucose > 140 mg/dl, 75 g OGTT according to WHO criteria was performed. 241 women have abnormal screening test and in 181 cases blood glucose were at range 140-160 mg/dl, in 39 at range 160-180 and 21 were > 180 mg/dl. Only 14 women in the first group (140-160 mg/dl) have diagnosed GDM (7.7%). In second group 24 pregnant women have GDM (61.5%). Overall GDM incidence is shown to be 3.7% (57 women). The mean age for the GDM was 28.8 +/- 0.9 years compared with 26.4 +/- 0.4 years (p < 0.05) uncomplicated pregnancy.     

Platelet-leukocyte-cross-talk in diabetes mellitus

The physiological meaning of platelets has been best documented for acute coronary syndromes where platelets act as "first responsive elements" triggering the final occlusive thrombus after plaque rupture has occurred. This situation is particularly relevant for patients with NIDDM-type diabetes regularly showing complicated plaque architecture. Predictive power for acute ischemic events e.g. following angioplasty has been proven, and this has dominated the attention exclusively towards the hemostatic function of platelets. Meanwhile, a variety of particularly important platelet features have been identified: a) promotion of liquid phase coagulation; b) regulation of the local vascular tone; c) active modulation of tissue modeling at lesion sites; d) adhesion molecule-mediated communication with a variety of corpuscular blood (and non-blood cells). With emerging recognition of the latter role, the pathophysiological scope of platelets exceeds the well-established role as microemboli, local atherosclerosis amplifiers and triggers of gross thrombosis. In diabetes mellitus of either type, increased populations of circulating platelets have been identified expressing activation dependent adhesion molecules such as activated alpha 2 beta 3 (GPIIbIIIa), lysosomal GP53, thrombospondin or, perhaps most importantly "P-selectin" (CD62 p). This suggests that these adhesion molecules among others can also mediate platelet-leukocyte interactions potentially resulting in inflammatory tissue damaging processes in addition to the immanent tendency towards (micro-)thrombosis. This review works out a more general view on the meaning of platelet activation beyond hemostaseology and updates the actual knowledge of platelet-leukocyte communication checkpoints with particular reference to the diabetic state outlining new pharmacological concepts for intervention.     

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.