Diminished insulin clearance during late pregnancy in patients with type I diabetes mellitus

OBJECTIVE: Published data on bone metabolism in diabetes mellitus are conflicting. We have measured pyridinium crosslinks, biochemical markers of bone resorption, in order to evaluate bone resorption in diabetes mellitus. We also wished to investigate whether, as a consequence of chronic hyperglycaemia, pyridinoline is glycosylated to a greater extent in patients with diabetes mellitus. DESIGN AND PATIENTS: This cross sectional study included 142 patients (64 males, 78 females) with insulin dependent and non-insulin dependent diabetes mellitus (IDDM and NIDDM). These patients were compared to a healthy control group of 99 individuals (39 males and 60 females). MEASUREMENTS: Pyridinium crosslinks, glycosylated, free and total pyridinoline (gPYD, fPYD, tPYD) and free and total deoxypridinoline (fDPD, tDPD) were measured in a spot urine sample by high performance liquid chromatography (HPLC). Urinary creatinine, albumin and glucose were also measured. RESULTS: In the diabetic group, values of urinary gPYD and tDYD were significantly lower than in controls. gPYD excretion was lowest in patients with severe glycosuria. Free pyridinium crosslinks, both fPYD and fDPD, were excreted to a significantly lower extent. The molar ratio of tPYD to tDPD was significantly increased in diabetes mellitus. CONCLUSIONS: Decreased excretion of tDPD suggests low bone resorption in IDDM and NIDDM. Pyridinoline is not glycosylated to a greater extent in diabetes mellitus and tends to be decreased in proportion to the degree of glycosuria. Excretion of gPYD, fPYD and fDPD is depressed in severe glycosuria. Diminshed degradation to the final products, fPYD and fDPD, might represent increased resistance to enzymatic activity or diminished enzymatic activity. The increased molar ratio tPYD/tDPD in urine suggests an increased ratio in bone collagen in diabetes mellitus.     

Fetal vascular responses to maternal glucose administration in streptozocin-induced ovine diabetes mellitus

Different pathophysiology causes different types of incontinence. Urge-, Stress-, Overflow-, Reflex- and Extrasphincteric incontinence therefore need different therapeutic strategies. The basic diagnostic work-up, which can be done by any doctor in free practice comprises history, clinical investigation, urine analysis, the micturition protocol (frequency-volume-chart = FVC) and post voiding residual urine (PVR). In 80% of the elderly incontinent persons incontinence can be evaluated by basic diagnostics to such an extent, that conservative therapy can be started. If after basic diagnostic work-up the type of incontinence remains unclear, if it is a postoperative recurrent urinary incontinence, if reflex incontinence is present, or if conservative therapy is not successful within 3 weeks a further diagnostic workup by the specialist is mandatory. The specialist will perform echography of the urinary tract, endoscopy and especially urodynamics to evaluate detrusor and sphincter dysfunction precisely, if necessary also combined with X-ray (video-urodynamics). In regards to urinary stress incontinence conservative treatment strategies e.g. pelvic floor training programs, if necessary combined with electrotherapy and biofeedback have gained increasing importance. For urge-incontinence continence training programs and pharmacotherapy as well as electrotherapy are the main therapies. Reflex-incontinence should be treated by the specialist. Overflow incontinence is easy to diagnose, however, the treatment of the underlying pathophysiology must be done by the urologist. Urinary incontinence in the elderly is a special problem. Treatment of incontinence with incontinence aids (pads) only is justified in immobile and demented people, in others active treatment, comprising continence training programs and pharmacotherapy should be the goal. A Foley catheter is only justified if urinary incontinence is combined with an insufficient bladder emptying with residual urine, which can not be treated otherwise.     

Wound healing process differences in type I and type II diabetes mellitus

In 88 patients with purulent wounds in diabetes mellitus the course of wound healing was studied depending on the type of the disease. Clinical and morphological distinctions of the wound process in type 1 and type 2 diabetes mellitus were revealed.     

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.     

Daily energy metabolism in patients with type 1 diabetes mellitus

The availability of markers for the 17p11.2 region has enabled the diagnosis of Smith-Magenis syndrome (SMS) by fluorescence in situ hybridization (FISH). SMS is typically associated with a discernible deletion of band 17p11.2 upon cytogenetic analysis at a resolution of 400-550 bands. We present a case that illustrates the importance of using FISH to confirm a cytogenetic diagnosis of del(17)(p11.2). Four independent cytogenetic analyses were performed with different conclusions. Results of low resolution analyses of amniocytes and peripheral blood lymphocytes were apparently normal, while high resolution analyses of peripheral blood samples in two laboratories indicated mosaicism for del(17)(p11.2). FISH clearly demonstrated a 17p deletion on one chromosome of all peripheral blood cells analyzed and ruled out mosaicism unambiguously. The deletion was undetectable by flow cytometric quantitation of chromosomal DNA content, suggesting that it is less than 2 Mb. We conclude that FISH should be used to detect the SMS deletion when routine chromosome analysis fails to detect it and to verify mosaicism.     

Similar rate of progression in the predialysis phase in type I and type II diabetes mellitus

Progression of diabetic nephropathy from the stage of macroproteinuria with near-normal renal function until start of dialysis was compared in 16 patients with type I and 16 patients with type II diabetes mellitus. The mean creatinine clearance at the beginning of the study was 89 +/- 13 ml/min/1.73 m2 in patients with type I and 81 +/- 6 ml/min/1.73 m2 in those with type II diabetes. Dialysis was started after a mean interval of 77 (44-133) months, when creatinine clearance had decreased to 8 +/- 2 ml/min/1.73 m2 in type I diabetic patients. The respective figures for type II diabetic patients were 81 (40-124) months and 7 +/- 2 ml/min/1.73 m2. The mean rate of decrease in creatinine clearance was 1.05 +/- 0.45 ml/min/month in type I and 0.91 +/- 0.41 ml/min/month in type II diabetes. The mean rate of decrease was 1.46 +/- 0.30 ml/min/month in type I diabetic patients with a systolic BP > 160 mmHg versus 0.80 +/- 0.42 ml/min/month with < 160 mmHg (P < 0.01). In the type II diabetics the respective figures were 1.38 +/- 0.40 ml/min/month versus 0.78 +/- 0.15 ml/min/month (P < 0.01). During the observation period the prevalence of coronary heart disease increased from 6 to 50% in type I and from 31 to 87% in type II diabetes. In conclusion, the rate of progression of diabetic nephropathy during the predialytic phase is similar in type I and type II diabetes; BP adversely affects the rate of progression to the same extent in both groups.     

Uptake and metabolism of lipoproteins from patients with diabetes mellitus type II by glomerular epithelial cells

BACKGROUND: Recent studies suggest that dyslipidaemia accelerates the progression of diabetic nephropathy, but the various pathomechanisms underlying such abnormalities are not completely delineated. METHODS: We isolated, radiolabelled, and characterized very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) from eight diabetic patients with moderate impairment of renal function and dyslipidaemia and studied their interaction with LDL receptors in human glomerular epithelial cells. RESULTS: While diabetic VLDL showed no compositional changes, LDL particles contained a higher proportion of triglycerides at the expense of cholesterol in comparison with healthy controls. Despite differences in composition, both VLDL and LDL from patients exhibited reduced receptor affinity and cellular uptake capacity by glomerular epithelial cells. Since LDL composition was altered intracellular cholesterol homeostasis was investigated. Due to reduced cholesterol content and lower uptake capacity, diabetic LDL were less effective in suppressing intracellular sterol synthesis and in activating acylcholesterol acyltransferase than LDL from controls. Electrophoretic mobility of apoB from diabetic patients was enhanced as compared to controls, most probably due to the higher degree of glycation (17 + 1.7 versus 11 + 1%, P < 0.05) but not to oxidation (TBARS 0.5 + 0.2 versus 0.2 + 0.1 mumol/1). Oxidized LDL was not taken up in significant amounts, indicating no scavenger receptor activity in glomerular epithelial cells. CONCLUSION: The receptor-specific uptake of diabetic VLDL and LDL by glomerular epithelial cells is impaired. Compositional changes of the LDL particle and glycation of the protein moiety may contribute to altered glomerular uptake. However, glycation of the protein moiety may be superior to compositional changes. Because glomerular structures like mesangial matrix and endothelial cells are known for preferential binding of modified lipoproteins, further studies are required to elucidate their potential role in the progression of diabetic glomerulosclerosis.     

Dermatoglyphics in type 1 diabetes mellitus

Although fingerprints and handprints are widely used in criminology, it is only recently that this approach has been applied to the field of medical and genetic diagnoses. In order to investigate dermatoglyphics in Type 1 diabetes mellitus, quantitative characteristics of fingers and palms (ridge count and main line indices) as well as qualitative parameters such as digital and interdigital patterns, the position of the palmar axial triradii and main line courses were analysed in 88 male and 108 female Type 1 diabetic patients and compared with data from 100 male and 99 female normal controls. Type 1 diabetic patients show a lower third finger ridge count (p < 0.05) and a-b ridge count (p < 0.001) and higher transversality of the main lines as indicated by the main line index value (p < 0.001) or the ending of the main line A in a specific sector 5, 5', and 5" (p < 0.001) compared with controls. In addition, diabetic patients show higher frequency of palmar axial t' and t" triradii (p < 0.001) and a lower frequency of 'true' patterns in the fourth interdigital and thenar area (p < 0.001) than controls. By multivariate analysis of quantitative and qualitative variables a predictive value of 78.6% and 77.3%, respectively, for male, and 81.4% and 82.2%, respectively, for female Type 1 diabetic patients was found. In conclusion, dermatoglyphics seem to be an interesting tool for genetic studies related to Type 1 diabetes.     

Enalapril versus bendroflumethiazide in type 2 diabetes complicated by hypertension

In a double-blind, double-dummy, randomized, multi-centre study, the effects of bendroflumethiazide vs. enalapril on blood pressure, glycaemic control, lipoprotein concentrations and albuminuria were compared in non-proteinuric, hypertensive type 2 diabetic patients; they were treated for 20 weeks with either bendroflumethiazide 2.5-5.0 mg (n = 59) or enalapril 10-20 mg (n = 55). Age, fasting plasma glucose, HbA1c and BMI were similar in the groups. Systolic and diastolic blood pressure were reduced in both groups. Bendroflumethiazide was accompanied by minor but significant elevations in fasting plasma glucose and serum C-peptide. HbA1c was increased during both treatments. Lipoproteins and urinary albumin/creatinine ratio were stable. Bendroflumethiazide caused a decrease in serum potassium and an increase in serum urate. No significant correlations were observed between the decline in blood pressure and changes in the metabolic risk factors. Baseline levels of age, sex, BMI, blood pressure or urinary albumin/creatinine ratio were not related to changes in blood pressure, metabolic parameters or urinary albumin/creatinine ratio.     

Improvement of lipid profile in type 2 (non-insulin-dependent) diabetes mellitus by insulin-like growth factor I

Type 2 (non-insulin-dependent) diabetes mellitus is associated with increased glucose, insulin, total and VLDL-triglyceride, and often total and LDL-cholesterol levels which promote vascular disease. Recombinant human insulin-like growth factor-I which mimics many effects of insulin, decreased insulin, total and VLDL-triglyceride, and total and LDL-cholesterol levels in healthy man as well as glucose and insulin levels in Type 2 diabetic patients. We, therefore, investigated total and fractionated triglyceride and cholesterol levels, lipoprotein(a), non-esterified fatty acid, and apolipoprotein levels in eight Type 2 diabetic patients during five control, five treatment, and three wash-out days. They received a constant diet throughout and daily 2 x 120 micrograms insulin-like growth factor-I/kg s.c. during the treatment period. Fasting total and VLDL-triglyceride, total and LDL-cholesterol control levels were (mean +/- SD) 3.1 +/- 2.6, 1.3 +/- 1.0, 6.3 +/- 1.3, and 4.5 +/- 1.1 mmol/l and decreased to 1.6 +/- 0.8, 0.6 +/- 0.4, 5.0 +/- 1.0, and 3.5 +/- 1.1 mmol/l, respectively, on the last treatment day (p < 0.01). During therapy, fasting lipoprotein(a) levels and the postprandial area under the triglyceride curve decreased by 48 +/- 22 and 32 +/- 18% of control (p < 0.01), respectively. In conclusion, insulin-like growth factor-I lowered lipid levels in Type 2 diabetic patients directly or indirectly or both because of decreased glucose and insulin levels. Long-term trials would be of interest with respect to the cardiovascular risk in Type 2 diabetes and patients with hyperlipidaemia.     

Deficiency of maternal recognition of fetal-placental antigens in pregnancy complicated by idiopathic growth retardation

We employed the leucocyte-migration inhibition assay to assess reactivity of cells from post-partum women to self placental antigens (SPA) and the presence of the migration inhibition blocking factor in the sera of these women. We also used complement dependent microcytotoxicity assay according to Terasaki to detect anti-fetal lymphocyte cytotoxic antibodies (AFCA) in these sera. Our study was performed in the group of 13 mothers of hypotrophic children and in the group of 14 mothers of eutrophic children. In none of the cases of both groups were AFCA detected. Using the migration inhibition assay we concluded that the deficiency of the response to ASPA occurs significantly more often in the "hypotrophic" than in the "eutrophic" mothers. Our study suggests: 1. lack of the maternal recognition of the fetus (lack of migration inhibition, or lack of the blocking factors) as the potential cause of the intrauterine growth retardation, 2. intrauterine growth retardation is not connected with the presence of AFCA in maternal serum.     

The genetics of human noninsulin-dependent (type 2) diabetes mellitus

Familial aggregation and concordance in monozygotic and dizygotic twins argue strongly for a genetic etiology to noninsulin-dependent diabetes (NIDDM). Nonetheless, studies of pathways implicated by the known physiology have failed to identify gene defects that can explain the genetic susceptibility. In contrast, studies of early onset dominant diabetes have revealed three major loci resulting in diminished insulin secretion. Recently, studies have taken a new approach to map the genes causing typical NIDDM using large numbers of families or sibling pairs. The first reports of these studies have suggested possible loci on chromosomes 1, 2 and 12, but no report has been confirmed. Other studies have examined the quantitative defects that may be precursors of clinical NIDDM such as hyperinsulinemia, hyperglycemia, insulin response to glucose and obesity. These studies have suggested additional loci that may contribute to NIDDM susceptibility, but the genes responsible for most of these loci remain unknown. Studies of NIDDM susceptibility and the role of obesity genes in that susceptibility have entered an exciting new phase, but the challenges of complex disease genetics in humans will have to be conquered to translate this research into preventive or therapeutic benefits.     

Women with insulin-dependent diabetes mellitus (IDDM) complicated by eating disorders are at risk for exacerbated alterations in lipid metabolism

OBJECTIVE: To examine lipid parameters that are affected in women with insulin-dependent diabetes mellitus (IDDM) who engaged in disordered eating behaviours. DESIGN: Randomized, unmatched. SETTING: Tertiary care. SUBJECTS: Ninety women (18-46 y) with IDDM. INTERVENTIONS: Classification of subjects based on severity of eating disorder: clinical (n = 14), subclinical (n = 13) and control (n = 63). Blood was analysed for glycosylated haemoglobin (HbA1c) and serum for triglycerides and cholesterol. Carotenoid and tocopherol concentrations were analysed by high performance liquid chromatography (HPLC). Dietary intake was assessed by the National Cancer Institute food frequency questionnaire. RESULTS: HbA1c was significantly increased im women demonstrating clinical and subclinical symptoms compared to control (10.4 +/- 2.6, 10.0 +/- 1.5 and 8.3 +/- 1.6%, respectively, P < 0.05). Triglycerides concentrations were significantly increased in women with subclinical eating disorders compared to controls. In women who intentionally omitted or reduced insulin, triglyceride cholesterol and HbA1c were significantly increased compared to controls. Women with IDDM and eating disorders who exhibited bulimic behaviours consumed significantly more energy, total fat and cholesterol compared to controls and women with eating disorders who were restrained eaters. CONCLUSION: While IDDM is known to perturb lipid metabolism, these data demonstrate that eating disorders, in combination with IDDM, results in additional alterations in lipid metabolism.     

Antihypertensive therapy in type 2 diabetes mellitus

Fifty-seven patients with failed sclerotherapy received a mesocaval interposition shunt with an externally supported, ringed polytetrafluoroethylene prosthesis of either 10 or 12 mm diameter. Thirty-one patients had Child-Pugh grade A disease and 26 grade B; all had a liver volume of 1000-2500 ml. Follow-up ranged from 16 months to 6 years 3 months. Three patients (5 per cent) died in the postoperative period. There were two postoperative recurrences of variceal haemorrhage and one recurrent bleed in the second year after surgery. The cumulative shunt patency rate was 95 per cent and the incidence of encephalopathy 9 per cent; the latter was successfully managed by protein restriction and/or lactulose therapy. The actuarial survival rate for the whole group at 6 years was 78 per cent, for those with Child-Pugh grade A 88 per cent and for grade B 67 per cent. Small-lumen mesocaval interposition shunting achieves portal decompression, preserves hepatopetal flow, has a low incidence of shunt thrombosis, prevents recurrent variceal bleeding and is not associated with significant postoperative encephalopathy.     

Rapid distal small bowel transit associated with sympathetic denervation in type I diabetes mellitus

BACKGROUND: The pattern of progression of a meal from the stomach to the caecum in diabetes mellitus is controversial and the differential roles of transit through the jejunum and the ileum have not been investigated in diabetes. AIMS: To determine gastric emptying and transit rates through proximal and distal regions of the small bowel in type I diabetic patients. SUBJECTS: The study included six diabetic patients with evidence of autonomic neuropathy (DM-AN group), 11 diabetics without autonomic dysfunction (DM group), and 15 control volunteers. METHODS: Gastric emptying and small bowel transit of a liquid meal were evaluated scintigraphically in these subjects. Transit through regions of interest corresponding to the proximal and distal small intestine up to the caecum was determined and correlated with gastric emptying rates, cardiovascular measurements of autonomic function, and the occurrence of diarrhoea. RESULTS: Gastric emptying and transit through the proximal small bowel were similar in the three groups. The meal arrived to the caecum significantly earlier in DM-AN patients (median; range: 55 min; 22-->180 min) than in the DM group (100 min; 44-->180 min, p < 0.05) or in controls (120 min; 80-->180 min, p < 0.02). Accumulation of chyme in the distal small bowel was decreased in DM-AN patients, who showed values for peak activity (30%; 10-55%) significantly lower than in the DM group (49%; 25-77%, p = 0.02) and controls (50%; 30-81%, p = 0.02). In DM patients (n = 17), the time of meal arrival to the caecum was significantly correlated with both orthostatic hypotension (coefficient of contingency, C = 0.53, p < 0.01) and diarrhoea (C = 0.47, p < 0.05), but not with gastric emptying rates. CONCLUSIONS: Patients with type I diabetes mellitus and sympathetic denervation have abnormally rapid transit of a liquid meal through the distal small bowel, which may play a part in diarrhoea production.