R. Navalesi

relation of Glucose Tolerance to Complications of Pregnancy in Nondiabetic Women

Abstract An increase in fetal and maternal complications has been documented in cases of gestational diabetes, but the glucose levels that predict an increased risk have not been clearly defined. We evaluated the frequency of several neonatal complications (macrosomia, congenital anomalies, perinatal mortality, and prematurity) and maternal complications (toxemia, cesarean section, or both) in relation to glucose tolerance in 249 women in the third trimester of pregnancy. None of the women had previous evidence of diabetes, and all had normal results on an oral glucose-tolerance test, according to accepted criteria. On the basis of their two-hour plasma glucose levels, women were divided into three groups: A (glucose <100 mg per deciliter), B (glucose 100 to 119 mg per deciliter), and C (glucose 120 to 164 mg per deciliter). The higher two-hour plasma glucose levels were associated with a significant increase in the incidence of macrosomia (9.9, 15.5, and 27.5 percent in Groups A, B, and C, respectively),...

COAGULATION AND FIBRINOLYTIC SYSTEM IMPAIRMENT IN INSULIN DEPENDENT DIABETES MELLITUS

Selected coagulation and fibrinolytic parameters were assessed in 40 insulin dependent diabetes mellitus patients with varying degrees of metabolic control; 30 healthy subjects matched for age and sex formed the control group. Activated Partial Thromboplastin Time, Prothrombin Time, Fibrinogen, Factor VII, Antithrombin III, Protein C, Plasminogen, alpha 2-Plasmin Inhibitor, Plasminogen Activator Inhibitor-1, tissue-Plasminogen Activator were functionally evaluated. Antigenic levels of tissue-Plasminogen Activator, Thrombin-Antithrombin complexes and fibrinolytic specific product B beta 15-42 were also determined. Compared to the control group diabetic patients displayed significantly higher levels of Fibrinogen (p < 0.01), Factor VII (p < 0.01), Thrombin-Antithrombin complexes (p < 0.01) and Plasminogen Activator Inhibitor-1 activity (p < 0.01). Regardless of the normal level of the tissue-Plasminogen Activator-related antigen, diabetic patients had tissue-Plasminogen Activator activity lower than the control group (p < 0.05). Coagulation Factor VII and Thrombin-Antithrombin complexes were increased only in the patients with poor metabolic control (p < 0.01). Activated Partial Thromboplastin Time, Prothrombin Time, Antithrombin III, Protein C, Plasminogen, alpha 2-Plasmin Inhibitor, B beta 15-42 fibrin peptide were found to be in the normal range. Fibrinogen correlated positively with fasting blood glucose (p < 0.05) and Thrombin-Antithrombin complexes with glycosylated haemoglobin (p < 0.05), whereas Factor VII was positively correlated with glycemia (p < 0.01) and glycosylated haemoglobin (p < 0.05). Higher levels of Fibrinogen were found in patients affected by nephropathy (p < 0.005) or neuropathy (p < 0.05). These results demonstrate an impairment of the haemostatic balance in diabetic patients, that is a possible hypercoagulable state, which represents an important factor in the pathogenesis of atherosclerotic complications.

Conservative surgical approach versus non-surgical management for diabetic neuropathic foot ulcers: a randomized trial

To test the efficacy of surgical treatment of non‐infected neuropathic foot ulcers compared to conventional non‐surgical management, a group of diabetic outpatients attending our diabetic foot clinic were studied. All patients who came to the clinic for the first time from January to December 1995 inclusive with an uncomplicated neuropathic ulcer were randomized into two groups. Group A received conservative treatment, consisting of relief of weight‐bearing, regular dressings; group B underwent surgical excision, eventual debridement or removal of bone segments underlying the lesion and surgical closure. Healing rate, healing time, prevalence of infection, relapse during a 6‐month period following intervention and subjective discomfort were assessed. Twenty‐four ulcers in 21 patients were treated in group A (17 Type 2 DM/3 Type 1 DM, age 63.24 ± 13.46 yr, duration of diabetes 18.2 ± 8.41 yr, HbA1c 9.5 ± 3.8%) and 22 ulcers in 21 patients in group B (19 Type 2 DM/2 Type 1 DM, age 65.53 ± 9.87 yr, duration of diabetes 16.84 ± 10.61 yr; HbA1c 8.9 ± 2.2%). Healing rate was lower (79.2% = 19/24 ulcers) in group A than in group B (95.5% = 21/22 ulcers; p < 0.05), and healing time was longer (128.9 ± 86.60 days vs 46.73 ± 38.94 days; p < 0.001). Infective complications occurred significantly more often in group A patients (3/24, 12.5% vs 1/22, 4.5%; p < 0.05), as did relapses of ulcerations (8 vs 3; p < 0.01). There were only two minor perioperative complications in group B patients. Patients reported a higher degree of satisfaction in group B (p < 0.01) as well as lower discomfort (p < 0.05) and restrictions (p < 0.05). Thus surgical treatment of neuropathic foot ulcers in diabetic patients proved to be an effective approach compared to conventional treatment in terms of healing time, complications, and relapses, and can be safely performed in an outpatient setting.

Increased Transcapillary Escape Rate of Albumin in Microalbuminuric Type II Diabetic Patients

OBJECTIVE To evaluate microvascular permeability by the transcapillary escape rate of albumin (TERalb) in type II diabetic patients with normo- and microalbuminuria. RESEARCH DESIGN AND METHODS The TERalb has been measured following intravenous injection of 125I-labeled human serum albumin in 32 normotensive type II diabetic patients and 9 healthy control subjects matched for sex and age. Type II diabetic subjects were grouped in normoalbuminuric, albumin excretion rate (AER) <20 μg/min (n = 18), and microalbuminuric, AER 20-200 μg/min (n = 14) categories. RESULTS In type II diabetic patients, no differences were noted between normo- and microalbuminuric groups for known diabetes duration (8.3 ± 5.9 vs. 11.7 ± 8.0 years), blood pressure (BP) (129/76 ± 16/8 vs. 131/76 ± 14/5 mmHg), current metabolic control (HbA1c: 8.0 ± 1.4 vs. 8.5 ± 1.6%), and serum lipids. However, previous 2-year mean HbA1c levels were significantly higher in microalbuminuric patients (8.7 ± 1.45 vs. 7.6 ± 1.29%; P < 0.05). The TERalb was similar in control subjects and normoalbuminuric patients (5.16 ± 1.09 vs. 5.71 ± 1.66 %/h) and significantly higher in the microalbuminuric group (8.98 ± 1.35 %/h; P < 0.0001). The increased leak of albumin was not explained by differences in diabetes duration, BP, or metabolic control at the time of investigation and was independently related to the presence of microalbuminuria (r = 0.63, percent explained variance ∼40) and mean “historical” HbA1c (multiple r = 0.705; total explained variance ∼50%). CONCLUSIONS Type II diabetic patients with microalbuminuria show an increased TERalb, i.e., a widespread microvascular damage that may be important in the pathogenesis of long-term complications. Our findings may contribute to the explanation of why albuminuria seems to be an independent cardiovascular risk factor in type II diabetes.

Pharmacokinetic-pharmacodynamic relationships of oral hypoglycaemic agents. An update

SummaryOral hypoglycaemic drugs, sulphonylureas and biguanides, occupy an important place in the treatment of Type II (non-insulin-dependent) diabetic patients who fail to respond satisfactorily to diet therapy and physical exercise. Although the precise mechanisms of action of these compounds are still poorly understood, there is sufficient agreement that sulphonylureas have both pancreatic and extrapancreatic effects, whereas biguanides have predominantly extrapancreatic actions. By using labelled compounds or measuring the circulating concentrations, the main pharmacokinetic properties of oral hypoglycaemic agents have been assessed and, in some cases, their pharmacokinetic-pharmacodynamic relationships have been evaluated. A correlation between diabetes control and plasma sulphonylurea or biguanide concentrations is generally lacking at the steady-state, with the possible exception of long-acting agents; after either oral or intravenous dosing, the reduction of plasma glucose is usually related to the increased circulating drug concentrations. The toxic effects of oral hypoglycaemic drugs are more frequent in the elderly and in the presence of conditions that may lead to drug accumulation or potentiation (increased dosage, use of long-acting compounds, hepatic and renal disease, interaction with other drugs); however, a relationship between toxic effects and drug plasma levels has been reported only for biguanides.

Kinetic Analysis of Plasma Insulin Disappearance in Nonketotic Diabetic Patients and in Normal Subjects: A TRACER STUDY WITH 125I-INSULIN

The studies so far reported on the metabolic clearance rate of insulin in human diabetes mellitus have given conflicting results, probably because they have been conducted on few patients and have used a variety of experimental techniques and data treatments. We investigated the kinetics of insulin distribution and degradation in 35 normal subjects and in 42 nonketotic, nonobese, overtly diabetic patients, of whom 26 were above 40 yr old and 16 were 40 yr old or less at diagnosis. The design of the study combined (a) the use of a tracer to perturb minimally the steady state and to avoid glucose infusion; (b) the preparation of purified [(125)I]-monoiodoinsulin, which has a metabolic behavior similar to that of native insulin; and (c) noncompartmental analysis of the plasma immunoprecipitable (125)I-insulin disappearance curves, which were recorded for 2 h after pulse i.v. injection of the tracer.Metabolic clearance rate was found to be similar in diabetics (404+/-18 ml/min.m(2), mean+/-SEM) and in normals (420+/-14), although the latter-onset patients had slightly, if not significantly, lower metabolic clearance rate values than the earlier-onset diabetics (385+/-19 and 443+/-36, respectively). The initial distribution volume of the hormone also did not significantly differ in diabetics and normals and was similar to plasma volume. The reentry rate into the initial distribution volume of the hormone and the total, plasma-equivalent distribution volume of insulin were both significantly raised in diabetics (251+/-12 ml/min.m(2) and 10.3+/-0.5 liters/m(2)) in comparison with normals (195+/-8 and 7.5+/-0.3). The posthepatic delivery rate of insulin was found to be slightly raised in later-onset diabetics (194+/-20 mU/h.m(2)), but somewhat reduced in earlier-onset diabetics (133+/-15) in comparison with normals (172+/-14); these differences reflected the different basal plasma insulin concentrations in these three groups. Chronic treatment with oral hypoglycemic drugs, age, duration of the disease, and degree of metabolic control appeared to have only little effect on the kinetics of insulin.On the basis of these results, we conclude that insulin-independent adult diabetics show, already in the fasting state, a combination of insulin resistance and insulin deficiency and a derangement in insulin distribution, the precise significance of which is uncertain.

Obesity modulates the expression of haptoglobin in the white adipose tissue via TNFα

Increase in adipose mass results in obesity and modulation of several factors in white adipose tissue (WAT). Two important examples are tumor necrosis factor α (TNFα) and leptin, both of which are upregulated in adipose tissue in obesity. In order to isolate genes differentially expressed in the WAT of genetically obese db/db mice compared to their lean littermates, we performed RNA fingerprinting and identified haptoglobin (Hp), which is significantly upregulated in the obese animals. Hp is a glycoprotein induced by a number of cytokines, LPS (Lipopolysaccharide), and more generally by inflammation. A significant upregulation of WAT Hp expression was also evident in several experimental obese models including the yellow agouti (/) Ay, ob/ob and goldthioglucose‐treated mice (10‐, 8‐, and 7‐fold, respectively). To identify the potential signals for an increase in Hp expression in obesity, we examined leptin and TNFα in vivo. Wild type animals treated with recombinant leptin did not show any alteration in WAT Hp expression compared to controls that were food restricted to the level of intake of the treated animals. On the other hand, Hp expression was induced in mice transgenically expressing TNFα in adipose tissue. Finally, a significant downregulation of WAT Hp mRNA was observed in ob/ob mice deficient in TNFα function, when compared to the ob/ob controls. These results demonstrate that haptoglobin expression in WAT is increased in obesity in rodents and TNFα is an important signal for this regulation. J. Cell. Physiol. 190: 251–258, 2002.

Sodium carboxyl-methyl-cellulose dressings in the management of deep ulcerations of diabetic foot.

SUMMARY

The metabolic effects of cyclosporin and tacrolimus

The introduction of cyclosporin and, more recently, tacrolimus in the immunosuppression of transplanted patients has lead to prolonged graft survival and increased patients’ life expectancy. It has been therefore possible to evaluate the effects of long-term treatment with these drugs and metabolic alterations in patients on cyclosporin or tacrolimus have been reported by several authors. In particular, the use of these drugs is associated with abnormalities of glucose and lipid metabolism. Post-transplant diabetes is more common with tacrolimus, probably due to more marked effects on the pancreatic beta-cells, whereas increased levels of cholesterol and triglycerides are more frequently associated with cyclosporin treatment, even though, in this latter case, steroid treatment seems to play a major role. Comparison and intervention studies must be planned to evaluate the best therapeutical approaches to control these abnormalities and to assess the possibility to further increase graft and patient survival by appropriate treatment of diabetes and hyperlipidemia.

Compound Heterozygosity for a Structural Apolipoprotein A-I Variant, Apo A-I(L141R)Pisa, and an Apolipoprotein A-I Null Allele in Patients With Absence of HDL Cholesterol, Corneal Opacifications, and Coronary Heart Disease

BACKGROUND The concentration of HDL cholesterol is inversely correlated with the risk of coronary heart disease (CHD). Some rare mutations in the apolipoprotein (apo) A-I gene are associated with low levels of HDL cholesterol. Their association with cardiovascular risk is controversial. METHODS AND RESULTS We studied the molecular defects underlying corneal opacities and absence of HDL cholesterol in three brothers and a sister. In a family study, the importance of these defects for lipid metabolism and manifestation of coronary heart disease was investigated. The frequency of these apo A-I defects was assessed by genotype and phenotype analysis of 477 DNA- and plasma samples, respectively, from the population. The four patients were compound heterozygotes for a null allele and a missense mutation in the apo A-I gene that leads to a leucine-->arginine substitution at residue 141 [apo A-I(L141R)Pisa]. Heterozygotes for either the null allele or the structural variant had half-normal concentrations of HDL cholesterol and apo A-I compared with unaffected family members. Apo A-I(L141R)Pisa was detected in one more unrelated subject. Coronary angiography of the four compound heterozygotes revealed the presence of CHD in all male patients, whose ages ranged between 45 and 52 years. They presented with additional risk factors, including elevated LDL cholesterol levels, obesity, and arterial hypertension. Despite complete HDL deficiency and hypercholesterolemia, CHD was absent in the 51-year-old premenopausal sister. CONCLUSIONS Apo A-I deficiency may lead to premature atherosclerosis if present in conjunction with additional cardiovascular risk factors.