Safety and efficacy of insulin lispro in patients with diabetes mellitus.

Lispro is a human insulin analogue with a very rapid onset of action, and a shorter duration of activity than soluble insulin. In order to assess the therapeutical value of lispro, we have had an open-label, non-comparative study, for 12 weeks, involving 19 IDDM patients. The treatment regimen with lispro and Humulin N has been adapted depending on each patient characteristics. Patients attended three visits, and the main metabolic control parameters included values of hemoglobin Alc, fasting and postprandial blood glucose monitoring. The patients themselves monitored their blood glucose using a glucometer. The mean age value of 19 patients (8 females and 11 males) was 22.32 (+/- 13.59) years. In patients previously receiving insulin treatment, therapy with lispro insulin significantly reduced postprandial glucose values. Lispro has been administered t.i.d. in 14 patients, and b.i.d. in 5 patients. At visit 1, mean value of HbAlc was 10.32% (+/- 1.63%); at visit 3, mean HbAlc was 9.90% (+/- 1.59%). Total insulin daily dose and the rate of short and long acting insulin did not change from visit 1 to visit 3. There has been reported only one serious adverse event during the study: a ketoacidosis due to a technical dosing error. Ten patients have reported mild hypoglycemic episodes. The outcomes of clinical study and of Quality of Life Questionnaire suggests that lispro--the first human insulin analogue used in humans--is effective, safe, and it is broadening beneficially the spectrum of insulins.

Early cystinuria, a risk factor for metabolic urolithiasis.

The levels of urinary amino acids (cystine, amino acids with basic character, branched chain amino acids and phenylalanine) were determined in the 24 hr urines of 5,500 newborns and in 20 subjects ranging in age from 2.5 to 20 years, with a suspicion of metabolic diseases. Seven newborns have shown a biochemical pattern of cystinuria. The urinary cystine levels in the first days of life appeared to correlate with an increased risk of developing, at the adult age, metabolic mono- or bilateral urolithiasis.

The relationship between the urinary level of some amino acids and the occurrence of metabolic diseases associated with psychic disorders.

Assays of the branched chain amino acids, of those with basic character, of phenylalanine and glutamic acid were performed in the 24 hrs urines of 50 patients with psychic disorders, ranging in age from 0 to 20 years, and in 30 normal controls. Similar investigations were carried out in the patients' parents. Abnormal levels of urinary amino acids in some of the adults suggested the existence of mutant genes in one or both parents of one or two descendents with mental handicap. The levels of urinary amino acids correlated with the severity of the predominant psychic manifestations, which were more severe in the cases with a wide deviation from normal of aminoaciduria.

Epidemiology of diabetes in Bucharest.

An analysis of the last 20,000 newly diagnosed diabetic patients consecutively registered from 1 January 1981 to 6 June 1991 in the Bucharest Registry of Diabetes showed the following: (1) primary insulin-dependence (Type 1 diabetes) was encountered in only 7% of cases: the rest were Type 2 diabetic patients (8745:43.7% treated with diet alone and 9856:49.3% treated with diet and oral drugs); (2) low body weight (BMI < 25) was encountered in 81.7% of patients in the age group 0-20 years, while obesity (BMI > 27) was encountered in 75.7% of cases in the age group 41-65 years; (3) the overall annual incidence of the Type 1 diabetes for all ages was 5.7/100,000, lowest (1.3/100,000) in the age group 0-4 years and the highest 10.1/100,000) in the age group 65-69 years; (4) the overall annual incidence for the Type 2 diabetes was 76.3/100,000, the lowest (2.4/100,000) in the age group 20-24 years and the highest (261.4/100,000) in the age group 60-64 years. Studying the relationship between the onset of Type 1 diabetes mellitus and age, we did not observe the previously reported strong relationship, so that the distribution of Type 1 diabetes can be considered relatively uniform, with the exception of extreme ages. In conclusion, each year, about 1 in 1000 inhabitants of Bucharest are registered as having diabetes, the majority (93%) had type 2 and only 7% had Type 1 diabetes, one of the lowest incidence rates in Europe.

The hair levels of unsaturated fatty acids (oleic, linoleic, and linolenic) indicators of the lipid metabolic balance.

The lipid metabolism was evaluated using a new method for assay of the hair contents in unsaturated fatty acids. Determinations in various hair segments and in the blood serum were performed before and after a hypolipemic diet and drug therapy in hypercholesterolemic patients in comparison with a control group. The correlation factors between the levels of the oleic, linoleic and linolenic acids in the serum and those in the hair were +0.967, +0.987 and +0.992, respectively. The method provides information on the therapy influence on the lipid metabolism variations within several weeks or months.

Clinical consequences of disorders in the intermediate metabolism of branched chain amino acids (valine, leucine and isoleucine).

Assays of the amino acid levels in 5,888 newborns and 20 subjects ranging in age from 1 to 20 years, suspected of metabolic diseases, revealed a case of "maple syrup urine disease" caused by disorders in the intermediate metabolism of valine, whose serum and urinary concentrations were followed up from the first days of life. This patient also showed frequent episodes of hypoglycemia. An early treatment with polyvitamins, minerals and trace elements for 18 months resulted in the partial reactivation of the deficient enzymatic systems and the return to normal of the serum and urinary valine and glucose values. Administration of the same treatment to patients over one year of age, showing clinical and biochemical data characteristic to the same disease, was much less effective, thus supporting the conclusion that the vitamins and minerals could be useful in the "maple syrup urine disease" only if they were administered immediately after the disease onset. The correlation index between the serum and urinary valine levels before and after therapy was +0.976 and +0.994, respectively.

Insulin resistance: the link between impaired glucose tolerance, body mass index and plasma lipids.

Body mass index defined as weight (Kg)/height (cm2) and plasma lipids (total lipids-TL, triglycerides-TG and cholesterol-CH) were determined in 131 patients (61 males and 70 females aged between 21 and 63 years) with impaired glucose tolerance (IGT) defined according to WHO criteria. Blood glucose (BG) values and plasma insulin (PI) levels (radioimmunological assay) were determined during 2 hours OGTT with samples obtained before and after 1 h and 2 h after the intake of 75 g glucose. The sum of blood glucose and plasma insulin levels (0 + 1h + 2h) were compared in each of the following 5 groups of subjects: A--25 cases with IGT but without obesity (BMI: 23.2 +/- 2.6) and hyperlipidaemia (PL: 627 +/- 112; TG: 102 +/- 109 and CH: 208 +/- 35 mg/dl); B--35 cases with IGT and obesity (BMI: 31.2 +/- 2.6) but without hyperlipidaemia (PL: 807 +/- 109; TG: 136 +/- 31 and CH: 254 +/- 41 mg/dl); C--23 cases with IGT and hyperlipidaemia (PL: 1013 +/- 217; TG: 214 +/- 85 and CH: 311 +/- 52 mg/dl) but without obesity (BMI: 25.4 +/- 1.9); D--48 cases with IGT and both obesity (BMI: 30.9 +/- 2.8) and hyperlipidaemia (PL: 1457 +/- 155; TG: 597 +/- 188 and CH: 483 +/- 184 mg/dl); a control group of 49 cases without IGT, obesity (BMI: 26.2 +/- 1.9) or hyperlipidaemia (PL: 726 +/- 99 mg/dl).(ABSTRACT TRUNCATED AT 250 WORDS)

Risk factors and risk determinants for the evolution of the diabetic nephropathy in IDDM: a case control study of 108 IDDM patients in the Bucharest Center of Diabetes.

The study included 108 IDDM patients (59 males, 49 females, aged 15-59 years) from the Bucharest Diabetic Centre which participated in the EURODIAB multicentric study. They were divided into three groups according to the duration of diabetes (less than 7 years; 8 to 14 years; more than 15 years) and we have made a comparison between the importance of some risk factors, as elevated blood pressures, age, elevated levels of the total plasma cholesterol, and glycosylated hemoglobin (HbA1C) on the progression of the microalbuminuria in these groups. Excluding the patients in the renal failure stage of the diabetic nephropathy or with other chronic diseases, our results confirm the data in the literature referring to the important role of the elevated diastolic blood pressure and elevated levels of the total plasma cholesterol in the rapid progression of the renal injury, especially after more than 8 years of IDDM evolution. We also found, between the long-term diabetics (over 15 years of evolution) a large proportion which appears to be genetically protected against the diabetic nephropathy. This point confirms some data from the literature (the Steno hypothesis). The HbA1C levels appears to lower with the duration of the diabetes and they are not correlated with the degree of the renal injury. These findings appear to be in contradiction with the data from the literature.

Impaired glucose tolerance in the third trimester of pregnancy: associated factors to its persistence postpartum.

Glucose tolerance (75 g OGTT, according WHO) during the third trimester of pregnancy, in 302 women, has formerly been evaluated. Of these, 37 women were reinvestigated, with the same methodology, in absence of pregnancy and lactation, 2 years postpartum. According to oral glucose tolerance three groups were differentiated: group A (n = 14) with normal glucose tolerance (NGT) both in pregnancy and postpartum. Group B1 (n = 12) with impaired glucose tolerance (IGT) in pregnancy but NGT postpartum. Group B2 (n = 11) with IGT both in pregnancy and postpartum. B2 group had increased values (mean + SD) for age (37.0 +/- 6.6 years) versus B1 (30.2 +/- 5.5; p < 0.02) and A (29.5 +/- 5.9); p < 0.02) groups and BMI (32.5 +/- 4.2) versus 26.4 +/- 5.2; p < 0.01 and 23.3 +/- 4.4; p < 0.001 respectively). The ratio between basal insulinogenic indexes (microU IRI/mg BG) during pregnancy and 2 years postpartum has been significantly reduced in B1 (1.4 +/- 0.8) and B2 (1.5 +/- 0.6) as compared to A (2.5 +/- 1.1; p < 0.01) group suggesting, by comparison, the persistence of an increased level of insulin resistance postpartum in B1 and B2 groups. Insulinogenic index, after oral glucose was lower in B2 (34.4 +/- +/- 7.8) versus B1 (53.5 +/- 20.9; p < 0.01) group. These results suggest that, on an increased insulin resistance background, the decrease in glucose induced insulin response and increase in age and BMI are associated to deterioration of glucose tolerance early in the natural history of NIDDM.

Predictive value of glucose and proteic sulphur levels in the hair for an early detection of the preclinical stage of IDDM.

Assays of glucose and proteic sulphur levels in the hair of patients with recently detected IDDM provided information on the preclinical stage of insulin secretion disorders, which was estimated at 6 +/- 2 months. Such investigations in subjects at high risk of developing an IDDM might reveal the period preceding the disease onset, thus enabling to start an early therapy.

Fear of hypoglycemia in type 1 (insulin-dependent) diabetic patients.

A clinical-psychological study was carried out in 224 insulin-dependent diabetic patients, distributed into two groups according to the frequency of hypoglycemic episodes. Group. A included 124 patients, 65 men and 59 women (mean age 35 +/- 18 years), who reported frequent episodes of hypoglycemia (HG). In the 100 patients of group B (46 men and 54 women with a mean age of 37 +/- 10 years), the HG episodes were only occasional. The degree and type of anxiety were evaluated using: (1) a semistructured interview to determine the HG frequency and intensity; (2) the anxiety scale for HG, with two sections: a) 15 items about the behaviour to prevent HG occurrence and b) 10 items for the anxiety level; (3) the questionnaire of anxiety with 40 items. Highly significant differences between groups were found for the degree of anxiety about HG, particularly for the frequency of high anxiety scores (with ideative ruminations or generalized anxiety, accompanied or not by agoraphobia) (73.86% in group A versus 34.09% in group B; p < 0.001). Relatively significant differences were recorded with respect to the compliance to treatment (preventive behaviour for HG) as well as for the anxiety index (47.95% in group A versus 33.45% in group B), with a prevalence of the covered anxiety in group A and of the overt anxiety scores, indicating a dissimilation tendency of the adaptative role of anxiety as a signal of communication.

Diabetic gangrene: medical and surgical causes and consequences.

Diabetic gangrene is the chronic complication which involves many medical, economic and social problems. In this study we have analyzed the medical and surgical causes and consequences of diabetic gangrene on three groups of patients: 120 patients (96 males and 24 females; aged (X +/- SD) 57 +/- 14 years hospitalised in the Clinic of Diabetes, Nutrition and Metabolic Diseases of the "N. Paulescu" Institute, 72 patients (59 males and 13 females; mean age 60 +/- 10 years) hospitalised in the Surgical Clinic of Cantacuzino Hospital; 29 patients (23 males and 6 females; mean age 58 +/- 11 years) hospitalised in the Cardiovascular Department of Fundeni Hospital. The analyses of data obtained showed: in 77% of cases the initial lesions might have been avoided by an appropriate education programme of the patients; in 66% of cases the progression of lesion from medical to surgical stage was caused by tardily coming of patient to physician; average duration of hospitalization was 27 days in the Clinic of Diabetes, Nutrition and Metabolic Diseases, 33 days in the Clinic of Surgery of "Cantacuzino" Hospital and 25 days in Cardiovascular Department of Fundeni Hospital; the surgical mortality was 8%; 47% operated patients were cured and 53% were incompletely cured and required more out patient care; 35% were thigh amputations, that shows the high invalidity potential of diabetic gangrene; the cost of medical and/or surgical care of diabetic gangrene is higher than the cost of hospitalisation for other patients; the diabetic gangrene predominantly neuropathic was better cured and the arteriopathic component breaks the medical curing and impose high amputations; diabetic gangrene is more frequent with older people, but with young people it is a cause of early retiring and psycho-social concern.

The relationship between aminoaciduria and plasma hemoglobin levels.

Investigations in newborns, children and young adults have revealed an inverse proportion between aminoaciduria and plasma hemoglobin (Hb) levels. Values above normal were recorded for alanine, leucine, valine, phenylalanine and glutamic acid, correlating proportionally with their increased blood levels, and preceding or being concomitant with the decrease of plasma Hb, both during the first 20 months of life and in young adults. The return to near normal values of aminoaciduria occurred generally only after an early treatment with minerals, vitamins and trace elements (Supradyn), activators of the enzymes involved in the amino acid metabolism. After treatment, the Hb levels also became almost normal. An early re-equilibration of the amino acid metabolism can prevent the risk of developing, at the adult age, certain anemias and other diseases (rachitism, mental handicap, urinary infections, conjunctivitis, stomatitis, a.o.). The correlation factor was r = 0.964 and the differences between the data recorded in patients and in controls were statistically significant (p < 0.01).

Not only quantitative but also qualitative changes of serum immunoglobulins in diabetes mellitus.

To extend previous observations on the quantitative changes of IgA and other serum Ig in diabetics, additional immunochemical investigations were carried out in 96 patients, 63 males and 33 females, mean age 43.5 +/- 15.7 years, 51 with type 1 (insulin-dependent) and 45 with type 2 (non-insulin-dependent) diabetes. The immunological data were correlated with the clinical-metabolic aspects. In the whole group, the IgA level was increased (144.1 +/- 57.2 I.U.). Significant differences were recorded with respect to age for IgG, to age and diabetes type for IgA, to sex for IgM. Qualitative Ig changes, reflecting disturbances of molecular structure, mainly for IgG, seldom for IgM, but never for IgA, were observed in 20% of the patients with both types of diabetes, more seldom in cases with long disease duration. The IgG with qualitative changes were purified and their functional capacity of inhibiting the natural cytotoxic activity (NK) was tested in comparison with that induced by pretreatment of the effectory cells with normal IgG. Some of these modified IgG showed a reduced capacity of inhibiting the NK activity. These data confirm the existence of certain quantitative changes of the main serum Ig in diabetics and reveal the presence of qualitative disorders of the IgG molecules, with consequences on their functionality.

No relationship between insulin antibodies and hypoglycemia in insulin-treated diabetic patients.

It has been speculated that insulin antibodies may contribute to the hypoglycemic attacks in insulin-treated diabetic patients. To address this hypothesis, we analyzed in a first part of the study the frequency to hypoglycemia in two groups of diabetic patients, one (Group A, 38 cases) with at least two episodes of severe hypoglycemia in the last year and another (Group B, 38 cases) without severe hypoglycemia in the last 3 years. In the second part of this study, we analyzed the frequency of severe and moderate episodes of hypoglycemia in another two groups of diabetics, one (Group C, 32 cases) with high insulin antibody titre (greater than or equal to 20% binding, mean +/- SD 31.2 +/- 8.1%) and another with low insulin antibody titre (less than 10% binding, mean +/- SD, 5.1 +/- 2.2%). No significant difference was found for bound insulin between diabetics with frequent hypoglycemic episodes (2.3 +/- 0.2/patient/year--Group A) and those without severe hypoglycemic episodes (Group B), i.e., bound insulin 4.89 +/- 3.21% in group A versus 5.32 +/- 4.5% in group B. Conversely, the frequency of severe episodes of hypoglycemia was similar in diabetic patients with high (31.2 +/- 8% binding in group C) and respectively low (5.1 +/- 2.1% binding in group D) insulin antibody titre, i.e., 0.15 episodes/patient/year in group C and 0.17 episodes/patient/year in group D.

Cholesterol and lipid levels in the hair: indicators of the lipid metabolism balance.

A new method of long term, retrospective evaluation of the lipid metabolism balance, by cholesterol and lipid assays in the human hair, is described. The correlation index between the blood and the hair cholesterol and lipid concentrations was + 0.980 and + 0.9925, respectively. The effects of hypolipemic diet and drug therapy on the cholesterol and lipid values were studied comparatively in the blood and in successive hair segments. The results demonstrate that the new method permits an evaluation of the therapy effectiveness and of the lipid metabolism variations during several weeks or months.

Peripheral sympathetic neuropathy evaluated by recording the evoked electrodermal response using an impedance reactometer.

Autonomic nervous dysfunction was indirectly evaluated on the basis of the skin electrical resistance relative variation (SERV), recorded by our recently developed system, with two pairs of surface electrodes placed on the palm and on the sole of the foot, after the application to the subject of a sensory stimulus (sound 60 dB, 860 Hz, 0.5 s duration) or in the course of a Valsalva manoeuvre. The results were digitally measured and recorded on thermosensitive millimetric paper analysing the following parameters: latency (LT), i.e. the time interval(s) between application of the stimulus and onset of SERV, both at palm (LTh) and foot (LTf); amplitude of the response (mm) recorded and evaluated in the form of SERV; velocity of the response as rate of time change (Vr) and autonomic conduction velocity, -ACV (m/s), calculated by the height/LT ratio. The present study refers to a group of 60 diabetic patients: 32 F/28 M; mean age +/- SD 46.8 +/- 11.8 years; 29 insulin-dependent, 21 non-insulin-dependent; duration of diabetes 8.6 +/- 4.6 years. The data were compared to those recorded in a group of 50 nondiabetics (22 F/28 M; mean age 47.5 +/- 14.1 years) who were apparently healthy. A significant statistical difference (P less than 0.001) was found between diabetic patients and controls for all studied parameters: LTh (s) 2.65 +/- 1.2 vs. 1.91 +/- 0.6; LTf(s) 3.6 +/- 1.4 vs. 2.6 +/- 0.7; SERV (mm) 7.5 +/- 4.8 vs. 18.5 +/- 6.6; Vr (mm) 4.4 +/- 2.1 vs. 13.5 +/- 5.3; ACT (m/s) 0.41 +/- 0.23 vs. 0.97 +/- 0.18.(ABSTRACT TRUNCATED AT 250 WORDS)

Pancreas transplantation. Experimental and clinical trials.

The ever increasing incidence of diabetes mellitus has stimulated the immunologic investigations concerned with the role of heredity and the toleration rate of transplants of pancreas organ or islet structures. Concomitant or subsequent trials have attempted to define or avoid the apparently diabetogenic factors. With respect to the effectiveness of diabetes therapy, one cannot deny the contrast between the practical and the theoretical aspects. Besides the technical difficulties, the pancreas organ or islet cell transplants are confronted with the still limited possibilities of immunosuppression. The recent concept of a bioartificial organ is an attempt to avoid such disadvantages. The present paper is a review of the main achievements of the experimental and the clinical trials in the above-mentioned directions of research work.