Romano Prando

Chronic Administration of Levosulpiride and Glycemic Control in IDDM Patients With Gastroparesis

OBJECTIVE We evaluated the effect of chronic administration of levosulpiride, a prokinetic drug that is a selective antagonist for D2 dopamine receptors, on the glycemic control of IDDM subjects. RESEARCH DESIGN AND METHODS The study was performed on 40 long-standing IDDM subjects with clinical signs of autonomic neuropathy and delayed gastric emptying. Gastric emptying time and glycemic parameters (diurnal glycemic profile and HbA1c) were checked under double-blind conditions before and after the administration of levosulpiride at the dosage of 25 mg t.i.d. orally for 6 months, or placebo. RESULTS No significant differences were noted in the glycemic and HbA1c values before and after 6 months of placebo administration. In contrast, after 6 months of levosulpiride, glycemic control had improved (HbA1c 6.7 ± 0.4 and 5.7 ± 0.3%, P < 0.01; mean daily glycemia 10.9 ± 0.8 and 8.8 ± 0.4 mmol/l, P < 0.05, at the start and at the end of the study), while the dosage of injected insulin (0.65 ± 0.02 IU · kg−1 · day−1) and the number of severe hypoglycemic episodes remained unchanged. After 6 months of levosulpiride therapy, the time of gastric emptying was significantly reduced from 321 ± 14 to 261 ± 9 min (P < 0.001) and dyspeptic symptoms had improved. CONCLUSIONS Our results show the importance of gastric emptying in the maintenance of glycemic control and the usefulness of chronic administration of levosulpiride in diabetic subjects with gastroparesis.

Is type 2 diabetes a different disease in obese and nonobese patients

OBJECTIVE The main purpose of this work was to study the possible differences in insulin secretion in a large group of type 2 diabetic patients in relation to diabetes duration, obesity, and the presence of secondary failure after treatment with oral hypoglycemic agents. RESEARCH DESIGN AND METHODS There were 147 nonobese and 215 obese type 2 diabetic subjects, aged 35–80 years, investigated in a cross-sectional descriptive study. Subjects were grouped according to whether glycemic control was good (mean blood glucose <8.5 mmol/l) or poor. β-Cell function was assessed by measuring meal-stimulated insulin and C-peptide concentrations, as the mean of the three postprandial increments above the premeal value. RESULTS Basal C-peptide concentrations were significantly higher in obese than nonobese patients of both groups. The mean of meal-stimulated C-peptide concentrations was also significantly higher in obese than nonobese patients with good glycemic control, but not in the secondary failure groups. In nonobese and obese patients considered separately, a significant negative correlation between the mean of daily blood glucose and meal-stimulated C-peptide was observed (r = −0.705 and r = −0.679, respectively, P < 0.001) and the residual β-cell function was significantly correlated with the known duration of diabetes and metabolic control, but not with BMI, in both groups. CONCLUSIONS On average, obese diabetic subjects showed higher meal-stimulated Cpeptide than nonobese subjects only in well-controlled groups. In both obese and nonobese patients, an inverse association between meal-stimulated insulin secretion and duration of diabetes was observed. In obese patients, as in nonobese patients, the lower β-cell function seems likely to be the major pathogenetic factor in the appearance of secondary failure, while being overweight plays only a minor role, thus showing that type 2 diabetes is the same disease in obese and nonobese patients.

Relationship between glutathione and sorbitol concentrations in erythrocytes from diabetic patients

Red blood cell (RBC) concentrations of sorbitol and reduced glutathione (GSH) were evaluated in 29 type 11 diabetic subjects and eight normal controls. In erythrocytes from diabetic subjects, sorbitol levels were higher (18.7 +/- 1.33 v 11.2 +/- 0.7 nmol/g hemoglobin [Hb], P < .001) and GSH levels were lower (5.48 +/- 0.19 v8.33 +/- 0.24 micromol/g Hb, P < .01) than in nondiabetics. RBC sorbitol levels were positively correlated with fasting blood glucose (r =.57, P < .001) but not with HbAlc (r =.16, P < .05). RBC GSH levels showed a negative correlation with fasting blood glucose (r = -.35, P <.05) and with HbA1c (r = -.34, P < .05) and a significant negative correlation with RBC sorbitol levels (r = -.62, P < .001). Stepwise regression analysis highlighted the fact that the hyperglycemia-dependent increase in RBC sorbitol was significantly influenced by GSH concentrations (partial F = 14.6, P < .001). These data suggest the hypothesis that the hyperglycemia-induced enhanced activity of the polyol pathway leads to GSH depletion and, in turn, GSH depletion, reducing the glycolytic flux to pyruvate, enhances the rate of glucose metabolism through the polyol pathway. The overall effect is a progressive worsening of metabolic pseudohypoxia and depletion of GSH, resulting in lower defense against oxidative stress.

I.V. Glucose tolerance test: Correlation between FFA, glucose and IRI in normal, obese and diabetic subjects

SummaryInsulin response and FFA behavior have been evaluated during an IVGTT in 63 subjects of whom 18 were normal, 31 were obese (with varying degrees of carbohydrate tolerance) and 14 were mild non insulin-dependent diabetics. The extreme reduction of insulin secretion in the early phase (Δ 0–15 min) and the less severe impairment of the late phase (Δ 15–60 min) have been confirmed; obese subjects showed on the average an active insulin response to venous loading; this was more marked and more consistent in the late phase. Compared to controls, FFA concentration both in basal conditions and during IVGTT was progressively higher in obese and diabetic patients. When analyzing the interplay between IRI, KG and FFA in the course of IVGTT, it was observed that: (1) a close correlation exists between KG and early insulin response (r=0.72); (2) a correlation between Δ IRI 0–15 min and percentage decrease of FFA at 45 min is found only in normal subjects; (3) a negative highly significant correlation is found between Kg and mean FFA plasma level 0–60 min. This last correlation is evidence of the important role played by FFA in carbohydrate tolerance. The conflicting results reported by others have been discussed.

ACTH 1–17 effects on intermediary metabolites in healthy subjects

SummarySome acute and chronic metabolic effects of a new ACTH analogue (ACTH 1–17, Synchrodyn®) were evaluated in healthy subjects and compared to those of the synthetic fragment ACTH 1–24. The peptides were injected at doses reportedly comparable with regard to their corticotropic effect, i.e. 100 μg ACTH 1–17 and 250 μg ACTH 1–24. A similar increase in blood glucose, NEFA and ketone bodies concentrations, without any significant modification of insulin, C-peptide and glucagon levels, was observed after injecting both peptides. The chronic treatment with ACTH 1–24 induced a significant increase in basal lactate, pyruvate and alanine blood concentrations. The levels of these metabolites resulted unaffected or slightly reduced after the corresponding treatment with ACTH 1–17. Our data are compatible with a certain degree of exhaustion of the adrenocortical reserve or, alternatively, a resetting of the circadian cortisol rhythm after prolonged treatment with the ACTH 1–17 analogue.

Exploration of the early insulin response by two small successive loads of I.V. glucose in normal and obese subjects.

SummaryTwo 5 g glucose loads at 1-h interval were given to healthy controls and obese subjects with slightly altered or normal OGTT in order to explore the capacity of restoration of the ‘rapid insulin response’ to i.v. glucose. In the normal subjects, the two successive loads gave rise to identical responses as far as maximum increase (Δmax), average increase at 2–5 min (Δ2–5 min), area of increase 0–15 min (Δ0–15 min) for both glucose and IRI, were concerned. Obese subjects could be divided on the basis of their insulin response to the first load into normal responders (group I) and high-responders (group II). In group I obese subjects, the responses to the second load were identical to those to the first. In group II obese subjects Δmax, Δ2–5 min and Δ0–15 min of the insulin response to the second load were reduced as compared to the first.

Diabetic Nephropathy: Prevalence and Risk Factors

In 103 diabetic subjects we evaluated the prevalence of diabetic nephropathy and its correlations with some risk factors for microangiopathy such as age, duration of diabetes, glycometabolic control, hypertension, smoking and overweight. Clinical proteinuria (> 500 mg/day) was found in 10% and in 22% of non-insulin dependent and insulin dependent diabetic subjects respectively. There was greater prevalence of proteinuria in males and in older diabetics who had a longer duration of disease, in those subjects with higher blood pressure values and in diabetics who required insulin treatment.

ACTH 1–17 effects in insulin dependent diabetes mellitus

SummaryThe aim of this study was to evaluate the metabolic effects of a new synthetic ACTH analogue (ACTH 1–17) in insulin-dependent diabetic subjects. ACTH 1–17 (100 μg, intramuscular injection) was administered at 0700–0730 every second day for 20 days. Changes in insulin dosage were carried out to maintain the same metabolic control during the period of the study. Before and after treatment diurnal plasma glucose profiles were superimposable and insulin requirement increased only in 16 out of 19 patients (mean: 6.7±2 U/die; range: 2–22 U/die). No changes were observed in diurnal profiles of blood alanine, glycerol, total ketone bodies and plasma NEFA, C-peptide, glucagon. The physiological blood lactate and pyruvate peaks following the evening meal were initially absent and could be detected after treatment. From our data it is not clear whether the more physiological pattern of blood lactate and pyruvate is caused by the modest increase in insulin dosage or is a specific effect of the treatment.

Il test al glucagone nei soggetti diabetici: Suo significato e sue modificazioni dopo trattamento con glibenclamide

RiassuntoIn una sperimentazione estensiva di 145 pazienti, suscettibili al trattamento con glibenclamide (Daonil®), si è notata la persistenza di taluni atteggiamenti metabolici favorevoli anche a distanza di tempo dalla sospensione temporanea del medicamento. Lindagine sulla responsabilità ormonale di questo fenomeno è stata condotta in un gruppo di pazienti in queste condizioni, utilizzando iltest al glucagone. Esso consiste nel rilievo dellinsulina (IRI), della glicemia e dei NEFA a vari intervalli di tempo dopo la somministrazione di mg 1 di glucagone in vena. La comparazione dei comportamenti dinamici di questi 3 parametri studiati consente una diagnostica dello stato dismetabolico ed una classificazione largamente indipendente dalletà del paziente, dalla durata della malattia, dalla presenza di sovrappeso corporeo e dalla stessa gravità delliperglicemia a digiuno. La maggioranza dei pazienti da noi esaminati, indipendentemente dal gruppo in cui potevano essere classificati, presentava un tipo unitario di alterazione costituito da una anomala reattività dellinsula agli stimoli e da unalterazione dei processi omeostatici a distanza dallo stimolo. Il trattamento con glibenclamide ha indotto una normalizzazione di questa lesione, persistente anche 24 h dopo la sospensione del trattamento stesso.ResumeEn étudiant laction de la glybenclamide (Daonil®) sur 145 sujets, lA. a observé la persistance de certaines effets métaboliques aussi après la suspension du médicament. LA. a étudié la dépendance hormonale de ce phénomène dans un groupe de sujets dans cettes conditions par le test au glucagone. Le test consiste dans le dosage de linsuline (IRI), de la glycémie et des NEFA à moments différents après ladministration de mg 1 de glucagone par voie intraveineuse. La comparaison des comportements dynamiques de ces trois paramètres permet un diagnostic de létat dismétabolique et une classification indipendente de lâge du sujet, de la durée de la maladie, de la presence dun surpoids corporel et même de la sévérité de la hyperglycémie à jeun. La majorité des sujets examinés indépendamment du groupe dans lequel on pouvait les classifier, presentait un type unique daltération constitué par une abnorme réactivité de linsule aux stimulus et une altération des processus omeostatiques à distance du stimulus. Le traitement avec glybenclamide a induit une normalisation de cette lesion, persistente 24 h encore, après la suspension du traitement.ResumenEn una experimentación que comprendía a 145 pacientes susceptibles de tratamiento con glibenclamida (Daonil®), ha sido notada la persistencia de algunas modificaciones metabólicas favorables, inclusive algun tiempo después de la suspensión temporánea del medicamento. La investigación de la responsabilidad hormonal de este fenómeno, ha sido efectuada en un grupo de pacientes en estas condiciones utilizando el test al glucagón. Este consiste en la observación de la insulina (IRI), de la glucemia y de los NEFA durante varios intervalos de tiempo luego de la suministración de mg 1 de glucagón intravenoso. La comparación de los comportamientos dinámicos de estos tres parámetros estudiados, permite un diagnóstico del estado dismetabólico y una clasificación que no depende de ninguna manera de la edad del paciente, de la duración de la enfermedad, de la presencia de sobrepeso corporal ni de la gravedad de la hiperglucemia en ayunas. La mayoría de los pacientes examinados por nosotros, independientemente del grupo donde se les podía clasificar, presentaba un tipo unitario de alteración, formado por una reactividad anormal de la insula a los estímulos, y una alteración de los procesos homeostáticos a distancia del estímulo. El tratamiento con glibenclamida ha producido una normalización de esta lesión, que persistía aún 24 horas después de la suspensión del tratamiento.ZusammenfassungIm Laufe einer Pruefung bei 145 Patienten, die sich fuer die Behandlung mit Glybenclamid (Daonil®) eigneten, wurde das Andauern einiger positiver Stoffwechselverhalten auch geraume Zeit nach dem voruebergehenden Absetzen festgestellt. Die Erforschung des hormonalen Eingriffs in dieses Phaenomen erfolgte unter diesen Bedingungen in einer Gruppe von Patienten unter Einsatz des Glukagon-Tests. Dieser besteht in der Bestimmung des Insulins (IRI), des Blutzuckers und der NEFA in verschiedenen zeitlichen Abstaenden nach der i.v. Verabreichung von mg 1 Glukagon. Der Vergleich des dynamischen Verhaltens dieser 3 untersuchten Parameter gestattet eine Diagnostik des dysmetabolischen Zustandes sowie eine Klassifikation, die weitgehend unabhaengig vom Alter der Patienten, der Dauer der Krankheit, der Anwesenheit von Gewichtsueberschuss und demselben Schweregrad der Nuechtern-Hyperglykaemie ist. Der Grossteil der von uns untersuchten Patienten zeitigte, unabhaengig von der Gruppe in welche sie einreihbar waren, einen einheitlichen Veraenderungstyp, der in einer abnormen Reaktivitaet der Insel gegenueber Reizen und in einer Aenderung der homoeostatischen Prozesse in zeitlichem Abstand von den Reizen bestand. Die Behandlung mit Glybenclamid bewirkte eine Normalisierung dieser Schaedigung, die auch 24 Stunden nach dem Abbruch der Behandlung selbst andauerte.SummaryIn an extensive trial on 145 patients responsive to glybenclamide (Daonil®) treatment it was noted that certain positive metabolic effects persisted even some time after suspension of the drug. The glucagon test was used to investigate the hormone-dependence of this phenomenon in one group of patients in this condition. The test consists in the determination of immunoreactive insulin (IRI), of blood sugar and of NEFA at several intervals after the intravenous administration of mg 1 of glucagon. Comparison of the trends of these 3 parameters permits diagnosis of the metabolic disorder and a classification regardless of patient age, duration of the disease, weight status or even fasting blood sugar level. The majority of the patients we examined, irrespective of their classification, all exhibited anomalous reactivity of the islets of Langerhans to stimulation and alteration of the homeostatic processes some time after stimulation. Glybenclamide induced normalisation of this lesion lasting for as much as 24 hrs after suspension of treatment.