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. Beta-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 beta-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 C-peptide 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 beta-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.

The effect of acute glutathione treatment on sorbitol level in erythrocytes from diabetic patients.

This study evaluated the effect of acute intravenous glutathione (GSH) infusion on red blood cell (RBC) sorbitol levels in 21 diabetic subjects and 6 normal controls of similar age and body mass index (Kg/m2). All patients received 1,200 mg of GSH in 500 ml of isotonic saline solution during one-hour intravenous administration. At the end of acute infusion of GSH, sorbitol concentration decreased from 20.90 +/- 1.16 to 16.24 +/- 0.81 nmol/g Hb (p < 0.001) in RBCs of diabetic subjects. No significant changes were observed in controls. These data support the hypothesis that GSH depletion, by reducing glycolytic flux to pyruvate, may enhance the rate of glucose metabolism through the polyol pathway and worsen the metabolic imbalance of diabetic tissues. The administration of exogenous GSH could interrupt this vicious circle.

Progressive deterioration of beta-cell function in nonobese type 2 diabetic subjects. Postprandial plasma C-peptide level is an indication of insulin dependency.

The purpose of the present study was to characterize secondary failure (SF) to oral hypoglycaemic agents by assessment of threshold insulin-secretion values in relation to diabetes duration. One hundred and forty-seven nonobese diabetic patients, 35 to 80 years of age, with disease duration ranging from 1 to 36 years, were studied. Beta-cell function was assessed by meal-stimulated (delta CP) and glucagon-stimulated (delta aCP) C-peptide concentrations. The quality of glycaemic control was considered good if mean daily blood glucose was less than 8.5 mmol/l. One group with good (NOb-GC) and another with poor control (NOb-SF) were established. Mean daily glycaemia was negatively correlated with delta CP or delta aCP (r = -0.703 vs r = -0.696; p < 0.001) more than with basal C-peptide (r = -0.453; p < 0.001). A close positive correlation between meal-stimulated (delta CP) and glucagon-stimulated (delta aCP) C-peptide concentrations was observed (r = 0.869; p < 0.001). Residual beta-cell function (delta CP and delta aCP) was significantly correlated with known disease duration in both groups (GC: r = -0.693 and SF: r = -0.680; p < 0.001). Nonobese patients with SF showed early impaired secretion during the first years of disease, meal-stimulated delta CP being below 0.350 mmol/l. The most useful result in this study was the incremental value of C-peptide (delta CP), which showed minimal overlapping between the two groups. Basal, postprandial or postglucagon absolute values were less discriminating. The daily profile allowed measurement of both glycaemic control and insulin production after a regular meal. The validity of this measurement was confirmed by the strong correlation between meal-stimulated and glucagon-stimulated delta C-peptide concentrations. This parameter is a useful physiological marker of secondary failure.

Metabolic alkalosis in diabetic ketosis: a case report.

A mixed metabolic alkalosis and metabolic acidosis, resulting in an alkalemic state, occurred in a hyperlipemic patient with previously diagnosed non insulin dependent diabetes. The metabolic alkalosis, due to large loss of gastric HCl, was more severe than the diabetic acidosis and resulted in an alkaline blood pH. Initially the metabolic acidosis was due to ketoacidosis and coexistent lactic acidosis. During the improvement of the alkalemic and hyperglycemic state, lactic acidosis disappeared but a paradoxical rise of plasma NEFA and ketone body concentrations supervened so that the high anion gap metabolic acidosis was virtually unchanged. The rise of plasma NEFA was probably related to the marked removal of plasma triglycerides, by insulin activation of lipoprotein lipase, and consequent saturation of the pathways of fatty acid incorporation into adipose tissue.

ACTH 1-17 effects on intermediary metabolites in healthy subjects.

Some 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 micrograms ACTH 1-17 and 250 micrograms 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.

[Multiple symmetrical lipomatosis. Metabolic effects of excision of lipomatous tissue]. / Lipomatosi multipla simmetrica. Effetti metabolici dell'exeresi di tessuto lipomatoso.

Multiple Symmetric Lipomatosis (MSL) is a syndrome characterized by the occurrence of symmetric lipomas over various regions of the body. No clear etiology has been recognized while a frequent association with systemic metabolic abnormalities has been described. The metabolic situation of a subject affected by MSL was assessed before and after surgical excision of lipomas. A condition of impaired glucose tolerance (IGT) was verified both before and after surgery by the performance of oral glucose tolerance test, glucagon test, and daily glucose profile. No significant differences were observed after the ablation of lipomatous masses with regard to glucose, IRI, IRCP and NEFA behaviour. We concluded that the resection of lipomas can not modify glucose tolerance in MSL and that lipomas can be considered as tissues metabolically independent from the rest of body fat.

[Dietary fiber in the dietetic therapy of diabetes mellitus. Experimental data with purified glucomannans]. / Le fibre alimentari nella terapia dietetica del diabete mellito. Dati sperimentali con glucomannani purificati.

In the last years the use of alimentary fibres in dietetic management of diabetic patients increased. The aim of this work was to evaluate, in type 2 diabetic subjects, the glycaemic and insulinemic increments after a standard breakfast with glucomannanos enriched biscuits and with common slices of toast containing the same amounts of carbohydrates and calories. The basal serum values of glucose and C-peptide were similar in the two days of the test. The mean increments of glucose and C-peptide were significantly higher (p < 0.001) after slices of toast than after glucomannanos enriched biscuits. In conclusion our results show a reduction in glycaemic increments after breakfast with glucomannanos-biscuits. The decreased insulin secretion and the reduction of insulin need can longer preserve the functional reserve of beta-cells.

[The utility of postprandial C-peptide evaluation in type 2 diabetes]. / Utilità del C-peptide postprandiale nella valutazione del diabete tipo 2.

The secondary drug failure is a well known phenomenon in the development of type 2 diabetes mellitus, but an exact definition of this situation is still lacking. The aim of this research was to evaluate the beta-cell reserve in non obese diabetic patients in relation to the metabolic control and the duration of disease. The main aim was to identify values of postprandial plasma C-peptide that can characterize the patients requiring insulin treatment. A daily profile was performed in 135 non obese diabetic patients, within 20% of their ideal body weight. The mean diurnal values (m) and the mean post-prandial increases (delta mpp) of plasma glucose (G), insulin (IRI) and C-peptide (CP) were assessed. Fourty-four patients showed good (NwD-GC: G-m = 138 +/- 3.2 mg/dl) and 91 poor metabolic control (NwD-SF: G-m = 210 +/- 4.8 mg/dl), according to the G-m lower or higher than 150 mg/dl. Beta-cell reserve (CP-delta mpp: 0.70 +/- 0.03 vs 1.39 +/- 0.04 ng/ml) and C-peptide/insulin molar ratio (CP/IRA-delta mpp: 2.36 +/- 0.06 vs 2.80 +/- 0.06) were significantly lower (p < 0.001) in NwD-SF than in NwD-GC. NwD-GC and NwD-SF were respectively divided into three subgroups, according to the duration of disease. A progressive reduction of CP-delta mpp and an increase in SF prevalence, from the first to the third decade of diabetes duration, was observed. In both NwD-Gc and NwD-SF the duration of disease inversely correlated with CP-delta mpp (NwD-GC: y = 1.59-0.019X, p < 0.001; NwD-SF: y = 1.01-0.023X, p < 0.001). The analysis of the two regression lines showed that patients with CP-delta values lower than 1.0 ng/ml require insulin treatment. In conclusion the duration of diabetes and the progressive reduction of beta-cell reserve represent the major pathogenetic factors in secondary failure.

Correlations between glycosylated haemoglobin and other metabolic parameters in insulin-dependent diabetics.

The metabolic parameters of 40 insulin-dependent patients (22 females and 18 males) have been studied to evaluate their intercorrelations. We obtained positive correlation between glycosylated haemoglobin and triglycerides (r = +0,460; p less than 0,01) and between HbA1 and mean diurnal plasma glucose (MDPG) (r = +0,652; p less than 0,001). There was a negative correlation between HbA1 and high density lipoproteins (HDL) cholesterol (r = -0,406; p less than 0,05). No significant correlation was found between HbA1 and either uric acid or total cholesterol. Correlations were also found between MDPG and triglycerides, MDPG and HDL-cholesterol, triglycides and HDL-cholesterol, uric acid and HDL-cholesterol. These correlations are discussed.