Recommendations for the use of cardiovascular tests in diagnosing diabetic autonomic neuropathy.

Despite its prevalence, clinical and prognostic impact, diabetic autonomic neuropathy, is widely under-diagnosed. The need for training and expertise to perform the cardiovascular tests (usually the task of diabetologists) is one possible reason. The availability of computer-assisted systems has allowed a wider diffusion of testing, but has also highlighted the need for an adequate knowledge of physiopathological backgrounds for their correct application and interpretation. The recommendations presented here were developed by the Neuropathy Study Group of the Italian Society of Diabetology and then endorsed by the Italian Association for the Study of Neurovegetative System, to promote the widespread adoption of good clinical practice in diabetic cardiovascular autonomic testing by outlining main evidence-based aspects, i.e. which tests, how to perform them, adequate interpretation of the results and their diagnostic use, confounding conditions that can impact on tests reliability. Therefore, these recommendations include the essential aspects of the physiopathological substrate of the tests, the controversial points in their analysis, their diagnostic characteristics, as well as safety. Detailed information is given on the physiological (age, weight, body position, resting heart rate and blood pressure, respiratory pattern, exercise, meals, acute blood glucose changes) and pathophysiological confounding factors, with emphasis on the effects of drugs. Instructions on how to perform the tests and interpret their results are also considered together with indications of candidate patients and periodicity of testing. A patient instruction sheet on why and how to perform the tests is included. Finally, the specific requirements for computerized systems to perform and evaluate cardiovascular tests are provided.

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.

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.

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.

[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.

Gastrokinetic effects of levosulpiride in dyspeptic patients with diabetic gastroparesis.

OBJECTIVE: Antidopaminergic drugs may be useful in diabetic gastroparesis because the inhibitory activity of hyperglycemia on gastric motility seems to be related to dopamine receptor stimulation. For this reason, we evaluated the effect of levosulpiride on gastric emptying, dyspeptic symptoms, and metabolic parameters of insulin-treated diabetic patients. METHODS: Under double-blind conditions, 40 longstanding, insulin-treated dyspeptic patients with autonomic neuropathy and delayed gastric emptying were randomly submitted, with an interval of 15 days, to 4 wk of administration of both levosulpiride 25 mg t.i.d. and placebo according to a cross-over design. At the beginning of the study and after levosulpiride or placebo treatment, the gastric emptying time of a standard meal was measured ultrasonically; gastrointestinal symptom scores and glycaemic control were also evaluated. RESULTS: Levosulpiride reduced significantly (p < 0.001) the gastric emptying time from 416 +/- 58 to 322 +/- 63 min, whereas placebo did not change it consistently (396 +/- 58 vs 372 +/- 72 min). Symptoms improved significantly (p < 0.001) with levosulpiride compared with placebo. However, there was no significant correlation between the acceleration of gastric emptying and the symptomatological improvement. The reduction of mean plasma glycosylated hemoglobin concentrations after levosulpiride (7.3 +/- 1.9 vs 5.8 +/- 1.3) was not significantly different (p = not significant) compared with placebo (6.8 +/- .7 vs 6.1 +/- 1.4). CONCLUSIONS: Our study first demonstrates that levosulpiride has an accelerating effect on the emptying of solids from the stomach of patients with diabetic gastroparesis. The drug is also effective in relieving upper gastrointestinal symptoms in patients whose gastric emptying times remain very slow. Our findings suggest, but do not prove, that better blood glucose control could be achieved with reduction of gastric emptying time; further trials are needed in this field.

[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.

Blood lactate behavior after glucose load in diabetes mellitus.

The aim of this study was to evaluate the relationships between blood lactate and plasma glucose, insulin (IRI) and C-peptide (IRCP) during the first hour of an oral glucose load (OGTT, 100 g). Twelve controls, sixteen non-insulin-dependent (NIDDM) and four insulin-dependent (IDDM) diabetic subjects were studied. A significant increase in blood lactate was observed at 15 min in normal subjects, whereas there was a delayed increase at 45 min in NIDDM subjects, in the presence of IRCP increments of 0.31 nmol/l. In order to have a minimum significant lactate increment, the threshold value of peripheral IRCP increment was about 0.30 nmol/l. In IDDM subjects, despite considerable hyperglycemia, blood lactate concentration remained unchanged throughout the test. In normal and NIDDM subjects there was a significant negative correlation between delta lactate and delta glucose (r = -0.89, p less than 0.001) and a significant positive correlation between delta lactate and delta IRCP (r = 0.78, p less than 0.001). In conclusion, hyperglycemia itself and the lack of increase in insulin secretion do not affect blood lactate increase during OGTT; blood concentration of this metabolite depends mainly on an early insulin secretion apt to enhance tissue glucose uptake and to inhibit gluconeogenesis.

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.

ACTH 1-17 effects in insulin dependent diabetes mellitus.

The 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 micrograms, intramuscular injection) was administered at 07(00)-07(30) 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.