Pier Marco Piatti

Metabolic control of type I (insulin dependent) diabetes after pancreas transplantation

A study was conducted of the circadian hormonal and metabolic patterns of 10 type I (insulin dependent) uraemic diabetic patients after pancreas and renal transplantation. A single 24 hour profile was obtained in each patient following as closely as possible his or her normal daily routine two to 15 months after transplantation. None of the patients were using insulin at the time of the study. Compared with a group of six normal subjects the transplant recipients had mildly raised blood glucose concentrations, hyperinsulinaemia between meals and at night, delayed postprandial insulin peaks, mild hyperketonaemia, and normal blood lactate and plasma glucagon concentrations. The findings showed that successful pancreas transplantation results in disappearance of the need for insulin and return to normal or near normal of the metabolic abnormalities of diabetes. The minor differences observed in comparison with normal hormonal and metabolic homoeostasis were probably due to intrinsic (reduced islet mass, denervation, peripheral hormone delivery) and environmental (immunosuppression, relatively impaired renal function) factors.

Incretin-based therapies in type 2 diabetes: a review of clinical results.

GLP-1 analogues (incretin mimetics) and DPP-4 inhibitors (incretin enhancers) represent new classes of anti-diabetic agents for the treatment of type 2 diabetes. The efficacy and safety of the incretin mimetic exenatide and of the DPP-4 inhibitors, sitagliptin and vildagliptin, have been clearly demonstrated by a very large number of clinical trials. Efficacy was demonstrated in terms of reduction of HbA1c, fasting and postprandial glucose. Moreover, exenatide showed a favourable effect on weight, while DPP-4 inhibitors were neutral with respect to this outcome. The low rate of hypoglycemic events seen in all studies confirms the glucose dependent action of incretins.

Nitric-oxide mediated effects of transdermal capsaicin patches on the ischemic threshold in patients with stable coronary disease.

Background Capsaicin has been shown to exert direct vasodilating effects through increased calcitonin gene-related peptide (CGRP) release. However, no data exist on its effect following systemic administration in humans. Methods Twelve male patients with stable coronary disease and a persistently positive exercise were selected for study. According to a double blind, placebo-controlled, cross-over study, patients were randomized to placebo or 3 g oleic capsaicin-containing patches, on 2 different days and with a 2-day interval between treatments. Patients performed treadmill exercise testing according to the Bruce protocol. Time to 1 mm ST segment depression and to peak exercise, maximal ST segment depression, and the number of ECG leads showing diagnostic changes were also measured. Blood samples for nitric oxide (NO) and CGRP were drawn at baseline, 2, 6, and 24 hours after exercise. Results On placebo, all patients had a positive ECG during exercise test. Only 1 patient experienced angina, on both treatments. With capsaicin, 1 patient had a negative exercise, while 8 patients significantly increased time to 1 mm ST depression from 328 ± 167 to 401 ± 174 seconds (P = 0.01). Of the remaining patients, 1 did not show any changes and 2 showed a worse ischemic threshold when on capsaicin. CGRP levels were not significantly different between placebo and capsaicin treatment. Conversely, when on capsaicin, NO significantly increased at 6 hours. Conclusions Transdermal capsaicin may improve ischemic threshold in patients with stable coronary disease, probably through arteriolar vasodilation. Increased capsaicin-induced NO availability could represent the principal mechanism of action.

Long-term continuous intraperitoneal insulin treatment in brittle diabetes

Attempts to achieve a fair metabolic equilibrium in a young woman with brittle diabetes by continuous subcutaneous, intramuscular, and continuous intravenous administration of insulin were unsuccessful. Continuous intraperitoneal administration of insulin through a permanently inserted polyethylene catheter connected to an open-loop peristaltic pump led to an appreciable improvement in mean blood glucose concentration, mean amplitude of glycaemic excursions, and M value and to normalisation of intermediate metabolic products. The peritoneal catheter was well tolerated for over 120 days without appreciable adverse effects. This case suggests that long-term intraperitoneal administration of insulin is a feasible therapeutic approach in the management of brittle diabetes.

Role of Endothelial Dysfunction and Insulin Resistance in Angina Pectoris and Normal Coronary Angiogram

Angina pectoris and a normal coronary angiogram or cardiac syndrome X is a heterogeneous syndrome that probably encompasses different pathophysiological entities. Patients affected by cardiac syndrome X are often women presenting with severe, invalidating chest pain. However, there is a significant discrepancy among the severity of symptoms, the lack of hemodynamic evidence of myocardial ischemia and the relatively benign long-term prognosis. The vascular endothelium has numerous important functions, including the regulation of vascular tone, blood flow and permeability, secreting both vasorelaxing and vasoconstricting factors. It has been found that both endothelium and non-endothelium-mediated coronary blood flow are impaired in patients with cardiac syndrome X. Interestingly, it has been shown that impaired nitric oxide-dependent vasodilation could increase coronary microvessel tone and produce spasm. It has also been reported that circulating endothelin-1 levels are elevated with a direct relationship between endothelin-1 levels and impaired coronary flow reserve in these patients. In addition, patients with high endothelin-1 levels showed a time onset of chest pain during exercise significantly lower compared to patients with low endothelin-1 concentrations. Moreover, the nitric oxide/endothelin-1 ratio was found decreased in patients with cardiac syndrome X and endothelin-1 levels were also positively correlated with fasting asymmetric dimethylarginine levels. All in all, these data suggest a role of endothelial dysfunction as a cause of regional myocardial and peripheral blood flow abnormalities. Further studies are necessary to characterize the prevailing mechanisms determining alterations in nitric oxide/endothelin-1 pathway in these patients, in order to find new therapies able to improve both quality of life and prognosis.ZusammenfassungAngina pectoris und ein normales Koronarangiogramm, auch kardiales Syndrom X genannt, umfasst unterschiedlichste pathophysiologische Entitäten. Syndrom-X-Patienten sind häufig Frauen mit schweren, auch die Lebensqualität beeinträchtigenden Symptomen bei Fehlen hämodynamisch nachweisbarer myokardialer Ischämien und relativ guter Langzeitprognose. Das vaskuläre Endothel hat viele wichtige Funktionen. Es regelt den vaskulären Tonus, den Blutfluss und die Permeabilität der Gefäßwand und sezerniert vasorelaxierende und vasokonstringierende Faktoren. Bei Patienten mit Syndrom X ist sowohl die endothelabhängige als auch die nicht endothelabhängige Vasomotion gestört. Interessant ist, dass die Stickstoffmonoxid-(NO-)abhängige Vasodilatation gestört ist und einen erhöhten Tonus der Mikrogefäße hervorrufen kann. Auch koronare Spasmen wurden beobachtet. Das zirkuläre Endothelin-1 ist erhöht und könnte für die eingeschränkte koronare Flussreserve bei diesen Patienten verantwortlich sein. Zusätzlich zeigen Patienten mit hohem Endothelinspiegel einen früher einsetzenden thorakalen Schmerz unter Belastung als Patienten mit niedrigem Endothelinspiegel. Das Verhältnis von NO zu Endothelin-1 ist bei Syndrom-X-Patienten niedrig. Der Endothelin-1-Spiegel korreliert positiv mit dem Nüchternspiegel des asymmetrischen Dimethylarginins. Diese Daten lassen vermuten, dass die endotheliale Dysfunktion eine Ursache für regionale myokardiale und periphere Flussanomalien ist. Weitere Studien sind notwendig, um den Mechanismus zu charakterisieren, der zur Veränderung der NO- und Endothelin-1-Metabolismen bei diesen Patienten führt, um neue therapeutische Ansätze zu finden und die Lebensqualität sowie Prognose der Patienten zu verbessern.

The increase in plasma PAI-1 associated with insulin resistance may be mediated by the presence of hepatic steatosis.

OBJECTIVE Recent evidence suggests that plasminogen-activator inhibitor-1 (PAI-1) is abundantly produced by the fatty liver, but it is unclear whether hepatic steatosis (HS) can mediate the increase in plasma PAI-1 induced by insulin resistance/compensatory hyperinsulinemia (IR/CH). METHODS AND RESULTS To address this issue, we cross-sectionally evaluated IR/CH as area under the curve of plasma insulin (AUC-PI) concentrations during OGTT, metabolic profile, and ultrasound degree of HS in 235 healthy volunteers (132M, age: 60+/-7 years) with normal transaminase concentrations. Circulating PAI-1 was increased in subjects with classical features of IR/CH (overweight, high fasting and post-OGTT insulin and glucose, high triglycerides (TG), and low HDL-cholesterol), and significantly correlated to prevalence and degree of HS, but not to alcohol intake. In a multivariate model, AUC-PI, TG and degree of HS were independent predictors of plasma PAI-1 (R(2)=0.32). However, AUC-PI was significantly correlated to PAI-1 only in subjects with HS, suggesting an interaction between AUC-PI and HS. In addition, in the presence of HS and IR/CH, PAI-1 concentrations were increased to a similar extent both in heavy and moderate drinkers, suggesting that metabolic and alcoholic steatosis have a similar effect on the relationship between IR/CH and PAI-1. CONCLUSION These results support the hypothesis that HS has a major impact on the relationship between IR/CH and plasma PAI-1 concentrations, and this effect seems to be unaffected by the etiology of the HS.

Correspondence Between the International Diabetes Federation Criteria for Metabolic Syndrome and Insulin Resistance in a Cohort of Italian Nondiabetic Caucasians The GISIR database

In 2005, the International Diabetes Federation (IDF) released a consensus definition of the metabolic syndrome. The definition, intended to provide a feasible predictor of cardiovascular disease and type 2 diabetes, includes elevated waist circumference plus two of the following factors: reduced HDL cholesterol or raised blood pressure, triglycerides, or fasting glucose (1). Insulin resistance is a major pathogenic factor for the metabolic syndrome and may independently contribute to the risk of cardiovascular disease and type 2 diabetes (2). We assessed the diagnostic accuracy of the IDF definition of metabolic syndrome in identifying subjects with insulin resistance, defined as being in the lower quartile of insulin-stimulated glucose disposal ( M clamp) determined by a standardized hyperinsulinemic-euglycemic …

Metabolic instability in type I diabetic patients. Studies on insulin absorption, hepatic production of metabolites and glucose counterregulation

SummaryIn order to investigate the causes underlying metabolic instability in type I diabetes mellitus, we studied 8 unstable (group 1) and 4 well-controlled (group 2) diabetic patients, matched for age and duration of diabetes. Subjects were connected overnight to an artificial pancreas and brought to normoglycemia. On the following morning, insulin administration was discontinued for 6 hours and both metabolic and hormonal studies were carried out during this period. After insulin withdrawal, group 1 showed a faster rise of blood glucose (peak: 324.63±24.93vs 175.25±42.63 mg/dl, p<0.01), β-OH-butyrate (peak: 2,273.25±415.78vs 550.50±158.17 µmol/1, p<0.01), and glycerol (164.10±38.90vs 28.25±10.6 µmol/1, p<0.01). C-peptide secretion increased in group 2 from 0.09±0.052 to 0.22±0.099 pmol/ml whereas it remained almost undetectable in group I (p<0.01, group 1vs group 2). Growth hormone, cortisol and immunoreactive glucagon were not significantly different in the two groups at any time after insulin withdrawal. Free insulin, after repeated s.c. or i.m. injection of porcine monocomponent insulin (10 IU), was not different in the two groups. We concluded that type I diabetic patients showing severe metabolic instability produced more glucose, ketone bodies and glycerol after insulin withdrawal than control ‘stable’ patients. This difference could not be accounted for by an excessive secretion of counterregulatory hormones or by an erratic insulin absorption from the injection sites and may have been related to the degree of B-cell failure, as measured by the absence of C-peptide and/or to the degree of insulin resistance.