Piero Micossi

Clinical Trial of Programmable Implantable Insulin Pump For Type I Diabetes

Objective The first step in the evolution of an artificial pancreas is the development of a reliable implantable pump for insulin delivery. Despite recent advances, significant issues remain, including small size of studies and frequent irreversible catheter obstructions. We report safety, feasibility, and efficacy results from 56 patients, representing 73 patient-yr of pump experience, entered into a multicenter trial with a new implantable programmable pump. Research Design and Methods All patients had insulin-dependent (type 1) diabetes, were 38 ± 8 yr old, and were not prone to severe hypoglycemia. The pump (Infusaid 1000) has a pulsatile mechanism powered by freon-vapor pressure. Its rate is regulated by battery-powered valves, operated via a hand-held programmer. The pump is refilled transcutaneously with 25 ml U100 insulin (Hoechst 21PH) on a monthly basis and has a second septum (side port) proximal to the catheter, which allows flushing the catheter or lavaging the pump unit. The pumps were implanted after 3 mo intensive subcutaneous insulin therapy and catheters were positioned either in the peritoneum (i.p., n = 38) or the superior vena cava (i.v., n = 18). Results All implanted pumps have functioned safely with no instance of overdelivery or stoppage. The most frequent complications were flow slow downs, presumably due to insulin precipitation within the pump, which occurred in 86% of pumps and were resolved in all but one case by lavaging the pump in situ with alkaline solution. Flow slow downs due to catheter obstruction occurred in 52% of the intravenous catheters but only 21% of the intraperitoneal catheters (P < 0.05) and were resolved in all but two cases by diluent flushing through the sideport. Incidence of severe hypoglycemia decreased from 0.47 before implant to 0.05 episodes/patient-yr after pump implantation (P < 0.001). Mean HbA1c fell from 7.4 ± 1.2% after intensive subcutaneous therapy to 7.1 ± 1.0% 12 mo after implantation. Only 2 patients withdrew from study after recurrent catheter problems, and quality-of-life questionnaires showed improvement in satisfaction with diabetes-specific quality of life when on implantable pump therapy. Conclusions Insulin therapy with implantable pumps is effective and safe for periods up to 1.7 yr with a decreased risk of severe hypoglycemia than with intensive subcutaneous insulin therapy.

Normalization of lipoprotein composition by intraperitoneal insulin in IDDM : role of increased hepatic lipase activity

OBJECTIVE To characterize the effects of intraperitoneal insulin pump therapy on lipoprotein composition and lipolytic enzyme activity in patients with insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS Ten IDDM patients were studied 3 times: when receiving conventional subcutaneous insulin therapy and at 3 and 9 months from the initiation of intraperitoneal insulin regimen. Ten nondiabetic subjects matched for age, sex, and body weight were studied as controls. Levels of cholesterol, triglycerides, apolipoprotein A-I (apoA-I) and B (apoB) were measured in total plasma and lipoprotein fractions (very-low-density lipoprotein [VLDL], intermediate-density lipoprotein [IDL], low-density lipoprotein [LDL], and high-density lipoprotein [HDL]: HDL2 and HDL3). Postheparin plasma lipoprotein lipase and hepatic lipase activities were determined by an immunochemical method. RESULTS IDDM patients showed higher levels of HDL3 and lower levels of HDL2 particles during intraperitoneal insulin therapy in comparison with subcutaneous insulin therapy. Both cholesterol and apoA-I significantly increased in HDL3 and decreased in HDL2 during intraperitoneal treatment. Plasma total cholesterol significantly decreased in the diabetic patients at 3 months of intraperitoneal insulin therapy compared with both subcutaneous insulin regimen and control subjects. IDL triglyceride concentrations during intraperitoneal treatment were significantly lower than those seen with subcutaneous therapy. Furthermore, triglyceride:apoB ratio in VLDL and cholesterol:apoB ratio in LDL significantly decreased in IDDM patients treated by intraperitoneal insulin. A significant increase in the activity of hepatic lipase with intraperitoneal insulin therapy by 9 months compared with subcutaneous insulin therapy has been shown. CONCLUSIONS The increased activity of hepatic lipase after intraperitoneal insulin administration in IDDM patients appears to be one of the main determinants of lipoprotein changes observed, resulting in the normalization of lipoprotein composition during this mode of therapy. The normal inverse relationship between VLDL triglycerides and HDL cholesterol, which was not present in IDDM patients with subcutaneous therapy, was restored with intraperitoneal insulin regimen.

Minimal models of glucose disappearance: lessons from the labelled IVGTT.

In this paper the domain of validity of the unlabelled and labelled minimal models of glucose disappearance is studied. Labelled intravenous glucose tolerance tests were performed in six normal subjects using 3‐3H‐glucose as the tracer. Insulin and unlabelled glucose data were analysed with the minimal model of glucose disappearance. The model provides estimates of glucose effectiveness (SG) and insulin sensitivity (SI) which measure the effects of glucose per se and insulin on both glucose production and disposal. Insulin and labelled glucose data were analysed with the labelled minimal model of tracer disappearance. Estimates of glucose effectiveness (SG*) and insulin sensitivity (SI*) which reflect disposal processes only were calculated. The results of the two minimal models suggest two areas of model error. Firstly, the relationships between labelled and unlabelled parameters contradict the theoretical expectation. Secondly, the time‐course of hepatic glucose production is unrealistic. Possible sources of these inconsistencies are an inadequate description of the glucose and/or insulin effect upon hepatic glucose production, and the assumption that glucose kinetics are monocompartmental. The monocompartmental description of glucose kinetics may affect both model parameters and hepatic glucose production and this leads to a critical reexamination of the previously published validation studies in which the minimal model metabolic indices have been compared with the analogous indices measured during glucose clamp studies.

Dopaminergic control of serum potassium

Metoclopramide, a dopaminergic inhibitor, injected in 9 normal volunteers, was followed by a prompt decrease of serum potassium (10--20 min; p less than 0.01) and by an increase of plasma aldosterone (p less than 0.01). Renin slightly increased at 45 min (p less than 0.05); insulin and cortisol did not show any significant increase. The urinary excretion of potassium rose after metoclopramide (p less than 0.05). A bolus of aldosterone (250 micrograms i.v.) in 4 normal subjects was not followed by any modification of serum potassium, but increased urinary potassium excretion (p less than 0.05); the injection of metoclopramide in two patients with an aldosterone-secreting adenoma of the adrenal and in one patient with Addisons disease induced a decrease of serum potassium in absence of any modification of plasma aldosterone. The decrease of serum potassium after metoclopramide is not explained by changes of aldosterone or insulin, considered the most important hormonal controls of potassium. The rapidity of potassium decrease implies a change of distribution of potassium between extra- and intracellular compartments, which, in turn, may stimulate aldosterone secretion. It is conceivable that the dopaminergic system has a role in the control of serum potassium.

Spectral analysis of short-term heart rate variability in diabetic patients.

Spectral analysis of short term R-R variability estimated by autoregressive modelling is a recently developed method for the evaluation of cardiovascular autonomic function. This new test also allows to study the interaction on heart rate variability of parasympathetic and sympathetic system. The sensitivity of the method for detection of cardiovascular autonomic neuropathy has been evaluated in a group of diabetic patients in comparison with the sensitivity of a battery of the most commonly used cardiovascular autonomic tests (deep-breathing, lying-to-standing, Valsalva Manoeuvre, postural hypotension and hand grip). Spectral analysis of heart rate variability resulted in a very sensitive method for early detection of diabetic autonomic neuropathy, about one-fourth of diabetic patients with normal traditional cardiovascular autonomic tests had abnormal results at spectral analysis. Both sympathetic and vagal control of heart rate resulted alterated in diabetic autonomic neuropathy.

Incidence and prevalence rates of diabetes mellitus in Italy from routine data: a methodological assessment.

This study was undertaken to identify and validate possible existing sources of information to estimate the prevalence of known diabetes and the incidence of Type I (insulin-dependent) diabetes in Italy.The prevalence of known diabetes was estimated on the basis of data on drug sale, using specific defined daily doses as index of drug consumption. The estimation of the average daily dose used for calculations was carried out on a consecutive series of 911 diabetic subjects from two outpatient clinics.The incidence of Type 1 (insulin-dependent) diabetes was obtained by processing data routinely collected by the Regional Health Services, related to hospital discharge diagnosis records mentioning diabetes mellitus. The validation was carried out in 12 hospitals of the same Region. The estimated prevalence rate of known diabetes was 1.7%, including patients on dietary treatment.In the Lombardia Region in 1982–83 the estimated annual average incidence of Type I (insulin-dependent) diabetes, under the age of 35 was 4.6/100,000. This rate appears much lower then that observed in Northern Europe and the United States while it is similar to the French rate. This is in agreement with the findings of studies showing changes with latitude of the incidence rates of Type 1 (insulin-dependent) diabetes.

Increased production of platelet thromboxane B2 in non-insulin-dependent diabetes. Relationship to vascular complications

Abstract. Platelet thromboxane B2 production was studied in forty‐seven non‐insulin‐dependent diabetics by incubating platelets with increasing concentrations of arachidonic acid. In comparison with thirty‐two healthy subjects, diabetics showed increased thromboxane B2 production at 0·7 mmol/l (mean: 236 pmol/108 platelets, SEM 201–277; v. 135, 105–174; P < 0·05) and at 1·0 mmol/l (673, 613–739; v. 405, 377–486, P < 0·01) but not at 0·5 mmol/l. Patients were subdivided according to the presence or absence of vascular complications. Patients without microangiopathy showed significantly greater thromboxane B2 production than healthy subjects at all the arachidonic‐acid concentrations (P < 0·02 or less). Patients with microangiopathy had platelet thromboxane production similar to that observed in healthy subjects at all the arachidonic‐acid concentrations (P > 0·30) but significantly lower than that of non‐microangiopathic patients at 0·5 (P < 0·01) and at 0·7 mmol/l arachidonic acid (P < 0·05). These results indicate that non‐insulin‐dependent diabetics have increased production of platelet thromboxane B2 only when they do not have microvascular complications.

Chronic continuous intraperitoneal insulin infusion (CIPII) in type I diabetic patients non-satisfactorily responsive to continuous subcutaneous insulin infusion (CSII).

SummarySix unstable C-peptide negative type I diabetic patients who had been previously treated with continuous subcutaneous insulin infusion (CSII) for at least one year without achieving satisfactory metabolic control, were admitted to this study and switched to continuous intraperitoneal insulin infusion (CIPII). The results obtained with the two treatments have been compared from the metabolic and clinical points of view. CIPII produced a decrease in HbA1c (p<0.05), in MAGE value (p<0.005), in the percentage of blood glucose determinations above 14 mmol/l (p<0.05) and below 3.9 mmol/l (p<0.05); an increase in serum cholesterol, and a decrease in HDL-cholesterol (p<0.05) due to a reduction of the HDL2 fraction (p<0.01). A mean body weight reduction of 3 kg was observed during CIPII (p<0.01), not related to dietary changes or to a reduction of the daily insulin dose. Twenty-four hour metabolic profiles during CIPII showed lower mean plasma glucose (p<0.001), serum free insulin (p<0.001), blood β-OH-butyrate (p<0.001), and higher serum glycerol (p<0.001) as compared to CSII. It is concluded that CIPII may be of clinical value in the out-patient management of unstable type I diabetic patients, and that metabolic modifications induced by CIPII are not limited to changes in glucose utilization and production, but include changes in triglyceride, cholesterol and lipid metabolism which may have clinical relevance.

Intravenous Infusion of Diarginylinsulin, an Insulin Analogue: Effects on Glucose Turnover and Lipid Levels in Insulin-Treated Type II Diabetic Patients

Diarginylinsulin is an intermediate in the conversion of proinsulin to insulin and is usually present in small amounts in vivo in humans. This study was designed to evaluate the following in insulin-treated type II diabetic patients: (1) the feasibility of an overnight intravenous infusion of diarginylinsulin, as compared with an overnight intravenous infusion of short-acting insulin, and the degree of early morning glycemic control; and (2) the effects of diarginylinsulin and human insulin on hepatic glucose production (HGO) in the postabsorptive state and on the glucose turnover rate and peripheral insulin sensitivity during an euglycemic hyperinsulinemic clamp. Diarginylinsulin and regular human insulin maintained a comparable degree of normoglycemia during the night, without significant glucose increases in the morning. Free-diarginylinsulin and free-insulin concentrations were not significantly different, and (HGO) was 2.1 +/- 0.5 versus 2.1 +/- 0.4 mg/kg/min with diarginylinsulin and regular human insulin, respectively (NS). During the euglycemic clamp, glucose infusion rate per unit of diarginylinsulin or human insulin infused (M/I ratio) was similar, and HGO was equally suppressed with diarginylinsulin and regular human insulin. No significant differences were seen in NEFA and triglyceride levels. In conclusion, these results indicate that diarginylinsulin is as potent as regular human insulin; it is normalizes HGO in the postabsorptive state; and its hepatic and peripheral actions on glucose and lipids are comparable to those of human insulin during an euglycemic hyperinsulinemic clamp.

Microalbuminuria and its associated risk factors in a representative sample of Italian Type II diabetics

A multicenter population-based study was undertaken from 1983 to 1985 in 12 diabetes centers in Lombardy, in order to assess the prevalence of microalbuminuria and clinical proteinuria. Out of a total population of 17,704 diabetics, 1,155 were randomly selected within four strata of duration of disease and albumin excretion rate (AER) assessment was carried out in 541 unselected subjects. Albuminuria was evaluated from an overnight urine collection using a radioimmunoassay. The overall prevalence rates were 25.8% for microalbuminuria (30 less than or equal to AER less than 350 micrograms/min) and 3.0% for macroalbuminuria (AER less than or equal to 350 micrograms/min). In Type II diabetes the rate of microalbuminuria increases with duration of disease up to 10 years and then tends to level off. This could be due to the existence of two subgroups of diabetics with different life expectancy and different degree of risk of nephropathy. The Italian prevalence of microalbuminuria appears to be rather similar to that of other studies, while the prevalence of macroalbuminuria is quite low with respect to middle and northern Europe, indicating a rather slow rate of progression to clinical proteinuria. This could be explained on the basis of differing protein intakes. The cases with AER greater than or equal to 30 micrograms/min, greater than or equal to 70 micrograms/min, and greater than or equal to 350 micrograms/min have been compared with matched diabetic controls with AER less than or equal to 15 micrograms/min.(ABSTRACT TRUNCATED AT 250 WORDS)