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.

Peritoneal and subcutaneous absorption of insulin in type I diabetic subjects.

We and others have shown that in type I diabetes, ip insulin delivery results in lower free insulin levels than sc delivery. The aim of this study was to compare the rate of appearance of insulin in the peripheral circulation during ip and sc insulin administration in type I diabetes, in steady state and nonsteady state. To do this, we determined free insulin levels during ip or sc infusion as well as the impulse response of the insulin system after iv injection of a 6-nmol bolus of insulin. Twelve hours after a constant basal insulin infusion (5.5 +/- 1.4 nmol/h) was started, five C-peptide-negative type I diabetic subjects showed a lower systemic rate of appearance of insulin (expressed as a percentage of the administered dose) with ip than sc administration (27 +/- 6% vs. 40 +/- 10%; P < 0.001). In nonsteady state, when the infusion rate was increased from basal to 15 nmol/h (0-150 min) and subsequently to 42 nmol/h (150-300 min), the percent increase in insulin's systemic rate of appearance was higher with ip than sc infusion (P < 0.05 from 60-150 min; P < 0.01 from 150-300 min), indicating faster absorption. Thus, we conclude that insulin is more rapidly absorbed from the peritoneal cavity than from sc tissue. However, with ip administration, a sizable amount of insulin, once absorbed, is extracted before reaching the peripheral circulation, most likely by the liver. This is indirect evidence that ip insulin delivery results in a portal-peripheral insulin gradient in humans.

Influence of meal ingestion on insulin profiles following intraperitoneal delivery.

This study evaluated the effect of meal ingestion on intraperitoneal insulin absorption in type I diabetic patients with an implanted pump for long-term intraperitoneal insulin delivery. On four separate occasions, patients (n = 7) were administered 15 IU insulin as a 20-minute square-wave infusion using their implanted device; hypoglycemia was prevented by intravenous infusion of 10% dextrose at a variable rate. Two studies were performed during fasting conditions (n = 2 fasting tests) and two studies after the administration of an 800-kcal standard meal (n = 2 postprandial tests). An insulin peak of 630 +/- 545.4 pmol/L (mean +/- SD) in fasting tests and 696 +/- 420.5 pmol/L in postprandial tests was reached in the peripheral circulation after 45 +/- 11.7 and 45 +/- 14.7 minutes, respectively, with no significant difference between the two experimental conditions. Areas under the insulin curves were not significantly different in fasting and postprandial tests (51,500 +/- 34,278 v 50,916 +/- 20,558 pmol/L.min-1, respectively; NS). In type I diabetic patients receiving long-term intraperitoneal insulin therapy, the increase in splanchnic blood flow following ingestion of a standard meal does not accelerate the appearance of insulin in the peripheral circulation.

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 less than 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 less than 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.

In vivo demonstration of insulin-receptor defect with 123I-labeled insulin and scintigraphic scanning in severe insulin resistance.

OBJECTIVE: Insulin-receptor function in humans is usually studied in vitro on readily available cells, e.g., erythrocytes and fibroblasts. Although these cells are not metabolically important targets for insulin action, information derived from them are often taken as representative of other tissues. The aim of this study was to investigate insulin receptors in vitro on erythrocytes and in vivo on one of the main insulin-target organs, the liver. RESEARCH DESIGN AND METHODS: A 16-yr-old girl affected by severe insulin resistance was identified. Insulin receptor binding was measured on the erythrocytes of the patient and of 6 nondiabetic volunteers. The biodistribution of 123I-labeled insulin was studied in vivo by scintigraphic scanning in the insulin-resistant patient and in 10 nondiabetic volunteers. RESULTS: Erythrocytes of this patient displayed a markedly reduced [125I]insulin binding. In vivo 123I-insulin biodistribution was characterized by lack of hormone uptake by the liver (4 vs. 21% of the injected dose in control subjects) contrasting with intense accumulation of radioactivity in the kidneys. CONCLUSIONS: Our studies show that defects of insulin binding can be directly demonstrated in vivo on liver receptors with a noninvasive technique with low radiotoxicity.

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.

Effect of soya and cellulose fibers on postprandial glycemic response in type II diabetic patients.

OBJECTIVE: We studied the effect on serum glucose and insulin of a preprandial ingestion of 7 g of soya fibers or of an equal amount of purified cellulose on eight non-insulin-dependent (type II) diabetic patients. RESEARCH DESIGN AND METHODS: Four tests were conducted in each patient in random order. In the first study, soya or cellulose was ingested before a standard breakfast, and postprandial glucose and insulin curves were determined. In the second study, intestinal absorption was investigated by means of a standard D-xylose absorption excretion test after the ingestion of soya or cellulose. RESULTS: Insulin profiles did not differ between the two treatments. The glycemic profiles after soya ingestion were lower than those after cellulose ingestion. The area under the glucose curve and glucose peaks were significantly higher after cellulose ingestion (area under the curve 20.2 +/- 3.88 vs. 15.57 +/- 4.42 mM x min, P = .05; glucose peaks 4.97 +/- 0.76 vs. 3.77 +/- 0.77 mM, P less than 0.02). The xylose tests were in the normal range, indicating that there was no interference with exose absorption, and no statistical difference was found between cellulose and soya treatment. CONCLUSIONS: It is concluded that soya fiber compared with purified cellulose has a favorable effect on the rise of postprandial glycemia in type II diabetic patients; moreover, the use of soya fibers did not carry any untoward side effect.

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.

[Evaluation of an impedance measurement method for determining body composition in diabetic subjects and normal controls]. / Validazione di una metodica di rilevazione impedenziometrica per la valutazione della composizione corporea in soggetti diabetici e controlli normali.

The reproducibility of impedance measurements made using the Human-IM system (Dietosystem, Milan-Italy) was assessed in a group of normal and diabetic subjects on the basis of three tests made under the same experimental conditions on three consecutive days. A total of 22 normal subjects, 29 insulin-dependent (IDD) and 6 noninsulin dependent (NIDD) diabetic patients were included in the study. The coefficient of variation between the three successive tests ranged between 0 and 2.7% (normals 1.1 +/- 0.7%, IDD 1.6 +/- 0.7%, NIDD 1.1 +/- 0.4%), thus confirming the good reproducibility of the method in all groups. There was no significant difference between impedance measurement tests in the two group of diabetic patients with regard to TBW, FAT and FFM. NIDD patients differed from normal subjects due to higher FAT levels, whereas there was no significant difference between IDD patients and normal subjects.

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 1 (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 1 (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.

Apolipoprotein (a) levels in type 1 and type 2 diabetes mellitus.

Type 1 and type 2 diabetes mellitus are both characterized by increased cardiovascular mortality and morbidity. Since several reports have indicated that apolipoprotein (a) [apo(a)] levels are positively associated with an increased risk of macrovascular disease, we investigated whether apo(a) levels are elevated in both types of diabetes mellitus and may thus represent an independent risk factor for atherosclerotic disease. Apo(a) concentrations in type 1 diabetic patients were not significantly different from matched controls (276 +/- 78 vs 149 +/- 46 units/l). Type 2 diabetic patients had considerably higher levels of apo(a) than matched controls (471 +/- 89 vs 221 +/- 61 units/l, P = 0.06), though the difference was not statistically significant. However, concentrations of apo(a) were above 300 units/l in 36% of type 1 and 67% of type 2 diabetic patients, but in only 14% and 25% respectively of matched control subjects. Plasma triglycerides were positively and independently correlated with apo(a) levels in both diabetic and non-diabetic subjects. On the other hand, no significant correlation was found between apo(a) levels and glycosylated haemoglobin, total cholesterol or high density lipoprotein cholesterol in any of the groups studied. In conclusion, apo(a) levels are not significantly elevated either in type 1 or type 2 diabetic patients without proteinuria and in moderate metabolic control; however, levels above 300 units/l were 2.6 times more frequent in both types of diabetes mellitus than in carefully age-, sex-, and weight-matched control subjects.

Identification of the cohort of type 1 diabetes presenting in Lombardy in 1983-84: a validated assessment.

An incidence register for Type 1 diabetes was started in Lombardy in 1983-84 for people under 35 years of age. The main information source was the Regional Health Service record system, which provides anonymous reports on all patients discharged from public and private hospitals. Great care was taken to assure the quality of the data in the register. The clinical diagnosis was validated by examining the case notes. Completeness of the register was assessed using multiple independent sources of case ascertainment such as the list of the Youth Diabetics Association, the files of three hospital endocrinology centres, and the registry of conscripts rejected because of diabetes. The estimated age-adjusted (world standard) annual incidence rate was 6.04 per 100,000 in the group 0-18 years and 5.96 per 100,000 in the age group 0-14 years. Females had peak incidence at 11 years of age, males had peak incidence 2 years later. These results confirm the low occurrence of Type 1 diabetes in northern Italy. A seasonal variation in onset of Type 1 diabetes was seen.

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.

Effects of intraperitoneal versus subcutaneous insulin administration on lipoprotein metabolism in type I diabetes.

In order to compare the effects of intraperitoneal (IP) versus subcutaneous (SC) insulin delivery on plasma lipoproteins, lipoprotein cholesterol, triglycerides, and very-low-density lipoprotein (VLDL) metabolism were compared in five type I diabetic patients while they were receiving continuous IP insulin (CIPII) or continuous subcutaneous insulin infusion (CSII). Each therapy regimen was of at least 1 month duration, and patients were treated in random order. Mean daily plasma insulin was lower on CIPII compared with CSII. CIPII was associated with lower VLDL triglycerides and VLDL apolipoprotein (apo) B, and higher high-density lipoprotein (HDL) and HDL3 cholesterol. The decreased VLDL on CIPII appeared to be the result of both decreased production and increased clearance of VLDL apo B. The results suggest that the more physiologic route of insulin therapy (CIPII) is associated with lipoprotein profiles of lower atherogenic potential.

Prevalence of retinopathy in diabetic subjects from out-patient clinics in Lombardy (Italy), and associated risk factors. A multicentre epidemiologic study.

There is little information on the prevalence of diabetic complications in Italy. For this reason, a multicentre population-based study was carried out in 1983-1985 in 12 representative out-patient clinics for the treatment of diabetes in the Lombardy region. Out of a total population of 17,704 patients 1160 diabetic subjects were randomly selected within strata based on their duration of disease (less than or equal to 5; 6-10; 11-20; greater than 20 years). Eight hundred and thirty-eight responders were examined using standardised protocols. The estimated prevalences (adjusted for duration of disease) for the total population involved in the study were 29.7% and 7.6% for background and proliferative retinopathy respectively. The overall standardised rates were higher in insulin-dependent diabetes mellitus (IDDM) (53.6%) than in non-insulin-dependent diabetes mellitus (NIDDM) (34.7%) for both background (41.1%, 28.4% respectively) and proliferative (12.5%, 6.2% respectively) retinopathy, and increased with the duration of disease. The analysis of the relationship between diabetic retinopathy and the calculated risk factors did not show any association with hypertension or metabolic control, except for post-prandial blood glucose in subjects with durations 6-10 and greater than 20 years; an association with azotaemia was found in subjects with durations less than or equal to 5 and 11-20 years. Diabetic retinopathy appeared to be independently associated with the type of treatment and not with the type of diabetes, metabolic control, or hypertension.

Glycerol-insulin raises circulating insulin antibodies in type I diabetic patients treated with permanently implanted devices.

The instability of insulin in the reservoirs of implantable insulin delivery devices has been a major obstacle in implementing this form of therapy. To overcome the problem of precipitation, a glycerol-insulin preparation has been used in large-scale long-term clinical trials. The aim of this study was to evaluate the stability of the glycerol-insulin solution and its effects on circulating insulin antibodies in eight type I diabetic patients who were implanted with an Infusaid pump (Infusaid Corporation, Norwood, MA) and followed for 1 year or more. Total insulin requirement did not change throughout the observation period. Plasma free insulin was higher during treatment with glycerol-insulin than with the standard insulin treatment (P less than .02). Insulin antibodies increased in all patients (P less than .05). High-performance liquid HPLC analysis of insulin samples from the pump reservoirs showed the generation of insulin modification products at a daily rate of 1.84%, reaching 40% to 50% of the total reservoir content 3 weeks after refilling; among these products, high molecular weight species accounted for about 15%. It is concluded that glycerol-insulin is not an adequate insulin preparation for use in implanted devices. Insulin deteriorated in the pump reservoirs, and insulin antibody concentration increased in the treated patients. It is believed that this antibody production is favored by circulating insulin fragments and polymers of insulin generated inside the pump reservoirs.