Catheter survival during long-term insulin therapy with an implanted programmable pump. The Implantable Insulin Pump Trial Study Group.

OBJECTIVE: To survey catheter complications and to analyze catheter survival during long-term intraperitoneal and intravenous insulin therapy with an implanted programmable pump with a sideport. RESEARCH DESIGN AND METHODS: Catheter occlusions were documented by measuring dynamic catheter resistance. Catheter migrations or breaks were demonstrated by X ray. When flushing the catheter with buffer solution through the sideport failed to clear the occlusion, catheters were replaced or laparoscopy was performed for the excision of fibrous tissue growth. Broken or migrated catheters were replaced. RESULTS: Occlusions were the most common catheter complications, and the majority of them (79% intraperitoneal and 84% intravenous) were cleared by flushing the catheter. Survival at 3 years was significantly higher for intraperitoneal catheters compared with intravenous catheters (60% intraperitoneal and 22% intravenous). CONCLUSIONS: Nonsurgical management of catheter occlusions contributed to extend catheter lifetime. Intraperitoneal catheters have a lower morbidity and a higher survival than intravenous catheters.

Long-term therapy of IDDM with an implantable insulin pump. The Implantable Insulin Pump Trial Study Group.

OBJECTIVE: To examine the long-term benefits and risks of treatment of IDDM with an implantable programmable insulin pump. RESEARCH DESIGN AND METHODS: Seventy-six patients with IDDM were studied at nine clinical centers. After 3-4 months of intensive subcutaneous therapy, the Infusaid Model 1000 pump was implanted, and insulin was delivered either intraperitoneally or intravenously for an average of 39.6 +/- 10 months (251 patient-years). Data was collected for glycemic control, lipid levels, weight gain, insulin requirements, adverse events, and quality of life. Sixty-three patients were also followed for 8.5 +/- 6.3 months (45 patient-years) after pump therapy was discontinued. RESULTS: Mean quarterly HbA1c fell with subcutaneous intensive therapy and remained stable on implantable pump therapy between 6.9 and 7.5%. Severe hypoglycemia was relatively rare, with only 4 episodes/100 patient-years of implantable pump therapy. This rate was significantly less than with subcutaneous intensive therapy before implantable pump initiation (33 episodes/100 patient-years) or after discontinuation of implantable pump therapy (36/100 patient-years) (P < 0.003). Weight did not increase significantly in the 1st year of therapy, but increased by 2.0 +/- 4.3 kg after 3 years of therapy. There were no significant differences in metabolic control or adverse events between intraperitoneal and intravenous insulin therapy except for minor differences in lipid levels and the more frequent development of catheter obstruction with intravenous delivery. Most pump slow-downs and catheter occlusions were corrected noninvasively. Quality of life, as measured by the Diabetes Control and Complications Trial instrument, showed high satisfaction and improved impact scores. CONCLUSIONS: Long-term implantable pump therapy maintained HbA1c in a range similar to intensive subcutaneous therapy, but with fewer episodes of severe hypoglycemia. Although pump and catheter occlusions remain a limitation, patient satisfaction with implantable pump therapy remains high.

Improved lipoprotein surface and core lipid composition following intraperitoneal insulin delivery in insulin-dependent diabetes mellitus.

To determine whether insulin delivered into portal circulation by an implanted pump reversed abnormalities in lipoprotein composition in insulin-dependent diabetes mellitus, 10 well-controlled normolipidaemic patients were studied after conventional intensive sub-cutaneous (ISC) insulin management and then 3 and 6 months after intraperitoneal pump implantation (IP). Glycated haemoglobin (ISC: 6.9 +/- 1.7% vs. IP-3 months 6.3 +/- 0.7; IP-6 months 6.3 +/- 0.8; mean +/- S.D.), plasma triglyceride and cholesterol levels, and the cholesterol content of HDL2 and HDL3 were normal and not significantly changed during these treatments. Fasting free insulin concentrations measured before and after 6 months of IP fell by more than half (ISC 8.22 +/- 6.5 vs IP 2.77 +/- 2.4 mU/ml; p < 0.025). The plasma-free cholesterol/lecithin ratio, a potential new cardiovascular risk factor, was increased during ISC, declined progressively after 3 months of IP, and approached normal by 6 months (ISC 0.96 +/- 0.37 mol/mol vs. IP-3 months 0.91 +/- 0.34; IP 6 months 0.86 +/- 0.10; reference group 0.83 +/- 0.33). In all lipoprotein fractions, sphingomyelin concentrations tended to fall, and lecithin concentrations to rise progressively during IP. As a result, the sphingomyelin/lecithin ratio, an index of the surface rigidity of lipoproteins, declined. The fact that some of the compositional modifications associated with ISC were reversed when insulin was administered intraperitoneally suggests that they may have been iatrogenic and resulted from high systemic insulin levels.

Use of an integrated sideport for diagnosis and management of decreased flow rates in a programmable implanted insulin delivery system. Implantable Insulin Pump Trial Study Group.

The aim of this study was to develop procedures for the diagnosis and nonsurgical management of decreased insulin flow in an implantable programmable pump for long-term intraperitoneal or intravenous insulin delivery featuring a sideport. Patency of the catheter lumen was tested by measuring the time needed for sideport pressure to decrease by 50% after the injection of 0.1 ml of buffer solution. Pumping unit performances were assessed by measuring the volume of pump pulses after diverting the pump flow at the sideport. A catheter flush with buffer solution through the sideport was effective in clearing 79% of intraperitoneal and 84% of intravenous catheter occlusions. Washing the pumping unit with an alkaline solution after diverting pump flow at the sideport was effective in dissolving insulin aggregates inside the pumping unit and in restoring normal pump flow. These procedures were associated with a 1.3% rate of hypoglycemic episodes.

Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients.

PURPOSE: To examine the mechanism of the decreased frequency of severe hypoglycemia with implantable pump therapy compared with subcutaneous intensive therapy. PATIENTS AND METHODS: Eight subjects with insulin-dependent diabetes mellitus (IDDM), enrolled in an implantable insulin pump study, were admitted to the General Clinical Research Center and on 2 separate days were given either a dose of preprandial insulin chosen to maintain normoglycemia for a standard (450 kcal, 50% carbohydrate) breakfast or 1.75 times the dose. The two doses were administered subcutaneously (by syringe or with an external pump) during one inpatient admission and by implantable pump (intraperitoneally, n=6; or intravenously, n=2) during a separate admission. Blood glucose, plasma-free insulin, and neurocognitive function were measured for 4 hours after the meal. RESULTS: Subcutaneous administration resulted in 7 episodes of hypoglycemia (2 with the usual dose and 5 with the 1.75-fold dose), defined as blood glucose less than 50 mg/dL; implantable pump treatment resulted in only 2 episodes, both with the 1.75-fold dose (P <0.05, Fisher's two-tailed test for implantable versus subcutaneous). Compared with subcutaneous delivery, implantable pump therapy provided significantly lower insulin levels during the final 2 hours after administration of the usual dose and the 1.75-fold dose (P <0.005). In addition to the decreased frequency of hypoglycemia, implantable pump therapy resulted in significantly lower area under the glycemia curve during the first 120 minutes with the 1.75-fold dose compared with subcutaneous administration. CONCLUSIONS: The lower frequency of severe hypoglycemia with intensive therapy administered by implantable pump therapy is explained by the more rapid clearance of insulin delivered intraperitoneally or intravenously compared with intensive subcutaneous injection regimens. The lower frequency of severe hypoglycemia with implantable pump therapy compared with subcutaneous therapy demonstrated in clinical trials is confirmed by this study, in which we attempted to induce hypoglycemia.

Intraperitoneal insulin therapy corrects abnormalities in cholesteryl ester transfer and lipoprotein lipase activities in insulin-dependent diabetes mellitus.

Patients with insulin-dependent diabetes mellitus (IDDM) have proatherogenic disturbances in cholesteryl ester transfer (CET) despite intensive subcutaneous insulin therapy (ISC). Since CET is activated by insulin-sensitive lipoprotein lipase (LPL), which normally increases postprandially, we queried whether iatrogenic hyperinsulinism from ISC stimulated LPL and CET by studying well-controlled IDDM patients after ISC and then 6 months after lowering systemic insulin levels by intraperitoneal (IP) insulin delivery. Although glycemic control (HbA1c IDDM, 6.9 +/- 1.7%; control, 4.5% to 8%) was excellent during ISC, CET was accelerated (P < .001) and both systemic insulin levels and LPL specific activity were increased (P < .05). Following IP, basal systemic insulin levels declined by more than one half (ISC, 8.22 +/- 6.5 versus IP, 2.77 +/- 2.4 microU/mL; mean +/- SD; P < .025), and both LPL and CET activities returned to normal. Plasma triglyceride, cholesterol, high-density lipoprotein-2 (HDL2) cholesterol, HDL3 cholesterol, cholesteryl ester transfer protein mass, and glycemic control (HbA1c, 6.3 +/- 0.8%) were unchanged and remained normal. These findings indicate that ISC is associated with high levels of basal CET and LPL. These alterations both appear to be closely linked to iatrogenic hyperinsulinemia resulting from ISC. The fact that they are both reversed when systemic insulin levels are reduced by IP suggests that insulin, acting through LPL, influences the nature of the interaction of the lipoproteins engaged in CET.(ABSTRACT TRUNCATED AT 250 WORDS)

Screening for microalbuminuria. A comparison of single sample methods of collection and techniques of albumin analysis.

OBJECTIVE: To evaluate single-sample urine collections to determine their ability to screen patients for the presence of microalbuminuria. Microalbuminuria in patients with type I diabetes predicts the development of diabetic renal disease. RESEARCH DESIGN AND METHODS: Cross-sectional analysis of single-sample urine collection techniques (first morning void, random upright void) and methods of albumin analysis (RIA, reagent tablet) were compared with conventional 24-h urine collections (RIA). The study included 94 patients (45 males, 49 females; mean serum creatinine 88 microM) with type I diabetes, selected from a screened population of 301 patients from the University Hospital Subspecialty Clinics. RESULTS: A 24-hour urine collection RIA analysis for albumin revealed 36 normal patients (< 30 mg), 27 with microalbuminuria (30-300 mg), and 31 with albuminuria (> 300 mg). Random upright urine samples were more sensitive (RIA 89%, tablets 78%) for the detection of microalbuminuria than first morning void specimens (RIA 70%, tablets 60%). Specificity was > 80% with both random and first morning voids. CONCLUSIONS: Screening for microalbuminuria can be performed in the clinic by random upright single-sample urine collections. When reagent tablets were used, these results are available immediately. Patients who screen positive should be confirmed by 24-h or other timed urine collections.

Plasma lipid and lipoprotein disorders in IDDM.

Abnormal lipoprotein metabolism contributes to the increased risk of premature atherosclerosis in people with insulin-dependent (type I) diabetes. Although hypertriglyceridemia is common in those with untreated IDDM, treatment with conventional insulin therapy usually restores fasting lipoprotein profiles to nondiabetic levels. Intensive insulin therapy improves glycemic control and lipoprotein concentrations, but does not ameliorate the changes in lipoprotein composition described in people with IDDM. Some of these persistent changes in lipoprotein composition have been attributed to peripheral hyperinsulinemia associated with s.c. insulin therapy. The recent availability of implantable insulin-infusion pumps for treatment of IDDM has allowed the study of the effect of i.p. insulin delivery on lipoprotein metabolism. i.p. insulin therapy is capable of maintaining near normal plasma glucose levels while reducing the peripheral hyperinsulinemia. Although results have been contradictory, studies of i.p. insulin therapy may eventually help to determine whether some of the observed changes in lipoprotein metabolism and composition in people with IDDM are due to the peripheral hyperinsulinemia associated with s.c. insulin therapy.

Effects of insulin treatment on lipoprotein composition and function in patients with IDDM.

Normolipidemic patients of both sexes with insulin-dependent diabetes mellitus have the same pervasive changes in lipoprotein surface and core lipid composition. The disproportionate increase observed in their lipoprotein free (unesterified) cholesterol relative to the predominant surface phospholipid lecithin (phosphatidylcholine) is reflected by elevation of the FC-L ratio in their whole plasma, VLDL, HDL2, and HDL3. As a possible consequence of this qualitative disturbance, cholesteryl ester transfer is pathologically increased and the mass of cholesteryl ester transferred from HDL to VLDL + LDL is significantly greater in IDDM patients than in control subjects at 1, 2, and 4 hr (P less than 0.001). Consistent with accelerated CET in vivo, the TG-CE core lipid ratio was decreased in VLDL from six subjects (IDDM 9.5 +/- 0.8 vs. control 12.9 +/- 3.4; P less than 0.01) and increased in their HDL (diabetic 0.55 +/- 0.11 vs. control 0.42 +/- 0.04: P less than 0.025). These abnormalities in lipoprotein composition and CET do not correlate with glycemic control and persist after intensive management with s.c. insulin. They may be related to the peripheral hyperinsulinemia that is an unavoidable consequence of conventional s.c. insulin administration because preliminary studies indicate that these disturbances in lipoprotein composition and function are reversed when systemic insulin levels are lowered and insulin is delivered into the portal circulation from an i.p. catheter connected to an implanted programmable s.c. insulin pump.

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.

Management of hyperlipidemia in diabetes mellitus.

Accelerated atherosclerosis is a major complication of long-term diabetes mellitus, and this is partly due to associated abnormalities of lipoprotein metabolism. Hypertriglyceridemia is usually due to poorly controlled diabetes and responds to improved glucose control. Hypercholesterolemia is usually not related to poor diabetic control and should be treated with a cholesterol lowering diet and drugs according to the National Cholesterol Education Program guidelines. Low HDL-C is common in NIDDM and does not fully return to normal with improved diabetic control. Dyslipidemia in diabetics should be aggressively identified and treated to decrease cardiovascular risk.

Treatment of lipid disorders in diabetes mellitus.

One reason for premature atherosclerosis in patients with diabetes mellitus is abnormal lipid metabolism. This article discusses the plasma lipid disorders associated with diabetes mellitus, and how to apply the new guidelines from the National Cholesterol Education Program for treatment of hypercholesterolemia in patients with diabetes mellitus.

Effect of fat-free diet on insulin requirements in type I diabetes controlled with artificial beta-cell.

We investigated the effect of eliminating calories derived from fat sources on postprandial and basal insulin requirements in five patients with type I (insulin-dependent) diabetes mellitus. The patients were studied on a metabolic ward on two solid-food diets with similar quantities of carbohydrate and protein with or without the addition of fat. Diet A was isocaloric (weight maintenance) with calories distributed as 45% carbohydrate, 15% protein, and 40% fat. Diet B contained the same carbohydrate and protein content as diet A but was virtually fat free and therefore hypocaloric (1233 +/- 106 vs. 1830 +/- 99 cal, mean +/- SE). The diets were given as five equal meals each day on consecutive days. Insulin requirements and blood glucose measurements were determined by use of the artificial beta-cell. During the study, mean (+/- SE) preprandial blood glucose levels were maintained at 85 +/- 11 mg/dl, and peak postprandial blood glucose levels were less than 180 mg/dl. The elimination of fat calories had no effect on total (68.9 +/- 10.3 vs. 69.3 +/- 4.9 U/day), postprandial (9.8 +/- 3.8 vs. 10.3 +/- 3.7 U/meal), or basal (1.9 +/- 0.2 vs. 1.8 +/- 0.2 U/h) insulin requirements. Thus, despite a hypocaloric diet, no change in insulin requirements was noted when fat-derived calories were deleted from the diet. We conclude that fat-derived calories do not alter short-term basal or postprandial insulin requirements in type I diabetes.

Treatment with artificial beta-cell decreases very-low-density lipoprotein triglyceride synthesis in type I diabetes.

The effect of restoration of euglycemia with the artificial beta-cell (Biostator GCIIS) on triglyceride metabolism was studied in seven normolipidemic patients with type I diabetes mellitus. Very-low-density lipoprotein triglyceride (VLDL-TG) transport was determined with [3H]glycerol as an endogenous precursor of VLDL-TG; the resultant kinetic data were evaluated by multicompartmental analysis. Studies of triglyceride metabolism were performed in diabetic patients taking their usual dose of subcutaneous insulin (control study) and after 72 h of euglycemia with the artificial beta-cell (Biostator study). Treatment with the artificial beta-cell resulted in a decrease in mean (+/- SE) 24-h plasma glucose levels from 199 +/- 9 to 123 +/- 7 mg/dl and an increase in mean plasma free-insulin levels from 12.3 +/- 1.9 to 27.6 +/- 4.2 microU/ml (P less than .05). These changes were accompanied by a decrease in mean plasma TG levels from 134 +/- 29 to 88 +/- 15 mg/dl (P less than .05). Kinetic studies demonstrated that the change in plasma triglyceride levels was primarily due to a decrease in VLDL-TG transport (i.e., synthesis), which fell from 11.7 +/- 2.5 mg X h-1 X kg-1 ideal wt during the control study to 7.5 +/- 2.0 mg X h-1 X kg-1 ideal wt during the Biostator study (P less than .05). There was no significant change in fractional catabolic rates of VLDL-TG between the two studies (0.35 +/- .05 vs. 0.38 +/- .07 h-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Diet-induced essential fatty acid deficiency in ambulatory patient with type I diabetes mellitus.

We report a case of symptomatic essential fatty acid deficiency (EFAD) occurring in a free-living individual with type I diabetes mellitus who was voluntarily following a high-carbohydrate, fat-restricted diet. The patient was 43 yr old with type I diabetes for 18 yr and no chronic complications. His self-imposed diet excluded all red meats, fats, and oils. After several months of this diet, the patient developed lethargy and a pruritic, diffuse, scaly, and erythematous rash. Biochemical studies revealed a mildly elevated SGOT and abnormally low levels of linoleic, linolenic, and arachidonic fatty acids. Treatment with linoleic acid supplementation in his diet improved the rash, normalized SGOT, and corrected the fatty acid profile. We conclude that EFAD may occur in a free-living individual after consuming a very-low-fat diet.