Conference on insulin pump therapy in diabetes. Multicenter study of effect on microvascular disease. Recruitment, Randomization, and baseline characteristics of the treatment groups.

The general and ophthalmologic eligibility criteria were applied in the course of formal screening of selected members of clinic populations at the six treatment centers between August 1980 and November 1981. Patients eligible on the grounds of the history and general physical examination underwent a detailed ophthalmologic examination and determination of C-peptide status. Initial rates of recruitment were slow, which occasioned modifications of the eligibility criteria and a prolongation of the recruitment phase. All six clinics approached their goal of at least six patients in each of the continuous subcutaneous insulin infusion (CSII) and conventional insulin treatment (CIT) groups, with a final total of 70 randomized subjects. The method of paired randomization was acceptable, but led to some delay during periods of slow recruitment activity. Data from two patients who chose to drop out of the study shortly after randomization are included in the baseline characteristics. There was no difference between treatment groups with respect to age or duration of known diabetes, body weight, systolic blood pressure, proportion of cigarette smokers, retinopathy level as assigned by analysis of stereofundus photographs, or microaneurysm counts performed on fluorescein angiograms. A trend toward milder retinopathy in the CIT group proved to be statistically insignificant. Subsequent assessment of stereofundus photographs at the Fundus Photograph Reading Center indicated that six patients were misclassified by treatment center ophthalmologists with respect to ophthalmologic eligibility. We conclude that recruitment goals were met and randomization was successful.

Eight-month correction of hyperglycemia in insulin-dependent diabetes mellitus is associated with a significant and sustained reduction of urinary albumin excretion rates in patients with microalbuminuria.

Persistent Albustix-positive proteinuria and subsequent chronic renal failure are frequently encountered in insulin-dependent diabetes mellitus (IDDM). Rates of decline of renal function may be modified by treatment of accompanying hypertension, but studies of the effects of long-term continuous subcutaneous insulin infusion (CSII) on deterioration of renal function provide no statistically significant evidence of benefit of near-normoglycemia. However, short-term studies in IDDM subjects with negative Albustix tests but subclinically raised levels of albumin excretion rate (AER) have shown that treatment with CSII significantly reduces this microalbuminuria. The prospective, controlled 8-mo Kroc Collaborative Study therefore offered the opportunity of examining more protracted effects of CSII-induced metabolic correction upon microalbuminuria. Twenty-four-hour urine collections obtained at baseline, 4, and 8 mo were available from 59 Albustix-negative patients. Beta 2-microglobulin excretion was normal. The 39 normoalbuminuric (AER less than 12 micrograms/min) patients did not differ from the 20 microalbuminuric (AER elevated between 13.2 and 192.6 micrograms/min) with respect to distributions of age, sex, and duration of diabetes. In both the normoalbuminuric and the microalbuminuric groups studied at 4 and 8 mo, percent glycosylated hemoglobin (%HbA1) and mean blood glucose were significantly decreased during CSII compared with baseline values, whereas no change occurred in the group continuing their conventional insulin therapy (CIT). AER did not differ between CIT and CSII treatments in the normoalbuminuric group. AER fell significantly in the CSII-treated microalbuminuric patients at 4 (P less than 0.05) and 8 (P less than 0.01) mo but showed no consistent change in the CIT microalbuminuric group.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal response to restricted protein intake in diabetic nephropathy.

Proteinuria in diabetes is associated with progressive glomerular damage. We studied the effects of 3-wk dietary protein restriction on proteinuria and renal function in 10 insulin-dependent diabetic men with diabetic nephropathy. Patients were randomly assigned by a crossover design to 40-g low-protein diet (LPD) or usual-protein diet (UPD). Glomerular filtration rate and renal plasma flow were measured by inulin and p-aminohippurate clearance at the end of each period under conditions of sustained euglycemia. Total calorie intake, body weight, serum albumin and total protein concentrations, hematocrit, blood pressure, and glucose control were similar during the two diets. Achieved protein intake was 46 +/- 3 g/day during LPD and 81 +/- 4 g/day during UPD (P less than .001). Urinary urea appearance and plasma urea were significantly lower on LPD. Median total urinary protein was reduced from 3.9 g/day (range 0.5-12.3) on UPD to 2.4 (range 0.2-9.0) on LPD (P less than .006), and there was a significant fall in the median fractional clearance of albumin from 2.0 x 10(-4) (range 0.1-90.9) on UPD to 1.0 x 10(-4) (range 0.1-51.4) on LPD and IgG from 2.1 x 10(-5) (range 0.2-238) to 1.5 x 10(-5) (range 0.1-77) (P less than .006 and P less than .02, respectively). The reabsorption rate of beta 2-microglobulin was similar on the two diets and glomerular filtration rate, renal plasma flow, and filtration fraction remained unchanged. Thus, short-term dietary protein restriction reduces diabetic proteinuria independently of blood glucose or systemic blood pressure changes by improving glomerular permselectivity.

Proteinuria and activated T-lymphocytes in diabetic nephropathy.

The reasons for the presence of activated T-lymphocytes (ATL) in some long-standing insulin-dependent diabetic (IDDM) patients are unknown. These cells have been implicated in the genesis of proteinuria in some forms of immune-mediated renal disease. We measured ATL in 18 IDDM patients with diabetic nephropathy, 10 with nonnephrotic proteinuria (total urinary protein excretion rate greater than 0.5 and less than 3.5 g/24 h) and 8 with nephrotic proteinuria (total urinary protein excretion rate greater than 3.5 g/24 h), and in 17 age-, sex-, and duration-of-diabetes-matched diabetic control subjects without clinical proteinuria (total urinary protein less than 0.5 g/24 h). T-lymphocytes purified from peripheral blood were stained by direct immunofluorescence with the fluorescein-labeled monoclonal antibody anti-HLA-DR. Absolute number and percent of DR-positive T-lymphocytes were significantly higher in patients with nonnephrotic proteinuria (median and range 162 x 10(6)/ml, 40-320 x 10(6)/ml; 13.9%, 8.1-19.4%) compared with nonproteinuric control subjects (81 x 10(6)/ml, 2-240 x 10(6)/ml, P less than .05; 6.2%, 0-13.1%, P less than .01). In 8 patients with nephrotic proteinuria, absolute and percent DR-positive T-lymphocytes tended to be lower (36 x 10(6)/ml, 14-56 x 10(6)/ml; 3.4%, 1.1-5.4%) than in nonproteinuric control subjects. An increased number of activated T-lymphocytes may be part of an immune-mediated process associated with the development of proteinuria in diabetic nephropathy. In advanced renal disease with nephrotic proteinuria, this immune process may become exhausted.

Rarity of a marked "dawn phenomenon" in diabetic subjects treated by continuous subcutaneous insulin infusion.

We assessed the quality of overnight glycemic control and the frequency of the "dawn phenomenon" (nadir-0800 h glycemic increase) in 41 insulin-dependent diabetic patients treated by continuous subcutaneous insulin infusion (CSII). Mean plasma glucose levels were near-normal during the 24 h and, in particular, constant throughout the night. In a subset of six patients overnight plasma free insulin concentrations were also constant during CSII. The majority of profiles (88%) showed a glucose nadir from 2.0 to 5.9 mmol/L (most frequently at 0600 h) and had an 0800 h value from 2.0 to 6.9 mmol/L (92%). A large proportion (46%) of profiles showed a zero or negative nadir-0800 h glycemic increase. In 22 patients with three or more profiles recorded at the same basal insulin infusion rate, only one of 103 profiles had a fasting glycemic increase greater than an arbitrary value of 5.0 mmol/L (5.3), although many patients exhibited small dawn glycemic increases (e.g., 14 of 22 had a mean increase of from 0 to 2 mmol/L). In 12 subjects a 15% reduction in basal insulin infusion rate increased the mean +/- SEM dawn glycemic increase from 0.58 +/- 0.25 mmol/L to 2.7 +/- 0.76 mmol/L (P less than 0.025) as well as significantly increasing the nocturnal nadir and 0800 h plasma glucose concentrations. Thus, a marked dawn phenomenon is rare when a single but adequate basal infusion rate is used for CSII, and this questions the need in the majority of patients for preprogrammable pumps with nocturnal infusion rate changes.

Meeting the problems of first-generation insulin infusion pumps: clinical trial of a new miniature infuser.

We designed and constructed a new miniature, open-loop insulin infusion pump specifically to overcome the problems of many first generation insulin infusers. Special features are small size, adjustable volumetric basal infusion rate, rapid electronically mediated prandial insulin boosts, facility for doubling and halving the basal infusion rate and/or prandial delivery, and alarms for low battery state, motor over-run, stoppage, and control circuit malfunction. The infuser takes a specially designed syringe prefilled with short-acting insulin, sufficient in most diabetic patients for at least 7 days treatment with 100 U/ml insulin. To test clinical efficacy nine insulin-dependent diabetic patients received continuous subcutaneous insulin infusion (CSII) with the new infuser for periods up to 6 mo. Four patients previously CSII-treated with a first-generation pump and five who were new to CSII achieved and maintained the expected degree of near-normoglycemia. There were no pump breakdowns and a questionnaire completed by patients during the study confirmed ease and simplicity of operation and an appreciation of the advantages of the new pump compared with one widely used first-generation infuser.

Hypoglycemia and counterregulation in insulin-dependent diabetic patients: a comparison of continuous subcutaneous insulin infusion and conventional insulin injection therapy.

Eleven insulin-dependent diabetic patients were treated in random order by 2-mo continuous subcutaneous insulin infusion (CSII) or 2-mo conventional injection treatment (CIT) with crossover to the alternative regimen. Mean plasma glucose concentrations throughout the day were significantly lower during CSII than during CIT, but the percentage of plasma glucose values less than 2.5 mmol/L, obtained from outpatient self-collected diurnal profiles, was similar for both treatments (CSII vs. CIT: 5.9 and 4.8%, respectively). Reported symptomatic hypoglycemia at home was not significantly different in the whole group of patients treated by CSII or CIT but was reduced by a mean of 57% (P less than .02) in the five patients on CSII who experienced frequent symptomatic hypoglycemic episodes (greater than 4/2 mo) during CIT. Neither the plasma glucose concentration at which the patients recognized induced hypoglycemia nor the glycemic or counterregulatory hormone responses for 60 min thereafter were changed by CSII treatment.

Frequency of diabetic ketoacidosis and hypoglycemic coma during treatment with continuous subcutaneous insulin infusion. Audit of medical care.

The frequency of diabetic ketoacidosis and hypoglycemic coma in a large series of patients with insulin-dependent diabetes treated by long-term continuous subcutaneous insulin infusion was compared with the frequency of these events in a matched group of patients treated by conventional insulin injections at the same hospital over the same period of time. Ketoacidosis and hypoglycemic coma occurred no more frequently in continuous subcutaneous insulin infusion-treated patients. Therefore, intensified insulin therapy achieved by continuous subcutaneous insulin infusion does not appear to be associated with a greater risk of ketoacidosis or hypoglycemic coma than does conventional insulin therapy.

Cerebrotendinous xanthomatosis: a family study of sterol 27-hydroxylase mutations and pharmacotherapy.

We examined the phenotypic characteristics, molecular genetics and optimal pharmacological treatment of cerebrotendinous xanthomatosis (CTX) in an English family with combined hyperlipidaemia. The proband presented in adulthood with classical clinical characteristics of CTX, a greater than tenfold elevation in plasma cholestanol and combined hyperlipidaemia. His brother also had typical features of CTX without the presence of dyslipidaemia. Genotyping revealed that the two brothers were compound heterozygotes for a novel missense mutation in exon 2 (R94Q) and for a recently described nonsense mutation in exon 5, of the sterol 27-hydroxylase gene (CYP27). Analysis of all available family members revealed that hyperlipidaemia did not co-segregate with the presence of a CYP27 mutant allele. Trial of therapy showed that the lowest plasma sterol and triglyceride concentrations and cholestanol:cholesterol ratio were achieved with the combination of chenodeoxycholic acid (CDCA) 750 mg/day, a primary bile acid, and simvastatin 40 mg/day, an inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase. CDCA alone and simvastatin alone significantly lowered plasma cholestanol concentration, but the decrease was greater with the former. After 1 year there was significant improvement in both cognitive and motor function with regression of tendon xanthomata on computerized tomography. We conclude that CTX in this English pedigree is probably due to compound mutant alleles in CYP27, that combined hyperlipidaemia in this family is unrelated to CTX, and that this complicated condition responds optimally to the combination of CDCA and simvastatin.

Spontaneous pneumothorax in pregnancy and labour.

A case of spontaneous pneumothorax occurring at the end of labour in a healthy 17-year-old primigravida is described. Its occurrence was accompanied by marked surgical emphysema of the face, neck, arms and thorax. The patient had had previous thyroid surgery and was coincidentally found to have bilateral cervical ribs on chest X-ray. Previously described cases are reviewed, and the management discussed. Hypoxia to the fetus is a definite threat, and spontaneous pneumothorax should be considered in the differential diagnosis of chest pain and dyspnoea during delivery. It is a potential extragenital cause of maternal mortality.

Protein restriction, blood pressure and the progression of diabetic nephropathy.

Diabetic nephropathy is the long-term complication of diabetes responsible for the greatest increased mortality. Clinical nephropathy is characterised by a triad consisting of persistent proteinuria (total urinary protein greater than 0.5 g/24 h), rising arterial pressure and declining renal function. The role of treatment of raised blood pressure and the influence of dietary protein restriction on the established progressive phase of the disease are discussed. Subclinical elevations of urinary albumin excretion rates (greater than 30 micrograms/min; microalbuminuria), glomerular hyperfiltration and marginal elevations of arterial pressure are early markers of later clinical nephropathy which appear to respond to strict blood glucose control, blood pressure treatment and lowered dietary protein intake. Recent evidence to suggest that an inherited predisposition to raised arterial pressure may confer the susceptibility to diabetic nephropathy is presented.

Diabetogenic effect of cyclosporin.

A young woman given a renal allograft for polycystic kidney disease developed insulin dependent diabetes mellitus 25 days after transplantation. There was no family history of diabetes, plasma glucose concentrations had been normal at presentation and on five subsequent occasions, and at no time were islet cell antibodies detectable. Plasma C peptide concentrations, however, were greatly suppressed after transplantation and remained so for up to six months. The immunosuppressive regimen had included cyclosporin A, which had been difficult to regulate and caused definite signs of toxicity in the patient. By virtue of its reported toxicity for beta cells and the reversal of the diabetes several months after the dose was reduced cyclosporin was incriminated as the probable causative agent. Dose related beta cell toxicity of cyclosporin A may be a risk in recipients of this drug and warrants careful monitoring of drug and glucose concentrations.

Hypothyroidism in the elderly: clinical assessment versus routine screening.

A total of 304 patients aged 65 years or over were prospectively studied over a four-month period to assess whether clinical findings or routine screening were more helpful in diagnosing biochemical hypothyroidism. The most useful symptom relevant to a possible diagnosis of hypothyroidism in the elderly was found to be dry skin. Dermatological signs and certain ECG abnormalities (especially atrial fibrillation) were helpful when querying a diagnosis of hypothyroidism. Almost 50% of patients receiving amiodarone had abnormal thyroid function tests (TFTs). Routine screening for hypothyroidism does not seem justifiable from our available data although this conclusion may have been different had hospital clinicians and general practitioners followed their patients up more closely after an initial abnormal result was obtained.

Effect of low protein diet on the renal response to meat ingestion in diabetic nephropathy.

We measured the renal haemodynamic and proteinuric response to a meat meal (MM) in ten persistently proteinuric insulin-dependent diabetic patients in a randomized cross-over study of 3 weeks on low protein diet (LPD) or normal protein intake (NPD). On LPD, protein intake (0.64 +/- 0.05 vs 1.15 +/- 0.09 g kg-1 body weight (BW) per day, P less than 0.001), plasma urea (6.6 +/- 1.3 vs 11.0 +/- 2.0 mmol l-1, P less than 0.01) and urea appearance (0.06 +/- 0.01 vs 0.16 +/- 0.03 gN kg-1 body weight per day, P less than 0.001) were lower. Baseline glomerular filtration rate (GFR), renal plasma flow (RPF) and renal vascular resistance (RVR) were similar on the two diets and there were no significant average changes in these variables after the meat meal on either diet (NPD, before vs after MM: GFR: 67 +/- 11 vs 71 +/- 13 ml min-1 1.73 m-2; RPF: 479 +/- 70 vs 512 +/- 81 ml min-1 1.73 m-2; RVR: 181 +/- 45 vs 179 +/- 52 mmHg min-1 l-1); (LPD, before vs after MM: GFR: 64 +/- 10 vs 67 +/- 11 ml min-1 1.73 m-2; RPF: 506 +/- 60 vs 533 + 52 ml min-1 1.73 m-2; RVR: 151 +/- 28 vs 146 +/- 32 mmHg min-1 l-1). However, all patients with baseline GFR above 60 ml min-1 1.73 m-2 showed a GFR rise in response to the meat meal on both diets, while patients with lower baseline values tended to reduce their GRF.(ABSTRACT TRUNCATED AT 250 WORDS)

Intermittent clinical proteinuria and renal function in diabetes: evolution and the effect of glycaemic control.

The evolution of renal disease was studied in 12 insulin dependent diabetics selected for intermittent clinical proteinuria. After a run in period during which patients were studied three monthly for at least 12 months members of pairs of patients matched for age and duration of diabetes were allocated either to receive continuous subcutaneous insulin infusion or to continue with their usual conventional insulin injection therapy (controls) and studied three monthly for a further year. Mean (SEM) plasma glucose concentration and glycosylated haemoglobin (HbA1) value improved significantly in the insulin infusion group (glucose 10.1 (1.0) v 5.3 (0.3) mmol/l (182 (18) v 95 (5) mg/100 ml); HbA1 9.6 (0.8) v 7.6 (0.5)%; p less than 0.001 and p less than 0.005, run in v experimental periods) but not in the control group. Blood pressure was kept normal throughout. Glomerular filtration rate fell significantly in the insulin infusion and control groups throughout the study, from mean (SEM) baseline values of 114 (16) and 119 (15) ml/min/1.73 m2 to final values of 92 (15) and 95 (13) ml/min/1.73 m2 respectively (p less than 0.05 and p less than 0.01). The mean rate of decline in glomerular filtration rate did not change significantly in either group (run in v experimental periods: insulin infusion group 1.0 v 0.8 ml/min/month; controls 0.8 v 0.9 ml/min/month). Mean (SEM) plasma creatinine concentration rose slightly in the insulin infusion group only (93 (5) to 109 (11) mumol/l (1.1 (0.06) to 1.2 (0.1) mg/100 ml), 0.1 greater than p greater than 0.05; controls 94 (6) to 96 (6) mumol/l (1.1 (0.07) and 1.1 (0.07) mg/100 ml]. The urinary excretion rate of albumin varied widely and unpredictably throughout, while beta 2 microglobulin excretion remained normal and unchanged in both groups. Thus a at the stage of intermittent clinical proteinuria when albumin excretion rate is unpredictably variable (breaking through the "clinically positive" threshold only episodically) renal function, though still in the "normal" range, is already declining progressively; and the study failed to show that sustained improvement in mean glycaemia exerts a significant effect on this early deterioration of renal function.

Long term correction of hyperglycaemia and progression of renal failure in insulin dependent diabetes.

The effect of long term correction of hyperglycaemia on the rate of deterioration of renal function was studied in six insulin dependent diabetics with proteinuria due to diabetic nephropathy. After a planned run in observation period of 10 to 24 months patients entered a programme of continuous subcutaneous insulin infusion for up to 24 months. Glycaemic control was promptly and significantly improved and optimal glycaemic values sustained throughout the study. Blood pressure was maintained stable. A control group of six nephropathic diabetics was studied receiving conventional insulin injection treatment but also with blood pressure control over the same period.Despite greatly improved metabolic control in the infusion treated group no significant change in the rate of decline of glomerular filtration rate could be shown, the plasma creatinine concentrations continued to increase, and the fractional clearance of albumin and IgG rose progressively, indicating progression of glomerular damage. The conventionally treated control group behaved similarly. In a single patient receiving the continuous infusion the rate of decline of the glomerular filtration rate slowed considerably, suggesting that the response to strict diabetic control may differ in some patients.These findings suggest that by the time glomerular function has started to fail in diabetic nephropathy the process culminating in end stage renal failure has become self perpetuating and is little influenced by the degree of metabolic control. A new definition of potential clinical diabetic nephropathy is proposed that will permit identification of patients at risk and earlier intervention by glycaemic correction in an attempt to arrest diabetic renal disease.

Human cysticercosis and intestinal parasitism amongst the Ekari people of Irian Jaya.

A random sample of 242 people showed that 42 had palpable cysts of Taenia solium. Faecal examination recovered eggs of T. solium in seven (3%), while Trichuris (83%), Ascaris (83%), hookworms (76%), Strongyloides stercoralis (10%) and Strongyloides sp. (29%), Entamoeba histolytica (14%), Entamoeba coli (22%), Entamoeba hartmanni (7%), Entamoeba polecki (7%), Balantidium coli (9%) and Dientamoeba fragilis (21%) were the most common other intestinal parasites encountered. ELISA tests, using antigens prepared from adults and eggs of T. solium and from cysticerci of T. saginata were not very sensitive, the last diagnosing less than half of known positives while still retaining good specificity.

Increased sodium-lithium countertransport activity in red cells of patients with insulin-dependent diabetes and nephropathy.

Susceptibility to diabetic nephropathy may be related to a predisposition to arterial hypertension. We have studied the activity of sodium-lithium countertransport in red cells, a marker of risk for essential hypertension, in white European adults with insulin-dependent diabetes and diabetic nephropathy, a matched group of patients with diabetes without renal disease, and nondiabetic patients with renal disease. Measures of metabolic control and concentrations of plasma free insulin and growth hormone were similar in the two diabetic groups. The degree of impairment in renal function was similar in the diabetic and nondiabetic patients with renal disease. Body-mass index and plasma potassium concentrations were similar in all three groups. Diastolic blood pressure was elevated to a similar degree in the two groups with renal disease, as compared with that in the diabetic patients without renal disease. The rates of sodium-lithium countertransport in red cells were significantly higher in the diabetic patients with renal disease (mean +/- SD, 0.55 +/- 0.19 mmol of lithium per liter of red cells per hour) than in the diabetic patients without renal disease (0.33 +/- 0.16; P less than 0.005) and in the nondiabetic patients with renal disease (0.31 +/- 0.14; P less than 0.001). Predisposition to hypertension, as indicated by elevated sodium-lithium countertransport activity in red cells, may serve as a marker for the risk of renal disease in patients with insulin-dependent diabetes.

Glycaemic control in diabetic nephropathy.

To investigate the quality of glycaemic control that is achievable in diabetic patients with persistent proteinuria and asymptomatic but declining renal function three matched groups of patients were studied. The first comprised diabetics with proteinuria receiving continuous subcutaneous insulin infusion; the second, diabetics without proteinuria receiving continuous subcutaneous insulin infusion; and the third, diabetics with proteinuria receiving conventional insulin treatment. Glycaemic control in patients receiving continuous subcutaneous insulin infusion was shown to be appreciably worse during the daytime in diabetics with proteinuria than in diabetics without proteinuria, although greatly superior to that in diabetics with proteinuria receiving conventional insulin treatment. The loss of glycaemic control in patients with proteinuria receiving continuous subcutaneous insulin infusion probably occurred as a response to daytime hypoglycaemia and a consequent reduction in the proportion of the total insulin dose given prandially. Difficulty in controlling blood glucose concentrations may be a factor in the failure of intensified insulin regimens to influence the progression of diabetic renal disease.