Jeremy J Bending

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.

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.

Restriction of dietary protein and progression of renal failure in diabetic nephropathy

In a study of the effect of a low-protein diet on the progression of renal disease 19 insulin-dependent diabetic patients with persistent clinical proteinuria were observed for 12-39 (mean 29) months while they were on a normal-protein diet (1.13 [0.06] g/kg per day), then for 12-49 (mean 33) months on a low-protein diet (0.67 [0.03] g/kg per day). The low-protein diet had no adverse effect on nutrition or glycosylated haemoglobin concentration. Mean supine blood pressure (BP) fell slightly on the low-protein diet and was probably due to the start or modification of antihypertensive medication in 9 patients. The mean rate of decline in glomerular filtration rate fell from 0.61 (SEM 0.14) ml/min per month with the normal-protein diet to 0.14 (0.08) with the low-protein diet, and this effect remained highly significant after adjustment for blood pressure, energy intake, and glycosylated haemoglobin. The rise in the fractional clearance of albumin during a normal-protein diet stopped with the low-protein diet, and there was a significant fall in albumin excretion from 467 (95% CI 234-895) micrograms/24 h on the normal-protein to 340 (138-719) on the low-protein diet. Thus, a low-protein diet, with its reduction in protein and possibly other dietary components such as phosphate or fat, seems to retard the rate of decline of glomerular filtration rate in diabetic nephropathy independently of blood pressure changes and glycaemic control.

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.

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 < .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 < .006), and there was a significant fall in the median fractional clearance of albumin from 2.0 × 10−4 (range 0.1–90.9) on UPD to 1.0 × 10−4 (range 0.1–51.4) on LPD and IgG from 2.1 × 10−5 (range 0.2–238) to 1.5 × 10−5 (range 0.1–77) (P < .006 and P < .02, respectively). The reabsorption rate of β2-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.

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 < 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.

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 >0.5 and <3.5 g/24 h) and 8 with nephrotic proteinuria (total urinary protein excretion rate > 3.5 g/24 h), and in 17 age-, sex-, and duration-of-diabetes–matched diabetic control subjects without clinical proteinuria (total urinary protein <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 × 106/ml, 40–320 × 106/ml; 13.9%, 8.1–19.4%) compared with nonproteinuric control subjects (81 × 106/ml, 2–240 × 106/ml, P < .05; 6.2%, 0–13.1%, P < .01). In 8 patients with nephrotic proteinuria, absolute and percent DR-positive T-lymphocytes tended to be lower (36 × 106/ml, 14–56 × 106/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.

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 CSIIinduced metabolic correction upon microalbuminuria. Twenty-four-hour urine collections obtained at baseline, 4, and 8 mo were available from 59 Albustix-negative patients. β2-microglobulin excretion was normal. The 39 normoalbuminuric (AER < 12 μ/min) patients did not differ from the 20 microalbuminuric (AER elevated between 13.2 and 192.6 μg/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 < 0.05) and 8 (P < 0.01) mo but showed no consistent change in the CIT microalbuminuric group. With respect to responses of patients at particularly high risk of progression to clinical nephropathy (i.e., AER > 30 μ/min), four of four improved during CSII, but only two of six during CIT. These observations demonstrate a sustained reduction of abnormal rates of urinary albumin excretion during therapy designed to achieve near-normoglycemia in IDDM.

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 <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 < .02) in the five patients on CSII who experienced frequent symptomatic hypoglycemic episodes (>4/2 mo) during CIT. Neither the plasma glucose concentration at which the patients recognizedinduced hypoglycemia nor the glycemic or counterregulatory hormone responses for 60 min thereafter were changed by CSII treatment.

A new miniature, open-loop, extracorporeal insulin infusion pump.

This extracorporeal insulin infuser has been designed to be compact, simple to operate, and suitable either for clinical investigations of insulin-dependent diabetes mellitus or for long term treatment of the condition. A syringe driver of unconventional design is used, and the syringe will be available prefilled with insulin, specially formulated at standard strength for long term infusion. The device is electronically controlled to give variable rates of basal infusion, preset by switch and supplemented by bolus infusions demanded by pushbutton prior to meals. Sufficient insulin is carried in the syringe to meet the needs of most diabetics for at least a week without refilling, and the battery life is commensurately long. Signalling of the mealtime dose regime, and of alarm and failure conditions is by audible means. Insulin will most commonly be delivered subcutaneously, though other routes are possible.