Alicia Schiffrin

Hyperglycemia After Intense Exercise in IDDM Subjects During Continuous Subcutaneous Insulin Infusion

Exercise is conventionally considered a modality for improvement of glycemia in diabetes. We have found that a short period of intense exercise (80% ) in normal lean subjects produces sustained postexercise hyperglycemia 20% above basal with a corresponding 100% increase in plasma insulin. In people with insulindependent diabetes mellitus (IDDM) incapable of this insulin response, it was predicted that postexercise hyperglycemia would be of greater magnitude and/or duration. To investigate this possibility, the effects of the same intense exercise (80% ) were studied in 8 IDDM subjects (2 on 2 occasions) in the postabsorptive state with continuous subcutaneous (abdominal) insulin infusion (CSII). When the preexercise plasma glucose was normal (n = 6, 86 ± 4 mg/dl), there ensued a postexercise hyperglycemia to 127 ± 7 mg/dl (P < .001) sustained for 2 h postexhaustion. Plasma free immunoreactive insulin (IRI) was 1.43 ± 0.12 ng/ml before exercise and did not change postexercise. When mean preexercise plasma glucose was 149 ± 9 mg/dl (n = 4), it rose progressively throughout the 2 h of recovery to 229 ± 28 mg/dl (P < .025). A small but statistically significant decrease in free IRI occurred during the last 80 min of recovery. Hyperglycemia in the diabetic subjects was not explained by abnormal or differing responses of glucagon or catecholamines. Thus, with intense exercise, diabetic control deteriorates rather than improves. Therefore, different therapeutic strategies may be required for intense compared with moderate exercise in IDDM patients.

Severe Hypoglycemia in IDDM Children

The incidence of severe hypoglycemia was determined in a 1-yr prospective study of 350 insulin-dependent diabetic (IDDM) children. There were no significant differences in mean glycosylated hemoglobin, age, and duration of disease between the patients who had severe hypoglycemia and those who did not. There were 25 episodes in 24 patients (6.8%). Their insulin doses at the time of the episode (U · kg−1 · day−1) were significantly higher than those of the nonhypoglycemic group (mean ± SD 1.01 ± 0.30 vs. 0.89 ± 0.29; P = .04). The hypoglycemic group had a significantly higher mean number of previous episodes of severe hypoglycemia than the nonhypoglycemic group (0.92 ± 1.18 vs. 0.25 ± 0.68; P = .01). In only 64% of the episodes, an unusual circumstance such as strenuous physical activity or missed or delayed meals preceded the event. Multivariate analysis of the data by logistic regression showed risks of developing hypoglycemia of 2.5 per 0.5 U/day insulin and of 2.0 per previous episode of severe hypoglycemia. We conclude that severe hypoglycemia may be a recurrent problem in some diabetic children, but it does not appear to be related to age or blood glucose control. The presence of previous episodes may be a guide to identify patients at greater risk of developing severe hypoglycemia. Adherence to regular testing, strict spacing and consistency of meals, and extra food for extra activity may reduce this serious complication.

Accommodating Planned Exercise in Type I Diabetic Patients on Intensive Treatment

To achieve optimal metabolic control in type I diabetic patients treated with continuous subcutaneous insulin infusion (CSII) and multiple subcutaneous injections of insulin (MSI) appropriate adjustments of the insulin prescription should be made for exercise, which is a normal component of everyday life. The present study describes the responses of seven type I diabetic adolescents treated with CSII and six patients treated with MSI to specific insulin dose changes in anticipation of postprandial exercise. The effect of 45 min of cycle ergometer exercise at 55% VO2 on glucose regulation was studied 2 h after morning insulin and a breakfast meal. To quantify the potential benefit of modifying the insulin dose before exercise, the subjects were studied on five different days in a random order: (1) resting control day, (2) postprandial exercise preceded by the usual dose of insulin, (3) postprandial exercise preceded by one-half of the usual dose of insulin, (4) postprandial exercise preceded by two-thirds of the usual dose of insulin, and (5) postprandial exercise without the usual dose of insulin. In all cases insulin was injected or infused subcutaneously in the anterior abdominal wall. When exercise was performed without changing the usual insulin dose, there was a significant fall in glycemia in both groups, with the nadir occurring after 45 min. In the CSII group, the ± SEM plasma glucose was 57 ± 5 mg/dl (P < 0.05 versus rest) with hypoglycemia occurring in four patients. In the MSI group, the mean ± SEM plasma glucose fell to 65 ± 10 mg/dl (P < 0.05 versus rest) and hypoglycemia occurred in three patients. This was corrected with the administration of approximately 25 g of glucose by mouth. When exercise was performed after one-half and two-thirds of the usual insulin dose, the plasma glucose profile observed during exercise in both groups was not statistically different from that observed during the rest day. Postprandial exercise without prior insulin resulted in significant hyperglycemia in both groups (P < 0.01). Plasma free insulin levels remained unchanged throughout the exercise period in all protocols. A 50–66% reduction of the insulin dose in anticipation of postprandial exercise of moderate intensity resulted in near-normal glycemic values and prevented hypoglycemia. Alternatively, in the case of unplanned postprandial exercise of 45 min duration, the intake of 25–30 g of glucose may prevent hypoglycemia in the CSII- and MSI-treated type I diabetic patients.

Effects of dietary protein restriction on glucose and insulin metabolism in normal and diabetic humans

We determined whether the amount of protein in the diet can affect insulin requirements in subjects with diabetes mellitus and glucose metabolism in normal subjects. Seven normal-weight volunteers with uncomplicated, intensively controlled, type I (insulin-dependent) diabetes and 12 similar nondiabetic subjects were studied on a metabolic ward before and after consuming a maintenance-energy but protein-free diet for 10 days. Blood glucose levels of diabetic subjects were measured seven times daily in response to insulin administration by continuous subcutaneous infusion. The plasma glucose appearance rate (Ra) was measured in seven normal subjects and all diabetic subjects using a primed-continuous infusion of D-[6,6-2H2]glucose. After adaptation to the protein-restricted diet, diabetic subjects experienced a 30% decrease in average preprandial and average daily blood glucose concentrations (P < .01); this occurred despite a concurrent 25% decrease in both basal and bolus insulin dosages (P < .001). Protein restriction decreased the postabsorptive glucose Ra (P < .05) and insulin concentrations (P < .01) of normal subjects by 20%, and increased their fasting glucagon concentrations by 24% (P < .01). We conclude that severe protein restriction decreases insulin requirements in type I diabetes and fasting hepatic glucose output and basal insulin levels in normal subjects. This effect appears to be mediated in part by decreased hepatic gluconeogenesis, but a contributory influence of increased insulin sensitivity is not ruled out.

Intensified Insulin Therapy in the Type I Diabetic Adolescent: A Controlled Trial

The effects of continuous subcutaneous insulin infusion (CSII), intensified conventional therapy (ICT), and a combination of CSII and ICT (CSII-ICT) on metabolic control were compared in a group of twenty type I diabetic adolescents who had previously failed to respond to twice-daily injections and home glucose monitoring. A marked improvement in control was observed when mean glycemia and glycosylated hemoglobin A1 (HbA1) were compared with conventional therapy (CT). In the course of CSII, a lower HbA1 (P < 0.05) and mean capillary blood glucose (CBG) (P < 0.04) were observed than during ICT and CSII-ICT. Acceptability of CSII was greater that of ICT and CSII-ICT, with 50% of the patients opting for this therapy at the end of the 1-yr trial. The marked improvement of control observed under CSII for the group as a whole was maintained after 6 mo of completion of the study. Thus, it appears that in type I diabetic adolescents CSII is more effective and acceptable than ICT and CSII-ICT.

Factors Predicting Course of β-cell Function in IDDM

OBJECTIVE The purpose of this study was to determine whether the severity o clinical presentation, sex, age, HLA type, and the presence of IAs and ICAs could predict the variation of residual insulin secretion as measured by the serum C-peptide response to a Sustacal meal. RESEARCH DESIGN AND METHODS A cohort of 151 newly diagnosed IDDM children (mean age 10.2 ± 4.6 yr) was followed prospectively for 3 yr. Thirty-five patients (12 males, 23 females) were still secreting C-peptide after 36 mo. RESULTS We found that age (P = 0.0001), sex (P = 0.003), presence of ICA (P = 0.006), severity of clinical presentation (P = 0.001), and symptom duration (P = 0.002) significantly predicted the rate of loss of C-peptide secretion. The risks of accelerated C-peptide disappearance decreased with increasing age, the risk ratios being 0.25 for the older group (> 12 yr) compared with the younger group (< 6 yr) and 0.50 for the intermediate group (6–12 yr) compared with the younger group. The risk for the presence of ICA was 1.7, and the risk for males was 1.7 also. There was a significant negative correlation between ICA titers and C-peptide at 18 and 24 mo after diagnosis (P = 0.04). There were no significant differences in HbA1 values between patients who secreted C-peptide and those who did not. CONCLUSIONS We conclude that younger age of onset, male sex, high titers of ICA, severe clinical presentation, and shorter symptom duration significantly predict accelerated rates of loss of C-peptide secretion.

Evaluation of Two Methods of Self Blood Glucose Monitoring by Trained Insulin-dependent Diabetic Adolescents Outside the Hospital

We studied the accuracy of the Chemstrip bG and Glucometer systems in the self-monitoring of blood glucose by trained adolescents. The determinations were done at home with simultaneous collection of whole blood into capillary tubes (Sarstedt) which were later analyzed by a glucose-Oxidase analyzer (Beckman Instruments). In both cases, there was an excellent correlation between laboratory concen-trations and Chemstrip bG (r = 0.96, P < 0.001) and Glucometer (r = 0.96, P < 0.001). Comparisonsmade at 8 mo remained with the same degree of accuracy. There was a trend toward greater deviation with higher plasma glucose values. Well-trained patients can achieve sufficientaccuracy to permit the use of either of the methods tested with similar results.

Prospective Study of Predictors of β-Cell Survival in Type I Diabetes

We conducted a prospective study to describe the course of the pancreatic β-cell function from the time of clinical diagnosis of insulin-dependent (type I) diabetes to determine whether DR type, presence of islet cell antibodies (ICA), presence of insulin antibodies (IA), age at onset, and sex could help in the prediction of residual endogenous insulin secretion. A cohort of 68 children was followed for 18 mo after diagnosis of type I diabetes. The outcome variables selected for analysis were 1)serum C-peptide peak concentration after a Sustacal meal, 2) time of disappearance of the serum C-peptide response, and 3) time after diagnosis at which the maximal serum C-peptide response was observed. After institution of insulin therapy, serum C-peptide peak concentrations rose temporarily for 1–6 mo and declined thereafter. Multivariate analysis of the data showed that DR type (P = .2488) and presence of IA (P = .1604) had no effect on serum C-peptide over time, but sex (P = .0146), age at onset (P = .0002), and presence of ICA (P = .0147) significantly contributed to the variation of serum C-peptide over time. Furthermore, age at onset, presence of ICA, and sex were also the only significant predictors of the time of disappearance of the β-cell function. The relative risks of β-cell-function disappearance were 0.87 (P = .0015), 9.43 (P = .0181), and 2.25 (P = .0468), respectively. In conclusion, there are distinct variations in the natural course of the β-cell function in type I diabetes. β-Cell-function survival is significantly shortened the younger the subject is at disease onset, if ICA are present at diagnosis, and if the subject is male.

Feasibility of strict diabetes control ininsulin-dependent diabetic adolescents

Nineteen insulin-dependent diabetic adolescents who had poor control on twice daily injections and home glucose monitoring participated in a study assessing the feasibility of improved control. Using a randomized crossover protocol, we examined the relative efficacy of continuous subcutaneous insulin infusion and of intensive conventional therapy with three or four daily injections of insulin. Both therapies were regulated with home glucose monitoring. A marked improvement in control with both therapies was observed when mean blood glucose and glycosylated hemoglobin A1 were compared with conventional therapy. However, pump therapy resulted in significantly lower HbA1 than intensive therapy (P less than 0.05), despite a significantly lower total insulin dose (P less than 0.01). We conclude that in adolescents with type I diabetes, continuous subcutaneous insulin infusion is more effective in achieving improvement of diabetes control than is intensive conventional therapy in the outpatient setting.

Impact of SMBG on control of diabetes as measured by HbA1. 3-yr survey of a juvenile IDDM clinic.

Three hundred twelve diabetic children and adolescents were seen in our diabetic clinic and instructed to test their capillary blood glucose (CBG) twice daily and to use an algorithm to adjust their short-acting insulin. Of this group, 219 youngsters had a full 3-yr period of observation. At each clinic visit, blood was obtained for fasting blood glucose and HbA, and, once a year, cholesterol and triglycerides were also measured. Patient and parent accuracy in measuring CBG was found to be adequate. The changes over time in HbA, were nondifferential across age and sex, and there was no difference in the level of HbA, between age and sex groups, the number of tests reported to have been done by the patients, the number of injections of insulin per day, or the serum cholesterol. There was a significant relationship between the HbA1 and the fasting blood glucose (P < .001) measured by the laboratory as well as with the serum triglyceride (P < .01). The failure to improve diabetic control, despite measures that would have been expected to do so, was believed to relate more to a lack of compliance than to a flaw in the therapeutic approach. It was interesting to note that the adolescent patients in the study were in no worse control than the younger children in the group. Although better technical skills are available today to manage diabetes, the psychosocial approach to patient motivation requires improvement.