Effect of continuous subcutaneous insulin infusion with lispro on hepatic responsiveness to glucagon in type 1 diabetes

OBJECTIVE: People with type 1 diabetes frequently develop a blunted counterregulatory hormone response to hypoglycemia coupled with a decreased hepatic response to glucagon, and consequently, they have an increased risk of severe hypoglycemia. We have evaluated the effect of insulin lispro (Humalog) versus regular human insulin (Humulin R) on the hepatic glucose production (HGP) response to glucagon in type 1 diabetic patients on intensive insulin therapy with continuous subcutaneous insulin infusion (CSII). RESEARCH DESIGN AND METHODS: Ten subjects on CSII were treated for 3 months with lispro and 3 months with regular insulin in a double-blind randomized crossover study After 3 months of treatment with each insulin, hepatic sensitivity to glucagon was measured in each subject. The test consisted of a 4-h simultaneous infusion of somatostatin (450 microg/h) to suppress endogenous glucagon, regular insulin (0.15 mU x kg(-1) x min(-1)), glucose at a variable rate to maintain plasma glucose near 5 mmol/l, and D-[6,6-2H2]glucose to measure HGP During the last 2 h, glucagon was infused at 1.5 ng x kg(-1) x min(-1). Eight nondiabetic people served as control subjects. RESULTS: During the glucagon infusion period, free plasma insulin levels in the diabetic subjects were 71.7+/-1.6 vs. 74.8+/-0.5 pmol/l after lispro and regular insulin treatment, with plasma glucagon levels of 88.3+/-1.8 and 83.7+/-1.5 ng/l for insulin:glucagon ratios of 2.8 and 3.0. respectively (NS). However, plasma glucose increased to 9.2+/-1.1 mmo/l after lispro insulin compared with 7.1+/-0.9 mmol/l after regular insulin (P < 0.01), and the rise in HGP was 5.7 +/-2.8 micromol x kg(-1) x min(-1) after lispro insulin versus 3.1+/-2.9 micromol x kg(-1) x min(-1) after regular insulin treatment (P=0.02). In the control subjects, HGP increased by 10.7+/-4.2 micromol x kg(-1) x min(-1) under glucagon infusion. CONCLUSIONS: Insulin lispro treatment by CSII was associated with a heightened response in HGP to glucagon compared with regular human insulin. This suggests that insulin lispro increases the sensitivity of the liver to glucagon and could potentially decrease the risk of severe hypoglycemia.     

Hyperinsulinemia and hypofibrinolysis: effects of short-term optimized glycemic control with continuous insulin infusion in type II diabetic patients

A defect in the fibrinolytic system results from an increase in type 1 plasminogen activator inhibitor (PAI-1) in diabetes. It can be considered an independent risk factor for the development of cardiovascular disease. In obese and type II diabetic patients, plasma PAI-1 level correlates with fasting insulinemia. However, during the euglycemic clamp, acute hyperinsulinemia does not increase PAI-1 production. The present study was undertaken to investigate the effect of optimized glycemic control by continuous subcutaneous insulin infusion (CSII) on the hypofibrinolytic state for 14 days in 16 type II diabetic patients with poor metabolic control despite maximal oral antidiabetic treatment. Plasma PAI-1 activity levels decreased from 13.38 +/- 2.85 IU/mL to 6.77 +/- 1.81 IU/mL (P = .002) during CSII, along with a concurrent improvement in insulin sensitivity (index obtained by basal glycemia-nadir glycemia/basal glycemia) during the insulin sensitivity test (0.121 +/- 0.03 v 0.057 +/- 0.02, P = .02). These results suggest that insulin resistance rather than hyperinsulinism may be involved in the hypofibrinolytic state in type II diabetic patients. The positive correlation between the changes in triglycerides and in PAI-1 activity (r = .589, P = .026) strongly suggests a role for triglycerides in the impairment of fibrinolysis, which could be a link between insulin resistance and hypofibrinolysis.     

Conrad Berens Lecture. The management of infectious keratitis as we approach the 21st century

We have assessed the capacity of continuous subcutaneous insulin infusion (CSII) to maintain good blood glucose metabolic control on Sundays, when waking is delayed, with reference to intensified conventional insulin therapy by multiple daily injections (MDI). The study lasted 3 weeks, including 3 week-ends. A total of 20 IDDM patients were selected for metabolic control: ten were treated by CSII and ten by MDI. Blood glucose was determined at least three times a day (fasting on waking, pre-lunch and pre-dinner). The times of blood glucose determinations and their values were recorded in a memory reflectance meter. Waking, the first blood glucose measurement and the first insulin injection (MDI) or bolus (CSII) were about 1 h later on Sundays than on a weekday (44 +/- 4 min in MDI group, P < 0.04; and 59 +/- 7 min in CSII group, P < 0.02). The times of the pre-lunch and pre-dinner blood glucose determinations were not significantly different. The mean waking and pre-lunch blood glucose values of the MDI group were higher on Sundays (11.5 +/- 3.8 and 9.7 +/- 4.5 mmol/l) than on weekdays (8.7 +/- 2.3 and 7.1 +/- 2.5 mmol/1)(P < 0.01). The pre-prandial blood glucose levels of the CSII group on Sundays and weekdays were not statistically different at any time. Changes in the waking time and the subsequent delay in the first insulin bolus on Sunday may alter blood glucose control in patients on MDI, but CSII allows such changes without any glycemic side effects.     

Molecular characterization of a single mitochondria-associated double-stranded RNA in the green alga Bryopsis

OBJECTIVE: To evaluate the effect of a moderate dose of fish oil on glycemic control and in vivo insulin action in type 2 diabetic men with elevated plasma triacylglycerols and to determine the effect of the same treatment on gene expression of GLUT4, lipoprotein lipase (LPL), and hormone-sensitive lipase (HSL) in the abdominal adipose tissue. RESEARCH DESIGN AND METHODS: A total of 12 type 2 diabetic men were randomly allocated to 2 months of 6 g daily of either fish oil or sunflower oil, separated by a 2-month washout interval, in a double-blind crossover design. RESULTS: For glucose metabolism, 2 months of fish oil supplementation compared with sunflower oil led to similar fasting plasma insulin, glucose, and HbA1c. Basal hepatic glucose production did not increase after fish oil. There was no difference in insulin suppression of hepatic glucose production nor in insulin stimulation of whole-body glucose disposal measured by the euglycemic-hyperinsulinemic clamp. Fish oil did not ameliorate the low mRNA level of GLUT4 in adipose tissue of these patients. For lipid profile, fish oil lowered plasma triacylglycerol more than sunflower oil (P < 0.05) and tended to increase the amount of mRNA of both LPL and HSL in adipose tissue. CONCLUSIONS: A moderate dose of fish oil did not lead to deleterious effects on glycemic control or whole-body insulin sensitivity in type 2 diabetic men, with preserved triacylglycerol-lowering capacities.     

Pulsed-field gel electrophoresis genomic fingerprinting of hospital Escherichia coli bacteraemia isolates

To study the effects of massive weight loss on insulin secretion, we analysed the oscillations of fasting peripheral insulin levels in obese patients who underwent vertical banded gastroplasty as treatment for morbid obesity. Patients were studied before and 6 months after surgery. Serial measurements of plasma free insulin levels were obtained in duplicates from 0 to 60 min at one-minute intervals. Insulin levels were then analysed by autocorrelation and Fourier transformation. In normal controls and obese patients, the first oscillatory insulin component was detected between 10 and 14 min. Compared to obese controls (n = 4), overt Type 2 diabetic patients (n = 4) had reduced amplitudes of insulin pulses and no oscillatory component. These defects were not as pronounced in patients with impaired glucose tolerance (IGT) after an oral glucose tolerance test (OGTT) (n = 5). When detected, the periodicity of the oscillations occurred at different periods. In 3/5 IGT patients, the first positive peak of correlation was found at 13.3 +/- 2.3 min. Weight loss (mean +/- SD) after 6 months was 24.3 +/- 3.7 for subjects with normal glucose tolerance (NGT), 37.9 +/- 9 for those with IGT and 29.8 +/- 5 kgs for Type 2 diabetic subjects. After weight loss, insulin oscillatory activity was detected in 4/5 IGT patients, with a period of 13 +/- 3 min. Weight loss did not reverse the defects observed in obese diabetic patients despite a significant reduction in peripheral insulin levels from 28.6 +/- 6 to 15.6 +/- 6 mU/l (p < 0.05). Insulin values remained higher than in obese controls (7.82 +/- 2, p < 0.05), and Type 2 patients remained mildly hyperglycaemic. These findings indicate that beta-cell activity is abnormal in Type 2 diabetic patients. The absence of modification after weight loss suggests that inherent beta-cell defects may contribute to hyperglycaemia.     

Effect of obesity on the response to insulin therapy in noninsulin-dependent diabetes mellitus

An initial improvement in glycemic control is often followed by gradual deterioration of glycemia during insulin treatment of patients with noninsulin-dependent diabetes mellitus (NIDDM). We examined the causes of such worsening in a 12-month follow-up analysis of 100 insulin-treated NIDDM patients in the Finnish Multicenter Insulin Therapy Study who were treated with either combination therapy with insulin or insulin alone. In the entire study group, glycemic control averaged 9.7 +/- 0.2% at 0 months and 8.0 +/- 0.1%, 8.0 +/- 0.1%, 8.2 +/- 0.1%, and 8.5 +/- 0.2% at 3, 6, 9, and 12 months (P < 0.001 for each time point vs. 0 months). Glycemic control at 12 months was significantly worse than that at 3 (P < 0.001), 6 (P < 0.001), and 9 months (P < 0.02). Baseline body mass index was the most significant predictor of deterioration in glycemic control. During 1 yr, hemoglobin A1c decreased almost 3-fold more (by 1.7 +/- 0.2%; P < 0.001 vs. 0 months) in patients whose baseline weight was below the mean baseline body mass index of 28.1 kg/m2 (nonobese patients) than in those whose weight exceeded 28.1 kg/m2 (obese patients; 0.5 +/- 0.2%; P = NS vs. 0 months; P < 0.01 vs. obese patients). Glycemic control improved similarly over 1 yr in the nonobese subjects and deteriorated similarly in the obese patients regardless of their treatment regimen. Insulin doses, per body weight, were similar in the nonobese and obese patients. The nonobese patients consistently gained less weight during 12 months of combination therapy with insulin (3.5 +/- 0.6 kg at 12 months) than during insulin therapy alone (5.1 +/- 0.6 kg; P < 0.05). The treatment regimen did not influence weight gain in the obese group, who gained 4.4 +/- 1.0 kg during combination therapy with insulin and 4.5 +/- 1.1 kg during insulin therapy alone. We reached the following conclusions: 1) after an initial good response, glycemic control deteriorates more in obese than in nonobese patients with NIDDM; 2) in obese patients, weight gain per se cannot explain the poor glycemic response to combination or insulin therapy, but it may induce a disproportionately large increase in insulin requirements because of greater insulin resistance in the obese than in the nonobese; 3) in nonobese patients, glycemic control improves equally during 1 yr with combination therapy with insulin and insulin alone, but combination therapy with insulin is associated with less weight gain than treatment with insulin alone; 4) weight gain appears harmful, as it is associated with increases in blood pressure and low density lipoprotein cholesterol.     

Effects of glycemic control on plasma 3-deoxyglucosone levels in NIDDM patients

OBJECTIVE: To clarify the effects of glycemic control on the level of 3-deoxyglucosone (3-DG), a reactive dicarbonyl compound, in plasma from diabetic patients. RESEARCH DESIGN AND METHODS: Fasting plasma samples were collected from 15 healthy volunteers and 27 patients with NIDDM. Samples were collected from six poorly controlled patients before and after improved glycemic control for at least 2 months. Plasma 3-DG was determined by high-performance liquid chromatography (HPLC) as a 2,3-diaminonaphthalene derivative. We observed the relationship of 3-DG levels with plasma glucose or HbA1c levels and examined changes in 3-DG levels after glycemic control in the six patients. RESULTS: Plasma 3-DG was significantly more increased in diabetic patients than in nondiabetic control subjects (31.8 +/- 11.3 vs. 12.8 +/- 5.2 ng/ml, means +/- SD, P < 0.001), but there was an approximately threefold difference in 3-DG levels among diabetic patients. 3-DG levels were well correlated with plasma glucose (r = 0.56, P < 0.005) and HbA1c levels (r = 0.74, P < 0.001) in diabetic patients. The improvement of hyperglycemia in six patients resulted in a significant decrease in 3-DG (35.2 +/- 13.2 vs. 21.3 +/- 3.4 ng/ml, P < 0.05). CONCLUSIONS: The results indicate that the plasma glucose level is a predominant determinant of the plasma 3-DG level in diabetic patients and good glycemic control would be important to reduce this reactive metabolite.     

Muscle sympathetic nerve activity is reduced in IDDM before overt autonomic neuropathy

Studies of heart-rate variability have demonstrated that abnormal cardiac parasympathetic activity in individuals with IDDM precedes the development of other signs or symptoms of diabetic autonomic neuropathy. To determine whether IDDM patients have impaired sympathetic activity compared with normal control subjects before the onset of overt neuropathy, we directly recorded MSNA. We also examined the effects of changes in plasma glucose and insulin on sympathetic function in each group. MSNA was recorded by using microneurographic techniques in 10 IDDM patients without clinically evident diabetic complications and 10 control subjects. MSNA was compared during a 15-min fasting baseline period and during insulin infusion (120 mU.m-2.min-1) with 30 min of euglycemia. A cold pressor test was performed at the end of euglycemia. Power spectral analysis of 24-h RR variability was used to assess cardiac autonomic function. IDDM patients had lower MSNA than control subjects at baseline (8 +/- 1 vs. 18 +/- 3 burst/min, P < 0.02). MSNA increased in both groups with insulin infusion (P < 0.01) but remained lower in IDDM patients (20 +/- 3 vs. 28 +/- 3 burst/min, P < 0.01). In the IDDM group, we found no relationships between MSNA and plasma glucose, insulin, or HbA1c concentrations. BP levels did not differ at rest or during insulin. Heart-rate variability and the MSNA response to cold pressor testing in IDDM patients did not differ from those in healthy control subjects. IDDM patients had reduced MSNA at rest and in response to insulin. The lower MSNA is not attributable to differences in plasma glucose or insulin, but, rather, is most likely an early manifestation of diabetic autonomic neuropathy that precedes impaired cardiac parasympathetic control.     

Optimization of evening insulin dose in patients using the short-acting insulin analog lispro

OBJECTIVE: A three-way, crossover, open-label, randomized study was designed to compare the evening and night (1800-0800) glycemic control when the evening premeal lispro dose was reduced by 20% and the bedtime basal NPH dose increased by 25%, or when the basal NPH dose was moved to before dinner at 1800, compared with the control arm on standard premeal human regular insulin and pre-bedtime NPH insulin. RESEARCH DESIGN AND METHODS: A total of 13 type 1 diabetic patients who use a premeal plus basal insulin regimen were studied on three separate days, with identical meals and snacks at the same times on each study day. On the control study day, patients received human regular insulin before dinner and NPH at bedtime in their usual doses. On another day, lispro was given before dinner with a dose reduction of 20%, and NPH at bedtime at 125% of usual dose. In the third regimen, the lispro and NPH were administered together in their usual dose before the evening meal by separate injections. The three regimens were tested in random order. RESULTS: Postprandial (1800-2200) blood glucose concentrations were lower after reduced-dose lispro compared with human regular insulin (6.0 +/- 0.3 [SEM] vs. 7.4 +/- 0.3 mmol/l, P < 0.05). Nighttime (2400-0400) blood glucose concentrations were not different (8.6 +/- 0.3 vs. 9.2 +/- 0.3 mmol/l, NS), and prebreakfast concentrations were also unchanged (7.7 +/- 0.9 vs. 8.7 +/- 0.8 mmol/l) after lispro with increased-dose NPH compared with standard insulin. By contrast, both nighttime (10.0 +/- 0.3 mmol/l, P < 0.05) and fasting glucose concentrations (10.8 +/- 0.6 mmol/l, P < 0.05) were significantly higher with dinnertime usual-dose lispro plus dinnertime usual-dose NPH compared with standard human insulin. Hypoglycemia at night (blood glucose < 3.0 mmol/l) did not differ between study days, but it was more frequent postprandially after dinner usual-dose lispro plus early NPH (2 vs. 7 patients, P = 0.062). CONCLUSIONS: With lower mealtime and higher basal bedtime insulin doses, patients using insulin lispro may be able to gain an overall improvement in evening blood glucose control without deteriorated nighttime glucose levels. Earlier basal NPH dosage alone does not ameliorate the nighttime hyperglycemia of short-acting insulin analog regimens.     

Seven years of remission in a type I diabetic patient

OBJECTIVE: To analyze factors contributing to a long-term remission in a patient with type I diabetes. RESEARCH DESIGN AND METHODS: The patient was treated with cyclosporin for 16 mo after a short duration of symptoms. During the 7-yr follow-up, we tracked his glycemic control, oral glucose tolerance, insulin sensitivity, endogenous insulin secretion, and beta-cell immunology. The results are compared with those of matched diabetic patients and healthy control subjects. RESULTS: Insulin therapy was discontinued after 5 wk. Thereafter the patient had normal fasting and home blood glucose concentrations and near-normal HbA1c without insulin therapy for 7 yr. During this period, he maintained islet cell antibodies, although his basal and glucagon-stimulated C-peptide concentrations were normal. He participated in active physical training and had an insulin sensitivity higher than in sedentary control subjects or trained diabetic patients and equal to that in healthy athletes. His oral glucose tolerance decreased gradually and became diabetic during the last 3 yr. CONCLUSIONS: In this patient, an early start of cyclosporin therapy probably contributed to the maintenance of endogenous insulin secretion, and insulin sensitivity was high because of physical training. Consequently, the patient was able to maintain normoglycemia without exogenous insulin therapy for 7 yr.     

Preservation of physiological responses to hypoglycemia 2 days after antecedent hypoglycemia in patients with IDDM

OBJECTIVE: To assess the effects of short-term antecedent hypoglycemia on responses to further hypoglycemia 2 days later in patients with IDDM. RESEARCH DESIGN AND METHODS: We studied eight type I diabetic patients without hypoglycemia unawareness or autonomic neuropathy during two periods at least 4 weeks apart. On day 1, 2 h of either clamped hyperinsulinemic (60 mU.m-2.min-1) hypoglycemia at 2.8 mmol/l or euglycemia at 5.0 mmol/l were induced. Hyperinsulinemic hypoglycemia was induced 2 days later with 40 min glucose steps of 5.0, 4.0, 3.5, 3.0, and 2.5 mmol/l. Catecholamine levels and symptomatic and physiological responses were measured every 10-20 min. RESULTS: When compared with the responses measured following euglycemia, the responses of norepinephrine 2 days after hypoglycemia were reduced (peak, 1.4 +/- 0.4 [mean +/- SE] vs.1.0 +/- 0.3 nmol/l [P < 0.05]; threshold, 3.4 +/- 0.1 vs. 2.9 +/- 0.1 mmol/l glucose [P < 0.01]). The responses of epinephrine (peak, 4.0 +/- 1.4 vs. 3.5 +/- 0.8 nmol/l [P = 0.84]; threshold, 3.8 +/- 0.1 vs. 3.6 +/- 0.1 mmol/l glucose [P = 0.38]), water loss (peak, 194 +/- 34 vs. 179 +/- 47 g-1.m-2.h-1 [P = 0.73]; threshold, 2.9 +/- 0.2 vs. 2.9 +/- 0.2 mmol/l glucose [P = 0.90]), tremor (peak, 0.28 +/- 0.05 vs. 0.37 +/- 0.06 root mean square volts (RMS V) [P = 0.19]; threshold, 3.2 +/- 0.2 vs. 3.1 +/- 0.2 mmol/l glucose [P = 0.70]), total symptom scores (peak, 10.6 +/- 2.1 vs. 10.8 +/- 1.9 [P = 0.95]; threshold, 3.3 +/- 0.2 vs. 3.6 +/0 0.1 mmol/l glucose [P = 0.15]), and cognitive function (four-choice reaction time: threshold, 2.9 +/- 0.2 vs. 3.0 +/- 0.2 mmol/l glucose [P = 0.69]) were unaffected. CONCLUSIONS: The effect on hypoglycemic physiological responses of 2 h of experimental hypoglycemia lasts for 1-2 days in these patients with IDDM . The pathophysiological effect of antecedent hypoglycemia may be of shorter duration in IDDM patients, compared with nondiabetic subjects.     

High glucose uptake by adipocytes in a type 1 diabetic patient with a partial 'honeymoon' period

Hypoglycaemic episodes and low insulin requirements are frequently seen in the early phase of treatment of Type 1 diabetes mellitus but the mechanism is not clear. We present a diabetic patient with recurrent hypoglycaemia in the early phase of insulin treatment. A very high glucose transport in adipocytes (basal: 176 and insulin stimulated glucose transport 10(-7) mol l(-1): 335 fl cell(-1) s(-1)) was found when compared with reference laboratory diabetic patients (basal: 59 +/- 10 and insulin 10(-7) mol l(-1): 106 +/- 7 fl cell(-1) s(-1), mean +/- SE) and with reference laboratory of non-diabetic subjects (basal: 106 +/- 6 and insulin 10(-7) mol l(-1): 188 +/- 15 fl cell(-1) s(-1)). Insulin binding to adipocytes was in the normal range. The patient was studied again 1 year later when the partial clinical remission had disappeared, and the glucose transport in adipocytes had decreased. In conclusion, an increase in glucose uptake by peripheral tissues may be among the mechanisms of the partial 'honeymoon' period of diabetic patients.     

Overnight normalization of glucose concentrations improves hepatic but not extrahepatic insulin action in subjects with type 2 diabetes mellitus

Subjects with poorly controlled type 2 diabetes are both hyperglycemic and insulin resistant. To determine whether short term restoration of normoglycemia improves insulin action, hyperinsulinemic (approximately 300 pmol/L) euglycemic clamps were performed in diabetic subjects after either overnight infusion of saline or overnight infusion of insulin in amounts sufficient to maintain euglycemia throughout the night. Fasting glucose concentrations (5.2 +/- 0.2 vs. 11.9 +/- 1.4 mmol/L; P < 0.01) and rates of endogenous glucose production (13.0 +/- 1.1 vs. 18.6 +/- 1.6 mumol/kg.min; P < 0.05) were both lower after overnight insulin than overnight saline. Insulin-induced stimulation of glucose uptake (to 34.9 +/- 6.8 vs. 28.8 +/- 3.4 mumol/kg.min; P = 0.2) and inhibition of free fatty acids (to 0.13 +/- 0.03 vs. 0.12 +/- 0.04 mmol/L; P = 0.6) did not differ after overnight saline and overnight insulin. In contrast, endogenous glucose production during the final hour of the hyperinsulinemic clamps (i.e. when glucose concentrations were the same) remained higher (P = 0.05) after overnight saline than after overnight insulin (5.5 +/- 1.5 vs. 0.02 +/- 1.4 mumol/kg.min). Thus, acute restoration of euglycemia by means of an overnight insulin infusion improves hepatic (and perhaps renal) but not extrahepatic insulin action.     

Insulin kinetics in type I diabetic patients treated by continuous intraperitoneal insulin infusion: influence of anti-insulin antibodies

Continuous intraperitoneal insulin infusion (CIPII) is a promising therapy of patients with Type 1 (insulin-dependent) diabetes mellitus (IDDM), since it improves metabolic control and decreases frequency of severe hypoglycaemia. This could be due to more appropriate insulin kinetics. Our aim, therefore, was to compare plasma free insulin levels achieved in patients with Type 1 diabetes chronically treated with CSII or CIPII. Furthermore, as anti-insulin antibodies increase with this treatment, we wanted to assess their influence upon insulin kinetics. Plasma free insulin profiles were obtained during the night and then after the bolus for breakfast and the bolus for lunch in 11 patients with Type 1 diabetes treated successively by CSII and CIPII. In another group of 16 patients with long-term Type 1 diabetes, treated by CIPII, we examined the influence of anti-insulin antibody level on insulin kinetics after a bolus. During the night, plasma free insulin levels were lower with CIPII than with CSII (12:00 am: 10.1 +/- 1.7 vs 18.5 +/- 2.6 mU l-1; 4:00 am: 9.1 +/- 2 vs 15 +/- 3 mU l-1), p < 0.01. After the bolus, CIPII lead to an earlier (1h vs 3h) and higher (25.8 +/- 3.3 vs 18 +/- 2.7, p < 0.05) plasma free insulin peak than CSII. With CIPII, the return to baseline level was observed within 3 h. Conversely, during CSII, insulin levels did not return to baseline until the next meal. After the bolus, high insulin-antibody levels were associated with a reduced maximal value of plasma free insulin peak. Taken together, these findings suggest that CIPII provides plasma free insulin profiles which are much closer to physiology than CSII. This could explain the lower rate of severe hypoglycaemia observed with this type of treatment. But in long-term CIPII treated patients with high anti-insulin antibody level, insulin profile could be moderately modified. This emphasizes the need for a less immunogenic insulin preparation.     

Nonfasting plasma glucose is a better marker of diabetic control than fasting plasma glucose in type 2 diabetes

OBJECTIVE: To evaluate the relative value of plasma glucose (PG) at different time points in assessing glucose control of type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Glycemic profiles, i.e., PG at prebreakfast (8:00 A.M.), prelunch (11:00 A.M.), postlunch (2:00 P.M.), and extended postlunch (5:00 P.M.) times over the same day, were obtained in 66 type 2 diabetic patients on an ambulatory basis. The different time points of PG were compared with a measurement of HbA1c made in a reference laboratory. RESULTS: Extended postlunch PG was lower than prebreakfast PG (104 +/- 21 vs. 133 +/- 35 mg/dl, P < 0.02) in patients demonstrating good diabetic control (HbA1c < or = 7.0%), was not different from prebreakfast PG (149 +/- 47 vs. 166 +/- 26 mg/dl, NS) in patients demonstrating fair diabetic control (7.0% < HbA1c < or = 8.5%), and was higher than prebreakfast PG (221 +/- 62 vs. 199 +/- 49 mg/dl, P < or = 0.01) in those demonstrating poor diabetic control (HbA1c < or = 8.5%). Prebreakfast, prelunch, postlunch, and extended postlunch PG values were all significantly correlated with HbA1c. Multiple linear regression analysis demonstrated that postlunch PG and extended postlunch PG correlated significantly and independently with HbA1c, but that prebreakfast PG and prelunch PG did not. Moreover, postlunch PG and extended postlunch PG demonstrated better sensitivity, specificity, and positive predictive value in predicting poor glycemic control than did prebreakfast PG or prelunch PG. CONCLUSIONS: In type 2 diabetes, postlunch PG and extended postlunch PG are better predictors of glycemic control than fasting plasma glucose (FPG). We therefore suggest that they be more widely used to supplement, or substitute for, FPG in evaluating the metabolic control of type 2 diabetic patients.     

Optimal provision of daytime NPH insulin in patients using the insulin analog lispro

OBJECTIVE: Insulin lispro improves early postprandial blood glucose control but can result in late interprandial hyperglycemia. As an approach to resolving this problem, we performed a randomized, crossover study with four treatment arms, comparing the daytime metabolic profile after either premeal lispro alone or premeal lispro with optimal daytime NPH insulin and with standard human regular insulin. RESEARCH DESIGN AND METHODS: Twelve C-peptide negative type 1 diabetic patients were studied on four separate study days, at least 7 days apart. On each study day, patients received one of the four study insulin treatments, in random order, with identical meals and snacks. The four treatments were 1) premeal human regular insulin before lunch and supper at unchanged dose; 2) premeal lispro (unchanged dose) at lunchtime and dinner; 3) pre-lunch reduced-dose lispro (70%) before lunch and supper with supplemental lunchtime NPH and with a 6-h interval until dinner; and 4) pre-lunch reduced-dose lispro (70%) before lunch and supper with supplemental lunchtime NPH and with a 8-h interval until dinner. All patients were using their usual premeal plus basal insulin regimen during the period of the study, with human regular insulin before meals and NPH insulin at bedtime. RESULTS: Postprandial blood glucose concentrations (1230-1500) were lower after reduced or usual lispro dose compared with human regular insulin (5.5+/-0.2 and 5.6+/-0.2 vs. 8.2+/-0.5 mmol/l, P < 0.001), with no difference between the lispro doses. However, prepran-Dial (1800) blood glucose levels deteriorated to higher levels after usual-dose lispro alone compared with either human regular insulin (P < 0.05) or reduced-dose lispro plus NPH (P < 0.05) (8.9+/-0.3 vs. 7.1+/-0.8 and 6.4+/-0.4 mmol/l), with no difference between human regular insulin and reduced-dose lispro plus NPH. During the 2 h between the usual and delayed mealtime, blood glucose concentrations remained controlled on lispro plus NPH (2000: 6.5+/-0.4 mmol/l). CONCLUSIONS: Reduced-dose lunchtime lispro plus NPH maintained the improvement in postprandial blood glucose control with no deterioration in interprandial blood glucose control, even up to a late meal.     

Improvement of host response to sepsis by photobiomodulation

OBJECTIVE: To evaluate the correlation between predialysis glycemic control and clinical outcomes for type II diabetic patients on continuous ambulatory peritoneal dialysis (CAPD). DESIGN: Sixty type II diabetic patients on CAPD were classified into 2 groups according to the status of glycemic control. In group G (good glycemic control), more than 50% of blood glucose determinations were within 3.3-11 mmol/L and the glycosylated hemoglobin (HbA1C) level was within 5-10% at all times. In group P (poor glycemic control), fewer than 50% of blood glucose determinations were within 3.3-11 mmol/L or HbA1C level was above 10% at least once during the follow-up duration. In addition to glycemic control status, predialysis serum albumin, cholesterol levels, residual renal function, peritoneal membrane function, and the modes of glycemic control were also recorded. SETTING: Dialysis Unit, Department of Nephrology of a single university hospital. PATIENTS: From February 1988 to October 1995, 60 type II diabetic patients receiving CAPD for at least 3 months were enrolled. MAIN OUTCOME MEASURES: Morbidities before and during the dialysis period, patient survival, and causes of mortality. RESULTS: The patients with good glycemic control had significantly better survival than patients with poor glycemic control (p < 0.01). There was no significant difference in predialysis morbidity between the two groups. No significant differences were observed in patient survival between the patients with serum albumin greater than 30 g/L and those with less than 30 g/L (p = 0.77), with cholesterol levels greater or less than 5.18 mmol/L (p = 0.73), and with different peritoneal membrane solute transport characteristics evaluated by peritoneal equilibration test (p = 0.12). Furthermore, there was no significant difference in survival whether the patients controlled blood sugar by diet or with insulin (p = 0.33). Cardiovascular disease and infection were the major causes of death in both groups. Although good glycemic control predicts better survival, it does not change the pattern of mortality in diabetics maintained on CAPD. CONCLUSIONS: Glycemic control before starting dialysis is a predictor of survival for type II diabetics on CAPD. Patients with poor glycemic control predialysis are associated with increased morbidity and shortened survival.     

Maternal country of origin and infant birthplace: implications for birth-weight

Insulin-dependent diabetes mellitus (IDDM) is characterized by altered composition of atherogenic lipoproteins, especially a depletion in choline-containing phospholipids (PL) of apolipoprotein (apo) B lipoproteins (LpB). To determine the effects of continuous intraperitoneal (IP) insulin infusion (CIPII) on this qualitative lipoprotein abnormality, we compared lipoprotein profiles of 14 IDDM patients treated by continuous subcutaneous insulin infusion (CSII) and at 2 and 4 months after treatment with CIPII using an implantable pump. IDDM patients were in fair metabolic control and were compared with 14 healthy control subjects matched for sex, age, body mass index, and plasma lipids. The following parameters were studies: hemoglobin A1c (HbA1c), monthly blood glucose, daily insulin dose (units per kilogram per day), total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol, apo A-I, and apo B. Choline-containing PL were assessed in plasma and in apo B- and no-apo B-containing lipoprotein particles (LpB and Lp no B). As compared with the control group, plasma PL and LpB-PL were significantly lower in IDDM patients treated by CSII (2.95 +/- 0.26 v 3.30 +/- 0.45 mmol/L,P<.05, and 1.09 +/- 0.45 v 1.68 +/- 0.33 mmol/L,P<.01, respectively). No significant differences were observed for Lp no B lipid determinations between both groups. After initiation of CIPII, IDDM patients did not experience any significant changes in mean values for body mass index, HbA1c, and monthly blood glucose throughout the study. Daily insulin doses were identical to those observed before IP therapy. Lipid parameters remained unchanged in IDDM patients (TC, TG, HDL and LDL cholesterol, apo A-I, and apo B). A moderate but progressive elevation of plasma PL was noted, and after 4 months of CIPII, PL and LpB-PL levels were no longer significantly different between IDDM patients and controls. The increase in plasma and LpB choline-containing PL observed after 2 and 4 months of CIPII is not linked to changes in blood glucose control, body weight or daily insulin requirements. These changes may be related to the route of insulin administration, which may be accompanied by a reduction of lipoprotein lipase (LPL) activity and consequently a reduction of phospholipase activity. These results suggest that IP insulin delivery may be a more physiological route that increases the choline-containing PL content of LpB particles.     

Metabolic efficacy of preprandial administration of Lys(B28), Pro(B29) human insulin analog in IDDM patients. A comparison with human regular insulin during a three-meal test period

OBJECTIVE: The objective of this study was to compare the efficacy of the rapid-acting Lys(B28), Pro(B29) human insulin analog, insulin lispro, with currently available short-acting human insulin in a multiple injection therapy (MIT) regimen with respect to blood glucose and plasma insulin profiles and to serum metabolites (lactate, free fatty acids, glycerol, and beta-hydroxybutyrate) in 12 well-controlled type 1 diabetic subjects (8 male, HbA1c 6.8 +/- 0.9% [mean +/- SD]). RESEARCH DESIGN AND METHODS: After a run-in period of 4 weeks, patients were treated with either lispro at mealtime or human insulin 30 min before the meal for two periods of 4 weeks in a randomized open-label crossover study. Intermediate-acting insulin (NPH insulin) was given at bedtime. At the end of both study periods, metabolic profiles were assessed from 10:00 P.M. to 7:00 P.M. the next day. RESULTS: During the treatment periods, glycemic control was stable during lispro but improved during human insulin (delta HbA1c lispro 0.1 +/- 0.48, NS; human insulin -0.41 +/- 0.34%, P < 0.05). Glucose excursions, as measured by the incremental AUC, during the day and for the 2-h postprandial periods, were lower, although not significantly, for lispro. Insulin profiles demonstrated a faster rise after administration of lispro as compared with human insulin, peaking at 61 +/- 11.9 and 111 +/- 48.1 min (P < 0.01). Glycerol levels showed a slight increase before lunch and dinner, suggestive of enhanced lipolytic activity and compatible with the lower insulin levels. CONCLUSIONS: Lispro insulin applied in an MIT regimen creates more physiologic insulin profiles and tends to lower the glycemic excursions during the day compared with short-acting insulin. The analog can be applied safely in an MIT regimen, with mealtime intervals up to 5 h.