Euglycemic Patients Research Articles

Stroke topography and outcome in relation to hyperglycaemia and diabetes.

In a prospective study to analyse stroke topography and outcome in diabetics and to determine the prognostic value of blood glucose and glycosylated haemoglobin estimation, we evaluated 176 patients with acute stroke. The patients were classified into four groups on the basis of history, fasting glucose, and glycosylated haemoglobin: euglycaemic patients with no history of diabetes, stress hyperglycaemia, newly diagnosed diabetics, and known diabetics. A high prevalence of undiagnosed diabetes was shown. No difference was found in the type or site of stroke between the four groups. No difference was found in the site of symptomatic or incidental lesions on computerised axial tomography. Patients with stress hyperglycaemia and known diabetics had more severe strokes. Mortality was higher in patients with stress hyperglycaemia, newly diagnosed diabetics, and the combined diabetes groups. This increased mortality was evident in the hyperglycaemic and diabetic groups, even after excluding patients with cerebral haemorrhage. Stroke severity and mortality also increased independently with blood glucose in the euglycaemic group. We conclude that there is a correlation between admission glucose concentration, diabetes, and poor stroke outcome, which may not be attributed to stroke type or location.

Perioperative Maternal and Neonatal Acid-Base Status and Glucose Metabolism in Patients With Insulin-Dependent Diabetes Mellitus

Maternal and neonatal acid-base status and glucose metabolism were studied in 20 patients with insulin-dependent diabetes mellitus (group 1) undergoing elective cesarean section under lumbar epidural anesthesia. All patients were given glucose/insulin infusion before delivery. Fifteen healthy patients with iatrogenic hyperglycemia (group 2) and 15 healthy euglycemic patients (group 3) served as controls. Results were expressed as mean +/- 1 SE and were analyzed using analysis of variance and chi 2 analysis at P less than 0.05. No significant differences were seen at delivery either in maternal arterial and neonatal umbilical venous and arterial blood acid-base status or in neonatal Apgar scores among the three groups. Patients in groups 1 and 2 had larger blood glucose concentrations than those in group 3 (P = 0.01). Diabetic mothers and their neonates had a 25%-50% reduction in pyruvate concentration in maternal venous, and neonatal umbilical venous and arterial blood compared with that in the other two groups (P = 0.001). Postpartum neonatal hypoglycemia (less than 30 mg/dL) developed in seven of the group 1 neonates (P = 0.05). Thus, epidural anesthesia in diabetic women is associated with normal acid-base status in the mother and in the neonate. The data also show an increased incidence of neonatal hypoglycemia and altered maternal and neonatal glycolysis in patients with diabetes mellitus.

Effects of Dietary Carbohydrates on Metabolism of Calcium and Other Minerals in Normal Subjects and Patients with Noninsulin-Dependent Diabetes Mellitus*

Transient hypercalciuria has been noted after high carbohydrate meals which is independent of dietary calcium and is probably due to impaired renal calcium reabsorption mediated by an increase in plasma insulin levels. Based on these observations, some investigators believe that long term intake of high carbohydrate diets may increase the risk of nephrolithiasis and possibly osteoporosis. Using a randomized cross-over design, we compared high carbohydrate diets (60% carbohydrate and 25% fat) with high fat diets (50% fat and 35% carbohydrate) for effects on metabolism of calcium and other minerals in eight normal subjects and eight euglycemic patients with noninsulin-dependent diabetes mellitus. All other dietary constituents, such as protein, fiber, fluid, minerals (including Ca, Mg, Na, K, and P), and caffeine intake, were kept constant. Despite higher daylong levels of plasma insulin on the high carbohydrate diets compared to the high fat diet in both normal and noninsulin-dependent diabetic subjects, no changes in daily urinary excretion of calcium or other constituents, associated with renal stone risk, were observed. Furthermore, there was no change in fractional intestinal 47Ca absorption. Although hypercalciuria may ensue transiently after high carbohydrate meals, we conclude that substitution of simple or complex carbohydrates for fats in an isocaloric manner for a longer duration does not result in significant urinary calcium loss, and therefore, high intakes of digestible carbohydrates may not increase the risk of nephrolithiasis or osteoporosis via this mechanism.

Schwangerschaftsausgang unter intensivierter Insulintherapie bei manifestem Diabetes*

In 1981, the intensified insulin therapy for achievement of euglycaemia in pregnant diabetics was introduced at the University Department of Obstetrics and Gynaecology in Cologne. This study compares the results of 112 pregnancies in women with overt diabetes monitored before (1971-1980) or after (1981-1988) changing the therapeutic regimen. In the period from 1981 to 1988, the proportion of euglycaemic patients (preconceptionally 19%, before delivery 79%) was clearly higher than from 1971 to 1980 (n = 42; 7% and 9%, respectively). The tight blood glucose control resulted in a doubling of hypoglycaemic episodes during pregnancy. The proportion of preterm deliveries was reduced from 47% to 24%. The rate of caesarean sections was nearly constant (1971-1980: 38%, 1981-1988: 34%). The marked success of therapy was the decrease of perinatal mortality from 20.9% to 2.9%. The perinatal morbidity also diminished, as shown by the decreasing rates (30-90%) of foetopathy, macrosomy, respiratory distress syndrome, birth trauma, hypoglycaemia, hypocalcaemia and polycythaemia. The malformation rate, however, remained high (1971-1980 = 7%, 1981-1988 = 11%). The results demonstrate the necessity of a strict blood glucose control during pregnancy, beginning before the time of conception.

POSTTRANSPLANT HYPERGLYCEMIA

The incidence of posttransplant diabetes mellitus (PTDM) was compared in two groups of renal allograft recipients. These were all nondiabetic patients who had been transplanted between 1979 and 1987 and received either azathioprine-methylprednisolone (group 1) or cyclosporine-methylprednisolone (group 2) therapy as maintenance immunosuppression. The incidence of PTDM in group 1 was 9.1% vs. 18.6% in group 2 (P less than .05). The mean daily dose of methylprednisolone during the initial 2 months posttransplant was not greater among the PTDM patients of groups 1 or 2. Cyclosporine levels and mean daily CsA doses during the initial 2 posttransplant months were also not different among the CsA-PTDM and euglycemic CsA patients. Posttransplant diabetes mellitus occurred rapidly (less than 2 months) and required insulin therapy in the majority of cases. Increased age (greater than 40 years) was associated with a higher risk for PTDM, however, the greater incidence accompanying increased body weight only approached significance. Patient gender and donor source were not associated with significant risk for PTDM. The development of PTDM was accompanied by a significant decrease in graft survival at 3 years in the entire PTDM population and at 4 years in the CsA-PTDM subgroup. Actuarial patient survival was not adversely affected. The current study suggests that CsA may be diabetogenic when administered with methylprednisolone to renal allograft recipients. The adverse effect on allograft survival requires further investigation. These results may also have important implications for pancreatic and islet cell transplantation.

Osmoregulation of thirst and vasopressin secretion in insulin-dependent diabetes mellitus.

1. Osmotically stimulated thirst and vasopressin release were studied during infusions of hypertonic sodium chloride and hypertonic D-glucose in euglycaemic clamped diabetic patients and healthy controls. 2. Infusion of hypertonic sodium chloride caused similar elevations of plasma osmolality in diabetic patients (288.0 +/- 1.0 to 304.1 +/- 1.6 mosmol/kg, mean +/- SEM, P less than 0.001) and controls (288.6 +/- 0.9 to 305.7 +/- 0.6 mosmol/kg, P less than 0.001), accompanied by progressive increases in plasma vasopressin (diabetic patients, 0.9 +/- 0.3 to 7.7 +/- 1.5 pmol/l, P less than 0.001; controls 0.5 +/- 0.1 to 6.5 +/- 1.0 pmol/l, P less than 0.001) and thirst ratings (diabetic patients 1.0 +/- 0.2 to 7.1 +/- 0.5 cm, P less than 0.001; controls 1.8 +/- 0.4 to 8.0 +/- 0.5 cm, P less than 0.001) in both groups. 3. Drinking rapidly abolished thirst and vasopressin secretion before major changes in plasma osmolality occurred in both diabetic patients and healthy controls. 4. There were close and significant correlations between plasma vasopressin and plasma osmolality (diabetic patients, r = +0.89, controls r = +0.93) and between thirst and plasma osmolality (diabetic patients r = +0.95, controls r = +0.97) in both diabetic patients and healthy controls during hypertonic saline infusion. 5. Hypertonic D-glucose infusion caused similar elevations in blood glucose in diabetic patients (4.0 +/- 0.2 to 20.1 +/- 1.2 mmol/l, P less than 0.001) and healthy controls (4.3 +/- 0.1 to 19.3 +/- 1.2 mmol/l, P less than 0.001) but did not change plasma vasopressin or thirst ratings.(ABSTRACT TRUNCATED AT 250 WORDS)

Defective suppression by insulin of leucine-carbon appearance and oxidation in type 1, insulin-dependent diabetes mellitus. Evidence for insulin resistance involving glucose and amino acid metabolism.

To determine whether a resistance to insulin in type 1, insulin-dependent diabetes mellitus (IDDM) is extended to both glucose and amino acid metabolism, six normal subjects and five patients with IDDM, maintained in euglycemia with intravenous insulin administration, were infused with L-[4,5-3H]leucine (Leu) and [1-14C]alpha ketoisocaproate (KIC). Steady-state rates of leucine-carbon appearance derived from protein breakdown (Leu + KIC Ra) and KIC (approximately leucine) oxidation were determined at basal and during sequential euglycemic, hyperinsulinemic (approximately 40, approximately 90 and approximately 1,300 microU/ml) clamps. In the euglycemic postabsorptive diabetic patients, despite basal hyperinsulinemia (24 +/- 6 microU/ml vs. 9 +/- 1 microU/ml in normals, P less than 0.05), Leu + KIC Ra (2.90 +/- 0.18 mumol/kg X min), and KIC oxidation (0.22 +/- 0.03 mumol/kg X min) were similar to normal values (Leu + KIC Ra = 2.74 +/- 0.25 mumol/kg X min) (oxidation = 0.20 +/- 0.02 mumol/kg X min). During stepwise hyperinsulinemia, Leu + KIC Ra in normals decreased to 2.08 +/- 0.19, to 2.00 +/- 0.17, and to 1.81 +/- 0.16 mumol/kg X min, but only to 2.77 +/- 0.16, to 2.63 +/- 0.16, and to 2.39 +/- 0.08 mumol/kg X min in the diabetic patients (P less than 0.05 or less vs. normals at each clamp step). KIC oxidation decreased in normal subjects to a larger extent than in the diabetic subjects. Glucose disposal was reduced at all insulin levels in the patients. In summary, in IDDM: (a) Peripheral hyperinsulinemia is required to normalize both fasting leucine metabolism and blood glucose concentrations. (b) At euglycemic hyperinsulinemic clamps, lower glucose disposal rates and a defective suppression of leucine-carbon appearance and oxidation were observed. We conclude that in type 1 diabetes a resistance to the metabolic effects of insulin on both glucose and amino acid metabolism is present.

Enhanced glycemic responsiveness to epinephrine in insulin-dependent diabetes mellitus is the result of the inability to secrete insulin. Augmented insulin secretion normally limits the glycemic, but not the lipolytic or ketogenic, response to epinephrine in humans.

To determine if the enhanced glycemic response to epinephrine in patients with insulin-dependent diabetes mellitus (IDDM) is the result of increased adrenergic sensitivity per se, increased glucagon secretion, decreased insulin secretion, or a combination of these, plasma epinephrine concentration-response curves were determined in insulin-infused (initially euglycemic) patients with IDDM and nondiabetic subjects on two occasions: once when insulin and glucagon were free to change (control study), and again when insulin and glucagon were held constant (islet clamp study). During the control study, plasma C-peptide doubled, and glucagon did not change in the nondiabetic subjects, whereas plasma C-peptide did not change but glucagon increased in the patients. The patients with IDDM exhibited threefold greater increments in plasma glucose, largely the result of greater increments in glucose production. This enhanced glycemic response was apparent with 30-min increments in epinephrine to plasma concentrations as low as 100-200 pg/ml, levels that occur commonly under physiologic conditions. During the islet clamp study (somatostatin infusion with insulin and glucagon replacement at fixed rates), the heightened glycemic response was unaltered in the patients with IDDM, but the nondiabetic subjects exhibited an enhanced glycemic response to epinephrine indistinguishable from that of patients with IDDM. In contrast, the FFA, glycerol, and beta-hydroxybutyrate responses were unaltered. Thus, we conclude the following: Short, physiologic increments in plasma epinephrine cause greater increments in plasma glucose in patients with IDDM than in nondiabetic subjects, a finding likely to be relevant to glycemic control during the daily lives of such patients as well as during the stress of intercurrent illness. Enhanced glycemic responsiveness of patients with IDDM to epinephrine is not the result of increased sensitivity of adrenergic receptor-effector mechanisms per se nor of their increased glucagon secretory response; rather, it is the result of their inability to augment insulin secretion. Augmented insulin secretion, albeit restrained, normally limits the glycemic response, but not the lipolytic or ketogenic responses, to epinephrine in humans.

A new test of peripheral insulin sensitivity [formula omitted][formula omitted] using artificial beta cell

A new in vivo test of insulin sensitivity is described. It utilizes closed-loop insulin delivery device (GCIIS, Biostator ®) capable of infusing glucose and insulin according to preselected algorithms. In euglycemic patients, insulin was infused by GCIIS to maintain euglycemia in the face of challenges with gradually increasing doses of intravenously administered glucose. Under the described experimental conditions, the endogenous insulin release was minimized as evidenced by serum C-peptide levels of less than 2 ng/ml, and thus the peripheral disposal of glucose should have depended entirely on the exogenous insulin. The amount of the insulin infused was considered to be a measure of peripheral insulin sensitivity. The test was applied to normal and non diabetic obese individuals, and to diabetics, both insulin dependent and independent. Significant insulin resistance was demonstrated in the obese and diabetic patients. In two obese females, the test was repeated after a prolonged period of starvation, and showed marked increase in insulin sensitivity. In two poorly controlled insulin dependent diabetics, marked increase in insulin sensitivity was also observed, here following a prolonged period of euglycemia (48 hours). It is concluded that the GCIIS controlled insulin sensitivity test is a simple, reliable test of peripheral insulin sensitivity, most convenient for clinical and experimental studies in vivo

Role of epinephrine-mediated beta-adrenergic mechanisms in hypoglycemic glucose counterregulation and posthypoglycemic hyperglycemia in insulin-dependent diabetes mellitus.

Initially euglycemic (overnight insulin-infused) patients with insulin-dependent diabetes mellitus (IDDM), compared with nondiabetic controls, exhibit similar, but somewhat delayed plasma glucose nadirs, delayed glucose recovery from hypoglycemia, and posthypoglycemic hyperglycemia after the rapid intravenous injection of 0.075 U/kg of regular insulin. These abnormalities are associated with and potentially attributable to markedly diminished glucagon secretory responses, partially reduced epinephrine secretory responses and delayed clearance of injected insulin in the diabetic patients. Because glucagon normally plays a primary role in hypoglycemic glucose counterregulation and enhanced epinephrine secretion largely compensates for glucagon deficiency, we hypothesized that patients with IDDM, who exhibit diminished glucagon secretory responses to hypoglycemia, would be more dependent upon epinephrine to promote glucose recovery from hypoglycemia than are nondiabetic persons. To test this hypothesis, glucose counterregulation during beta-adrenergic blockade with propranolol was compared with that during saline infusion in both nondiabetic controls and in patients with IDDM. Glucose counterregulation was unaffected by beta-adrenergic blockade in controls. In contrast, glucose recovery from hypoglycemia was significantly impaired during beta-adrenergic blockade in diabetic patients. This finding confirms the hypothesis that such patients are more dependent upon epinephrine-mediated beta-adrenergic mechanisms to promote glucose recovery from hypoglycemia and indicates that the measured deficiency of glucagon secretion is functionally important in patients with IDDM. Further, in the time frame of these studies, posthypoglycemic hyperglycemia was prevented by beta-adrenergic blockade in these patients. There was considerable heterogeneity among the diabetic patients with respect to the degree to which beta-adrenergic blockade limited the posthypoglycemic rise in plasma glucose. This rise was directly related to the degree of residual glucagon secretion and inversely related to plasma-free insulin concentrations.THUS, WE CONCLUDE: (a) that patients with IDDM are, to varying degrees, dependent upon epinephrine-mediated beta-adrenergic mechanisms to promote glucose recovery from hypoglycemia and that the degree of this dependence upon epinephrine is an inverse function of the residual capacity to secrete glucagon in response to hypoglycemia in individual patients; (b) that sympathoadrenal activation, coupled with the inability to secrete insulin, plays an important role in the pathogenesis of posthypoglycemic hyperglycemia in patients with IDDM.