Molecular and immunopathology studies of oncogenes and tumor-suppressor genes in bladder cancer

The aim of the study was to evaluate glucose tolerance, B cell secretion and hepatic clearance of insulin during the process of aging. 100 subjects of both sexes, in age range of 17 to 92 years and with BMI < 27 kg/m2 were studied. All subjects were divided in 4 groups according to age: 18 patients were in age from 17 to 59 years (group I--mean 46 +/- 12 (SD) years, 23 patients in age from 60 to 69 years (group II--mean 64 +/- 3 years), 33 patients in age from 70 to 79 years (group III--mean 75 +/- 3 years), 26 patients in age from 80 to 92 years (group IV--mean 84 +/- 4 years). In all participants oral glucose tolerance test (75 g) and the i.v. glucagon test (1 mg) were carried out and blood glucose, serum insulin (IRI) and C-peptide (CP) were measured. Hepatic clearance of insulin was calculated from the serum CP/IRI ratio. With advanced age the increase in fasting glycaemia (group I 4.25 +/- 0.6, group IV 4.7 +/- 0.5 mM, p = 0.02) and after applied stimuli, and a decrease in fasting (group I 0.6 +/- 0.2, group IV 0.35 +/- 0.13 nM, p < 0.05) and stimulated serum CP with no differences in serum IRI concentrations between groups was observed. Consequently the serum CP/IRI ratio decreased from 10 +/- 3.8 in group I to 5.4 +/- 1.7 in group IV (p < 0.05) indicating reduced insulin clearance in liver, probably as a compensatory adaptation to the deterioration of B cell secretory activity.     

Alcohol with a meal has no adverse effects on postprandial glucose homeostasis in diabetic patients

OBJECTIVE: To examine the effect of moderate alcohol intake with a meal on glucose homeostasis in diabetic patients. RESEARCH DESIGN AND METHODS: Alcohol (1 g/kg, an aperitif before, wine during, and a drink after a meal) or an equal amount of mineral water was given during a dinner. Blood glucose and insulin concentrations were measured before, during, and after the meal until the next morning. This study was conducted at the Helsinki University Hospital Metabolic Ward and the Finnish Diabetes Association Education Center. The participants in the study included 10 type I diabetic patients treated with insulin and 16 type II diabetic patients treated with diet alone or with diet and oral drugs. In each subject, we examined hypoglycemic episodes or differences in blood glucose or serum insulin concentrations between alcohol and the control study. RESULTS: In type I diabetic patients, blood glucose and insulin concentrations were virtually identical in both studies. In type II diabetic patients, alcohol slightly enhanced the meal-induced insulin secretion resulting in lower blood glucose concentrations next morning. No hypoglycemic glucose concentrations were observed in either group after alcohol ingestion. CONCLUSIONS: Moderate alcohol intake with a meal does not lead to hypo- or hyperglycemia in diabetic patients.     

Secretory protein 7B2 response to oral glucose loading and intravenous glucagon injection in patients with diabetes mellitus

Serum 7B2 concentrations in control subjects and patients with diabetes mellitus were measured following a 75 g oral glucose load and following intravenous glucagon infusion. In response to oral glucose, serum 7B2 levels increased in the controls (n = 10) and in the diabetic patients (n = 7). The increment of the serum 7B2 level was smaller in the diabetic patients than the controls. During the 75 g oral glucose tolerance test (75g OGTT), serum 7B2 levels were significantly positively correlated with serum C-peptide levels. In contrast, following intravenous glucagon infusion, serum 7B2 levels increased only in diabetic patients treated with oral hypoglycemic agents (n = 20) and did not increase in controls (n = 5): the group having the highest insulin secretion activity in the present study, nor in diet or insulin-treated diabetic patients. No correlation between serum 7B2 levels and serum CPR levels was observed in the intravenous glucagon infusion study. These data suggest that an extra-pancreatic source which produces the observed serum 7B2 increase following oral glucose intake can not be excluded and that 7B2 may not be secreted concomitantly with insulin from the pancreatic beta cell in response to intravenous glucagon injection.     

Intensive 50-week evaluation of glipizide administration in 50 cats with previously untreated diabetes mellitus

OBJECTIVE: To evaluate use of the oral hypoglycemic drug glipizide in diabetic cats. DESIGN: Prospective study. ANIMALS: 50 cats with recently diagnosed but untreated diabetes mellitus. PROCEDURE: Each cat received glipizide (5 mg, q 12 h) for 16 weeks. Medication was not given during the subsequent 16 weeks; then glipizide treatment was repeated. Each cat was evaluated prior to treatment and at 2, 4, 8, 12, and 16 weeks during each of the 3 phases: blood samples for serum glucose and insulin determinations were obtained every 2 hours, from 8 AM to 6 PM. A preprandial blood glycosylated hemoglobin percentage was determined for the first sample obtained at each visit. RESULTS: During the first 22 weeks of the study, diabetes worsened in 28 of the 50 cats, which then were disqualified from the study and treated with insulin. Of the remaining 22 cats that improved clinically, 7 had corresponding metabolic improvement in each diabetes-related parameter assessed and did not become hypoglycemic. Six of the 22 cats became hypoglycemic. Glipizide was discontinued, and diabetes did not recur. Serum glucose concentration did not improve in 6. Three cats had metabolic and clinical improvement during initial glipizide treatment, but had recurrence of the disease during repeated treatment; glipizide was discontinued and insulin was administered. None of the 50 treated cats died, and observed morbidity was mild and transient. Transient anorexia and vomiting were observed in 8 cats, and 4 became transiently icteric with abnormal liver enzyme activities. CLINICAL IMPLICATIONS: Trial use of glipizide is feasible in diabetic cats of owners who are unable or unwilling to administer insulin.     

Portal and peripheral blood immunoreactive insulin concentrations after glucose infusion during gastrectomy

We evaluated portal and peripheral blood immunoreactive insulin concentrations (IRI) after glucose infusion in patients undergoing gastrectomy. Seventy-four patients were divided into following two groups: 68 received 25g glucose infusion in an hour (glucose group), and the remainder received no glucose (control group). Portal blood IRI level in glucose group was about thirty-fold higher than that in control group. However, peripheral blood IRI did not correlate with portal blood IRI in glucose group. In addition, significant negative correlation between portal blood IRI and blood glucose was observed in glucose group. Our results reveal that adequate pancreatic insulin secretion occurs after glucose infusion during gastrectomy, but peripheral blood IRI does not reflect this pancreatic insulin secretion. The results also suggest that blood glucose may be regulated by the liver under these conditions.     

Use of a subcutaneous glucose sensor to detect decreases in glucose concentration prior to observation in blood

The development of a hypoglycemic alarm system using a subcutaneous glucose sensor implies that a decrease in blood glucose is rapidly followed by a decrease in the signal generated by the sensor. In a first set of experiments the linearity and the kinetics of the response of sensors implanted in the subcutaneous tissue of normal rats were investigated during a progressive increase in plasma glucose concentration: the sensitivities determined between 5 and 10 mM and between 10 and 15 mM were not significantly different, and a 5-10 min delay in the sensor's response was observed. In a second set of experiments, performed in diabetic rats, the kinetics of the decrease in subcutaneous glucose concentration following insulin administration was monitored during a decrease in plasma glucose level, from 15 to 3 mmol/L. During the 20 first min following insulin administration, the sensor monitored glucose concentration in subcutaneous tissue with no lag time. Subsequently, the decrease in the estimation of subcutaneous glucose concentration preceded that of plasma glucose. This phenomenon was not observed when the same sensors were investigated in vitro during a similar decrease in glucose concentration and may be due to a mechanism occurring in vivo, such as the effect of insulin on glucose transfer from the interstitial space to the cells surrounding the sensor. It reinforces the interest of the use of implantable glucose sensors as a part of a hypoglycemic alarm.     

Insulin-like growth factors (IGF) I and II and IGF binding proteins 1, 2 and 3 during low-dose growth hormone (GH) infusion and sequential euglycemic and hypoglycemic glucose clamps: studies in GH-deficient patients

To evaluate the short-term effects of growth hormone (GH), insulin and different levels of glycemia on insulin-like growth factors (IGF) I and II and IGF binding proteins (IGFBP) 1, 2 and 3, we studied six GH-deficient adolescents during a night and the following day in the postabsorptive (basal) state followed by sequential euglycemic (5 mmol/l) and hypoglycemic (3 mmol/l) glucose clamps concomitant with an intravenous infusion (starting at 24.00 h) of GH (35 micrograms/h) or saline. Current GH therapy was withdrawn 24 h prior to each study. Nocturnal levels of IGF-I, IGF-II, IGFBP-2 and IGFBP-3 remained stable during both studies. Nocturnal serum IGFBP-1 increased and correlated inversely with insulin in both studies. Regression analysis revealed a significant inverse correlation between mean nocturnal IGFBP-2 and IGFBP-3 levels. During the daytime, serum IGF-I declined slowly during saline infusion, whereas serum IGF-II remained stable in both studies. Serum IGFBP-1 displayed a gradual significant decline during the basal state and the euglycemic and hypoglycemic clamps seemed to be unaffected by GH levels. By contrast, serum IGFBP-2 remained stable during the same period in both the GH and the saline study. Serum IGFBP-3 declined insignificantly during the daytime in the saline study.(ABSTRACT TRUNCATED AT 250 WORDS)     

Retrospective analysis of the incidence of severe hypoglycemia in 458 type 1 diabetic patients

During 1 year a retrospective study concerning frequency and risk markers of severe hypoglycemia was conducted in type-1 diabetic patients undergoing their annual routine check-up. The aim was to contribute to the epidemiology of severe hypoglycemia and to investigate, whether severe hypoglycemia is associated with specific features of therapy (strategy of insulin treatment, level of metabolic control expressed as mean blood glucose and glycosilated hemoglobin, insulin species, use of betablocking agents) or with patient characteristics (age, duration of diabetes, awareness of hypoglycemic symptoms, late complications of diabetes). From the cohort of 710 eligible patients 458 agreed to participate in the study, 61% had experienced severe hypoglycemia at least once, 17% during the last year. The incidence calculated for the whole diabetes duration is 21/100 patient years, and for the last year 56/100 patient years. The following were risk markers for severe hypoglycemia: older age, longer duration of diabetes, reduced awareness of hypoglycemic symptoms, decreasing frequency of symptomatic hypoglycemic episodes, and lower HbA1c. No association was found with the following variables: Serum creatinine, autonomic neuropathy, use of betablocking agents, and presence of anti-insulin antibodies. Intensive insulin therapy with individualized treatment goals in terms of blood glucose control was successful in avoiding severe hypoglycemia in patients who had already experienced them before.     

Behavior of C-peptide, insulin and glucose levels in blood during conditions of evaluating selected antihypertensive drugs in patients with hypertension and non-insulin-dependent diabetes (type 2)

In 60 patients divided in three groups, each of 10 non-diabetic patients with essential hypertension (h) and of 10 hypertensive type 2 (non-insulin-dependent) diabetics (h+c), aged 31-63 years, the effect of 2-week treatment with nifedipine, captopril and prazosin on glycaemia, serum insulin (IRI) and C peptide (CP) after oral and i.v. glucose loading was compared. Nifedipine resulted in higher glycaemia levels in the oral test in both groups. This drug caused in group (h), but not in group (h+c), reduction of the glucose-dependent early increases of serum IRI and CP, more marked in respect to CP, what was expressed by the decrease of the serum CP:IRI ratio. These results prove that in non-diabetic patients nifedipine reduces the early response of the B-cells to glucose, but this effect is partly compensated by decreased insulin uptake by the liver. In patients with type 2 diabetes this phenomenon has not become manifest because of absence or reduction of early glucose-dependent insulin release. After captopril in both groups lower values of glycaemia and serum IRI and CP were found. Prazosin did not change the determined blood parameters. Conclusion: nifedipine, captopril, prazosin have a small influence on secretory function of pancreatic B-cells and may be recommended for the treatment of hypertension in patients with type 2 (non-insulin-dependent) diabetes.     

Spontaneous glucose intolerance in the progeny of low dose streptozotocin-induced diabetic mice

Multiple low doses of streptozotocin (LDS) induce low-incidence diabetes mellitus in Balb/cHan and high-incidence diabetes in CD-1 mice. We studied offspring of diabetic parents in both strains. Group 1 consisted of litters from control mice with no streptozotocin treatment. Group 2 litters had an LDS diabetic mother and a control father, group 3 litters had control mother with LDS diabetic father, and group 4 litters had both, LDS diabetic mother and father. Diabetes was induced by 5 x 40 mg streptozotocin per kg on five consecutive days. Progeny of diabetic mothers showed a state of reduced glucose tolerance associated with reduced glucose disappearance during intravenous glucose tolerance test and increased insulin secretion of isolated islets of Langerhans. These metabolic abnormalities predominated in the male litters of both strains of mice. Amniotic insulin was increased in diabetic mothers during pregnancy. No histologic abnormalities were observed in group 2 progeny. Pancreases in male offspring of LDS diabetic CD-1 fathers (group 3) were studied for insulitis. Insulitis was found in 40% of mice with normal glucose tolerance. A single subdiabetogenic dose of streptozotocin (40 mg/kg) induced insulitis in 90% of pancreases accompanied by reduced insulin release of isolated islets. By contrast, male Balb/cHan progeny of diabetic fathers failed to develop insulitis. In conclusion, we found (1) parental LDS diabetes was transmitted more often to male offspring, (2) maternal LDS diabetes was associated with hyperinsulin secretion and glucose intolerance in the offspring and (3) paternal LDS diabetes was accompanied by insulitis and insulin secretion deficiency in CD-1 progeny.     

Disproportionately elevated proinsulin levels precede the onset of insulin-dependent diabetes mellitus in siblings with low first phase insulin responses. The Childhood Diabetes in Finland Study Group

The objective of this study was to test whether levels of proinsulin immunoreactivity (PIM) relative to those of insulin immunoreactivity (IRI) or C-peptide are changed and related to subclinical beta-cell dysfunction in siblings of insulin-dependent diabetes mellitus (IDDM) patients. Twenty-three siblings, previously found positive for islet cell antibodies and/or insulin autoantibodies, were divided into 2 groups according to their first phase insulin response (FPIR) to i.v. glucose tolerance tests (IVGTTs) sequentially performed during an observation period of 2 yr. Eleven siblings had diminished FPIR on at least 1 occasion (group 1), whereas 12 siblings had a normal FPIR on all occasions studied (group 2). All underwent a further IVGTT (0.5 g glucose/kg BW), and serum samples were taken at 0, 1, 3, 6, 10, 20, 30, 40, 50, and 60 min. The 2 groups had comparable median age, female/male ratio, weight, height, fasting blood glucose, immunoreactive insulin, C-peptide, and insulin autoantibodies levels, but group 1 had significantly higher islet cell antibodies levels. Fasting median PIM/IRI and PIM/C-peptide ratios were 2- to 3-fold higher in group 1 [10.5% (range, 1.8-93.8%) vs. 5.2% (range, 1.9-14.3%) and 3.3% (range, 0.4-23.1%) vs. 1.3% (range, 0.7-2.6%; P < 0.05]. Fasting PIM/C-peptide ratios correlated inversely with FPIRs (rs = -0.68; P < 0.01). During glucose stimulation, maximal responses of IRI and C-peptide were 4-fold lower in group 1, and the time of maximal responses of IRI and C-peptide occurred later in group 1 than in group 2. In contrast, no difference in maximal responses of PIM was found, but the time of maximal responses of PIM occurred later in group 1. Nine of 11 siblings in group 1 presented with IDDM 1-28 months after the test, compared to none in group 2. In group 1 a paradoxical inhibitory response of PIM was observed during the first 6 min of the IVGTT. These data indicate that fasting PIM/IRI and/or PIM/C-peptide ratio reflects subclinical beta-cell dysfunction in prediabetic subjects with evidence of immunological beta-cell assault and suggests that an elevated ratio may be an additional marker for later development of IDDM.     

Breathing pattern and additional work of breathing in spontaneously breathing patients with different ventilatory demands during inspiratory pressure support and automatic tube compensation

OBJECTIVE: To identify predictors of hypoglycemic and hyperglycemic episodes in hospitalized patients with diabetes with special attention to the effectiveness of sliding scale insulin regimens. DESIGN: Prospective cohort study. SETTING: Urban university hospital. PARTICIPANTS: One hundred seventy-one adults with diabetes mellitus as a comorbid condition admitted consecutively to medical inpatient services during a 7-week period. MEASUREMENTS: Demographic, clinical, and laboratory data from inpatient medical records. MAIN OUTCOMES: Rates of hypoglycemic (capillary blood glucose, < or = 3.3 mmol/L [< or = 60 mg/dL]) and hyperglycemic (capillary blood glucose, > or = 16.5 mmol/L [> or = 300 mg/ dL]) episodes. RESULTS: Of the patients, 23% experienced hypoglycemic episodes, and 40% experienced hyperglycemic episodes. The overall rates of hypoglycemic and hyperglycemic episodes were 3.4 and 9.8 per 100 capillary blood glucose measurements, respectively. Independent predictors of hypoglycemic episodes included African American race (relative risk [RR], 2.13) and low serum albumin level (RR, 1.92 per 100-g/L decrease); corticosteroid use was associated with a reduced risk of hypoglycemic episodes (RR, 0.32; P < .05). Independent predictors of hyperglycemic episodes included female gender (RR, 1.67), severity of illness (RR, 1.22 per 10 Acute Physiology and Chronic Health Evaluation III units), severe diabetic complications (RR, 2.32), high admission glucose level (RR, 1.33 per 5.5 mmol/L), admission for infectious disease (RR, 2.14), and corticosteroid use (RR, 3.74; P < .05). Of 171 patients, 130 (76%) were placed on a sliding scale insulin regimen. When used alone, sliding scale insulin regimens were associated with a 3-fold higher risk of hyperglycemic episodes compared with individuals following no pharmacologic regimen (RRs, 2.85 and 3.25, respectively; P < .05). CONCLUSIONS: Suboptimal glycemic control is common in medical inpatients with diabetes mellitus. The risk of suboptimal control is associated with selected demographic and clinical characteristics, which can be ascertained at hospital admission. Although sliding scale insulin regimens are prescribed for the majority of inpatients with diabetes, they appear to provide no benefit; in fact, when used without a standing dose of intermediate-acting insulin, they are associated with an increased rate of hyperglycemic episodes.     

Insulin-like growth factor binding protein-1 induces insulin release in the rat

Injections of human insulin-like growth factor binding protein (hIGFBP-1) are reported to induce hyperglycemia in the rat, suggesting that IGFBP-1 acutely regulates glucose homeostasis. We now report the effects on glucose and insulin levels of administering recombinant (r) hIGFBP-1. In a series of studies, normal and streptozotocin (STZ) diabetic male Wistar rats (180-210 g), fasted for 6 or 16 h, were injected with rhIGFBP-1 (i.v., 80-500 microg/rat). rhIGFBP-1 did not affect blood glucose acutely but did stimulate insulin release in normal rats (5 min post injection; PBS, 103.5 +/- 8.5; rhIGFBP-1 (500 microg), 166.8 +/- 15.7; rhIGFBP-1 (100 microg); 151.4 +/- 14.1% initial). rhIGFBP-1 pretreatment, in normal and diabetic rats, reduced the hypoglycemic response to rhIGF-I (diabetic rats after 20 min: PBS, 103.4 +/- 11.4; BP-1 (500 microg) +/- rhIGF-I (50 microg), 97.6 +/- 3.6; rhIGF-I, 48.2 +/- 4.3% initial) but did not affect the hypoglycemic response to des(1-3)IGF-I or insulin (0.5 U/kg). These studies show that rhIGFBP-1 causes insulin release, has a minimal effect on blood glucose, and inhibits the hypoglycemic effect of rhIGF-I. These data suggest that endogenous IGF-I tonically suppresses insulin secretion and imply that aberrant IGFBP levels or reduced IGF-I bioactivity may lead to chronic hyperinsulinemia.     

Inhibitory effect of pregnancy on counterregulatory hormone responses to hypoglycemia in awake rat

Intensive insulin treatment during diabetic pregnancy is complicated by maternal hypoglycemia. To investigate whether pregnancy may contribute as an independent hypoglycemia risk factor, awake pregnant rats that were near term underwent stepped insulin hypoglycemic (3.4 and 2.3 mM) clamp studies in the fasted and nonfasted states. In the fasted state, the glucagon response to hypoglycemia was completely suppressed in the pregnant rats (P < 0.01). Epinephrine, but not norepinephrine, was also diminished by approximately 70-75% at both hypoglycemic steps, and more exogenous glucose was needed to maintain hypoglycemia during pregnancy. To avoid the potential confounding effect of increased ketone levels (beta-hydroxybutyrate was approximately 170% higher in the pregnant rats), experiments were repeated in the nonfasting state when ketosis was eliminated in both groups. The nonfasted pregnant rats continued to show near complete suppression of the glucagon response, even at glucose levels of 2.3 mM. In contrast, a brisk response occurred in nonpregnant controls when glucose fell to 3.4 mM. Although epinephrine levels in the pregnant rats were also markedly suppressed during the milder hypoglycemic stimulus, they approached values seen in nonpregnant controls when glucose was lowered further to 2.3 mM. We concluded that in the rat, pregnancy markedly suppresses glucagon responses to hypoglycemia. The release of epinephrine, but not norepinephrine, is also blunted, especially during mild hypoglycemia. These findings suggest that pregnancy may impair glucose counterregulation by inhibiting glucagon and epinephrine release during hypoglycemia.     

Experiences with endoscopic surgery in treatment of carpal tunnel syndrome. Preliminary results of a prospective study

We evaluated the association between coronary spasm and hyperinsulinemia (high immunoreactive insulin, IRI) in patients with angina pectoris. The study cohort comprised 30 patients with spastic angina pectoris, 30 patients with angina pectoris showing fixed-obstructive coronary sclerosis and 30 control subjects who were matched for body mass index, age and sex. A 75-gram oral glucose test was performed, and blood sugar and IRI were serially measured concomitant with serum total cholesterol, triglyceride and HDL cholesterol. The IRI level at 60 min, the peak IRI during the test, sigma IRI and sigma IRI/sigma blood sugar were significantly higher in the patients than in the controls. Total cholesterol and LDL cholesterol levels were significantly increased in patients showing fixed-obstructive coronary sclerosis compared to controls.     

Functional insulin therapy and pregnancy

Pregnant type-I diabetic women have to be treated in an experienced diabetes center where optimal cooperation and exchange of knowledge between obstetrician, diabetologist and neonatologist is guaranteed. Given optimal preconceptional metabolic control and thorough guidance throughout pregnancy maternal and fetal risk of type-I diabetic patients without severe diabetic late complications is similar to that of healthy pregnant women. "Near-normoglycemic" metabolic control and meticulous prevention of severe and long-standing hypoglycemic episodes can be achieved throughout pregnancy by functional insulin therapy employing a basis-bolus regime of insulin administration with frequent blood glucose self control (more than 6 times a day). Non-compliant diabetic patients and those with severe diabetic late complications represent a high-risk group for complications in pregnancy. To avoid such risks special care and preconceptional information is mandatory.     

Reduction of postprandial hyperglycemia and frequency of hypoglycemia in IDDM patients on insulin-analog treatment. Multicenter Insulin Lispro Study Group

Insulin lispro, an insulin analog recently developed particularly for mealtime therapy, has a fast absorption rate and a short duration of action. We compared insulin lispro and regular human insulin in the mealtime treatment of 1,008 patients with IDDM. The study was a 6-month randomized multinational (17 countries) and multicenter (102 investigators) clinical trial performed with an open-label crossover design. Insulin lispro was injected immediately before the meal, and regular human insulin was injected 30-45 min before the meal. Throughout the study, the postprandial rise in serum glucose was significantly lower during insulin lispro therapy. At the endpoint, the postprandial rise in serum glucose was reduced at 1 h by 1.3 mmol/l and at 2 h by 2.0 mmol/l in patients treated with insulin lispro (P < 0.001). The rate of hypoglycemia was 12% less with insulin lispro (6.4 +/- 0.2 vs. 7.2 +/- 0.3 episodes/30 days, P < 0.001), independent of basal insulin regimen or HbA1c level. The reduction was observed equally in episodes with and without symptoms. When the total number of episodes for each patient was analyzed according to the time of occurrence, the number of hypoglycemic episodes was less with insulin lispro than with regular human insulin therapy during three of four quarters of the day (P < 0.001). The largest relative improvement was observed at night. In conclusion, insulin lispro improves postprandial control, reduces hypoglycemic episodes, and improves patient convenience, compared with regular human insulin, in IDDM patients.     

Differential regulation of genes encoding 1-aminocyclopropane-1-carboxylate (ACC) synthase in etiolated pea seedlings: effects of indole-3-acetic acid, wounding, and ethylene

OBJECTIVE: To compare the efficacy of the short-acting insulin analog lispro (LP) with that of regular insulin in IDDM patients treated with an external pump. RESEARCH DESIGN AND METHODS: Thirty-nine IDDM patients (age, 39.4 +/- 1.5 years; sex ratio, 22M/17W; BMI, 24.4 +/- 0.4 kg/m2; diabetes duration, 22.5 +/- 1.6 years) who were treated by external pump for 5.1 +/- 0.5 years were involved in an open-label, randomized, crossover multicenter study comparing two periods of 3 months of continuous subcutaneous insulin infusion with LP or with Actrapid HM, U-100 (ACT). Boluses were given 0-5 min (LP) or 20-30 min (ACT) before meals. Blood glucose (BG) was monitored before and after the three meals every day. RESULTS: The decrease in HbA1c was more pronounced with LP than with ACT (-0.62 +/- 0.13 vs. -0.09 +/- 0.15%, P = 0.01). BG levels were lower with LP (7.93 +/- 0.15 vs. 8.61 +/- 0.18 mmol/l, P < 0.0001), particularly postprandial BG levels (8.26 +/- 0.19 vs. 9.90 +/- 0.20 mmol/l, P < 0.0001). Standard deviations of all the BG values (3.44 +/- 0.10 vs. 3.80 +/- 0.10 mmol/l, P = 0.0001) and of postprandial BG values (3.58 +/- 0.10 vs. 3.84 +/- 0.10 mmol/l. P < 0.02) were lower with LP. The rate of hypoglycemic events defined by BG < 3.0 mmol/l did not significantly differ between LP and ACT (7.03 +/- 0.94 vs. 7.94 +/- 0.88 per month, respectively), but the rate of occurrences of very low BG, defined as BG < 2.0 mmol/l, were significantly reduced with LP (0.05 +/- 0.05 vs. 0.47 +/- 0.19 per month, P < 0.05). At the end of the study, all but two (95%) of the patients chose LP for the extension phase. CONCLUSIONS: When used in external pumps, LP provides better glycemic control and stability than regular insulin and does not increase the frequency of hypoglycemic episodes.     

Disappearing subdural hematomas in children

Serum glucose and plasma C-peptide response to i.v. glucagon administration was evaluated in 24 healthy dogs, 12 dogs with untreated diabetes mellitus, 30 dogs with insulin-treated diabetes mellitus, and 8 dogs with naturally acquired hyperadrenocorticism. Serum insulin response also was evaluated in all dogs, except 20 insulin-treated diabetic dogs. Blood samples for serum glucose, serum insulin, and plasma C-peptide determinations were collected immediately before and 5, 10, 20, 30, and (for healthy dogs) 60 minutes after i.v. administration of 1 mg glucagon per dog. In healthy dogs, the patterns of glucagon-stimulated changes in plasma C-peptide and serum insulin concentrations were identical, with single peaks in plasma C-peptide and serum insulin concentrations observed approximately 15 minutes after i.v. glucagon administration. Mean plasma C-peptide and serum insulin concentrations in untreated diabetic dogs, and mean plasma C-peptide concentration in insulin-treated diabetic dogs did not increase significantly after i.v. glucagon administration. The validity of serum insulin concentration results was questionable in 10 insulin-treated diabetic dogs, possibly because of anti-insulin antibody interference with the insulin radioimmunoassay. Plasma C-peptide and serum insulin concentrations were significantly increased (P < .001) at all blood sampling times after glucagon administration in dogs with hyperadrenocorticism, compared with healthy dogs, and untreated and insulin-treated diabetic dogs. Five-minute C-peptide increment, C-peptide peak response, total C-peptide secretion, and, for untreated diabetic dogs, insulin peak response and total insulin secretion were significantly lower (P < .00l) in diabetic dogs, compared with healthy dogs, whereas these same parameters were significantly increased (P < .01) in dogs with hyperadrenocorticism, compared with healthy dogs, and untreated and insulin-treated diabetic dogs. Although not statistically significant, there was a trend for higher plasma C-peptide concentrations in untreated diabetic dogs compared with insulin-treated diabetic dogs during the glucagon stimulation test. Baseline C-peptide concentrations also were significantly higher (P < .05) in diabetic dogs treated with insulin for less than 6 months, compared with diabetic dogs treated for longer than 1 year. Finally, 7 of 42 diabetic dogs had baseline plasma C-peptide concentrations greater than 2 SD (ie, > 0.29 pmol/mL) above the normal mean plasma C-peptide concentration; values that were significantly higher, compared with the results in healthy dogs (P < .001) and with the other 35 diabetic dogs (P < .001). In summary, measurement of plasma C-peptide concentration during glucagon stimulation testing allowed differentiation among healthy dogs, dogs with impaired beta-cell function (ie, diabetes mellitus), and dogs with increased beta-cell responsiveness to glucagon (ie, insulin resistance). Plasma C-peptide concentrations during glucagon stimulation testing were variable in diabetic dogs and may represent dogs with type-1 and type-2 diabetes or, more likely, differences in severity of beta-cell loss in dogs with type-1 diabetes.     

Protein deficiency and nutritional recovery modulate insulin secretion and the early steps of insulin action in rats

Maternal malnutrition was shown to affect early growth and leads to permanent alterations in insulin secretion and sensitivity of offspring. In addition, epidemiological studies showed an association between low birth weight and glucose intolerance in adult life. To understand these interactions better, we investigated the insulin secretion by isolated islets and the early events related to insulin action in the hind-limb muscle of adult rats fed a diet of 17% protein (control) or 6% protein [low (LP) protein] during fetal life, suckling and after weaning, and in rats receiving 6% protein during fetal life and suckling followed by a 17% protein diet after weaning (recovered). The basal and maximal insulin secretion by islets from rats fed LP diet and the basal release by islets from recovered rats were significantly lower than that of control rats. The dose-response curves to glucose of islets from LP and recovered groups were shifted to the right compared to control islets, with the half-maximal response (EC50) occurring at 16.9 +/- 1.3, 12.4 +/- 0.5 and 8.4 +/- 0.1 mmol/L, respectively. The levels of insulin receptor, as well as insulin receptor substrate-1 and phosphorylation and the association between insulin receptor substrate-1 and phosphatidylinositol 3-kinase were greater in rats fed a LP diet than in control rats. In recovered rats, these variables were not significantly different from those of the other two groups. These results suggest that glucose homeostasis is maintained in LP and recovered rats by an increased sensitivity to insulin as a result of alterations in the early steps of the insulin signal transduction pathway.