Novel D-ring analogues of podophyllotoxin as potent anti-cancer agents

Insulin is one of the hormonal regulators of leptin synthesis and participates in adipose tissue maintenance. The present study was undertaken to clarify the association of endogenous insulin secretion and mode of therapy with body fat and serum leptin levels in diabetic subjects. We measured the fasting serum C-peptide level, as an estimate of endogenous insulin secretion, and the serum leptin level in 176 Japanese diabetic subjects (79 men and 97 women; age, 55.9+/-14.3 years; body mass index [BMI], 23.8+/-4.1 kg/m2 [mean+/-SD]). Thirty-one subjects were treated with diet therapy alone, 66 with sulfonylurea (SU), and 79 with insulin (including 29 with type I diabetes mellitus). Body fat was analyzed by the impedance method. Serum leptin levels significantly correlated with the BMI and body fat and were higher in women, mainly because of their greater body fat. Serum C-peptide concentrations positively correlated with body fat and serum leptin in subjects treated with diet and SU. In insulin-treated type II diabetic subjects, both serum C-peptide and the daily insulin dose were weakly associated with body fat and serum leptin. In those subjects, despite a lower percent body fat and body fat mass, serum leptin concentrations (10.3+/-8.4 ng/mL) were comparable to the levels in subjects treated with diet (8.8+/-8.5 ng/mL). When compared within the same BMI and body fat groups (BMI 20 to 25 and > 25 kg/m2) including the control subjects matched for age and sex, serum leptin levels were higher in insulin-treated type II diabetic subjects versus the control subjects and diabetic patients treated with diet or SU. Stepwise regression analysis for all of the diabetic subjects showed that both the serum C-peptide level and exogenous insulin administration, as well as the BMI, gender, and age, were determinants of the serum leptin level. In conclusion, endogenous insulin secretion is closely associated with body fat and serum leptin in diabetic subjects treated with diet therapy and SU. In Japanese insulin-treated type II diabetic subjects, both endogenous and exogenous insulin are associated with body fat and serum leptin, which is maintained at levels comparable to or somewhat higher than the levels in control subjects and diabetic patients treated without insulin.     

Comparison of different endocrine stimulation tests in nondiabetic patients with chronic pancreatitis

BACKGROUND/AIMS: The purpose of this study was to evaluate endocrine functional impairment in nondiabetic patients with chronic pancreatitis and to determine its reliability in the staging of this disease. METHODOLOGY: Eighteen patients with chronic pancreatitis and fasting normoglycemia (fasting blood glucose level < 100 mg/dl) and 10 healthy subjects underwent an oral glucose tolerance test (OGTT), an intravenous glucose test (IGT) and an arginine stimulation test (AST). Blood glucose and serum concentrations of insulin, C-peptide and glucagon were measured before and after stimulation. Exocrine pancreatic function was assessed by the pancreolauryl serum test (PLT), and morphological changes were staged by endoscopic retrograde pancreaticography (ERP), which were rated as I (mild), II (moderate) or III (severe). RESULTS: Glucagon and C-peptide secretions after arginine stimulation were reduced in patients with moderate and severe chronic pancreatitis while no parameter was able to show impaired endocrine function in the early stage (ERP I) of the disease. Serum insulin concentrations proved to be of no use in the diagnosis of pathological B-cell function, since even patients with severe chronic pancreatitis and fasting normoglycemia demonstrated normal insulin secretion. CONCLUSIONS: We conclude that there is a close correlation between morphological changes of the pancreas and functional endocrine reserve capacity, whereas endocrine stimulation tests were not shown to be helpful in the clinical assessment of nondiabetic patients with chronic pancreatitis.     

Detection of Salmonella in animal protein by Rappaport-Vassiliadis broth using indirect impediometry

To determine if glipizide could enhance remission induction in new onset type 1 diabetes compared to intensive insulin treatment alone, 27 patients with type 1 diabetes were intensively treated in an open randomized trial with subcutaneous injections for one month. The insulin was randomly either discontinued (Group A) or the insulin discontinued and glipizide begun (Group B) Three patients in Group A (22%) and 7 in Group B (54%, p < .05) underwent insulin-free remissions for 10.3 +/- 4.4 and 8.7 +/- 2.6 months, respectively (p = NS). Mean blood glucose levels during insulin treatment were lower in patients entering remissions (94 +/- 3 mg/dl versus 102 +/- 5 mg/dl, p < 0.05). C-peptide levels were performed 0, 4, 8, and 24 weeks after insulin treatment. When all patients were examined, mean stimulated C-peptide levels at 4 weeks (0.58 +/- 0.09 pm/ml) were increased compared to time 0 (0.32 +/- 0.05 pm/ml, p < 0.02). Patients not entering remission had higher 4-week stimulated values (0.67 +/- 0.12 pm/ml) compared to time 0 values (0.29 +/- 0.06 pm/ml, p < .01), whereas remission patients' mean C-peptide levels remained similar at 0, 4, 8 and 24 weeks. These data indicate that a) insulin treatment plus glipizide induces higher rates of remission compared to intensive insulin treatment alone, b) the intensity of initial metabolic control may be an important determinant for remission induction, and c) endogenous insulin secretion is not associated with remission induction, suggesting that glipizide alters insulin sensitivity or is immunomodulatory in the context of new onset type 1 diabetes.     

The characteristics of disorders in carbohydrate metabolism and insulin and C-peptide secretion in patients with chronic glomerulonephritis in developing chronic kidney failure

The authors studied hormonal regulation of carbohydrate metabolism by secretion of insulin, C-peptide in 86 patients with chronic glomerulonephritis with different functional condition of the kidneys. There was a decrease in glucose tolerance, basal and reactive hyperinsulinemia, elevated level of C-peptide (relative insulin insufficiency). Mechanism of arising changes in the carbohydrate and insulin metabolism is complex and multicomponent. This includes renal lesion and consequent inhibition of hormone metabolism. Intensification of glomerular filtration is associated with inhibition of filtration of insulin and C-peptide derivants. Accumulation of nitrogen metabolism products results in changed response of pancreatic beta-cells to glucose. General disturbances of metabolism are accompanied by increasing levels of hormonal and nonhormonal contrainsular substances.     

Lack of insulin feedback inhibition in non-obese and obese men

The existence of insulin feedback inhibition is a controversial issue. The present study adopted a novel approach to determine whether insulin feedback inhibition exists in vivo during physiologic hyperinsulinemia and if it could contribute to enhanced insulin secretion in obesity. Serial plasma insulin and C-peptide levels were determined during a basal state and a hyperinsulinemic clamp (287 pmol/min/m2) and following discontinuation of the insulin infusion under euglycemic conditions. Insulin secretion rates were derived from plasma C-peptide levels and individual C-peptide kinetics using a two-compartment model. Eight non-obese and nine obese men were recruited for the studies, which were performed in random order. Men with significant variations in glucose levels during hyperinsulinemia were excluded from the analysis. Plasma glucose levels were similar between the non-obese and obese groups during all phases of the study, and similar plasma insulin levels were achieved in both groups during euglycemic hyperinsulinemia. In obese men, C-peptide levels were significantly greater compared with non-obese men during euglycemic hyperinsulinemia (P < .05). However, neither the non-obese nor the obese group demonstrated significant suppression of insulin secretion rates during euglycemic hyperinsulinemia. Expressing the data in absolute terms or as a percent of basal did not alter the results. Moreover, there was no significant change between the non-obese and the obese group during the rapid onset and cessation of hyperinsulinemia. Under euglycemic conditions, physiologic hyperinsulinemia does not induce suppression of endogenous insulin secretion in non-obese or obese men.     

Granulocyte and granulocyte-macrophage colony-stimulating factors, their receptors and interleukin-3 levels in newborns

OBJECTIVE: The objective of this study was to determine the incidence of macrosomia in infants of diabetic mothers (IDM) and to analyze its possible correlation with insulin, C-peptide, growth hormone (GH) and IGF-I levels in umbilical cord blood. PATIENTS AND METHODS: A prospective study of 58 IDM and 58 control newborns (33 males and 25 females in both groups) was carried out. RESULTS: The incidence of macrosomia was 25.8% in the IDM group and 61.5% in the IIDDM group (infant of insulin-dependent diabetic mother) compared to 5% in the control group. There was a positive correlation between maternal Hgb Alc levels in the third trimester of gestation and insulin and C-peptide levels with newborn weight in the IDM group (especially in the IIDDM group). IGF-I levels were positively correlated with newborn weight in both control and IDM groups. There was no correlation between GH and IGF-I levels in any group.     

Proinsulin levels in newborn siblings of type 1 (insulin-dependent) diabetic children and their mothers

Elevated proinsulin levels have been observed in healthy first degree relatives of Type 1 (insulin-dependent) diabetic patients. This elevation could reflect a sequele after a previous attack on the beta-cells not necessarily leading to diabetes, or represent a family trait related to the development of diabetes. When cord plasma levels of proinsulin, insulin and C-peptide from 14 newborn siblings of Type 1 diabetic patients were compared with 21 newborn control siblings unrelated to diabetic subjects, no differences were observed. Neither were any differences observed between their mothers at delivery when comparing the same parameters. In cord plasma the proinsulin levels (median and range) were higher than those in plasma from 35 adult fasting women unrelated to diabetic subjects (10, 5-83 pmol/l vs 4, 2-33 pmol/l; p < 0.001) whereas the C-peptide levels (median and range) were lower (0.20, 0.11-0.56 nmol/l vs 0.37, 0.21-0.69 nmol/l; p < 0.001). No differences in insulin levels using a highly specific insulin assay were observed. The results suggest that newborn children have high proinsulin and low C-peptide levels unrelated to heredity of diabetes and that the previously described elevated proinsulin level observed in older first degree relatives of diabetic subjects occurs later in life.     

The influence of oral glucose intake on binding and degradation of 125I-insulin by receptors on erythrocytes as well as on insulin and C-peptide serum levels in patients after myocardial infarction and healthy individuals

In this study, we investigated the influence of glucose administration on binding and degradation of 125I-insulin by receptors on erythrocytes as well as on insulin and C-peptide serum levels in 15 patients after myocardial infarction and in 15 age-matched healthy persons. Venous blood samples were taken directly before and at 30, 60 and 120 minutes after oral administration of 75 g of glucose. In the collected blood samples serum glucose, insulin and C-peptide levels were determined. Binding and degradation of 125I-insulin by specific receptors on red blood cells were evaluated using the method described by Gambhir and modified by the authors. Serum insulin and C-peptide levels were significantly higher while binding of 125I-insulin to erythrocytes was decreased in patients after myocardial infarction. These results seem to support the hypothesis that insulin resistance and hyperinsulinism play a role in the pathogenesis of ischaemic heart disease. Impaired degradation of 125I-insulin during the oral glucose tolerance test in the patients after myocardial infarction indicates that insulin resistance is located at the receptor level.     

Clinical pathways in home nutrition support

Ten liver transplant patients were studied in basal conditions and after ingestion of a standard mixed test meal. Control groups included 10 normal subjects, 10 patients with nonalcoholic liver cirrhosis, and seven kidney transplant patients. Plasma somatostatin, blood glucose, and plasma insulin, C-peptide, and glucagon were determined before and 15, 30, 45, 60, 90, 120, and 180 minutes after the start of the meal. In liver transplant patients, basal somatostatin and insulin levels were significantly lower than in cirrhotics and were comparable to those recorded in controls and in kidney transplant patients. The time course of the somatostatin secretory response after the meal was similar in any group, but the increase, evaluated as the incremental area above baseline, was significantly higher in liver transplant patients than in controls and cirrhotics and comparable to that recorded in kidney transplant patients. Insulin incremental areas were also lower than in cirrhotics and comparable to those recorded in controls and kidney transplant patients. The data suggest that in liver transplant patients an increased somatostatin response to a meal may be related to a relative beta-cell secretory defect, which in turn seems consequent to immunosuppressive treatment.     

Role of endogenous and exogenous cholecystokinin in experimental acute pancreatitis induced in rats by the duodenal loop technique

The role of endogenous cholecystokinin (CCK) release and exogenous CCK-8 administration in the development and progression of acute pancreatitis and in the early recovery phase of acute pancreatitis were investigated in rats with closed duodenal loop (CDL)-induced pancreatitis. The subcutaneous injection of CCK-8 (2 micrograms/kg) stimulated a physiological level of pancreatic enzyme secretion in normal control rats, but did not lead to any biochemical or histological evidence of acute pancreatitis. A higher dose of CCK-8 (8 micrograms/kg), however, did produce both biochemical and histological evidence of acute pancreatitis in the normal control rats. When 2 micrograms/kg of CCK-8 was injected subcutaneously in rats 6 and 12 h after the creation of the CDL, neither the biochemical nor the histological findings of acute pancreatitis showed any progression compared with the changes in controls given no CCK-8. Serum CCK levels, measured by radio-immunoassay, increased significantly from mean levels of 5.39 pg/ml (+/- 0.95 SD) before creation of the CDL to 42.06 pg/ml (+/- 2.27 SD) 6 h after, and 41.95 pg/ml (+/- 1.88 SD) 12 h after its creation (P < 0.01). The difference between serum CCK levels at 6 and 12 h was not statistically significant. Following the release of the loop, serum CCK levels decreased gradually, especially in rats in which the loop was released 6 h after being created. Although no marked biochemical and histological changes of acute pancreatitis were observed following the administration of 2 micrograms/kg of CCK-8 to rats upon release of the loop 6 h and 12 h after its creation, a higher dose of CCK-8 (8 micrograms/kg) in these rats adversely affected both the biochemical and histological findings of acute pancreatitis. Based on these findings, it was concluded that neither endogenous CCK release, as a result of the CDL, nor physiological stimulation of the pancreas by exogenous CCK-8 administration, caused progression from edematous to hemorrhagic acute pancreatitis, and neither CCK treatment had any adverse effect on the early recovery phase of CDL-induced acute pancreatitis. A pharmacological dose of CCK, however, exacerbated the acute pancreatitis, even in the early recovery stage.     

Effects of high dose octreotide on retrograde bile salt-induced pancreatitis in rats

The effects of somatostatin and octreotide (a long acting somatostatin analogue) in acute pancreatitis are inconclusive. This study examined the prophylactic and therapeutic effects of different doses of octreotide on retrograde sodium taurodeoxycholate-induced acute necrotizing pancreatitis in rats. The rats were divided into 4 groups receiving subcutaneous injection of saline, octreotide 10 microg/kg, 20 microg/kg at 0, 8 and 16 h and octreotide 20 microg/kg at 5, 13 and 21 h, separately. The serum levels of amylase and lipase, pancreatic histopathology, mortality and hemodynamics were examined. Octreotide significantly reduced serum levels of amylase and lipase at 12 h and the degree of pancreatic edema, necrosis and hemorrhage at 18-24 h as compared to the control group. Prophylactic octreotide 10 microg/kg significantly decreased the 24-h mortality from 100% to 44.4% (p < 0.05). The 24-h mortality further reduced to 12.5% and 10% with prophylactic and therapeutic octreotide 20 microg/kg, respectively. The decrease of mean arterial pressure at 12 h was significantly lower in octreotide groups than in the control group. We conclude that octreotide improves pancreatic histopathology and survival in acute necrotizing pancreatitis in rats.     

Preliminary characterization of glial-secreted factors responsible for the induction of high electrical resistances across endothelial monolayers in a blood-brain barrier model

Low levels of sex hormone-binding globulin (SHBG) are considered to be an indirect index of hyperinsulinemia, predicting the later onset of diabetes mellitus type 2. In the insulin resistance state and in the presence of an increased pancreatic beta-cell demand (e.g. obesity) both absolute and relative increases in proinsulin secretion occur. In the present study we investigated the correlation between SHBG and pancreatic beta-cell secretion in men with different body compositions. Eighteen young men (30.0 +/- 2.4 years) with normal glucose tolerance and body mass indexes (BMI) ranging from 22.6 to 43.2 kg/m2 were submitted to an oral glucose tolerance test (75 g) and baseline and 120-min blood samples were used to determine insulin, proinsulin and C-peptide by specific immunoassays. Baseline SHBG values were significantly correlated with baseline insulin (r = -0.58, P < 0.05), proinsulin (r = -0.47, P < 0.05), C-peptide (r = -0.55, P < 0.05) and also with proinsulin at 120 min after glucose load (r = -0.58, P < 0.05). Stepwise regression analysis revealed that proinsulin values at 120 min were the strongest predictor of SHBG (r = -0.58, P < 0.05). When subjects were divided into obese (BMI > 28 kg/m2, N = 8) and nonobese (BMI < or = 25 kg/m2, N = 10) groups, significantly lower levels of SHBG were found in the obese subjects. The obese group had significantly higher baseline proinsulin, C-peptide and 120-min proinsulin and insulin levels. For the first time using a specific assay for insulin determination, a strong inverse correlation between insulinemia and SHBG levels was confirmed. The finding of a strong negative correlation between SHBG levels and pancreatic beta-cell secretion, mainly for the 120-min post-glucose load proinsulin levels, reinforces the concept that low SHBG levels are a suitable marker of increased pancreatic beta-cell demand.     

The effect of two frequent amino acid variants of the hepatocyte nuclear factor-1alpha gene on estimates of the pancreatic beta-cell function in Caucasian glucose-tolerant first-degree relatives of type 2 diabetic patients

The objective of the present study was to investigate whether the frequent amino acid polymorphisms, Ile/Leu27 and Ser/Asn487, of the hepatocyte nuclear factor-1alpha gene were associated with alterations in glucose-induced serum C-peptide and serum insulin responses among glucose-tolerant first-degree relatives of type 2 diabetic patients. The study comprised 2 independent Danish cohorts. Among 74 unrelated type 2 diabetic relatives, 12 homozygous carriers of the Ile/Leu27 polymorphism had a 32% decrease in the 30-min serum C-peptide level (P = 0.01), as well as a 39% decrease in the 30-min serum insulin level (P = 0.02) during an oral glucose tolerance test. Ten homozygous carriers of the Ile/Leu27 variant did, however, not differ from wild-type carriers, with respect to the acute circulating insulin and serum C-peptide responses during an i.v. glucose tolerance test in the same study cohort. In a larger (more than 3-fold) study group of 230 glucose tolerant offspring of 62 type 2 diabetic probands, 33 homozygous carriers of the Ile/Leu27 variant did not differ, with respect to either serum insulin and serum C-peptide levels during an oral glucose tolerance test or acute serum insulin and serum C-peptide responses during an i.v. glucose tolerance test. We therefore consider the former positive finding as a statistical type I error. There were no differences in the above mentioned variables between carriers of the Ser/Asn487 polymorphism and wild-type carriers within any of the 2 study populations. Nor did carriers of combined genotypes, i.e. carriers of both the Ile/Leu27 and the Ser/Asn487 variants, show any associations with the examined variables. In conclusion, the Ile/Leu27 and Ser/ Asn487 polymorphisms of the hepatocyte nuclear factor-1alpha gene have apparently no major impact on the pancreatic beta-cell function, after an oral and i.v. glucose challenge, in Caucasian first-degree relatives of type 2 diabetic patients.     

The Veterans Affairs Implantable Insulin Pump Study: effect on cardiovascular risk factors

OBJECTIVE: To determine whether implantable insulin pump (IIP) and multiple-dose insulin (MDI) therapy have different effects on cardiovascular risk factors in insulin-requiring patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A randomized clinical trial was conducted at seven Veterans Affairs medical centers in 121 male patients with type 2 diabetes between the ages of 40 and 69 years receiving at least one injection of insulin per day and with HbA1c, levels of > or =8% at baseline. Weights, blood pressures, insulin use, and glucose monitoring data were obtained at each visit. Lipid levels were obtained at 0, 4, 8, and 12 months, and free and total insulin levels were obtained at 0, 6, and 12 months. All medications being taken were recorded at each visit. RESULTS: No difference in absolute blood pressure, neither systolic nor diastolic, was seen between patients receiving MDI or IIP therapy, but significantly more MDI patients required anti-hypertensive medications. When blood pressure was modeled against weight and time, IIP therapy was significantly better than MDI therapy for systolic blood pressure in patients with BMI <33 and for diastolic blood pressure in patients with BMI >34 kg/m2. Total cholesterol levels decreased in the overall sample, but IIP patients exhibited significantly higher levels than MDI patients. Triglyceride levels increased over time for both groups, with IIP patients having significantly higher levels than patients in the MDI group. BMI was a significant predictor of, and inversely proportional to, HDL cholesterol level. No difference in lipid-lowering drug therapy was seen between the two groups. Free insulin and insulin antibodies tended to decrease in the IIP group as compared with the MDI group. C-peptide levels decreased in both groups. CONCLUSIONS: IIP therapy in insulin-requiring patients with type 2 diabetes has advantages over MDI therapy in decreasing the requirement for antihypertensive therapy and for decreasing total and free insulin and insulin antibodies. Both therapies reduce total cholesterol and C-peptide levels.     

Insulin and glucagon response in patients with chronic pancreatitis

The oral glucose tolerance test and arginine infusion test were carried out on 22 patients with chronic pancreatitis and 11 normal control subjects. According to the glucose tolerance curve, the patients were divided into three groups; group I (normal or slightly impaired), group II (mildly diabetic) and group III (moderately diabetic). Markedly impaired insulin responses to oral glucose as well as to arginine infusion were observed in groups II and III. In group I, the mean plasma insulin levels during glucose tolerance test were the same as those in the controls, but the insulin response to arginine was reduced except in two cases. On the other hand, the glucagon levels during arginine infusion test were within the normal range in group I and slightly reduced in the other groups with diabetic glucose tolerance. The ratio of increment area of insulin to that of glucagon during arginine infusion in the patients was slightly decreased in comparison with the controls. Neither insulin nor glucagon response after arginine infusion showed a significant correlation with pancreatic exocrine function. It is concluded that in chronic pancreatitis insulin response to glucose as well as to arginine is markedly decreased, and that glucagon rise after arginine infusion is lowered compared with the controls.     

Oxidative stress: an important phenomenon with pathogenetic significance in the progression of acute pancreatitis

BACKGROUND: Reactive oxygen species and related oxidative damage have been implicated in the initiation of acute pancreatitis. Changes in these parameters during disease progression merit further investigation. AIMS: To evaluate changes and the clinical relevance of superoxide radicals, endogenous antioxidants, and lipid peroxidation during the course of acute pancreatitis. PATIENTS AND METHODS: Superoxide radicals (measured as lucigenin amplified chemiluminescence), ascorbic acid, dehydroascorbic acid, alpha tocopherol, and lipid peroxidation (measured as thiobarbiturate reactive substances) were analysed in blood samples from 56 healthy subjects, 30 patients with mild acute pancreatitis, and 23 patients with severe acute pancreatitis. The association with grades of disease severity was analysed. Measurements were repeated one and two weeks after onset of pancreatitis. RESULTS: In the blood from patients with acute pancreatitis, there were increased levels of the superoxide radical as well as lipid peroxides. There was notable depletion of ascorbic acid and an increased fraction of dehydroascorbic acid. Changes in alpha tocopherol were not great except in one case with poor prognosis. Differences between severe and mild acute pancreatitis were significant (p < 0.01). Variable but significant correlations with disease severity scores were found for most of these markers. The normalisation of these indexes postdated clinical recovery one or two weeks after onset of disease. CONCLUSIONS: Heightened oxidative stress appears early in the course of acute pancreatitis and lasts longer than the clinical manifestations. The dependence of disease severity on the imbalance between oxidants and natural defences suggests that oxidative stress may have a pivotal role in the progression of pancreatitis and may provide a target for treatment.     

Relation of obesity to insulin secretion and clearance in adolescents: the Bogalusa Heart Study

OBJECTIVE: Earlier we found elevated insulin levels in obese children and adolescents. The present study examines whether alterations in insulin secretion and/or clearance contribute to hyperinsulinemia in obese adolescents. METHODS: Fasting circulating insulin and C-peptide concentrations were examined in 1157 adolescents, aged 11-18 y, from a biracial (black/white) community. In this epidemiologic study, plasma C-peptide was used as a noninvasive measure of insulin secretion by beta cells, C-peptide to insulin ratio as an indicator of hepatic insulin extraction, and insulin to glucose ratio as a measure of insulin sensitivity. Body mass index (BMI) was used as an index of obesity, since it is strongly associated with insulin levels and the C-peptide to insulin ratio more so than with measures of skinfolds and percent body fatness. RESULTS: Obese individuals (BMI > 90th P) had higher levels of plasma insulin (23.7 mu/ml vs 11.7 mu/ml), C-peptide (2.7 ng/ml vs 1.7 ng/ml), and insulin to glucose ratio (0.29 vs 0.15), and lower C-peptide to insulin ratio (0.13 vs 0.16) than non-obese adolescents (all P < 0.001). Elevated C-peptide and decreased C-peptide to insulin ratio were noted in subjects with both obesity and hyperinsulinemia (insulin > 90th P) versus those without these conditions (P < 0.001). Individuals with obesity and low insulin clearance (C-peptide/insulin < 10th P) had 18-fold higher prevalence of hyperinsulinemia versus those without these conditions. Although black adolescents, despite their lower percent body fat, had higher insulin and lower C-peptide and C-peptide to insulin ratio than their white counterparts, BMI related positively to insulin and C-peptide, and inversely with C-peptide to insulin ratio in both races. CONCLUSIONS: These data suggest that both increased insulin secretion and decreased insulin clearance contribute to hyperinsulinema in obese adolescents.     

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.     

Effect of bacille Calmette-Guérin vaccination on C-peptide secretion in children newly diagnosed with IDDM

OBJECTIVE: To determine whether administration of bacille Calmette-Guérin (BCG) vaccination to newly diagnosed IDDM patients can help preserve C-peptide secretion over the subsequent 18 months. RESEARCH DESIGN AND METHODS: Twenty-six IDDM patients, all of whom had been diagnosed within the previous year, had basal C-peptide levels >0.06 nmol/l, and had negative reactions to Mantoux's test, were randomized pairwise as they presented and were given either 0.1 ml (100 microg) BCG vaccine or 0.1 ml saline intradermally Both the patients and the investigators were blinded to the treatment. Fasting and glucagon-induced C-peptide levels and HbA1c were measured in all patients at enrollment and at 1, 3, 6, 9, 12, and 18 months after vaccination, and insulin dose was recorded at each visit. RESULTS: At enrollment, there was no significant difference in age, duration of diabetes, insulin dose, HbA1c, or fasting C-peptide levels between the BCG-vaccinated and control groups. The mean basal and stimulated C-peptide levels in the BCG-treated group did not differ significantly from those in the control group at any time during the 18 months of follow-up, and there was no difference in insulin dose or HbA1c at any time between the groups. CONCLUSIONS: BCG vaccination in children who have been recently diagnosed with IDDM does not affect the progressive decline in C-peptide levels or alter the clinical course of the disease.     

Effects of diet composition and ketosis on glycemia during very-low-energy-diet therapy in obese patients with non-insulin-dependent diabetes mellitus

To determine whether high-ketogenic very-low-energy diets (VLEDs) can reduce hepatic glucose output (HGO) and hyperglycemia more effectively than can low-ketogenic VLEDs in obese patients with non-insulin-dependent diabetes mellitus (NIDDM), seven patients were treated with a high-ketogenic VLED for 3 wk and were compared with six patients treated with a low-ketogenic VLED. All patients were then crossed over and treated with the alternate diet for another 3 wk. Basal HGO, fasting ketone bodies, and glycemia, insulin, and C-peptide after fasting and an oral-glucose-tolerance test (OGTT) were measured. Before treatment, prediet weight and fasting, OGTT, and HGO measurements were not different between groups. After dieting, weight loss was not different between the groups. However, fasting and OGTT glycemia were lower during treatment with the high-ketogenic VLED than with the low-ketogenic VLED (treatment effect: P < 0.05, by analysis of variance). Moreover, there was a strong correlation between basal HGO and fasting plasma ketone bodies (r = -0.71 at 3 wk, r = -0.67 at 6 wk; both P < 0.05). In contrast, fasting and OGTT plasma insulin and C-peptide concentrations were not different between treatment groups. These data indicate that in obese patients with NIDDM, high-ketogenic VLEDs have a more clinically favorable effect on glycemia than do low-ketogenic VLEDs.