Circulating glucagon antibodies in children who have insulin-dependent diabetes mellitus. Clinical significance and characterization.

A substance present in the sera of diabetic children that interferes with the radioimmunoassay for glucagon was found in six of 66 children who were participating in an inpatient study of diabetic control. Detailed studies documented unequivocally that this glucagon-binding substance is a specific antibody to glucagon and is located in the immunoglobulins. In a survey of diabetic children in the outpatient diabetes clinic and in a diabetes summer camp, antibodies to glucagon were found in about 12% of those evaluated. However, no children who had had diabetes for less than three years were found to have antibodies, and there appeared to be an increase with increasing duration of disease of up to greater than 20% at eight years' duration. The presence of glucagon antibodies may be of pathologic significance in that the patients have a greater tendency to develop hypoglycemia than do diabetic children without glucagon antibodies.     

Plasma pancreatic polypeptide response to insulin-induced hypoglycemia as a marker for defective glucose counterregulation in insulin-dependent diabetes mellitus

Defective glucose counterregulation occurs in some insulin-dependent diabetic subjects (IDDMs) as a result of a combined deficiency of glucagon (IRG) and epinephrine (EPI) secretion in response to insulin-induced hypoglycemia. To determine whether the deficient glucagon response, the deficient epinephrine response, or both are manifestations of autonomic dysfunction, we used the pancreatic polypeptide (PP) secretory response to insulin-induced hypoglycemia as a marker for autonomic neuropathy. Seven nondiabetic controls and 21 IDDMs were given insulin at 40 mU/kg/h after overnight euglycemia. Eight of the IDDMs had defective counterregulation (-CR), and 13 had adequate counterregulation (+CR) by our previously published criteria. Those with -CR had a blunted EPI (delta EPI = 102 +/- 16 pg/ml; mean +/- SEM) and PP (delta PP = 12 +/- 13 pg/ml) response as compared with controls (delta EPI = 310 +/- 49; delta PP = 498 +/- 43) and IDDMs with +CR (delta EPI = 291 +/- 32; delta PP = 521 +/- 86). In controls, IRG rose by 31 +/- 6 pg/ml; in IDDMs, IRG failed to rise significantly above baseline regardless of counterregulatory status. Although the PP and EPI responses correlated well (r = 0.626, P less than 0.001), the IRG response failed to correlate with either the EPI or the PP response. We conclude that the deficient epinephrine, but not glucagon, secretory response to hypoglycemia in diabetic subjects is a result of autonomic neuropathy.(ABSTRACT TRUNCATED AT 250 WORDS)     

A reliable and reproducible test for adequate glucose counterregulation in type I diabetes mellitus

The safety, reproducibility, and reliability of an insulin infusion test for assessment of adequate glucose counterregulation were evaluated in 18 patients with type I (insulin-dependent) diabetes mellitus. When the test (a 60-min, 30-mU/m2/min insulin infusion) was administered on three separate occasions at 3-4-wk intervals, coefficients of variation for plasma glucose and counterregulatory hormone (glucagon, epinephrine, cortisol, and growth hormone) responses averaged less than 8%. No patient experienced symptoms requiring discontinuation of the test and plasma glucose concentrations increased spontaneously after stopping the insulin infusion. Using objective criteria based on plasma glucose nadirs or postnadir rates of plasma glucose recovery, no patient judged to have adequate glucose counterregulation by the test (postnadir rates of plasma glucose recovery or plasma glucose nadir above 0.4 mg/dl/min and 45 mg/dl) developed severe hypoglycemia (plasma glucose less than 40 mg/dl) during up to 7 mo of intensive insulin therapy, whereas nearly all patients with inadequate counterregulation did. We conclude that this test, when performed in standardized conditions, is safe and reproducible and can reliably predict those patients with type I diabetes who are at risk of developing severe hypoglycemia during intensive insulin therapy.     

An association between complement-fixing cytoplasmic islet cell antibodies and endogenous insulin secretion in children with insulin-dependent diabetes mellitus

Cytoplasmic islet cell antibodies and endogenous insulin secretion were studied in 184 children and adolescents having insulin-dependent diabetes mellitus (IDDM) in a cross-sectional study. The mean age of the subjects was 12.3 yr (range: 2.8-19.2 yr), and the mean duration of diabetes was 4.6 yr (range: 0.1-15.6 yr). Islet cell antibodies (ICA) were determined by both the indirect immunofluorescence (IF-ICA) and the complement-fixing (CF-ICA) methods. Forty-four patients (23.9%) were positive with respect to both IF- and CF-ICA, 54 patients (29.3%) had only IF-ICA, and 86 patients had no ICA. The patients having CF-ICA had a significantly higher endogenous insulin secretion in comparison with the patients who were only IF-ICA positive. The difference between the groups remained significant even when the age at onset of diabetes and the duration of the disease were taken into account. This finding, revealing an association between CF-ICA and endogenous insulin secretion, suggests that complement-fixing antibodies are seen only if the beta-cell mass is sufficiently preserved. The result contradicts the hypothesis, based on studies in vitro, that CF-ICA should be involved in the selective beta-cell damage in IDDM.     

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.     

Lilly lecture 1988. Glucose counterregulation and its impact on diabetes mellitus

Glucose counterregulation is the sum of processes that protect against development of hypoglycemia and that restore euglycemia if hypoglycemia should occur. In order of importance, the key counterregulatory factors are glucagon, epinephrine, growth hormone, cortisol, and hepatic autoregulation. These act primarily by increasing hepatic glucose output, initially via breakdown of glycogen and later by gluconeogenesis. In people without diabetes and in people with type II (non-insulin-dependent) diabetes, suppression of endogenous insulin secretion during hypoglycemia is also important in permitting full expression of the effects of counterregulation. People with diabetes are more prone to develop hypoglycemia for various reasons (e.g., insulin overdose, skipped meals, and intensive exercise); one that has recently been identified is impaired glucose counterregulation: patients with type I (insulin-dependent) diabetes (and to a lesser extent, patients with type II diabetes) lose the glucagon response to hypoglycemia; subsequent development of autonomic neuropathy with concomitant loss of the epinephrine response leads to almost complete paralysis of counterregulation and loss of recognition of hypoglycemia. To make matters worse, an episode of hypoglycemia that causes activation of counterregulation can lead to rebound hyperglycemia (Somogyi phenomenon); if this is improperly treated, brittle diabetes may follow. Thus, abnormalities in glucose counterregulation may predispose to severe hypoglycemia and prevent achievement of optimal glycemic control in patients with diabetes.     

Effects of long-term optimization and short-term deterioration of glycemic control on glucose counterregulation in type I diabetes mellitus

To assess the effects of glycemic control on glucose counterregulation, rates of plasma glucose recovery from hypoglycemia and counterregulatory hormonal responses were studied in 18 C-peptide-negative patients with insulin-dependent diabetes mellitus (IDDM) before and after either improvement, no change, or deterioration in glycemic control. Hypoglycemia was induced by an i.v. insulin infusion (30 mU/m2 X min for 1 h) after maintenance of euglycemia overnight with i.v. insulin. In 13 patients with long duration of IDDM (9 +/- 0.5 yr, mean +/- SEM) and initially poor glycemic control (mean diurnal blood glucose, MBG 199 +/- 8 mg/dl, ketoamine-HbA1 12.4 +/- 0.2%; nondiabetic subjects 104 +/- 4 mg/dl and 6.8 +/- 0.09%, respectively), rates of plasma glucose recovery from hypoglycemia (0.30 +/- 0.01 versus 0.60 +/- 0.01 mg/dl X min in nondiabetic subjects, P less than 0.001) and plasma glucagon (AUC 0.56 +/- 0.09 versus 6.3 +/- 0.50 ng/ml X 150 min in nondiabetic subjects, P less than 0.01) and epinephrine (AUC 16.9 +/- 0.2 versus 25.7 +/- 0.2 ng/ml X 150 min in nondiabetic subjects, P less than 0.001) responses to hypoglycemia were impaired. Intensive therapy (three daily injections of insulin) instituted in 7 out of 13 IDDM patients for up to 9 mo improved MBG (124 +/- 6 mg/dl, P less than 0.01) and ketoamine-HbA1 (7.9 +/- 0.02%, P less than 0.01) but not rates of plasma glucose recovery (0.31 +/- 0.01 mg/dl X min) and plasma glucagon (AUC 0.69 +/- 0.07 ng/ml X 150 min) and epinephrine (AUC 14.9 +/- 0.17 ng/ml X 150 min) responses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prevalence of diabetes mellitus and impaired glucose tolerance among second-generation Japanese-American men

We describe the initial findings from a multidisciplinary, epidemiologic study of diabetes mellitus conducted in a population of second-generation Japanese-American (Nisei) men born between 1910 and 1939 who reside in King County, Washington (n = 1746). From this study population, 487 volunteered, and 229 were enrolled to comprise the study sample. A random sample of Nisei men was also drawn from the population to develop a reference sample of 189 men. All subjects participated in a 75-g oral glucose tolerance test; the National Diabetes Data Group (NDDG) and World Health Organization (WHO) diagnostic criteria as well as a modification of the WHO criteria were used to classify individuals with normal glucose tolerance, impaired glucose tolerance (IGT), or diabetes. Within the study sample, 79 men were found to have normal glucose tolerance, 72 had IGT, and 78 had type II diabetes. The mean age of the study sample was 61.4 yr. Based on comparison of the study sample to the reference sample, the study sample was ascertained to be representative of Nisei men in King County. Extrapolating from our observations in the reference sample and in the study sample, we have estimated that approximately 56% of Nisei men in the study population have abnormal glucose tolerance. Much of this is undiagnosed because only approximately 13% of the reference sample of Nisei men reported a prior diagnosis of diabetes. Of the men who enrolled in the study as nondiabetic subjects, 11.1% had diabetes and 39.2% had IGT; i.e., 50.3% had previously unknown abnormalities in glucose tolerance. We estimate that approximately 20% of Nisei men have diabetes (both previously diagnosed and undiagnosed) and approximately 36% have IGT.     

Insulin resistance and impaired insulin secretion in subjects with histories of gestational diabetes mellitus

NIDDM is characterized by decreased insulin secretory responses to glucose and to nonglucose stimuli, hyperglucagonemia, and decreased tissue sensitivity to insulin. However, it has been unclear which of these abnormalities, if any, precedes the others. Since women with histories of gestational diabetes mellitus (GDM) are at high risk for eventual development of NIDDM, we measured B- and A-cell function and tissue sensitivity to insulin in eight normoglycemic, postpartum women with recent histories of GDM and in eight control subjects pair-matched for age and percent of ideal body weight. Fasting plasma glucose levels in subjects with former GDM tended to be slightly higher than in matched controls (98 +/- 3 versus 92 +/- 2 mg/dl, P = 0.07). Basal plasma insulin in subjects with former GDM was significantly higher than in controls (22 +/- 4 versus 14 +/- 2 microU/ml, P = 0.05). During an intravenous glucose tolerance test (IVGTT), relative first- and second-phase insulin responses to glucose were decreased in subjects with former GDM (2316 +/- 560 versus 7798 +/- 1036% of basal X min, P = 0.004; and 8340 +/- 946 versus 14,509 +/- 2556, P = 0.04). An index of sensitivity to insulin, SI, calculated from the IVGTT, was also lower in former GDM (1.23 +/- 0.69 X 10(-4) versus 3.58 +/- 0.78 X 10(-4) min-1/microU/ml, P = 0.001). Acute insulin responses to 5 g i.v. arginine were measured at plasma glucose levels of approximately 95, 215, and 600 mg/dl. The response at 600 mg/dl is termed the AIRmax and is used as an index of glucose-regulated insulin secretory capacity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term glycemic control and kidney function in insulin-dependent diabetes mellitus.

In this paper we examined the relationship between blood glucose control and initiation and progression of increased urinary albumin excretion. In this seven year Oslo study 45 insulin-dependent diabetes mellitus patients were initially randomized into three different modes of treatment: continuous subcutaneous insulin infusion (CSII), multiple injections, or two injections a day. After four years, the patients were free to choose their treatment, and therefore the data were analyzed according to mean HbA1 during seven years. The mean HbA1 was 11.2% (2.2) (SD) at start, and 9.5% (1.5) at seven years, which was a significant long-term improvement (P less than 0.001). Eight out of 10 patients with mean seven year HbA1 less than 8.5% improved their albumin excretion rate, and patients with mean HbA1 greater than 10% had an increased albumin excretion rate (from 26 mg/24 hr to 91 mg/24 hr, P less than 0.02). The glomerular filtration rate decreased slightly regardless of mean HbA1 level. Systolic blood pressure increased significantly regardless of mean HbA1. Diastolic blood pressure was unchanged in the patients with mean HbA1 less than 10%, but increased slightly (NS) in patients with HbA1 greater than 10%. We conclude that mean blood glucose as measured by glycosylated hemoglobin is a main determinant in the progression of urinary albumin excretion in insulin dependent diabetics, and near normoglycemia improves urinary albumin excretion.     

Hypertension in diabetic patients and differences between insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus

In insulin-dependent diabetes mellitus (IDDM), BP levels in subjects with normal or only mildly increased levels of albumin excretion do not differ systematically from those in non-diabetic reference populations. However, it is not known whether increased albuminuria and raised blood pressure are causally related. Several studies have observed higher average BP levels in glucose-intolerant subjects, even allowing for effects of age and adiposity. This applies to subjects with glucose intolerance below and above the World Health Organization criteria for diagnosing non-insulin-dependent diabetes mellitus (NIDDM). However, there are very few satisfactory studies comparing established patients with NIDDM with appropriate reference populations, and although it is widely believed that high BP (or hypertension) is a feature of NIDDM, the evidence for this belief is scant.     

C-peptide response to a glucose load in young blacks and Indians with insulin-dependent diabetes mellitus

Residual beta cell function based on C-peptide assays was estimated in 39 patients (27 Blacks, 12 Indians) with insulin-dependent diabetes mellitus and 18 controls (9 Blacks, 9 Indians) using glucose as a stimulus. The diabetic patients showed significantly lower maximal C-peptide values (mean 0,53 +/- 0,08 nmol/l) and delayed peak levels (mean 137 minutes after ingestion of glucose) compared with the controls (mean 2,15 +/- 0,31 nmol/l and 54 minutes respectively). Just over 20% of the patients had no residual beta cell function, this conclusion being made on the basis of undetectable basal C-peptide levels which failed to rise after glucose stimulation. A significant correlation was seen between glycosylated haemoglobin levels and maximal C-peptide levels (r = 0,45, P less than 0,01). C-peptide levels tended to be lower in Black than in Indian patients, but the difference was not significant.     

Prevalence of diabetes mellitus and impaired glucose tolerance in factory workers from Transkei, South Africa.

OBJECTIVE: To determine the prevalence of diabetes mellitus and impaired glucose tolerance (IGT) in a group of peri-urban black South Africans. DESIGN: Cross-sectional study in which an oral glucose tolerance test (OGTT) was performed on each subject. SETTING: Two of the largest factories in the surroundings of Umtata, the capital of the former homeland of Transkei, South Africa. SUBJECTS: A total of 374 Xhosa-speaking factory workers. MAIN OUTCOME MEASURES: Frequency of diabetes mellitus and IGT according to age group and gender using the current World Health Organisation (WHO) criteria for the diagnosis of abnormal glucose tolerance and its relationship to obesity. RESULTS: The crude prevalences for diabetes mellitus and IGT were 2.45% and 2.7% respectively. The age-adjusted prevalences using a standard world population were 4.5% (confidence interval (CI) 1.54-7.42) and 5.1% (CI 2.45-5.51) for diabetes and IGT respectively. The prevalence of diabetes was similar in male and female workers (P = 0.31), with the highest incidence observed in the age group from 40 to 59 years. No subject below the age of 40 years was found to be diabetic, and the prevalence of the disease was found to increase with age. Obesity was present in 22.2% of all subjects. Prevalence of obesity was similar in subjects with diabetes and in those with impaired and normal glucose tolerance (P = 0.71). However, overweight, identified in 26.8% of subjects, was more frequently observed in the IGT group than in the other two groups (P = 0.01). IGT was observed in 3.4% of male and 1.5% of female workers respectively (P = 0.13), with peak prevalences occurring between the ages of 30 and 49 years. CONCLUSION: In conclusion, this study found a prevalence of diabetes and IGT comparable to prevalence results reported in other black South African communities. The implications with regard to this community merit further study.     

Comparison of insulin-mediated and glucose-mediated glucose disposal in patients with insulin-dependent diabetes mellitus and in nondiabetic subjects

To determine whether glucose-mediated as well as insulin-mediated regulation of glucose utilization and glucose production is impaired in patients with insulin-dependent diabetes mellitus (IDDM), six nonobese, diabetic patients and seven age-, sex-, and weight-matched nondiabetic subjects were studied. Despite slightly higher free insulin concentrations in the diabetic patients than in the nondiabetic subjects during 0.2 mU/kg X min (22 +/- 3 versus 15 +/- 2 microU/ml) and 1.0 mU/kg X min (98 +/- 10 versus 75 microU/ml) insulin infusions, glucose utilization at plasma glucose concentrations of 95, 135, and 175 mg/dl was lower in the diabetic patients than in the nondiabetic subjects. The increment in glucose utilization per increment in plasma glucose (i.e., slope) in the diabetic and nondiabetic subjects, respectively, did not differ significantly during either the 0.2 (1.7 +/- 1.3 versus 1.4 +/- 0.5 dl/kg X min) or 1.0 (4.4 +/- 1.1 versus 6.2 +/- 1.0 dl/kg X min) mU/kg X min insulin infusions, although they tended to be higher in the nondiabetic subjects during the latter infusion. Thus, although stimulation of glucose utilization by insulin is impaired in patients with IDDM, the ability of an increase in glucose concentration to increase glucose utilization does not appear to differ from that present in nondiabetic subjects, at insulin concentrations in the low physiologic range. Whether differences exist in the high physiologic range remains to be determined.     

Normalization by sodium salicylate of the impaired counterregulatory glucagon response to hypoglycemia in insulin-dependent diabetes. A possible role for endogenous prostaglandins

The present study was undertaken to evaluate the influence of sodium salicylate on the counterregulatory glucagon response to insulin-induced hypoglycemia in both insulin-dependent diabetic subjects (IDDM) and normal controls. The IDDM group consisted of 5 patients with recent onset of disease (less than 45 days), a normal glucagon response to hypoglycemia, and no detectable insulin antibodies (group 1); and 7 patients with duration of disease between 1 and 5 yr, a reduced glucagon response to hypoglycemia, and no insulin antibodies (group 2). Ten healthy subjects served as a control group. The infusion of sodium salicylate (40 mg/min) during insulin-induced hypoglycemia (1 mU/kg-min for 60 min) in normal subjects caused a significant increase of the counterregulatory glucagon response both in terms of glucagon peak and integrated areas. Sodium salicylate itself significantly increased basal insulin and decreased glucose, but did not change basal glucagon. In the diabetic subjects of group 1, sodium salicylate amplified the glucagon response to the same degree of hypoglycemia without affecting the rates of glucose fall and recovery. Compared with normals and diabetic subjects of group 1, diabetic subjects of group 2 presented, in basal conditions, a reduced glucagon response to hypoglycemia and a slower rate of glucose recovery. Sodium salicylate normalized both defects. These results indicate that sodium salicylate may augment glucagon responses by improving the recognition of hypoglycemia in both normals and IDDM. Moreover, the restoration by sodium salicylate of a normal glucagon response to hypoglycemia in diabetic subjects of group 2 suggests a role for endogenous prostaglandins in this selective deficiency of the counterregulatory response.     

Low plasma zinc and androgen in insulin-dependent diabetes mellitus

Plasma zinc and pituitary and testicular hormone concentrations were measured in two groups of male adolescents. One group comprised insulin-dependent diabetes mellitus patients, aged 14-19 years; the other, as control, included 12 healthy youngsters aged 13-19 years. Plasma concentration of zinc, prolactin, testosterone, and dihydrotestosterone were lower in diabetics than in controls, whereas the ratios of androstenedione and androstenedione to testosterone + dihydrotestosterone were higher. Plasma FSH and LH were normal. These results suggest a diminished conversion of androstenedione to testosterone and relate zinc with the 17-beta-hydroxysteroid dehydrogenase enzyme activity.